PROGRESS REPORT JUNE 2013
PROGRESS REPORT JUNE 2013 National Heart, Lung, and Blood Institute Building 31, Room 5A52, 31 Center Drive MSC 2486, Bethesda, MD 20892 USA Phone: (301) 592-8573 Fax: (240) 629-3246 National Cancer Institute 6116 Executive Boulevard, Suite 300, Bethesda, MD 20892-8322 Phone: (800) 422-6237 Center for International Blood and Marrow Transplant Research 9200 W. Wisconsin Avenue, Suite C5500, Milwaukee, WI 53226 USA Phone: (414) 805-0700 Fax: (414) 805-0714 The EMMES Corporation 401 N. Washington Street, Suite 700, Rockville, MD 20850 USA Phone: (301) 251-1161 Fax: (301) 251-1355 National Marrow Donor Program 3001 Broadway Street NE, Suite 100, Minneapolis, MN 55413 USA Phone: (612) 627-5800 Fax: (612) 362-3415 This is a publication of the Blood and Marrow Transplant Clinical Trials Network Data and Coordinating Center © 2013 All Rights Reserved Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Table of Contents Table of Contents 1.0 Overview and Significance .................................................................................................................................................. 1 1.1 The Value the BMT CTN Brings to the HCT Community ........................................................................................ 2 1.1.1 Extensive Areas of Study ......................................................................................................................................... 2 1.1.2 Accrual Leverage ....................................................................................................................................................... 2 1.1.3 Dissemination of Results .......................................................................................................................................... 3 1.1.3.1 Abstracts ................................................................................................................................................................ 3 1.1.3.2 Publications ........................................................................................................................................................... 3 1.1.4 Significant Findings and Impact ............................................................................................................................. 3 1.1.5 Biorepository Resource............................................................................................................................................. 7 1.1.6 Funding Leverage...................................................................................................................................................... 7 1.1.7 Key Collaborations .................................................................................................................................................... 8 1.1.8 Goals for Next Reporting Period ............................................................................................................................ 8 1.1.8.1 Anticipated Results .............................................................................................................................................. 8 1.1.8.2 Studies to be Activated........................................................................................................................................ 8 1.1.8.3 Future Study Concepts........................................................................................................................................ 8 2.0 BMT CTN Organizational Overview ............................................................................................................................... 10 2.1 Data and Coordinating Center (DCC) ........................................................................................................................ 10 2.2 Clinical Centers ............................................................................................................................................................... 11 2.2.1 Core Centers ............................................................................................................................................................. 11 2.2.2 Affiliate Centers ....................................................................................................................................................... 11 2.3 BMT CTN Committee Structure .................................................................................................................................. 11 2.3.1 Steering Committee................................................................................................................................................. 11 2.3.2 Protocol Teams......................................................................................................................................................... 11 2.3.3 Technical Committees ............................................................................................................................................ 12 2.3.3.1 Biomarkers Committee ..................................................................................................................................... 12 2.3.3.2 Clinical Research Associates Committee ....................................................................................................... 13 2.3.3.3 Pharmacy Committee ........................................................................................................................................ 13 2.3.3.4 Special Populations Committee....................................................................................................................... 13 2.3.3.5 Toxicity and Supportive Care Committee ..................................................................................................... 13 2.3.4 Administrative Committees .................................................................................................................................. 14 2.3.4.1 Executive Committees ....................................................................................................................................... 14 2.3.4.2 Publications, Abstracts, and Presentations Committee............................................................................... 14 2.3.5 Ad Hoc Committees................................................................................................................................................ 14 2.3.6 Scientific Advisory Committees ........................................................................................................................... 14 2.3.7 Review Committees ................................................................................................................................................ 15 i Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Table of Contents 3.0 Administrative Functions of the DCC ............................................................................................................................. 16 3.1 DCC Partner Organizations .......................................................................................................................................... 16 3.2 Policies and Procedures ................................................................................................................................................. 19 3.3 Administrative Support ................................................................................................................................................. 19 3.4 Fiscal Planning and Contracting Support .................................................................................................................. 20 3.4.1 Cost-Saving Mechanisms ....................................................................................................................................... 20 3.5 Communication ............................................................................................................................................................... 21 3.5.1 Maintaining BMT CTN Websites ......................................................................................................................... 21 3.5.2 Developing Patient Support and Marketing Materials .................................................................................... 22 3.5.3 Communicating Trial Results ............................................................................................................................... 22 3.6 Training… ........................................................................................................................................................................ 22 3.7 Transplant Center Monitoring...................................................................................................................................... 23 3.8 Specimen Repository Support ...................................................................................................................................... 23 3.8.1 Specimen Collection................................................................................................................................................ 23 3.8.2 BMT CTN Research Sample Repository and Central Processing Lab ........................................................... 25 3.8.3 Maximizing Sample Handling .............................................................................................................................. 25 4.0 Concept to Publication: The Protocol Process ................................................................................................................ 27 4.1 Concept Evaluation and Approval .............................................................................................................................. 27 4.1.1 DCC Review ............................................................................................................................................................. 28 4.1.2 Executive Committee Review ............................................................................................................................... 28 4.1.3 Steering Committee Review .................................................................................................................................. 28 4.2 Protocol Development ................................................................................................................................................... 28 4.2.1 Establishment of a Protocol Team ........................................................................................................................ 28 4.2.2 Statistical Design...................................................................................................................................................... 29 4.2.3 Accrual Planning ..................................................................................................................................................... 29 4.2.4 Budget Preparation ................................................................................................................................................. 30 4.2.5 Federal Regulations................................................................................................................................................. 30 4.2.6 Final Draft Protocol ................................................................................................................................................. 30 4.3 Protocol Approval........................................................................................................................................................... 30 4.3.1 Steering Committee Review .................................................................................................................................. 31 4.3.2 Protocol Review Committee .................................................................................................................................. 31 4.3.3 Data and Safety Monitoring Board Review ........................................................................................................ 31 4.3.4 Final Review Prior to Release to Centers ............................................................................................................ 32 4.4 Protocol Pre-Activation.................................................................................................................................................. 32 4.4.1 Designing Case Report Forms............................................................................................................................... 32 4.4.2 Educational materials and other study documents .......................................................................................... 33 4.4.3 Release to Center Institutional Review Boards .................................................................................................. 33 ii Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Table of Contents 4.4.4 Site Initiation Training ............................................................................................................................................ 33 4.4.5 Medical Monitor Assignment ............................................................................................................................... 33 4.5 Protocol Activation ......................................................................................................................................................... 34 4.6 Protocol Maintenance..................................................................................................................................................... 34 4.6.1 Accrual Monitoring and Intervention ................................................................................................................. 34 4.6.2 High-Quality Clinical and Laboratory Data Collection ................................................................................... 34 4.6.2.1 AdvantageEDC................................................................................................................................................... 35 4.6.2.2 Specimen Tracking with GlobalTrace and Staff ........................................................................................... 35 4.6.2.3 CIBMTR Data Reports ....................................................................................................................................... 36 4.6.3 Data Audits............................................................................................................................................................... 36 4.6.4 Amendments ............................................................................................................................................................ 36 4.7 Study Completion ........................................................................................................................................................... 36 4.7.1 Notice to Cease Enrollment ................................................................................................................................... 36 4.7.2 Follow-up Data Collection after Closure ............................................................................................................ 37 4.7.3 Data Review and Analysis ..................................................................................................................................... 37 4.8 Dissemination of Results ............................................................................................................................................... 37 4.8.1 Authorship................................................................................................................................................................ 37 4.9 Ancillary and Correlative Studies................................................................................................................................ 38 5.0 Collaborations with other NIH-funded Research Networks ...................................................................................... 44 6.0 Future Directions ................................................................................................................................................................. 45 6.1 Planning for the Current Grant Cycle ......................................................................................................................... 45 6.2 Protocol Projections 2013-2014 ..................................................................................................................................... 45 6.2.1 Protocols Nearing Completion ............................................................................................................................. 45 6.2.2 Protocols Activated During the Reporting Period ............................................................................................ 46 6.2.3 Protocols Anticipated to be Activated ................................................................................................................. 46 6.3 Conclusions ...................................................................................................................................................................... 47 7.0 Protocol Descriptions .......................................................................................................................................................... 48 7.1 Protocols Open to Accrual............................................................................................................................................. 49 BMT CTN 0301 .................................................................................................................................................................. 50 BMT CTN 0601 .................................................................................................................................................................. 52 BMT CTN 0702 .................................................................................................................................................................. 54 BMT CTN 0801 .................................................................................................................................................................. 56 BMT CTN 0803 .................................................................................................................................................................. 58 BMT CTN 0804 / CALGB 100701 ................................................................................................................................... 60 BMT CTN 0805 / SWOG 0805......................................................................................................................................... 62 BMT CTN 0901 .................................................................................................................................................................. 64 iii Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Table of Contents BMT CTN 0903 .................................................................................................................................................................. 66 BMT CTN 1101 .................................................................................................................................................................. 68 7.2 Protocols that Completed Accrual ............................................................................................................................... 71 BMT CTN 0101 .................................................................................................................................................................. 72 BMT CTN 0102 .................................................................................................................................................................. 74 BMT CTN 0201 .................................................................................................................................................................. 76 BMT CTN 0202 .................................................................................................................................................................. 78 BMT CTN 0302 .................................................................................................................................................................. 80 BMT CTN 0303 .................................................................................................................................................................. 82 BMT CTN 0401 .................................................................................................................................................................. 84 BMT CTN 0402 .................................................................................................................................................................. 86 BMT CTN 0403 .................................................................................................................................................................. 88 BMT CTN 0501 .................................................................................................................................................................. 90 BMT CTN 0502 / CALGB 100103 ................................................................................................................................... 92 BMT CTN 0603 .................................................................................................................................................................. 94 BMT CTN 0604 .................................................................................................................................................................. 96 BMT CTN 0701 .................................................................................................................................................................. 98 BMT CTN 0703 / SWOG 0410....................................................................................................................................... 100 BMT CTN 0704 / CALGB 100104 / ECOG 100104..................................................................................................... 102 BMT CTN 0802 ................................................................................................................................................................ 104 BMT CTN 0902 ................................................................................................................................................................ 106 7.3 Protocols Released to Centers ..................................................................................................................................... 109 BMT CTN 1202 ................................................................................................................................................................ 110 Attachment A: Data and Coordinating Center Organizational Structure .................................................................... 113 Attachment B: Core and Affiliation Centers ....................................................................................................................... 114 Attachment B1: Core Centers............................................................................................................................................ 114 Attachment B2: Affiliate Centers...................................................................................................................................... 117 Attachment C: Publications, Abstracts, and Presentations .............................................................................................. 120 Attachment C1: Publications............................................................................................................................................. 120 Attachment C2: Abstracts and Presentations................................................................................................................. 126 Attachment D: Committee Rosters ....................................................................................................................................... 132 Attachment D1: Steering Committee............................................................................................................................... 132 Attachment D2: Publications, Abstracts & Presentations Committee....................................................................... 134 Attachment D3: Biomarkers Committee......................................................................................................................... 135 Attachment D4: Clinical Research Associates Committee .......................................................................................... 136 Attachment D5: Pharmacy Committee ........................................................................................................................... 137 iv Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Table of Contents Attachment D6: Special Populations (Pediatrics/Human Subjects) Committee ..................................................... 138 Attachment D7: Toxicity and Supportive Care Committee ........................................................................................ 139 Attachment E: Center Performance Report ........................................................................................................................ 140 Attachment F: Center Performance Rating ......................................................................................................................... 147 Attachment G: Total Accrual by Month .............................................................................................................................. 149 Attachment H: Accrual Plan Assessment ........................................................................................................................... 150 Attachment I: Review Checklist ............................................................................................................................................ 151 Attachment J: Terms and Abbreviations ............................................................................................................................. 155 v Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 This page intentionally left blank. vi Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 1.0 Overview and Significance 1.0 Overview and Significance The Blood and Marrow Transplant Clinical Trials Network (BMT CTN1 or the “Network”) was established in October 2001 to conduct large, multi-institutional clinical trials to improve the outcomes of hematopoietic cell transplantation (HCT) for patients facing life-threatening disorders. The BMT CTN allows the HCT community to conduct prospective, collaborative, clinical research within an infrastructure expressly designed to: Facilitate effective communication and cooperation among transplant centers and collaborators at the National Institutes of Health (NIH), particularly the National Heart, Lung, and Blood Institute (NHLBI) and National Cancer Institute (NCI); Implement and complete well-designed, multicenter trials of high scientific merit; Offer participation in HCT clinical trials to patients in all regions of the United States. Almost 18,000 HCTs are performed in the United States (US) annually, and the number increases by approximately 5% per year. This increase reflects the utility of HCT in treating both malignant and nonmalignant diseases, higher donor availability, and treatment advances that allow HCT to be performed in older and sicker patients. While HCT is a rapidly evolving field, HCT clinical trials face unique challenges, including the relatively small number of transplantations performed at any single center, the diverse indications for HCT, the complexities of the procedure, and multiple post-transplant complications. The BMT CTN was established to address these challenges and execute multicenter HCT trials with broad national participation. The Network: Effectively fosters development of innovative and important concepts into well-designed trials that answer questions in the most efficient manner; Supports timely implementation and completion of those trials; Ensures protection of subjects (both donors and recipients); Provides high-quality data and adherence to regulatory requirements in an increasingly complex environment. This Progress Report highlights the following: Accomplishments of the BMT CTN, including a detailed report of the Network’s progress for the period of April 1, 2012, through March 31, 2013, (highlighted by bold font throughout the report) as well as plans for the upcoming year; Organizational structure of the Network; Responsibilities and focus of the Network’s Data and Coordinating Center (DCC); Structure and collaborations of the Network; Protocol selection, development, and management processes; Status of past, current, and planned protocols. 1 A glossary of terms and abbreviations used in this report can be found in Attachment J. 1 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 1.0 Overview and Significance 1.1 The Value the BMT CTN Brings to the HCT Community The BMT CTN and its network of Core and Affiliate Centers (Attachment B) play a critical role in improving patient outcomes and advancing the science of hematopoietic cell transplantation. The BMT CTN’s many scientific achievements include: Launching 28 trials, including two this reporting period; Completing accrual to 18 trials, including two this reporting period; Accruing almost 5,300 patients to its trials from more than 100 centers, including almost 600 patients this reporting period; Achieving an overall accrual rate of 104% of projections among trials that are currently open for enrollment; Engaging in 28 ancillary and correlative studies, including three that were completed this reporting period. 1.1.1 Extensive Areas of Study The BTM CTN studies various treatment options, including both allogeneic and autologous transplants. During this reporting period, approximately 40% of the transplants performed on BMT CTN studies were allogeneic transplants. Comparatively, 49% of the US transplants reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) were allogeneic transplants. The BMT CTN has answered relevant research questions in both common and rare diseases. Its research portfolio includes studies in leukemia, myelodysplasia, lymphoma, and multiple myeloma as well as rare transplant indications, such as aplastic anemia, sickle cell disease, and human immunodeficiency virus (HIV)associated cancers. Additional areas of study include: Conditioning regimens; Graft source (autologous, human leukocyte antigen [HLA]-identical and haploidentical related donors, unrelated donors, and umbilical cord blood); Graft manipulation; Acute and chronic graft-versus-host disease (GVHD); Post-transplant infection; Treatment-related mortality; Disease control; Biomarkers; Patient populations of various ages, including children and older adults; Quality of life. 1.1.2 Accrual Leverage Several BMT CTN studies have been designed for co-enrollment, including studies on quality of life (0902), consent form evaluation (1205), and a biomarker repository protocol (1202). Over 100 patients have been coenrolled on BMT CTN studies. 2 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 1.0 Overview and Significance 1.1.3 Dissemination of Results 1.1.3.1 Abstracts The Network has presented 37 abstracts from 15 trials and the DCC/Network at the following national and international meetings: American Society of Clinical Oncology (ASCO); American Society of Hematology (ASH), including the 2011 Plenary Session; BMT Tandem Meetings; European Group for Blood and Marrow Transplantation; International Myeloma Workshop (April 2013); International Society for Cellular Therapy; NCI-American Society of Clinical Oncology Cancer Trial Accrual Symposium; Public Responsibility in Medicine and Research; Society for Clinical Trials. Nine abstracts were presented during this reporting period at the meetings listed in bold above. 1.1.3.2 Publications The Network has published 31 manuscripts, including nine primary study results papers, from 12 trials and the DCC/Network in the following peer-reviewed journals: American Journal of Health-System Pharmacy; Biology of Blood and Marrow Transplantation; Blood; Clinical Infectious Diseases; Journal of Clinical Oncology; Journal of the National Cancer Institute; Journal of the Society for Clinical Trials; Lancet Oncology; New England Journal of Medicine. Seven manuscripts were published or are in press during this reporting period in the journals listed in bold above. Two of these manuscripts were primary results papers, and an additional seven manuscripts are in preparation. 1.1.4 Significant Findings and Impact The research findings of the BMT CTN provide information with effects on clinical practice. To date, BMT CTN trials have provided important insights into several areas of HCT (Table 1). 3 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 1.0 Overview and Significance Table 1. Significant findings and impact of BMT CTN studies BMT CTN Study Significant Findings and Impact of BMT CTN Studies Results Impact / Future Outlook CONDITIONING REGIMENS 0301: Fludarabine-based conditioning for allogeneic marrow transplantation from HLA-compatible unrelated donors in severe aplastic anemia Identified high toxicity and high graft failure rates after unrelated donor transplantation for aplastic anemia with cyclophosphamide doses of 150 and 0 mg/kg, respectively, for conditioning Optimizing conditioning regimens for transplantation for rare diseases is difficult and requires a multicenter effort to determine the role of new agents. This study determined that fludarabine is not sufficiently immune suppressive to replace cyclophosphamide in standard conditioning regimens for unrelated donor transplantation for aplastic anemia. Additionally, the finding of excess toxicity with a commonly used dose of cyclophosphamide when combined with fludarabine was unexpected and will guide further exploration of new agents as well as informing current practice. Evaluation of 50 mg/kg and 100 mg/kg of cyclophosphamide is ongoing. 0401: Phase III Rituxan/BEAM versus Bexxar/BEAM with autologous hematopoietic stem cell transplantation for persistent or relapsed chemotherapy-sensitive diffuse large B cell nonHodgkin lymphoma (DLBL) Determined the use of a radiolabelled antibody in addition to carmustine, etoposide, cytarabine, and melphalan (BEAM) increases toxicity but does not decrease relapse after autologous transplantation for DLBL Although several small Phase II studies suggested that dose-intensification might decrease relapse, the primary cause of treatment failure after autologous HCT for DLBL, this study failed to show a benefit with this approach. Future trials will focus on maintenance strategies and/or immune therapies after HCT to improve disease control. 0502: A Phase II study of allogeneic transplant for older patients with acute myeloid leukemia (AML) in first morphologic complete remission using a nonmyeloablative preparative regimen Demonstrated that allogeneic transplantation with reducedintensity conditioning is feasible and effective in elderly patients with acute myelogenous leukemia with acceptable rates of regimen-related toxicity Results of conventional chemotherapy in elderly patients are dismal and have improved little over the past two decades. This study demonstrates that, with reduced intensity conditioning, patients older than 60 can benefit from the graft-versus-leukemia effects of allogeneic HCT with outcomes similar to younger patients. These data should increase the use of HCT in older AML patients and provides justification to increase the age of inclusion for BMT CTN allograft trials. 0601: Unrelated donor hematopoietic cell transplantation for children with severe sickle cell disease using a reducedintensity conditioning regimen Determined that a reducedintensity conditioning regimen of alemtuzumab, fludarabine, and melphalan prior to cord blood transplantation was associated with unacceptably high levels of graft failure in children with sickle cell anemia This disappointing finding indicates the need for novel transplant strategies for the large number of patients with this disease who cannot find an HLAmatched adult donor. This trial continues for patients with HLA-matched unrelated adult donors to determine the success rate of a regimen that potentially avoids some long term effects of allogeneic transplantation, including infertility. 4 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 BMT CTN Study 1.0 Overview and Significance Significant Findings and Impact of BMT CTN Studies Results Impact / Future Outlook GRAFT SOURCES 0201: A Phase III randomized, multicenter trial comparing G-CSF mobilized peripheral blood stem cell with marrow transplantation from HLA compatible unrelated donors Determined there is no difference in survival for recipients of unrelated donor peripheral blood versus bone marrow grafts, though there is increased risk of chronic GVHD with peripheral blood grafts 0501: Multicenter, open label, randomized trial comparing single versus double umbilical cord blood transplantation in pediatric patients with leukemia and myelodysplasia Demonstrated no survival benefit for children with highrisk hematologic malignancies receiving infusion of two umbilical cord blood units versus one umbilical cord blood unit after myeloablative conditioning for hematologic malignancies 0603/0604: Multicenter, Phase II trials of nonmyeloablative conditioning and transplantation of partially HLA-mismatched bone marrow / umbilical cord blood from unrelated donors in patients with hematologic malignancies Confirmed promising singlecenter results in a multicenter setting using reduced-intensity conditioning and either haploidentical bone marrow transplantation or double cord blood transplantation in adults with hematologic malignancies Peripheral blood has largely replaced bone marrow as a graft source for unrelated donor transplantation. This study suggests that this may not be appropriate in the myeloablative conditioning setting since it offers no survival advantage but produces higher rates of chronic GVHD requiring prolonged immune suppression. Whether this will substantially change current practice remains to be determined, although requests to the National Marrow Donor Program for bone marrow grafts have increased since publication of these data. This is the largest study of unrelated donor transplantation ever performed and would not have been possible without the infrastructure provided by the BMT CTN. This study indicates that increasing cell dose beyond the accepted minimum by adding another cord blood unit does not improve survival after cord blood transplantation in children and increases the risk of acute GVHD. This has important implications for designing future strategies for improving hematopoietic recovery and decreasing transplantrelated mortality after cord blood transplantation. Acceptable outcomes of double cord and haploidentical bone marrow transplantation suggest that many more adults should be offered HCT, even when an HLA-matched adult donor is not available. These approaches are now being compared in a randomized Phase III trial (BMT CTN 1101). GVHD PREVENTION AND TREATMENT 0302: Initial systemic treatment of acute GVHD: a Phase II randomized trial evaluating etanercept, mycophenolate mofetil, denileukin diftitox (Ontak), and pentostatin Determined that GVHD biomarker panels can be used for early identification of patients at high or low risk for treatment non-responsiveness or death and that biomarker panels may provide opportunities for early intervention and improved survival following HCT 5 The wider use of biomarkers to identify patients at high risk of GVHD will allow us to tailor our therapies to better control this complication in these patients and to reduce toxicity in patients who are unlikely to benefit from intensive immune suppression. We will use these biomarkers in designing future BMT CTN trials of GVHD prevention. Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 BMT CTN Study 1.0 Overview and Significance Significant Findings and Impact of BMT CTN Studies Results Impact / Future Outlook 0303: A single-arm, multicenter Phase II trial of transplants of HLA-matched, CD34+ enriched, T cell depleted peripheral blood stem cells isolated by the CliniMACS system in the treatment of patients with AML in first or second morphologic complete remission Confirmed in a multicenter setting the feasibility and consistency of T cell depletion by CD34 selection, with results in AML that warranted consideration of a phase III trial versus non-T cell depleted transplantation These data are being used by the Food and Drug Administration in its consideration of approving a CD-34 selection column for clinical use in the US. A Phase III trial comparing outcomes of CD34-selected transplants using this approach with standard bone marrow transplants followed by calcineurin-inhibitor based GVHD prophylaxis is in development. 0402: A Phase III randomized, multicenter trial comparing sirolimus / tacrolimus with tacrolimus / methotrexate as GVHD prophylaxis after HLAmatched, related peripheral blood stem cell transplantation Identified a high risk of toxicity when sirolimus is substituted for standard methotrexate for GVHD prophylaxis when the conditioning regimen includes busulfan and no advantage in acute GVHD-free survival Although the study showed a modest improvement in grade III-IV acute GVHD, the findings do not support substituting sirolimus for methotrexate since it may increase toxicity in patients who receive busulfan for conditioning, it was associated with higher risks of chronic GVHD, and it did not improve survival. Novel approaches to preventing GVHD are needed and are being explored in a BMT CTN trial (1203) now in development. 0802: A multicenter randomized, double blind, Phase III trial evaluating corticosteroids with mycophenolate mofetil versus corticosteroids with placebo as initial systemic treatment of acute graftversus-host disease Showed the addition of mycophenolate mofetil to steroids as a first line therapy for patients with acute GVHD does not result in improved GVHD free survival compared to treatment with steroids alone This trial, closed early for futility, failed to show a beneficial effect of adding mycophenolate mofetil to steroids as initial treatment for acute GVHD. Corticosteroids remain the standard approach. Newer agents are being considered for evaluation by the Network. SUPPORTIVE CARE 0101: A randomized doubleblind trial of fluconazole versus voriconazole for the prevention of invasive fungal infections in allogeneic blood and marrow transplant recipients Demonstrated that fluconazole, a low-cost antifungal agent, generally has similar efficacy as and is generally more costeffective than the newer and more expensive drug, voriconazole, in preventing serious fungal infections in the first six months after HCT but that voriconazole may be costeffective for those undergoing an allogeneic HCT for AML 6 This ancillary study of a Phase III comparison of fluconazole and voriconazole indicates that newer is not always better and that, for most patients, standard fluconazole is an effective fungal prophylaxis agent. However, an ancillary study suggested there is a subset of patients for whom primary antifungal prophylaxis with voriconazole may be cost-effective, allowing more informed treatment planning by transplant centers. Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 BMT CTN Study 0102: A trial of tandem autologous stem cell transplants with or without post-second autologous transplant maintenance therapy versus single autologous stem cell transplant followed by matched sibling nonmyeloablative allogeneic stem cell transplant for patients with multiple myeloma 0704: A Phase III, randomized, double-blind study of maintenance therapy with CC-5013 or placebo following autologous stem cell transplantation for multiple myeloma 1.0 Overview and Significance Significant Findings and Impact of BMT CTN Studies Results Impact / Future Outlook MULTIPLE MYELOMA TREATMENT Determined, in the largest study of HCT for multiple myeloma ever conducted, that tandem autologous HCT and autologous HCT followed by allogeneic HCT offer similar progression-free survival rates in patients with standard risk disease This study highlights the need to reduce transplantrelated toxicity in the allogeneic HCT setting to allow the graft-versus-tumor effect of allografts to translate into survival benefits. It also indicated that the graft-versus-tumor effect in standard risk myeloma may not be as important as previously thought. The use of tandem autologous-allogeneic HCTs has decreased substantially over the past few years, in part, because of the data from this trial. Evaluation of the high-risk cohort is in progress and will inform the Network's next allogeneic transplant trial in this disease. Determined lenalidomide maintenance therapy prolongs remission and survival after autologous HCT for multiple myeloma The BMT CTN was an important contributor to this study, which was led by CALGB. The data have led to a major change in clinical practice, with most myeloma patients now receiving lenalidomide maintenance after transplantation. 1.1.5 Biorepository Resource The Network’s Research Sample Repository is a valuable resource. To date, protocols have yielded a biological research sample collection of more than 105,000 stored specimens. Over 18,314 specimens were added during this reporting period. Additionally, an inventory of BMT CTN research samples collections has been added to the Network’s public website as a resource for investigators planning correlative and ancillary studies. This website section lists biological samples available for all BMT CTN studies by time point and sample type, and it provides two summary tables: GVHD treatment trial samples and allogeneic transplant trial samples. 1.1.6 Funding Leverage The BMT CTN DCC encourages investigators to apply for supplemental funding to support ancillary or correlative studies. During this reporting period, investigators sought and, in some cases, have been awarded the following funding opportunities: BMT CTN 1101 cost-effectiveness ancillary study (R01; awarded) BMT CTN 1202 biomarkers ancillary study (R24; scored; funding determination unknown) BMT CTN 1205 easy-to-read consent form (U10 supplement; awarded) BMT CTN 0303 follow-on calcineurin inhibitor-free study proposal (R01 supplement; to be submitted in June 2013) 7 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 1.0 Overview and Significance 1.1.7 Key Collaborations The BMT CTN fosters successful collaborations with other networks and organizations, including: AIDS Malignancy Consortium; Canadian Blood and Marrow Transplant Group; Cancer and Leukemia Group B (CALGB)/Alliance for Clinical Trials in Oncology; Centers for Disease Control and Prevention Office of Minority Health & Health Disparities; Children’s Oncology Group (COG); Eastern Cooperative Oncology Group (ECOG); NCI-sponsored Cancer Trials Support Unit; NIH Sickle Cell Disease Clinical Research Network; Pediatric Blood and Marrow Transplant Consortium (PBMTC); SWOG. 1.1.8 Goals for Next Reporting Period 1.1.8.1 Anticipated Results In the coming year, several trials will reach primary or secondary endpoints. The results will be analyzed to address important questions: Hodgkin’s Lymphoma. Is the approach of tandem HCT for patients with recurrent Hodgkin’s lymphoma efficacious in a multicenter setting? (BMT CTN 0703/SWOG 0410 primary analysis) Quality of Life. Does exercise and/or stress management improve patients’ functional status and symptoms after HCT? (BMT CTN 0902 primary analysis) Multiple Myeloma. Is there a difference in longer-term survival between the patient groups receiving tandem autologous versus autologous/allogeneic HCT? (BMT CTN 0102 follow-up analysis) Graft Sources. Is there a difference in longer-term survival between patients receiving haploidentical HCT and double cord HCT? (BMT CTN 0603/0604 tandem studies follow-up analyses) 1.1.8.2 Studies to be Activated Four protocols are in late stages of development and are anticipated to be activated in 2013: BMT CTN 1102: A multi-center Phase III trial comparing reduced intensity allogeneic hematopoietic cell transplant to hypomethylating therapy or best supportive care in patients aged 50-75 with intermediate-2 and high risk myelodysplastic syndrome; BMT CTN 1203: A multi-center Phase II trial randomizing novel approaches for graft-versus-host disease prevention compared to contemporary controls (the PROGRESS study: prevention and reduction of GVHD and relapse enhancing survival after stem cell transplantation). BMT CTN 1204: Reduced-intensity conditioning for children and adults with hemophagocytic syndromes (the RICHeS study). BMT CTN 1205: Easy-to-read informed consent (ETRIC) for hematopoietic cell transplantation clinical trials. 1.1.8.3 Future Study Concepts Two study concepts are in early development: BMT CTN 1201 (in collaboration with the Alliance for Clinical Trials in Oncology): Phase II randomized three arm study of maintenance therapy for diffuse large B-cell lymphoma Calcineurin inhibitor-free proposal (BMT CTN number to be assigned): Phase III randomized three arm 8 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 1.0 Overview and Significance study of calcineurin inhibitor-free interventions for prevention of graft-versus host-disease In addition, the BMT CTN will host a State of the Science Symposium during the next reporting period to survey the HCT landscape and identify areas with the greatest need for high-impact Phase II and III clinical trials. Thirteen committees will present high-priority study concepts, which will be evaluated for potential development. 9 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 2.0 BMT CTN Organizational Overview 2.0 BMT CTN Organizational Overview The BMT CTN is comprised of a network of organizations that work together to achieve common goals. It includes the following elements, each of which is described in this section: Data and Coordinating Center; Twenty Core Centers/Consortia; Affiliate Centers; Steering Committee; Protocol Teams; Technical Committees; Administrative Committees; Ad Hoc Committees; Scientific Advisory Committees; Review Committees. 2.1 Data and Coordinating Center (DCC) The DCC is managed by three organizations with extensive HCT research expertise: the CIBMTR, the National Marrow Donor Program (NMDP), and The EMMES Corporation (a contract research organization). Together they are responsible for maintaining continuity of operations and effective communications, data management, and statistical support for the Network. Figure 1 illustrates the DCC’s relationship to the organization as a whole, which is explained more fully in Section 3. Figure 1. BMT CTN Organizational Structure 10 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 2.0 BMT CTN Organizational Overview 2.2 Clinical Centers 2.2.1 Core Centers The BMT CTN has 20 Core Clinical Centers (Attachment B1), some of which are consortia of two of more centers. Each Core Center holds a cooperative agreement with the NHLBI to participate in the BMT CTN. These centers were chosen by virtue of the scientific merit of their grant applications to the NIH, as well as evidence of their ability to collaborate in carrying out the Network mission of developing and completing high-quality trials as efficiently as possible. 2.2.2 Affiliate Centers The BMT CTN has more than 100 Affiliate Centers (Attachment B2) that accrue patients to Network trials. About 23% of the BMT CTN’s overall accrual comes from Affiliate Centers; for this reporting period, the figure is 26%. The Network encourages and facilitates broad participation of the HCT community through its Affiliate Center system. Affiliate Centers participate in one or more BMT CTN trials through individual subcontracts with the DCC. Applications for participation in Network trials can be found at www.bmtctn.net. 2.3 BMT CTN Committee Structure The BMT CTN committee structure ensures the Network works toward common goals. Each committee is described in this section. 2.3.1 Steering Committee The Steering Committee consists of the Principal Investigator of each Core Center or Consortium, the DCC Principal Investigator and Co-Principal Investigators, the NHLBI Project Officer, the NCI Project Officer, a representative of each of the NCI-funded Cancer Cooperative Groups, and representatives of Affiliate Centers that meet standards for exemplary accrual and participation in BMT CTN trials. Other members of the DCC, Core Centers, and NIH regularly participate in Steering Committee meetings. The Steering Committee roster is listed in Attachment D1. The Steering Committee sets the scientific agenda and oversees the selection, design, execution, and analysis of all BMT CTN studies. The Committee ensures the most relevant studies are chosen, they are appropriately designed and executed, and data analyses are properly conducted. Additionally, the Steering Committee works in collaboration with the DCC to ensure participating transplant centers adhere to BMT CTN policies and procedures. The Committee also resolves any operational issues raised by investigators, Clinical Research Associates, laboratory and repository staff, DCC members, or others. The Steering Committee selects a Committee Chair who first serves a one-year term as Vice-Chair, then a oneyear term as Chair-Elect, followed by a two-year term as Chair, and finally a one-year term as Immediate PastChair. During this reporting period, the Steering Committee also approved appointment of the Vice-Chair role, which consists of a one year term preceding the Chair-Elect position. Ginna Laport, MD, (Stanford Medical Center) began a two-year term as Chair on January 1, 2012. Frederick Appelbaum, MD, (Fred Hutchinson Cancer Research Center) is the Chair-Elect, and Steven Devine, MD, (Ohio State University Medical Center) is the ViceChair. 2.3.2 Protocol Teams Each Protocol Team consists of one to three Chairs; three to five co-investigators from Core and Affiliate Centers; an NHLBI and/or NCI representative; an NHLBI Statistician; and a DCC Protocol Officer, Coordinator, Statistician, and Contracts Representative. A Protocol Team is formed when a proposal is accepted by the 11 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 2.0 BMT CTN Organizational Overview Network. This team develops the study concept into a working study design and provides scientific oversight for the trial throughout its life cycle. The Protocol Team also: Reviews applications for participation from Affiliate Centers; Develops patient and physician educational materials; Monitors accrual and compliance with protocol requirements; Prepares amendments as necessary; Analyzes and interprets study data; Prepares manuscripts. 2.3.3 Technical Committees Standing and ad hoc Technical Committees generally consist of a maximum of nine members who are not associated with the DCC or NIH. Each Technical and Administrative committee is also assigned one or more NHLBI and NCI representatives and one or more DCC staff members. These committees conduct specified functions of Network activity, advise the Steering Committee on certain Network policies and procedures, and provide technical expertise to protocol design. Most Technical and Administrative Committee meetings are conducted by conference call. Committee members are appointed by the Executive Committee to three-year terms. Several Technical and Administrative Committee members completed their terms of service as of December 31, 2012. Nominations were open to participating Core and Affiliate centers. A Nominating Committee reviewed the nominations and proposed a slate of candidates. These candidates were approved by the Executive and Steering Committees. The current Technical Committee rosters are listed in Attachment D. 2.3.3.1 Biomarkers Committee The Biomarkers Committee, which is made up of Core and Affiliate Center transplant physicians, was formed to: Inform the Network’s scientific agenda with a focus on questions involving analysis of biologic specimens for genomic and proteomic markers; Review new and existing studies for opportunities to collect blood and tissue samples for analysis of potential prognostic markers; Advise the Network protocol teams in their review of ancillary study proposals that request the use of BMT CTN-related research samples. This committee participated in the review of two ancillary study concepts that were originally presented to BMT CTN protocol teams. Recommendations and comments regarding the potential impact of the proposed study concepts and the use of the research biospecimen collections were submitted to the protocol teams for consideration as they made final decisions regarding study approvals. The proposed research sample collection strategy incorporated into the BMT CTN 1102 study was reviewed by the committee and guidance provided to the protocol team for consideration as they finalized the study and obtained necessary NHLBI approvals. The Biomarker Committee-initiated proposal, “Prospective multi-center cohort for the evaluation of biomarkers predicting risk of complications and mortality following allogeneic HCT,” was recently released to core BMT CTN centers as protocol 1202, which will be opened soon. The primary aim of this proposal is to establish a national, multi-center cohort of biologic samples to be collected prospectively from patients treated in US transplant centers. This biospecimen collection and high-quality clinical data resource is designed to serve as a national resource supporting future genomic, proteomic, functional, and transcriptional BMT-related research. The design of the resource will support important future analyses aimed at identifying risk factors for 12 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 2.0 BMT CTN Organizational Overview development and severity of acute GVHD, chronic GVHD, organ toxicity, relapse, mortality, and other clinically significant complications occurring after allogeneic HCT. This committee played a significant role in the development of a CIBMTR-lead R24 application for funding opportunity PAR-11-090, “NHLBI investigator-initiated resource-related research projects.” The national effort proposed in this application extends the research scope of the BMT CTN 1202 study, furthering the potential impact of this national resource. A final NHLBI determination of funding is expected within the next two or three months. 2.3.3.2 Clinical Research Associates Committee The Clinical Research Associate Committee consists of Clinical Research Associates and Data Managers from Core and Affiliate Centers. This committee: Reviews each BMT CTN protocol before it is distributed to centers, focusing on reviewing and resolving logistical issues (e.g., shipping and receipt of specimens or drugs); Assists in developing and reviewing Case Report Forms; Reviews educational materials for use at participating clinical centers; Provides input for the BMT CTN Coordinators’ meeting held during the BMT Tandem Meetings. 2.3.3.3 Pharmacy Committee The Pharmacy Committee consists of transplant physicians and pharmacists from Core and Affiliate Centers. It reviews BMT CTN protocols for appropriate use and administration of pharmaceuticals. It also advises Protocol Teams about possible pharmacokinetic or other ancillary studies. The Pharmacy Committee must review each protocol before it is distributed to centers for implementation. 2.3.3.4 Special Populations Committee The Special Populations Committee consists of pediatric and adult transplant physicians from Core and Affiliate Centers as well as an ethicist. It ensures that children, women, and minority study participants are considered for inclusion in all appropriate investigational protocols developed by the Network. It also ensures that, for studies involving pediatric participants, appropriate modifications are addressed in informed consent, patient care, and monitoring documents. The Special Populations Committee reviews each protocol before it is distributed to centers for implementation. Evaluation of HCT in the pediatric population presents some unique challenges. The Network is committed to developing strategies to address these challenges and increase the participation of children in HCT clinical trials. Thirteen Network trials have enrolled or are enrolling children (BMT CTN 0101, 0201, 0301, 0302, 0402, 0501, 0601, 0603, 0604, 0801, 0802, 0803 and 0903); two of them focus specifically on pediatric issues (BMT CTN 0501 and 0601). There is a protocol in development for children with hemophagocytic syndromes or primary immune deficiencies (BMT CTN 1204) that is anticipated to be opened during the next reporting period. In addition, children are eligible to participate in the soon-to-be open biomarkers study (BMT CTN 1202). The proportion of BMT CTN trial participants under age 16 is only slightly lower than the overall proportion in the US transplant population. Since many US pediatric HCT recipients also have access to HCT trials through the COG, Network leadership feels these enrollment figures are appropriate. 2.3.3.5 Toxicity and Supportive Care Committee The Toxicity and Supportive Care Committee consists of Core and Affiliate Center transplant physicians. It works with the DCC to define methods for evaluating adverse events and toxicities after transplantation; reviews the evaluation and monitoring requirements for toxicities on BMT CTN protocols; and designs and approves forms and procedures for collecting toxicity data, including standards for expedited reporting of certain adverse 13 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 2.0 BMT CTN Organizational Overview events. The Toxicity and Supportive Care Committee must review each protocol before it is distributed to centers for implementation. 2.3.4 Administrative Committees 2.3.4.1 Executive Committees The Executive Committee consists of the Steering Committee Chair, Chair-Elect or Immediate Past Chair, ViceChair, NHLBI and NCI Project Officers, and DCC Principal Investigator and Co-Principal Investigators. Executive Committee members are indicated by an asterisk (*) in Attachment D1. The Executive Committee is a subcommittee of the Steering Committee and works in collaboration with the DCC. The Executive Committee ensures participating transplant centers adhere to BMT CTN policies and procedures, and it works together with the Steering Committee to resolve operational issues raised by investigators, Clinical Research Associates, laboratory and repository staff, members of the DCC, and others. It appoints Technical and Administrative Committee members. The Executive Committee also: Addresses policy making issues; Reviews contractual arrangements and financial matters affecting the Network as a whole; Makes recommendations to the Steering Committee; Reviews and approves Transplant Center Performance Reports, audits, and corrective action plans; Provides initial review of research proposals submitted to the BMT CTN for new trials and ancillary studies; Assists in developing Steering Committee meeting agendas. 2.3.4.2 Publications, Abstracts, and Presentations Committee The Publications, Abstracts, and Presentations Committee consists of Core and Affiliate Center transplant physicians. This committee develops publication and presentation policies. It also reviews publications and presentations to ensure confidentiality of study participants and proprietary information as well as to ensure appropriate acknowledgements of contributions, sponsorship, and authorship. 2.3.5 Ad Hoc Committees Additional administrative and technical committees are convened as needed. For example, a Nominating Committee is formed to propose candidates for open committee positions. Several technical committees are also convened as needed to discuss new study concepts, provide an update to the Steering Committee on recent advances in the field, or provide input into the Network’s Technical Manual of Procedures. These committees include GVHD, Graft Characterization, Cellular Therapy, and Infectious Disease. 2.3.6 Scientific Advisory Committees As a result of the Network’s 2007 State of the Science Symposium, twelve Scientific Advisory Committees were formed to address specific areas pertinent to HCT trials. Additionally, the symposium resulted in a publication that provided a road map of high-priority studies recommended for implementation by the US transplant community using the resources of the BMT CTN, NCI Cooperative Groups, and other programs (Ferrara J, Anasetti C, Stadtmauer E, Antin J, Wingard J, Lee SJ, Levine J, Schultz K, Appelbaum F, Negrin R, Giralt S, Bredeson C, Heslop H and Horowitz M. BMT CTN State of the Science Symposium 2007. Biology of Blood and Marrow Transplantation. 2007;13:1268-128. Also listed in Attachment C1.) These Scientific Advisory Committees continued to operate and meet on an ad hoc basis to review and prioritize the Network’s scientific agenda. In summer 2011, the committees reviewed and summarized protocol concepts 14 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 2.0 BMT CTN Organizational Overview submitted by Core Center applicants, for discussion at the July Steering Committee Meeting, the first meeting with new Core Center representatives. During this reporting period, the Committees were redesigned and reconvened to start planning for a State of the Science Symposium in 2014. (See Section 6 for more information about this symposium.) 2.3.7 Review Committees Two independent Review Committees provide additional oversight for BMT CTN trials: Protocol Review Committee. The Protocol Review Committee is appointed by the NHLBI and consists of a Chairperson and Members whose experience reflect areas of expertise necessary to evaluate the scientific merit and design of BMT CTN protocols. Consultants may be added on an ad hoc basis if needed. The Protocol Chair (or designee), Protocol Officer, Statistician, and senior members of the DCC represent the Protocol Team at Protocol Review Committee meetings. Data and Safety Monitoring Board. The Data and Safety Monitoring Board, an independent board appointed by the NHLBI and/or NCI, is composed of a Chair and Members with expertise in biostatistics, clinical trials, bioethics, and the specific research area(s) of the Network studies. Consultants may be added on an ad hoc basis if needed. The Network currently employs two Data and Safety Monitoring Boards for its large number of active studies. 15 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 3.0 Administrative Functions of the DCC 3.0 Administrative Functions of the DCC The DCC is a collaborative partnership of three organizations with extensive experience in multicenter, HCTrelated clinical research. The DCC is led by Mary Horowitz, MD, MS, (CIBMTR), Shelly Carter, ScD, (The EMMES Corporation), and Dennis Confer, MD, (NMDP). The DCC supports and manages the efficient development, implementation, and completion of high-quality Phase II and III clinical trials for the Network, including: Evaluating and prioritizing study concepts; Developing protocols with appropriate statistical designs; Activating studies and developing plans to accrue patients in a timely manner; Monitoring for safety, regulatory, and protocol compliance as well as data accuracy; Collecting complete clinical and laboratory data; Analyzing and sharing research results. The DCC also coordinates and supports overall BMT CTN activities to enhance Network effectiveness, including: Maintaining the Administrative and Technical Manuals of Procedures; Facilitating communication and maintaining public and private websites; Maintaining a state-of-the-art research database; Maintaining systems for acquisition and storage of biologic specimens; Managing contractual arrangements and fiscal activities; Monitoring and improving overall center performance; Supporting all Network committees and activities with meeting planning and other logistical support; Collaborating with government organizations to avoid competing studies, facilitate study completion, and publish results in a timely manner. 3.1 DCC Partner Organizations The DCC consists of three partners: CIBMTR (Milwaukee, Wisconsin, and Minneapolis, Minnesota) is a research organization formed in 2004 from the affiliation of the International Bone Marrow Transplant Registry at the Medical College of Wisconsin (MCW) and the Research Department of NMDP. The CIBMTR has a proven history of clinical research and publication in both HCT and statistical methodology. It has fostered effective collaborations with a large network of transplant centers. It also maintains an extensive observational research database of virtually all allogeneic transplantations and most autologous transplantations performed in the United States. EMMES Corporation (Rockville, Maryland) is a contract research organization established in 1978 that has managed more than 350 Phase I-III trials and registries for over 15 years. EMMES provides experience in planning, implementing, and managing multicenter clinical trials in a variety of areas, including HCT; statistical design and analysis; clinical trial design and management; complex data collection system design and implementation; site monitoring; and regulatory support. NMDP (Minneapolis, Minnesota) was established in 1987. It is the world leader in HCT donor registry and graft procurement management, and it operates the world’s largest HCT-related Research Sample Repository. NMDP has a large network of donor, collection, transplant centers, and cord blood banks; a skilled Contracts and Procurement Department that manages contracts with 176 US and international transplant centers and maintains contractual relationships with specimen repositories and contract 16 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 3.0 Administrative Functions of the DCC laboratories; an experienced Patient Services department that provides educational and counseling services to patients in need of a transplant; and a Case Management department that facilitates most of the unrelated donor transplantations performed in the United States. Figure 2 illustrates the relationship among DCC organizations and its distribution of responsibilities, and Table 2 describes the specific responsibilities of each DCC member. Appendix A displays the organizational structure of the DCC. Figure 2. DCC Organization EMMES CIBMTR Overall coordination Statistical design & analysis Data management Real-time electronic data collection Scientific leadership Protocol development & implementation Medical monitoring Trial oversight & monitoring Research Sample Repository management Patient advocacy Contracting NMDP 17 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 3.0 Administrative Functions of the DCC Table 2. Responsibilities of DCC members DCC Member Responsibilities CIBMTR NMDP EMMES Lead Support Support Support Support Lead Support Lead Support Support Support Lead Manage electronic communications (general and study-specific) Support Support Lead Maintain roster of participants Support Support Lead Prepare budget and track financials Support Lead Support Lead Support Support Shared Shared Shared Serve as Protocol Officer Shared Shared ----- Serve as Protocol Statistician Shared ----- Shared Serve as Patient Services Representative ----- Lead ----- Serve as Protocol Coordinator ----- ----- Lead Support Support Lead Shared Shared Shared Lead Support Support Support Support Lead Contract with centers Support Lead Support Identify laboratories/repositories Support Lead Support Contract with laboratories Support Lead Support Support ----- Lead Support Support Lead Develop Case Report Forms Support Support Lead Coordinate laboratory & repository functions Support Lead Support Ensure quality of therapeutic & diagnostic modalities Support Support Lead ----- ----- Lead Train site personnel Support Support Lead Develop patient materials Support Lead Support Monitor Adverse Events Support Support Lead Develop and implement accrual plan Shared Shared Shared Provide Data and Safety Monitoring Board support Support Support Lead Review performance of centers Shared Shared Shared Monitor accrual Shared Support Shared Administrative Functions Provide overall scientific /administrative leadership Develop Manuals of Procedures/Standard Operating Procedures Facilitate meeting logistics a Coordinate meeting materials b Trials Development & Management Develop/review concepts Develop protocols Protocol Team Manage Protocol Document Provide Protocol Review Committee support c Protocol Implementation Identify centers Certify centers d Maintain roster of study participants Manage data management system e Manage site activation process, including monitoring regulatory compliance 18 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 3.0 Administrative Functions of the DCC DCC Member Responsibilities CIBMTR NMDP EMMES Monitor data accuracy and conduct data review sessions Support ----- Lead Prepare reports/manuscripts Shared Shared Shared Coordinate dissemination of results Shared Shared Shared Develop Statistical Methodology Shared ----- Shared a Schedule site location, travel arrangements, conference calling, travel reimbursements b Develop agendas, supporting materials and reports, minutes c Support Steering and Protocol Review Committees during review process, identify and address reasons for delay d Certify ability of centers to execute special requirements of protocol e Including systems for registration, Web-based data entry, database design, study archive backup, contingency plans 3.2 Policies and Procedures The BMT CTN has two Manuals of Procedures: Administrative and Technical. The Administrative Manual includes policies and procedures related to: Participation in Network protocols including detailed steps for proposing, drafting and executing studies; Roles and duties of Core and Affiliate Centers and Network committees; Roles of CIBMTR, NMDP, and EMMES within the DCC; Transplant center site monitoring; Adverse event reporting; Human subject protection and regulatory procedures; Publications, abstracts, and presentations; Ancillary studies. The Technical Manual of Procedures is a composite of policies and procedures pertinent to practice guidelines and laboratory evaluations unique to HCT. The Technical Manual includes detailed policies and procedures regarding: Acute and chronic GVHD; Characterization and processing for hematopoietic cellular products; Diagnosing and grading infectious diseases; Technical Committees’ policies. Several updated chapters of the Technical Manual were released to the Steering Committee in March 2013. The remaining chapters, and the Administrative Manual, will be revised and distributed within the next reporting period. These and other procedural documents are available at http://www.bmtctn.net (public website) and http://www.bmtctnsp.net (password-protected, secure website for Network members). 3.3 Administrative Support The DCC coordinates and schedules meetings and conference calls for the Steering, Executive, Scientific Advisory, Administrative, and Technical Committees as well as for Protocol Teams. From April 1, 2012, through March 31, 2013, the DCC managed 302 conference calls. DCC representatives attend and participate in all Network meetings, providing logistical support to ensure the meetings are conducted efficiently and effectively. Two or more DCC staff members participate on all Technical Committee and Protocol Team calls, preparing and 19 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 3.0 Administrative Functions of the DCC circulating agendas and minutes for these committees. The DCC also maintains version control of protocols during development and after their approval, including all amendments. 3.4 Fiscal Planning and Contracting Support NMDP manages fiscal planning and contract support for the BMT CTN. Personnel from the NMDP Contracts and Procurement Department participate in DCC conference calls, protocol development calls, Executive and Steering Committee calls, and in-person Steering Committee meetings. NMDP develops and executes Requests for Proposals, service agreements, and agreements for laboratory and pharmacy services to support specific protocols. Throughout the history of the BMT CTN, and in collaboration with both NHLBI and NCI, NMDP has negotiated a number of Memoranda of Agreement to sponsor contributions that offset the cost of individual protocols or provide pharmaceutical products. Master Agreements and corresponding Clinical Study Protocol Riders for each protocol facilitate participation of Affiliate and Core Centers in BMT CTN protocols. Due to a change in management of the COG and the PBMTC, the NMDP Contracts Department collaboratively negotiated a new Master Agreement and Clinical Study Protocol Riders with the Children’s Hospital of Philadelphia. NMDP also manages and distributes Core Center budgets for protocol-specific funds. Pharmacy agreements with Eminent Pharmacy Services on BMT CTN Protocols 0402, 0701, 0702, and 0802 were managed in the past year. NMDP coordinates with Eminent to ensure accurate and timely drug distribution for such studies. The agreement for 0702 remains open; the other protocols are complete. In order to assist with financial planning, NMDP also coordinates and manages the protocol budget development process, generates financial reports on protocol spending, and provides forecasts of future spending based on observed patterns, when requested. BMT CTN leadership understands that optimizing external funding is critical at any time but particularly in the current economic environment. The Network works hard to leverage NIH support as well as direct and in-kind contributions to further its scientific agenda. The DCC develops relationships and contracts with pharmaceutical companies and laboratory vendors for additional budgetary support and for drugs used in studies, always with proper attention to avoiding potential conflicts of interest. All contributions are made through NHLBI-approved Memoranda of Agreement. On behalf of the BMT CTN and in collaboration with both NHLBI and NCI, NMDP negotiated several Memoranda of Agreement to sponsor contributions that offset the cost of individual protocols or provide pharmaceutical products. 3.4.1 Cost-Saving Mechanisms The DCC carefully manages the resources of the Network. It established a uniform budgeting model to project trial costs accurately and uses a competitive bid process to procure laboratory, pharmacy, and other services, ensuring that NIH funds are used wisely. To minimize delays associated with contracting with private companies, the DCC established a policy of face-to-face meetings with potential contributors early in the protocol development process. These meetings familiarize potential contributors with the Network, its membership, and its research activities, and they allow the DCC to identify specific corporate contract liaisons. Additionally, the Steering Committee encourages Protocol Teams to consider cost-saving mechanisms such as: Restricting study requirements, such as research repository samples, to those that are essential to 20 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 3.0 Administrative Functions of the DCC answering the primary and secondary questions; Limiting the number of secondary questions to the most scientifically important; Reducing the length of follow-up periods and using the established CIBMTR Research Database for longterm follow-up of enrolled patients beyond the primary endpoint. 3.5 Communication Managing the large Network and its protocol activity requires excellent communication. Information must flow among DCC members, Network committees, transplant centers, laboratory and repository facilities, the medical community, and the lay public. Weekly teleconferences for leadership and DCC members and monthly teleconferences for the Executive Committee are conducted. Steering Committee meetings are scheduled either in-person or by teleconference each month. Additional communication efforts are described in this section. 3.5.1 Maintaining BMT CTN Websites The DCC maintains a public website (www.bmtctn.net) and a secure, password-protected website (www.bmtctnsp.net). The Network’s public website features: A BMT CTN organizational overview and contact information; A current BMT CTN Progress Report; Current versions of open protocols; Educational materials for all open protocols; Applications to participate in BMT CTN protocols as an Affiliate Center; Administrative and Technical Manuals of Operations; A new section of BMT CTN research samples collections listing biological samples available for all studies, by time point and sample type, and two summary tables: GVHD treatment trial samples and allogeneic transplant trial samples; A password-protected page for BMT CTN Coordinators that includes: o Data and Safety Monitoring Board reviews and data reports; o Links to private BMT CTN, AdvantageEDC data collection, and GlobalTrace specimen tracking websites; o Links to AdvantageEDC and GlobalTrace training modules; o Presentations from the BMT CTN Coordinators' Meeting; o Quarterly BMT CTN Coordinator newsletters; o Links to related DCC and government partner websites; o Panels featuring BMT CTN news, health news, and links to related medical articles. The Network’s secure, password-protected website uses Microsoft SharePoint Server™ software to allow Network participants to share confidential information. It features: Meeting materials, including agendas, minutes, and conference call materials; Protocol Team materials including the current version of each protocol; Rosters of personnel at participating centers; Rosters for the Steering, Administrative, and Technical Committees as well as Protocol Teams; Study accrual reports; Monthly recruitment reports. The DCC uses a separate password-protected area of the secure site to post Data and Safety Monitoring Board meeting materials, share confidential information, and distribute monthly safety monitoring reports. All necessary meeting materials are posted two weeks before scheduled meetings. Adverse events reports and 21 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 3.0 Administrative Functions of the DCC stopping guideline (safety) tables and graphs are posted monthly. Data and Safety Monitoring Board members can access the accrual, monthly recruitment, data quality, and site activation status reports, which are updated nightly or monthly depending on the report. The CIBMTR’s public website, www.cibmtr.org, has a page dedicated to the Network, including an overview of its functions, a list of all BMT CTN protocols, and a link to the BMT CTN public website. Additionally, the CIBMTR displays information about the Network and its protocols at national and international meetings. NMDP’s public website, www.bethematch.org, also has a page dedicated to the BMT CTN, including an overview of the Network and links to the BMT CTN and government partner websites. 3.5.2 Developing Patient Support and Marketing Materials NMDP’s Patient Services Department assists the Network in developing patient-friendly study materials. This department managed an extensive project to reformat the Network’s patient consent and assent forms for easier readability and comprehension. This resulted in a 2011 manuscript that summarized recommendations of the review team for the development and formatting of accessible consent forms for multicenter clinical trials (Denzen et al., Biology of Blood and Marrow Transplantation, full citation listed in Attachment C1.) The intent of these recommendations is to guide the informed consent form writing process, simplify local Institutional Review Board review of consent forms, enhance patient comprehension, and improve patient satisfaction. The recommendations will be tested in a randomized study of the updated consent vs. the standard format in the upcoming Easy-to-Read Informed Consent study (BMT CTN 1205) to be released to centers this year. Several members of the original Patient Services team who revised the consent form format are on the BMT CTN 1205 protocol team. The Patient Services Department and NMDP Marketing and Communications Department also support communications for accrual enhancement, help develop patient education materials, and help design Network publicity materials such as protocol flyers and posters used for national meetings and emailed accrual updates. 3.5.3 Communicating Trial Results Communicating trial results rapidly and accurately is a fundamental activity of the DCC. Efficient and accurate data collection, processing, and analysis — each stage of which is supported by the DCC — ensure the integrity of Network trials and provide the foundation for publication and dissemination of study results. The DCC helps Protocol Teams disseminate study results and publish as quickly as possible, assisting investigators in developing study slide sets and poster presentations for national and international meetings. The DCC also provides administrative support to the Publications Committee in its oversight of the publication process and assures proper acknowledgement of trial contributors. DCC staff members coordinate, compile, and distribute the annual BMT CTN Progress Report to the research community and the public to provide them with updated information on protocol activity including published findings. These reports are available in print and digital format, and they are posted on the Network’s public website (www.bmtctn.net). 3.6 Training Ongoing education is imperative for ensuring protocol compliance and data quality. DCC staff members conduct site visits and calls to transplant centers to initiate protocols and educate center personnel on Network policies and procedures. Research staff members at the center receive an initiation report. Clinical Research Associate training sessions are held annually in conjunction with the BMT Tandem Meetings. These sessions cover data entry, quality control issues, and reviews of procedures and protocol requirements. They also provide the DCC with useful feedback from centers. General Clinical Research Associate calls are held 22 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 3.0 Administrative Functions of the DCC at least quarterly, and protocol-specific calls are held as necessary with minutes distributed to research staff. Additionally, the Network provides online training in its AdvantageEDC and GlobalTrace software packages that includes training modules with a training practicum (AdvantageEDC) and competency assessments (GlobalTrace). The Network also prepares a quarterly electronic newsletter for research staff and provides a variety of materials to assist centers in understanding and implementing protocol requirements. 3.7 Transplant Center Monitoring The DCC regularly monitors the performance of BMT CTN Core Centers and their contributions to the Network. Daily or monthly reports include each center’s accrual rate, number of eligible patients, reasons for nonenrollment, number of ineligible patients, and reasons for ineligibility, for most protocols. The DCC also tracks each center’s form delinquency, number of data queries, and major and minor protocol violations. The Data and Safety Monitoring Board routinely reviews these data. Center Performance Reports (Attachment E) are prepared annually (most recently in January 2013). Overall scores on Center Performance Rating (Attachment F) are based on five categories: Scientific/administrative contributions (10 points); Patient accrual (60 points); Activation and enrollment (10 points); Data quality (10 points); Laboratory compliance (10 points). Final scoring is a composite of category-specific metrics associated with each of these measures of commitment and involvement. The few centers that receive a “needs improvement” score in any area must submit an action plan for resolving problems within six weeks of receiving the report. Additionally, Center Performance “snapshots” of actual-versus-projected accrual and laboratory compliance reports are distributed to Core Centers quarterly. 3.8 Specimen Repository Support 3.8.1 Specimen Collection Each BMT CTN protocol creates an important new opportunity for the scientific community to collect baseline and post-transplant/post-treatment biologic specimens for clinical research. For most protocols, biologic samples are collected for use in protocol-defined research aimed at answering specific questions for that patient population and its transplantation outcomes. Collection of supplementary samples was incorporated into most protocols for use in future research. These samples and the associated clinical data will be made available as a valuable resource for investigators at large. During this reporting period, a new section of BMT CTN research samples inventory has been added to the Network’s public website to help investigators better utilize this resource. The section lists biological samples available for all studies by time point and sample type, and it provides two summary tables: GVHD treatment trial samples and allogeneic transplant trial samples. The DCC receives requests for the use of its research samples for transplantation or post-transplantation treatment-related ancillary studies. The procedures for judging the scientific merit of such studies, including evaluations by the parent study Protocol Team, Biomarkers Committee, DCC and Steering Committee, are defined in the BMT CTN Administrative Manual of Procedures. Samples for early Network studies (BMT CTN 0101 to 0402) were processed at the clinical sites and shipped to the NHLBI Repository for storage and future distribution for protocol-defined correlative studies and additional ancillary studies. In 2009, the storage and management of all future BMT CTN protocol-related research sample 23 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 3.0 Administrative Functions of the DCC collections was moved to the NMDP Research Sample Repository. As of March 27, 2013, a total of 105,875 specimens were stored by the BMT CTN Repository Network: NHLBI Repository, BMT CTN Sample Repository operated by NMDP, and the AIDS and Cancer Specimen Resource Repository. A total of 18,314 specimens were added during this reporting period. A summary of currently available research samples is shown in the following tables. Table 3a. BMT CTN center processed samples received and stored at the NHLBI Repository BMT CTN Protocol Total Biospecimens Received Currently Available Biospecimens Subjects with Available Biospecimens 0101 24,354 NHLBI Managed Open Collection (data unavailable) NHLBI Managed Open Collection (data unavailable) 0102 13,070 10,507 615 patients 85 donors 0201 15,282 7,235 437 patients 0302 1,554 1,033 137 patients 0401 233 221 116 patients 0402 20,048 19,395 312 patients 178 donors Table 3b. Samples processed and stored at the BMT CTN Repository BMT CTN Protocol Total Biospecimens Stored Currently Available Biospecimens Subjects with Available Biospecimens 0701 99 94 57 patients 0702 21,265 19,380 581 patients 0801 2,449 2,198 81 patients 0802 5,833 4,559 207 patients 0901 744 665 136 patients 1101 298 298 7 patients 4 donors Table 3c. Samples processed and stored at the AIDS and Cancer Specimen Resource Repository BMT CTN Protocol Total Biospecimens Received Currently Available Biospecimens Subjects with Available Biospecimens 0803 566 566 31 patients 0903 80 80 4 patients During this reporting period, 24,345 frozen sample aliquots were shipped to project laboratories for the following protocol-defined correlative studies: BMT CTN 0101: 713 samples – Voriconazole & fluconazole pharmacokinetics BMT CTN 0101: 21,875 samples – Investigational fungal diagnostic assays BMT CTN 0201: 1,359 samples – Immune reconstitution assays 24 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 3.0 Administrative Functions of the DCC BMT CTN 0801: 60 samples – Plasma B cell activating factor testing BMT CTN 0802: 338 samples – Plasma biomarker panel testing BMT CTN 0802: 361 samples reserved – Expanded plasma biomarker panel testing (funding pending) 3.8.2 BMT CTN Research Sample Repository and Central Processing Lab The central processing laboratory at the BMT CTN Research Sample Repository plays an important role in standardizing complex specimen processing procedures and expanding the collection of quality sample types for correlative studies. The availability of these services, which will be applicable to many future studies, helps reduce the research sample processing burden for clinical sites. The laboratory is currently processing peripheral blood samples into serum, plasma, viable peripheral blood mononuclear cell (PBMC) and granulocyte sample types. Bone marrow aspirates, buccal swabs, and viable marrow product mononuclear cell sample types are also being processed and stored at the BMT CTN Research Sample Repository. 3.8.3 Maximizing Sample Handling The DCC invested substantial efforts throughout this reporting period to improve Network procedures for research sample collection, associated data accuracy, sample storage, and research sample testing. Highlights of these efforts and benefits include: Continued integration of standardized sample acquisition forms and sample tracking (AdvantageEDC and GlobalTrace). Systematic sample data collection and specimen tracking provides additional realtime center assessment opportunities to increase the accuracy and compliance of sample collection information at each critical time point. The availability of sample acquisition forms in AdvantageEDC forms grid provides centers an additional reminder of future sample collection target dates, facilitating patient appointment scheduling. Continued development of a network of research and clinical laboratories that support current and future studies. There are currently 16 active laboratory agreements, some of which were established through competitive Requests for Proposals. Announcements of future laboratory support opportunities are communicated on the BMT CTN Public website and via email to current and past Core and Affiliate Center PIs at pre-screened clinical and research laboratories. Additionally, the American Society for Blood and Marrow Transplantation and the American Society for Clinical Pharmacology and Therapeutics send notification emails to their members regarding Request for Proposal opportunities for laboratory support of BMT CTN ancillary studies. Continued review of all pending sample shipments to the NHLBI Repository for older protocols. This process continues to provide an opportunity to review key procedures with center staff and to discuss effective sample management strategies, build relationships with research staff, and receive feedback on transplant center needs. The DCC continues to work with Network Centers and NHLBI BioLINCC staff to proactively review sample manifest inventory data to ensure accurate linkage of clinical data associated with research samples being submitted for inclusion in BMT CTN biospecimen collections. Review of comprehensive center-specific sample collection and required laboratory testing compliance reports. Clinical centers receive the information they need to assess their achievements and areas of deficiencies and to facilitate discussions with DCC staff. These reports are periodically reviewed by DCC staff members who contact centers to discuss opportunities for improvement and process optimization. Focus on more complete instructional materials, training, and educational opportunities for research staff. Education efforts have improved understanding of the purpose and importance of the research sample collections by transplant center staff. Staff members are encouraged to discuss and develop best 25 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 3.0 Administrative Functions of the DCC practices for tracking upcoming research sample collections and improving accuracy of patient information associated with biologic research samples. Dedicated DCC personnel and Research Sample Repository staff are always available to answer questions and support transplant center staff. 26 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 4.0 Concept to Publication: The Protocol Process 4.0 Concept to Publication: The Protocol Process Since its establishment in 2001, the Network has refined its processes for supporting selection, development, and implementation of studies. Current procedures reflect the Network’s commitment to efficient use of its resources to implement well-designed studies that accrue sufficient numbers of patients as rapidly as possible. This section describes the typical sequence of events. There is substantial overlap in the timeframes of these steps, as the Network seeks to implement tasks in parallel rather than sequentially whenever possible. Transplant center investigators, Protocol Team members, DCC staff members, external oversight bodies (Protocol Review Committee and Data and Safety Monitoring Board), NCI Cooperative Group collaborators, and funding partners (NHLBI and NCI) are all involved in developing, implementing, and completing studies. The Steering Committee is responsible for: Reviewing and prioritizing all concepts proposed for Network consideration; Approving final draft protocols prior to Protocol Review Committee and Data and Safety Monitoring Board review; Overseeing execution and analysis of approved Network trials. Figure 3 displays the protocol development and implementation processes described in this section. Figure 3. Schema for protocol development and implementation Protocol Development Proposal Concept Evaluation / Approval Protocol Approval Protocol Development Steering Committee PRC DSMB IRBs Technical Committees Protocol Implementation / Completion Activation Case Report Forms* / Study documents and procedures* / Data systems* / Contracts / Accrual plan* / Educational materials* / Site training Maintenance Accrual / Compliance / Data quality / Safety / Amendments / Continued site training Closure Data review / Data files / Analysis / Abstracts / Publications *Work on these documents / tasks begins during the protocol development phase and is generally close to complete by the time the first IRB approvals are available. 4.1 Concept Evaluation and Approval Any investigator may submit study concepts for consideration. Study proposal requirements are posted on the Network’s public website (www.bmtctn.net). 27 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 4.0 Concept to Publication: The Protocol Process 4.1.1 DCC Review Study concepts are submitted first to the DCC, which performs a preliminary review to ensure the proposed study does not conflict with an active study and the proposal is complete. The DCC then distributes the study concept to the Executive Committee for discussion at a regularly scheduled monthly meeting. 4.1.2 Executive Committee Review The Executive Committee reviews the study concept to ensure that it is consistent with the Network’s mission, does not compete with active BMT CTN protocols or BMT CTN protocols in development, and poses no major conflicts of interest. Eligible proposals are scheduled for review by the Steering Committee. 4.1.3 Steering Committee Review Study concepts are scheduled for discussion at the monthly Steering Committee conference calls or in-person meetings, which are held three times per year. The Steering Committee evaluates concepts for scientific merit, feasibility, and Network members’ willingness to participate. The Steering Committee may accept, reject, or recommend changes to the study concept. The DCC assists in the review process, using CIBMTR data to assess feasibility based on study population and eligibility requirements. The DCC supports the Steering Committee in its deliberations by providing the following information whenever possible: Numbers of patients currently undergoing transplantation at Core and Affiliate Centers who might meet eligibility criteria; Outcomes of interest in the specified population; Evaluation of sample size requirements; Suggestions for alternate study designs; Special requirements for research samples and/or necessary agents; Potential competing protocols. 4.2 Protocol Development 4.2.1 Establishment of a Protocol Team When the Steering Committee approves a study concept, the DCC assigns it a protocol number, and a Protocol Team is formed. The Protocol Team meets weekly by teleconference during the development process, and the Steering Committee reviews team progress as needed. The Protocol Team includes: Protocol Chairs (Study Principal Investigators). The Protocol Chairs, generally the investigators who submitted the original concept, have primary responsibility for the protocol’s development and progress. Most Network protocols have two Chairs. Core and Affiliate Centers representatives. Most Protocol Teams have four to six representatives (coinvestigators) from Core and Affiliate centers. Protocol Officer. The Protocol Officer (physician DCC member) helps address scientific and medical issues. Protocol Coordinator. A DCC Protocol Coordinator manages logistical and practical issues such as coordinating meetings, preparing minutes, and maintaining protocol version control. Protocol Statisticians. DCC and NHLBI statisticians create and coordinate the Statistical Analysis Plan (Section 4.2.2). Contracts Representative. A DCC Contracts Representative manages laboratory and supply 28 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 4.0 Concept to Publication: The Protocol Process procurements and contributor agreements. 4.2.2 Statistical Design Statistical analyses of study data are prepared and documented in a Statistical Analysis Plan within the protocol document. This plan includes a synopsis of the study design; endpoints; hypotheses; randomization and stratification procedures; sample size and power calculations; stopping rules for efficacy, futility and/or toxicity; planned analyses of primary and secondary endpoints; adjustment for multiple testing; and control of type I error and subgroup analyses. Since the potential pool of patients for HCT trials is limited, statistical designs must make optimal use of available patients. Additionally, HCT trials face some unique challenges: When donors and recipients are consented and randomized separately, delays in this process can lead to dropout, as seen in BMT CTN 0201. There is the potential for multiple complications (infection, organ toxicity, GVHD, relapse, etc.) during the early post-transplantation period. Therefore, competing risks must be considered with all study endpoints. Competing risks are commonly addressed using composite endpoints as the primary outcome measure, as in BMT CTN 0101 and 0402. The CIBMTR Research Database helps identify patient candidates for study exclusion due to high risks of competing events. Cumulative incidence estimators are used to approximate probabilities of individual events occurring in the presence of competing risks. Non-proportional hazards and crossing survival curves occur when treatments under investigation have different timing of events, as with allogeneic versus autologous HCT (BMT CTN 0102), or with different regimen intensities (BMT CTN 0901). If this occurs, the usual log-rank test is inappropriate, and a pointwise comparison of survival probabilities is often performed instead. CIBMTR data are again useful in identifying an appropriate follow-up time point, a time when most events of interest have occurred. More efficient methods for comparing groups with non-proportional hazards were recently proposed for the analysis of BMT CTN 0901. Analysis of quality-of-life data must consider non-ignorable missing data due to early mortality, particularly when quality of life is the primary endpoint, as in BMT CTN 0902. EMMES and CIBMTR statisticians are experts in analysis of HCT data, with many methodological publications to their credit. This expertise is an invaluable resource for addressing statistical challenges. DCC statisticians hold conference calls that include PhD and Master’s-level statisticians to discuss current analyses and approaches to statistical issues. These discussions help ensure consistent, high quality, and appropriate statistical analyses for BMT CTN studies. 4.2.3 Accrual Planning Accrual planning is an important step in the protocol development process. The BMT CTN Project Manager works with Protocol Team members to develop a customized accrual plan for each study, including an Accrual Plan Assessment (Attachment H). When eligibility criteria are established, the Protocol Coordinator invites Core Centers to participate and provide projected accruals. Using the CIBMTR Research Database, accrual projections are checked against each center’s reported activity, and discrepancies are resolved. If there are not enough potentially eligible patients from participating Core Centers, the DCC contacts Affiliate Centers that have both the potential for contributing substantively to accrual and the necessary expertise to execute the study. The accrual plan for each study includes projected accrual rates from Core and Affiliate Centers, a list of advocacy and other groups that should receive information about the trial, and materials for referring physicians and study participants. 29 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 4.0 Concept to Publication: The Protocol Process 4.2.4 Budget Preparation When a draft protocol is available, the NMDP-based Financial Analyst arranges a teleconference with the Protocol Chair(s), Officer, and Coordinator as well as other key parties to initiate budget preparation. The Financial Analyst drafts a budget based on the final draft protocol as well as laboratory and services requirements. Costs of labor for center and DCC personnel, medications, other therapies, shipping, and supplies are also considered. The Protocol Chair(s) and Protocol Officer review the draft budget, which is included in the materials that are distributed to the Protocol Review Committee. Before submission to NHLBI and NCI for approval, the NMDP Chief Financial Officer (or appropriate designee), Steering Committee Chair, and DCC Principal Investigator review and sign the final draft budget. 4.2.5 Federal Regulations The DCC maintains regulatory files for the Network, including Food and Drug Administration (FDA) 1572 forms, investigator curriculum vitae, Institutional Review Board approvals and approved consent forms, financial disclosures, medical licenses, pharmacy licenses (if applicable), and evidence of Human Subjects Research Training staff certification for each Core and Affiliate Center. The DCC prepared and submitted three Investigational Device Exemption applications, which were required for BMT CTN protocols 0101, 0303, and 0801. The DCC also submitted eight Investigational New Drug applications to the FDA for BMT CTN protocols 0102, 0201, 0302, 0401, 0403, 0701, 0702, 0801, and 1101. The FDA subsequently deemed Investigational New Drug applications unnecessary for BMT CTN protocols 0701, 0801, and 1101. 4.2.6 Final Draft Protocol The development process results in a final draft protocol document that provides the necessary details to perform a clinical trial. This document includes: An outline of the study design; Study background, scientific rationale, and objectives; Detailed description of treatments; Detailed description of experimental design, including the Statistical Analysis Plan; Definition of primary and secondary endpoints; Eligibility requirements; Follow-up schedules and requirements for patient exams; Specimen submission schedules; Safety measurements and adverse event reporting procedures; Registration and randomization procedures; Procedures for blinding study treatments; Protocol-specific technical guidelines (e.g., donor selection criteria and graft processing techniques); Informed consent template; References; Appendices. The final draft protocol then undergoes a multi-step review process, as follows. 4.3 Protocol Approval The final draft protocol requires approval by the Steering Committee, several BMT CTN Technical Committees, 30 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 4.0 Concept to Publication: The Protocol Process the Protocol Review Committee, the Data and Safety Monitoring Board, and, finally, local Institutional Review Boards. 4.3.1 Steering Committee Review Two weeks in advance of Steering Committee review of a final draft protocol, the Steering Committee Chair assigns two or three members as primary reviewers. These reviewers study the final draft protocol in detail. They complete a BMT CTN Review Checklist (Attachment I) and evaluate the study’s background and rationale, design, endpoints, clinical and laboratory tests, statistical considerations, informed consent, and ancillary studies. They also provide an overall assessment of the protocol. The final draft of the protocol is then presented at a Steering Committee meeting. If approved by the Steering Committee, a Protocol Review Committee presentation is scheduled. Simultaneously, the final draft protocol is distributed to the four Technical Committees responsible for final draft protocol review. 4.3.2 Protocol Review Committee The Protocol Review Committee assessment is scheduled through NHLBI. This group performs scientific review of each study. The DCC submits review materials (final draft protocol, a Frequently Asked Questions document, accrual plan, and budget) to the Protocol Review Committee several weeks in advance. The Protocol Review Committee conducts a preliminary evaluation of the documents and returns comments to the Protocol Team. The Protocol Team sends its written responses back to the Protocol Review Committee prior to the scheduled presentation. This approach makes deliberations more efficient and usually avoids the need for follow-up meetings and potential delays in implementation of the protocol. Once it receives Protocol Review Committee approval, the protocol is scheduled for Data and Safety Monitoring Board review. 4.3.3 Data and Safety Monitoring Board Review Each BMT CTN trial is approved and monitored by one of two NHLBI-appointed Data and Safety Monitoring Boards. Boards have scheduled Webcasts in March, May, October, and December as well as in-person meetings in April and November to review the safety and efficacy endpoints outlined in the statistical sections of each protocol being presented. The DCC is responsible for providing the Boards with the information necessary for them to make their determinations. The Data and Safety Monitoring Boards must approve all new protocols or protocol amendments before implementation. When protocols or amendments are scheduled for review, the Data and Safety Monitoring Board provides written comments to the Protocol Team for response prior to the Data and Safety Monitoring Board meeting, similar to the Protocol Review Committee process. The BMT CTN’s Data Safety Monitoring Plan has been reviewed by the Data and Safety Monitoring Boards and approved by NHLBI. All clinical sites enrolling patients on BMT CTN trials must adhere to the reporting requirements in the Data Safety Monitoring Plan, approved by NHLBI. The DCC prepares all materials for Data and Safety Monitoring Board meetings and posts them for the Board on a password-protected area of the website: http:www.bmtctnsp.net. The DCC also posts monthly safety monitoring reports, including adverse event reports and stopping guideline safety tables and graphs. These reports, in addition to accrual, monthly recruitment data quality, and site activation status reports, are available to the Data and Safety Monitoring Board members and to NIH program staff. After all Data and Safety Monitoring Board reviews, the DCC disseminates the Board’s recommendations (after approval by NHLBI) to the Protocol Chairs; Protocol Officer; additional protocol team members; and 31 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 4.0 Concept to Publication: The Protocol Process Investigators, Coordinators and other key personnel at the participating centers. These memos are also posted on the appropriate protocol-specific pages of the Network website (www.bmtctnsp.net). The DCC ensures center compliance with the recommendations, including center Institutional Review Board review and approval, training, accrual closure, and additional data review, as needed. 4.3.4 Final Review Prior to Release to Centers After the Data and Safety Monitoring Board approves the protocol, the two Protocol Chairs and the Protocol Officer review the protocol a final time, using a review checklist. Starting in 2011, a final sign-off process was implemented: After the review is complete, at least two of the three reviewers must sign the first page of the protocol before it is distributed to centers. 4.4 Protocol Pre-Activation To expedite study implementation and facilitate timely activation and successful accrual, the following activities occur concomitantly with protocol development: Creating Case Report Forms; Preparing and distributing other protocol-specific materials, including a Laboratory Research Sample Information Guide, Data Management Handbook and User’s Guide, and guides for pharmacy procedures; Modifying data systems to receive and monitor protocol-specific data; Developing systems to acquire, store, distribute, and analyze protocol-specific biospecimens; Contracting with centers, laboratories, pharmacies, and contributors. The Protocol Team also forms an Endpoint Review Committee, with a charter, before the study opens to accrual. The Protocol Coordinator and Statistician are responsible for preparing review materials for the Endpoint Review Committee, which: Outlines the primary and secondary endpoints to be evaluated; Identifies the endpoints to be adjudicated and the process for adjudication; Defines procedures for resolving discrepancies and recording results; Outlines the mechanisms for assessing subject eligibility and protocol compliance; Conducts final reviews of the study data in a blinded manner whenever possible. 4.4.1 Designing Case Report Forms Designing data collection forms is a collaborative venture involving each study’s scientific and clinical leadership, statisticians, laboratory collaborators, and the DCC. Standard processes ensure the study will have clear, easy-to-use forms that provide data to support its objectives without overwhelming study resources. The DCC is responsible for developing Case Report Forms and, to date, has developed 14 core Case Report Forms for use in all protocols. Another 311 protocol-specific forms were developed and are in use. Protocolspecific forms capture data on particular endpoints, important covariates, protocol-specified treatments, severe adverse events, and protocol compliance. Draft forms are distributed to the Protocol Team for review and input, and the revised forms are then reviewed by the Clinical Research Associate Committee, which evaluates them from a practical use perspective. Each data element is explicitly defined in a User’s Guide to minimize variability in responses. DCC staff members test each form prior to release. 32 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 4.0 Concept to Publication: The Protocol Process 4.4.2 Educational materials and other study documents The NMDP’s Patient Services department works with the Network to develop patient education materials to support new clinical trials. These materials help educate potential patients about the basics of clinical trials and provide a patient-friendly summary of the specific clinical trial. Educational materials are created for each new study and are available with the protocol when it is released for initial Institutional Review Board submission. Patient Services staff members also help design Informed Consent documents so that they are patient-friendly and readable at an eighth-grade reading level. The Network is evaluating a new two-column template for Informed Consent documents via the upcoming randomized Easy-to-Read Informed Consent study (BMT CTN 1205). 4.4.3 Release to Center Institutional Review Boards Once approved by the Data and Safety Monitoring Board, the DCC releases the protocol materials to centers that agreed to participate so that they can submit the materials to their local Institutional Review Boards. Each Protocol includes a template for documenting Informed Consent that can be modified by participating sites to meet their local Institutional Review Board requirements. 4.4.4 Site Initiation Training Prior to protocol implementation, the Protocol Coordinator arranges either an initiation site visit or activation call with key center personnel to review materials and processes. The purpose of these contacts is to make certain the responsibilities and communication lines within the center are clear. Study procedures are discussed, including procedures for data and sample collection. If local pharmacies or laboratories are involved in a study, representatives from those departments participate in the site initiation meetings, as well. A site initiation visit report is issued to all site personnel involved in the protocol within 60 days. The Network’s Sample Repository Research Administrator plays an important role in preparing centers for their biospecimen submissions by: Creating a protocol-specific Research Sample Information Guide that is distributed to sites; Providing telephone and email support for site-specific questions regarding the Institutional Review Board, project laboratories, repositories, or information in the Research Sample Information Guide; Providing training and ongoing technical and contractual support for all project laboratory staff on the protocol. Customized initiation training is provided when needed, as in BMT CTN 0901 and BMT CTN 1101. BMT CTN 0901 has complex sample data and sample collection/processing requirements that differ from previous studies. In a new initiative related to this trial, the Sample Repository Research Administrator holds additional research sample-specific training calls for the clinical centers that activate this trial. The Research Administrator will also review sample submission for compliance for the first few patients enrolled by each center. BMT CTN 1101 also has cord blood training requirements that differ from other trials, requiring additional training calls for clinical centers activating this trial. 4.4.5 Medical Monitor Assignment The DCC assigns a Medical Monitor to each study when it is activated. Medical Monitors are transplant physicians familiar with the conduct of clinical research and regulatory requirements for safety monitoring and reporting. When applicable, Medical Monitors with disease-specific expertise are also recruited to monitor the study (e.g. sickle cell disease, HIV). The Network’s Medical Monitors hold teleconferences quarterly to ensure uniformity in assessing adverse events and to share updates on regulatory requirements. As a matter of policy 33 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 4.0 Concept to Publication: The Protocol Process and to avoid bias, these physicians may not enroll patients or care for patients enrolled in a study on which they serve as Medical Monitor. 4.5 Protocol Activation A protocol is activated when a sufficient number of committed centers receive Institutional Review Board approval and provide all necessary documents to the DCC. Each center must provide proof of approval from its Institutional Review Board and submit required regulatory documents. Centers must also demonstrate proficiency in data submission by reviewing an online training module and completing a post-module practicum. 4.6 Protocol Maintenance 4.6.1 Accrual Monitoring and Intervention The success of a clinical trial depends on timely accrual, which is influenced by many factors. To ensure that problems relating to accrual are minimized, and promptly identified and addressed if they occur, the Protocol Team develops an accrual plan that includes monitoring accrual milestones, planning and holding trial promotion events, and assessing off-protocol transplantation activity through data obtained from the CIBMTR Research Database. Centers receive a quarterly report that compares their actual versus projected accrual to each protocol, and centers submit monthly recruitment reports detailing the numbers of patients screened versus enrolled for each protocol, with reasons for non-enrollment. The CIBMTR Research Database provides the denominator of total transplantations performed in patients potentially fulfilling clinical trial eligibility, and these data are used to interpret accrual by transplant centers. When accrual to a study lags, the Protocol Team intervenes quickly to identify and resolve delays. These actions may include: Holding calls with investigators to discuss accrual challenges and strategies; Resending accrual surveys to participating centers to obtain new or revised accrual projections; Amending the protocol to address unanticipated accrual barriers; Submitting regular study update emails to participating center investigators and coordinators to highlight current and target accrual; Contacting investigators from participating centers that have not enrolled patients to encourage them to enroll; Preparing protocol-specific educational materials to facilitate accrual; Recruiting additional centers. Among the eight Network-led protocols currently open, the overall accrual rate is at 104% of target projections. See Attachment G for a graph of BMT CTN total accrual by month. 4.6.2 High-Quality Clinical and Laboratory Data Collection One measure of the Network’s success is its efficient and accurate collection, processing, and retrieval of clinical and laboratory data. The Network uses several tools, described in this section, to ensure the integrity of each trial. In doing so, the Network provides the foundation for study results that can be analyzed properly and disseminated for use by physicians caring for patients. 34 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 4.0 Concept to Publication: The Protocol Process 4.6.2.1 AdvantageEDC The EMMES AdvantageEDC system is a Web-based, interactive data entry system,which serves as the Network’s primary data collection tool. To ensure high-quality data collection, the system performs field-level checks during data entry to ensure accuracy, consistency, and completeness of data. If an entry does not pass the validation check or the data do not meet the specified requirements, the system requires the user to resolve the inconsistency. As data are entered, they are maintained in data entry transaction master files, which are periodically processed into master files for analysis. Data entry transaction files are stored separately from the master analysis databases. This procedure provides the statisticians with a stable, fixed data set for a predetermined period that can be used for multiple or frequently repeated analyses without the need for making private copies. It also preprocesses data for anomalies. Master files are updated nightly and typically stored in SAS® format. These files are the basis for all project reports and analyses. A dynamic forms grid provides an online list of currently submitted, due, and delinquent forms. During the past year, 39,698 forms were submitted in the AdvantageEDC system for BMT CTN. Accrual reports stratified by center, gender, and ethnicity are updated nightly. Reports summarizing each trial’s progress are updated either weekly or monthly, depending on the report. The DCC developed an integrated, Web-based Severe Adverse Events module. Notification of severe adverse events is provided to Medical Monitors and other key personnel through an automated email system, allowing rapid dissemination of critical information. Source data regarding severe adverse events is available to the Medical Monitors, and review of severe adverse events is incorporated into the data system. Integration of Medical Monitoring functionality in the data entry system has facilitated rapid review and reporting of events to study sponsors and regulatory bodies. 4.6.2.2 Specimen Tracking with GlobalTrace and Staff GlobalTrace is a proprietary EMMES product that the Network uses for all studies. This product is a unique, Web-based application for specimen tracking, inventory, and shipping. It uses bar-coded specimen labels to improve the reliability of specimen inventories by tracking individual samples shipped to either project laboratories or a repository. Individual centers and the NMDP Repository can use GlobalTrace to generate electronic manifests and trace/track each individual specimen. The application allows the study management team to know in real-time which specimens have been collected, where they are, and when they were received by the NMDP Repository. This system has been used by the BMT CTN for more than 10 years for several clinical trials. An online training and competency assessment module for the GlobalTrace application is available on the secured BMT CTN website for all new clinical site staff. A GlobalTrace user guide can be easily accessed from the AdvantageEDC website to review functionality of specific elements of procedures related to this system. The HCT-knowledgeable staff at the NMDP Research Sample Repository and Central Processing Laboratory is a unique asset of the DCC. The Research Sample Repository maintains a local database of processed and stored Network inventory that supports DCC queries. In addition to GlobalTrace, the DCC also has a unique asset in the HCT-knowledgeable staff at the NMDP Research Sample Repository and Central Processing Laboratory. The Repository staff maintains a local database of processed and stored Network inventory that supports DCC queries. 35 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 4.0 Concept to Publication: The Protocol Process 4.6.2.3 CIBMTR Data Reports All transplant centers in the United States, including Network centers, are required by law to report pre-and post-transplantation clinical data on allogeneic HCT recipients to the Stem Cell Transplant Outcomes Database, which is a component of the C.W. Bill Young Cell Transplantation Program and is managed by CIBMTR. The Network stipulates that Core and Affiliate Centers must also report similar data for autologous transplant recipients. Some pre-and post-HCT information collected by CIBMTR is deliberately not captured by AdvantageEDC, but rather is transferred from the CIBMTR database to the EMMES database for incorporation into study files. All long-term follow-up for Network studies (beyond the primary and secondary endpoints) is captured through CIBMTR report forms to avoid a duplicative long-term follow-up program. The Network is committed to maximizing two-way data sharing between the two databases, AdvantageEDC (EMMES) and FormsNet™ (CIBMTR), as a means of minimizing transplant center reporting burden. A detailed description of CIBMTR data collection procedures can be found at http://www.cibmtr.org/DataManagement. 4.6.3 Data Audits Data quality is critical to the BMT CTN’s success and is an important element for assessing transplant center performance. Data audits are performed at each center at least every three years and as often as biannually for centers with high enrollment. The target error rate for Network studies is less than 2%. Centers exceeding 2%, or with other deficiencies, must submit a corrective action plan for improving performance. These visits provide an opportunity for information exchange between the centers and the DCC as well as an opportunity to provide continuing education on protocol adherence and case report forms completion to help maximize data and overall study quality. During the past year, the DCC conducted data audit site visits at 49 BMT CTN centers. The Auditors/Protocol Monitors evaluated data submission compliance (missing forms/missing values completion), laboratory sample compliance (collection and shipment of protocol-defined research samples), regulatory compliance, protocol compliance, and data quality. Reports are issued to the participating transplant centers after each visit, detailing what was reviewed during the visit, such as regulatory files, pharmacy procedures, laboratory compliance, forms completion, and data accuracy. Findings from the visit, as well as an action items list, are included in the report, and center staff members are expected to successfully address all action items before the site visit is considered complete. Reports are reviewed by the NHLBI and DCC and referred to the Executive Committee if results are below expectations or other issues of concern are identified. 4.6.4 Amendments Protocol amendments are necessary for a variety of reasons, including clarifying study procedures, addressing unexpected toxicities, and improving accrual. The Protocol Coordinator, in consultation with the Protocol Team, drafts amendments and coordinates the Data and Safety Monitoring Board approval process. The DCC ensures that centers have the most current amendments and provides training, if necessary, for changes in study procedures. 4.7 Study Completion 4.7.1 Notice to Cease Enrollment As a trial nears its accrual goal, a memo is sent to each participating center notifying them of the closing date, after which no patient may be enrolled. Centers are required to maintain Institutional Review Board approval for 36 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 4.0 Concept to Publication: The Protocol Process each study that has completed accrual until follow-up is finished, endpoint data review is complete, the first manuscript is published, and the BMT CTN DCC protocol coordinator has notified the site that it is appropriate to permanently close the study with their Institutional Review Board. 4.7.2 Follow-up Data Collection after Closure Once the protocol has closed to accrual, centers may be queried by the Endpoint Review Committee to submit outstanding report forms, follow-up data, or source documentation. 4.7.3 Data Review and Analysis The Endpoint Review Committee reviews and adjudicates complex primary and secondary study endpoints. The process involves central review of Case Report Forms and source documents, clarification of discrepant information, and review of complex grading or staging of clinical conditions, such as GVHD and myeloma disease status. When centers have provided all required data and data review is complete, the dataset is locked for analysis. The DCC completes data analysis and prepares reports in accordance with the Statistical Analysis Plan (Section 4.2.2). Upon completion of the statistical analysis, the DCC issues an analysis report (technical data report) for the study. In general, the analysis report is available within two months of locking the trial dataset. Study results are available for presentation after final analyses are reviewed by the Protocol Team, Endpoint Review Committee, and Steering Committee. 4.8 Dissemination of Results Substantial effort is made by Protocol Teams to move forward quickly with manuscript preparation. When completed, the Publications Committee reviews proposed publications and presentations to ensure scientific validity and appropriate authorship and acknowledgements. To date, 31 papers are published or are in press for 13 studies. Additionally, 37 abstracts and presentations, representing 16 studies, have been accepted or presented. See Attachment C for a complete list of manuscripts, abstracts, and presentations from Network activities, including study results and methodology reports. 4.8.1 Authorship Network authorship guidelines are outlined in the Administrative Manual of Procedures, available on the public website (www.bmtctn.net). Authorship status is based on intellectual input and effort throughout the lifecycle of the trial. The Publications Committee maintains authorship policy guidelines, which are ratified by the Steering Committee and consistent with American Medical Association guidelines. Authorship credit on BMT CTN publications is a privilege commensurate with both personal and center contribution to the research, including: Membership and active participation on the Protocol Team; Active accrual to the protocol; Timely and accurate reporting of data; Active participation in data review and analysis. These activities may involve participation in hypothesis generation, concept development, protocol development, study implementation, subject enrollment, data collection, data analysis, and manuscript preparation. 37 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 4.0 Concept to Publication: The Protocol Process 4.9 Ancillary and Correlative Studies BMT CTN ancillary studies use data, biospecimens, and/or analyses that are outside the specific objectives of the primary study. Within the BMT CTN, most ancillary studies are protocol-defined, but some are independent (not included in the primary objective of any specific protocol). Independent ancillary studies must be reviewed and approved by the BMT CTN Steering and Biomarkers Committee before the Network can endorse them. Figure 4 illustrates this process. Figure 4. Ancillary study proposal approval process Ancillary Proposal Proposals utilizing samples or data from a specific protocol Primary Review DCC Proposals utilizing samples or data from multiple trials BMT CTN Steering/Exec Committees Protocol Team Secondary Review Biomarkers Committee External Reviewers Expert review of methodologies Oversight of all biospecimen-related ancillary studies During this funding period, a new section of BMT CTN research samples collections has been added to the Network’s public website as a resource for investigators planning correlative and ancillary studies. This website section lists biological samples available for all BMT CTN studies by time point and sample type, and it provides two summary tables: GVHD treatment trial samples and allogeneic transplant trial samples. Correlative studies are defined in the protocol and are secondary analyses performed after the primary analysis is complete. Funding for ancillary and correlative studies may come from Network resources or non-Network public or private funding agencies. For lists of ongoing, completed, and discontinued ancillary and correlative studies, see Tables 4a, 4b, and 4c, respectively. During this reporting period, there were 20 protocol-defined correlative or approved ancillary studies proposed or ongoing. The Network’s protocol-defined correlative and ancillary studies in progress are described in Table 4a. 38 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 4.0 Concept to Publication: The Protocol Process Table 4a. BMT CTN correlative and ancillary studies in progress BMT CTN Correlative and Ancillary Studies in Progress Protocol Project Status Laboratory/Location Antimicrobial Pharmacodynamics and Therapeutics Laboratory Department of Molecular and Clinical Pharmacology University of Liverpool Pharmacokinetic studies of voriconazole and fluconazole BMT CTN administered for prevention of 0101 invasive fungal infections in allogeneic blood and marrow transplant recipients BMT CTN approved protocol-defined correlative study Testing of research samples completed Initiation of data analysis and pharmacokinetic data modeling is in progress Investigational fungal diagnostic BMT CTN assays to diagnose aspergillus and 0101 other infections BMT CTN approved protocol-defined correlative study University of Florida Research samples have been shipped College of Medicine Clinical data file being transferred Initiation of various projects to begin soon Free light chain analysis in patients BMT CTN approved ancillary study undergoing autologous or allogeneic BMT CTN Results presented at ASH in 2011 by hematopoietic stem cell 0102 P Hari, et al. transplantation for multiple Manuscript in progress myeloma The Binding Site BMT CTN approved protocol-defined correlative study BMT CTN Immune reconstitution studies Results presented at ASH in 2011 by 0201 Donor HCT graft characterization EK Waller, et al. Manuscript in progress Emory University Winship Cancer Institute Immune reconstitution studies Immunophenotype assays of BMT CTN approved protocol-defined lymphoid subsets and dendritic correlative study BMT CTN cells 0201 Final review of data and data analysis in Assays for antigen-specific T cells progress TREC assay for de novo T cell generation Emory University Winship Cancer Institute BMT CTN Immune reconstitution studies 0201 Antibody and cytokine levels BMT CTN approved protocol-defined correlative studies Testing of stored samples in last phases Esoterix Clinical Trials Services (Division of LabCorp) Pharmacogenetics of steroid BMT CTN responsive acute graft-versus-host 0302 disease BMT CTN approved revised protocoldefined correlative study Sample testing completed Data analysis in progress University of Minnesota 39 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 4.0 Concept to Publication: The Protocol Process BMT CTN Correlative and Ancillary Studies in Progress Protocol Project Status Laboratory/Location BMT CTN Immune reconstitution studies 0402 immunophenotyping BMT CTN approved protocol-defined correlative study In progress – final patient samples to be collected by the end of 2013 Esoterix Clinical Trials Services (Division of LabCorp) BMT CTN Immune reconstitution studies 0501 BMT CTN approved protocol-defined correlative study In progress Duke University BMT CTN Obesity and multiple myeloma 0702 ancillary study BMT CTN approved ancillary study In progress Participating clinical sites PRIMeR study: minimal residual BMT CTN approved ancillary study BMT CTN disease in multiple myeloma by flow 0702 In progress cytometry Roswell Park Cancer Institute Participating Centers Regulatory T cell / B-cell BMT CTN approved protocol-defined BMT CTN Immunophenotyping and B cell correlative study 0801 activating factor biomarker levels by In progress ELISA Dana-Farber Cancer Institute Analysis of acute GVHD biomarkers BMT CTN measured before and during 0802 treatment BMT CTN approved protocol-defined correlative study All testing completed Data analysis pending American Red Cross, Penn-Jersey Histocompatibility/ Molecular Biology Laboratory BMT CTN Microbial translocation marker 0803 measurements BMT CTN approved protocol-defined correlative study In progress University of North Carolina Characterization of HIV infection in BMT CTN AIDS-related malignancies: HIV 0803 single-copy HIV viral titer measurements BMT CTN approved protocol-defined correlative study In progress Johns Hopkins University BMT CTN Plasma DNA tumor monitoring 0803 BMT CTN approved protocol-defined correlative study In progress Johns Hopkins University Immunophenotypic and functional BMT CTN characterization of immune 0803 reconstitution BMT CTN approved protocol-defined correlative study In progress Ohio State University 40 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 4.0 Concept to Publication: The Protocol Process BMT CTN Correlative and Ancillary Studies in Progress Protocol Project Status Laboratory/Location BMT CTN Busulfan pharmacokinetics study 0901 BMT CTN approved protocol-defined correlative study In progress Seattle Cancer Care Alliance Pharmacokinetics Laboratory Immunophenotypic and functional BMT CTN characterization of immune 0903 reconstitution BMT CTN approved protocol-defined correlative study In progress Ohio State University BMT CTN Microbial translocation marker 0903 measurements BMT CTN approved protocol-defined correlative study In progress University of North Carolina BMT CTN Characterization of HIV Infection and 0903 latent HIV Reservoirs BMT CTN approved protocol-defined correlative study In progress Johns Hopkins University Characterization of HIV infection in BMT CTN AIDS-related malignancies: HIV 0903 single-copy HIV viral titer measurements (PBMC & plasma) BMT CTN approved protocol-defined correlative study In progress University of Pittsburgh Seven protocol-defined correlative or approved ancillary studies have been completed. These studies are described in Table 4b. Table 4b. BMT CTN correlative and ancillary studies completed BMT CTN Correlative and Ancillary Studies Completed Protocol Project Status BMT CTN 0101 Cost-effectiveness analysis of voriconazole compared with fluconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation BMT CTN 0302 BMT CTN approved protocol-defined correlative study Study completed Analysis of serum biomarkers during treatment of acute GVHD Results presented at EBMT in 2011 by JE Levine, et al. Manuscript published in Blood in 2012 by JE Levine, et al. BMT CTN approved ancillary study Study completed Practice report in press with American Journal of Health System-Pharmacy in 2013 by J Mauskopf 41 Laboratory/Location RTI Health Solutions University of Michigan Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 4.0 Concept to Publication: The Protocol Process BMT CTN Correlative and Ancillary Studies Completed Protocol Project Status Laboratory/Location BMT CTN 0302 BMT CTN approved protocol-defined Mycophenolate pharmacokinetics correlative study and association with response to Study completed University of Minnesota acute GVHD treatment from the Manuscript published in Biology and Blood BMT CTN and Marrow Transplantation in 2010 by PA Jacobson, et al. BMT CTN 0302 BMT CTN approved correlative study Study completed Graft-versus-host disease N/A treatment: predictors of survival Manuscript published in Biology and Blood and Marrow Transplantation in 2010 by JE Levine, et al. BMT CTN 0302 Lymphocyte phenotype during therapy for acute graft versus host disease: a brief report from BMT-CTN 0302 BMT CTN 0303 BMT CTN approved correlative study Characteristics of CliniMACS(®) system CD34-enriched T cell Study completed depleted grafts in a multicenter Manuscript published in Biology and Blood N/A trial for acute myeloid leukemiaand Marrow Transplantation in 2011 by C BMT CTN protocol 0303 Keever-Taylor, et al. BMT CTN 0303 Comparative outcomes of donor graft CD34+ selection and immune suppressive therapy as BMT CTN approved correlative study graft-vs-host disease prophylaxis Study completed for patients with acute myeloid Manuscript published in Journal of leukemia in complete remission Clinical Oncology in 2012 by M Pasquini, undergoing HLA-matched sibling et al. allogeneic hematopoietic cell transplantation BMT CTN approved correlative study Study completed Manuscript published in Biology and Blood and Marrow Transplantation in 2012 by J Bolanos-Meade, et al. 42 N/A N/A Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 4.0 Concept to Publication: The Protocol Process One approved ancillary study was discontinued during this reporting period. This study is described in Table 4c. Table 4c. BMT CTN ancillary study discontinued BMT CTN Ancillary Study Discontinued Protocol BMT CTN 0102 Project Status Laboratory/Location BMT CTN approved ancillary study Baseline samples shipped and testing Detection of t(4;14) in circulating started peripheral blood nucleated cells Project discontinued due to determination Mayo-Arizona of multiple myeloma patients that overall sample quality was not using a RT-PCR approach consistently sufficient to support the recovery of high quality RNA (a suspected concern that needed to be evaluated) 43 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 5.0 Collaborations with other NIH-funded Research Networks 5.0 Collaborations with other NIH-funded Research Networks The mission of the BMT CTN overlaps with the mission of NCI-sponsored Cancer Clinical Trials Cooperative Groups and other NIH-sponsored networks. A major responsibility of DCC leadership is to enhance communication among these groups to minimize the number of competing trials and to foster collaboration to decrease the time required to complete studies. To that end, the Network has: Shared accrual on 12 protocols: o BMT CTN-led studies: BMT CTN 0102 – SWOG BMT CTN 0501 – COG BMT CTN 0601 – COG, Sickle Cell Disease Clinical Research Network BMT CTN 0701 – CALGB, ECOG, SWOG BMT CTN 0702 – CALGB, ECOG, SWOG BMT CTN 0803 and 0903 – AIDS Malignancy Consortium o Cooperative group-led studies: CALGB 100103 – BMT CTN 0502 SWOG 0410 – BMT CTN 0703 CALGB 100104 – BMT CTN 0704 CALGB 100701 – BMT CTN 0804 SWOG 0805 – BMT CTN 0805 Implemented a shared national agenda for myeloma transplantation trials that is represented by CALGB 100104/BMT CTN 0704 and BMT CTN 0702 and was led by the BMT CTN-initiated Multiple Myeloma Intergroup, including representatives from CALGB/Alliance for Clinical Trials in Oncology, ECOG, and SWOG; Participated in the NCI Lymphoma, Myeloma, and Leukemia Steering Committees; Included cooperative group representation on the Network Steering Committee to promote communication and collaborative partnerships with these groups; Partnered with the AIDS Malignancy Consortium to support innovative trials for AIDS-associated malignancies (BMT CTN 0803 and 0903). 44 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 6.0 Future Directions 6.0 Future Directions 6.1 Planning for the Current Grant Cycle In October 2010, a leadership group of current and past BMT CTN Steering Committee Chairs and DCC Principal Investigators met to lay out short-, mid-, and long-term goals for the DCC and the Network. The primary goals of this meeting were to enhance the BMT CTN’s proficiency and efficiency, identify optimal uses of funds, and refine processes to promote success and scientific productivity of the Network. This early work laid the foundation for the activities that the Steering Committee and DCC took on when new funding was authorized. Due to these initial efforts, both were poised to move forward quickly into planning and implementing new trial ideas using guidelines established during the previous year. Continuing these efforts for the remainder of the grant cycle, the DCC and Executive Committee proposed hosting another State of the Science Symposium in 2014 to survey the HCT landscape and identify greatest areas of need. The Steering Committee agreed with this plan. Frederick Appelbaum, Steering Committee Chair-Elect, was selected to Chair the State of the Science Symposium. Twelve of the 2007 State of the Science Committees have been reestablished with the addition of a second pediatric committee. The committees are: Clinical Trial Design Comorbidity and Regimen Related Toxicity Gene & Cell Therapy GVHD Infection / Immune Reconstitution Late Effects / Quality of Life Leukemia Lymphoma Multiple Myeloma Non-Malignant Diseases Optimal Donor & Graft Source Pediatric Transplant—Indications / Approaches Pediatric Transplant—Outcomes / Late Effects The State of the Science Symposium will be held in February 2014. External reviewers will be invited to review trial concepts and lead the discussions. Prioritized concepts will be brought to the Executive and Steering Committees for consideration. 6.2 Protocol Projections 2013-2014 In addition to developing new protocols chosen by the Steering Committee, the Network will continue working toward completion of protocols already in progress, in particular: 6.2.1 Protocols Nearing Completion BMT CTN 0601: Unrelated donor reduced intensity bone marrow transplant for children with severe sickle cell disease (The SCURT study: sickle cell unrelated transplant) The Data and Safety Monitoring Board approved reducing the target accrual to 30 marrow HCT patients. There are 22 patients enrolled. Accrual in anticipated to be completed by the end of the next reporting period. BMT CTN 0702: A trial of single autologous transplant with or without consolidation therapy versus tandem autologous transplant with lenalidomide maintenance for patients with multiple myeloma (The 45 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 6.0 Future Directions STaMINA study: stem cell transplantation for multiple myeloma incorporating novel agents) The study was opened in July 2010. Accrual is several months ahead of projected and is anticipated to be completed in early fall 2013. To date, there are 600 of 750 patients enrolled. BMT CTN 0803: High dose chemotherapy with autologous stem cell rescue for aggressive B cell lymphoma and Hodgkin lymphoma in HIV-infected patients The study was activated in July 2010. Like its sister study, BMT CTN 0903, this trial is a partnership with the NCI-supported AIDS Malignancy Consortium. The NCI Cancer Therapy Evaluation Program for Non-AIDS-Defining Cancers provides additional funding for this protocol. To date, 38 of 42 patients have been enrolled. BMT CTN 0805/SWOG 0805: A Phase II study of combination of hyper-CVAD and dasatinib with or without allogeneic stem cell transplant in patients with Philadelphia chromosome positive and/or BCRABL positive acute lymphoblastic leukemia (a BMT study) This collaborative study is being led by SWOG, with active involvement of BMT CTN and ECOG. It opened to accrual in SWOG centers in September 2009 and through the CTSU in August 2010. Several BMT CTN centers have either activated or are in the process of activating the study. Total target accrual is 85 patients, of which 74 patients have been enrolled. 6.2.2 Protocols Activated During the Reporting Period BMT CTN 0903: Allogeneic hematopoietic cell transplant for hematological cancers and myelodysplastic syndromes in HIV-infected individuals. This protocol received Data and Safety Monitoring Board approval in March 2011 and was released to centers in April. There were delays as an amendment was released prior to study activation. The trial was opened to accrual in May 2012. Like its sister study, BMT CTN 0803, this trial is a partnership with the NCI-supported AIDS Malignancy Consortium. The NCI Cancer Therapy Evaluation Program for Non-AIDS-Defining Cancers provides additional funding for this protocol. Target accrual is 15 patients. BMT CTN 1101: A multi-center, Phase III, randomized trial of reduced intensity conditioning and transplantation of double unrelated umbilical cord blood versus HLA-haploidentical related bone marrow for patients with hematologic malignancies. This Phase III randomized trial is a follow-on study to the BMT CTN 0603 and BMT CTN 0604 Phase II studies that completed accrual in spring 2010. The Data and Safety Monitoring Board approved the protocol in January 2012, and it was released to sites in February. The trial was activated in June 2012. Target accrual is 410 patients. 6.2.3 Protocols Anticipated to be Activated Four protocols are in late stages of development and are anticipated to be activated in 2013: BMT CTN 1102: A multi-center Phase III trial comparing reduced intensity allogeneic hematopoietic cell transplant to hypomethylating therapy or best supportive care in patients aged 50-75 with intermediate-2 and high risk myelodysplastic syndrome. This protocol received Protocol Review Committee approval in early 2013 and is undergoing Data and Safety Monitoring Board review. Target accrual is 338 patients to be enrolled over a three year accrual period. BMT CTN 1203: A multi-center Phase II trial randomizing novel approaches for graft-versus-host disease prevention compared to contemporary controls (The PROGRESS study: prevention and reduction of GVHD and relapse enhancing survival after stem cell transplantation) This protocol received Protocol Review Committee approval in early 2013 and is undergoing Data and Safety Monitoring Board review. Target accrual is 270 patients (90 per arm) to be enrolled over a two and a half year accrual period. Patients will be compared to a minimum of 270 controls from the CIBMTR. 46 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 6.0 Future Directions BMT CTN 1204: Reduced-intensity conditioning for children and adults with hemophagocytic syndromes (The RICHeS study) The protocol was presented to the Steering Committee in early 2013 and will be re-presented after incorporating the Committee’s study design recommendations. The trial is slated to accrue 35 patients over a three year period. BMT CTN 1205: Easy-to-read informed consent (ETRIC) for hematopoietic cell transplantation clinical trials The protocol was approved by the Protocol Review Committee and Data and Safety Monitoring Board. It is anticipated to be released to centers in the spring of 2013 and activated in early fall. Target accrual is 160 patients (80 per arm) over an 18 month accrual period. 6.3 Conclusions The Blood and Marrow Transplant Clinical Trials Network has created a successful and efficient infrastructure for conducting important HCT trials. Network trials address critical issues in optimal graft sources, conditioning intensity, regimen-related toxicity, engraftment, GVHD, infection, disease control, and quality of life. Because of this comprehensive portfolio, the Network is recognized as the leading group to facilitate and complete HCT clinical trials. This is clearly evidenced by successful collaborations with affiliate transplant centers, NIH cooperative groups, the CTSU, other consortia and research networks, and pharmaceutical and device companies. These trials have accrued almost 5,300 patients in a timely manner through the involvement of more than 100 transplant centers. Of the eight studies opened since 2010, two are already complete, in large part due to fast accrual. BMT CTN 0902 finished 17 months ahead of projections, and 0802 was four months ahead of projected accrual before being closed to futility. Five studies, which are currently open to accrual, are also ahead of accrual projections. More than 65 publications/presentations have been published and shared since 2004, including seven publications (two of primary study results) and nine presentations during this reporting period. These results, as well as results from pending trials, will help define future transplant practice. BMT CTN is committed to sharing these results in HCT, hematology, oncology, and medical peer-reviewed journals as well as at scientific meetings. The BMT CTN plays a crucial role in advancing the field of HCT and is dedicated to its original mission: to improve the outcomes of HCT for patients with life-threatening disorders. While multicenter trials pose logistical and scientific challenges beyond those of a single-center study, these trials address questions that are unanswerable in single institutions. Well-designed studies offer answers for future patients. Even non-randomized Phase II approaches bring the strength of broader multi-institutional enrollment to confirm, amplify, or simply clarify conclusions from prior, more limited experience. The HCT community must remember that innovative and multi- institutional trials can address the hardest questions facing patients with life-threatening hematopoietic diseases. The DCC and the Network’s Core and Affiliate Centers represent the highest level of commitment and participation by patients, researchers, transplant center staff, and support personnel—all working together in this valuable endeavor. 47 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.0 Protocol Descriptions 7.0 Protocol Descriptions The following section describes each BMT CTN research study. Accrual graphs, included as appropriate, are based on the period from study inception through March 31, 2013. Protocols are grouped by study development stage: Open to accrual and actively accruing patients (10) Completed accrual (18) Released to centers (1) 48 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.1 Protocols Open to Accrual 7.1 Protocols Open to Accrual BMT CTN Protocols Open to Accrual (as of March 31, 2013) BMT CTN Protocol # 0301 Protocol Title Fludarabine-based conditioning for allogeneic marrow transplantation from HLA-compatible unrelated donors in severe aplastic anemia 0601 Unrelated donor HCT for children with severe sickle cell disease using a reduced-intensity conditioning regimen 0702 A trial of single autologous HCT with or without consolidation therapy versus tandem autologous HCT with lenalidomide maintenance 0801 A Phase II/III randomized, multicenter trial comparing sirolimus plus prednisone and sirolimus/calcineurin inhibitor plus prednisone for the treatment of chronic GVHD 0803 High-dose chemotherapy with autologous stem cell rescue for aggressive B cell lymphoma and Hodgkin lymphoma in HIV-infected patients 0804 / Phase II study of reduced-intensity allogeneic HCT for high-risk chronic CALGB 100701 lymphocytic leukemia 0805 / A Phase II study of combination of hyper-CVAD and dasatinib with or without SWOG 0805 allogeneic HCT in patients with Philadelphia chromosome positive and/or BCR-ABL positive acute lymphoblastic leukemia (ALL) (a BMT study) 0901 A randomized, multicenter, Phase III study of allogeneic HCT comparing regimen intensity in patients with myelodysplastic syndrome or acute myeloid leukemia 0903 Allogeneic HCT for hematological cancers and myelodysplastic syndromes in HIV-infected individuals 1101 A multi-center, Phase III, randomized trial of reduced-intensity conditioning and transplantation of double unrelated umbilical cord blood versus HLAhaploidentical related bone marrow for patients with hematologic malignancies 49 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.1 Protocols Open to Accrual BMT CTN 0301 Protocol Number: BMT CTN 0301 Status: Open to Accrual Title: Fludarabine-based conditioning for allogeneic marrow transplantation from HLA-compatible unrelated donors in severe aplastic anemia Rationale: Allogeneic HCT is an effective treatment for severe aplastic anemia; however, only about 25% of patients have a suitable HLA-matched sibling donor. Those who lack such a donor could benefit from a matched unrelated donor transplant, but transplant-related mortality (TRM) and graft rejection jeopardize the successful outcomes of these transplants. The optimal conditioning regimen for unrelated donor transplantation for aplastic anemia remains to be determined. Efforts to minimize graft rejection with more intensive preparative regimens generally lead to more TRM; whereas, attempts to reduce TRM often lead to graft failure. Purine analogs, such as fludarabine, have profound immunosuppressive activity with low rates of systemic toxicities. Introduction of fludarabine led to development of a new class of conditioning known as reduced-intensity preparative regimens, now commonly employed in a variety of hematologic malignancies. This study was designed to determine the feasibility and toxicity of employing a fludarabine-based conditioning regimen to reduce TRM while maintaining (or ideally, improving) engraftment after marrow transplantation from unrelated donors in patients with severe aplastic anemia. The study will determine the degree of cyclophosphamide dose reduction achievable with the introduction of fludarabine, with a goal of maintaining (or improving) engraftment, reducing major transplant-related toxicity and early deaths, and thereby, ultimately improving long-term survival. Primary Objective: To select the optimal cyclophosphamide dose in a regimen of fludarabine, cyclophosphamide, total body irradiation and antithymocyte globulin, based on day 100 assessments of graft failure (primary and secondary), regimen-related toxicity, and early death. Second. Objectives: Team Principals: To evaluate post-transplant survival, graft failure, TRM, and acute and chronic GVHD. Name: Email: PRC Approval Date: 03/31/2005 Paolo Anderlini [email protected] DSMB Approval Date: 07/15/2005 Chairs: Joachim Deeg [email protected] Opened to Accrual: 01/24/2006 Officer: Mary Eapen [email protected] Closed to Enrollment: N/A Coordinator: Iris Gersten [email protected] Target Accrual: 78-81 Medical Monitor: Christopher Bredeson [email protected] Total Accrual as of 3/31/13: 81 Statistician: Shelly Carter [email protected] Reporting Period Accrual 16 Contract Rep: Pamela Budnick [email protected] IND Number: N/A Additional Members: Email: Recent Version Released: 02/03/2010 Joseph Antin [email protected] Additional Members: Email: Nancy DiFronzo [email protected] Elizabeth Murphy [email protected] Mary Horowitz [email protected] Ryotaro Nakamura [email protected] Mitchell Horwitz [email protected] Michael Pulsipher [email protected] Eric Leifer [email protected] Jakub Tolar [email protected] Key Highlights: This study was activated January 24, 2006. Twenty centers have enrolled patients. The accrual rate was slower than projected, primarily due to the study design, which requires review of day 100 outcomes data to ensure that stopping boundaries will not be crossed. Another factor is the lack of severe aplastic anemia patients referred for unrelated donor transplantation (about 85/ year in the US). Accrual on the trial was temporarily suspended in May 2008 for DSMB review of toxicities. An amendment was released to centers in August 2008 to address the findings of the 150 mg/kg (excess toxicity) and 0 mg/kg cyclophosphamide (excess graft failure) cohorts. The stopping rules were also revised to reflect a combined day 100 endpoint of graft failure and TRM. Accrual resumed in December 2008. An amendment 50 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Protocol Number: 7.1 Protocols Open to Accrual BMT CTN 0301 was released to centers in February 2010 to allow accrual on parallel tracks using cyclophosphamide at the 100 mg/kg and 50 mg/kg levels, with the proviso that if a stopping threshold is reached on 100 mg/kg for graft failure, the DCC will notify the DSMB before enrolling to the 50 mg/kg dose. As a result, the protocol temporarily closed less often while patients were followed to the day 100 safety point. This amendment enhanced accrual, and the DSMB recommendation in fall 2011 to preferentially enroll on the 50mg/kg dose level to until a minimum of 20 patients with 8/8 HLA match were accrued has been met. Reporting Period Update: This year, the DSMB recommended accrual continue beyond the accrual goal of 78-81 patients while the protocol team develops a plan to extend accrual, a possible modification in primary endpoints, and the future direction of the study. The plan will be reviewed by the DSMB in April 2013. Results of the lowest and highest cyclophosphamide dose levels were presented at EBMT and subsequently published. Publications: 1. Optimization of therapy for severe aplastic anemia based on clinical, biological and treatment response parameters: conclusions of an international working group on severe aplastic anemia convened by the BMT CTN, March 2010. Biology of Blood and Marrow Transplantation. 2011 Mar;17(3)291-299. Epub 2010 Oct 27. 2. Fludarabine-based conditioning for marrow transplantation from unrelated donors in severe aplastic anemia: early results of a cyclophosphamide dose deescalation study show life-threatening adverse events at predefined cyclophosphamide dose levels. Biology of Blood and Marrow Transplantation. 2012 July 18(7):1007-1011. Epub 2012 Apr 30. Presentations: 1. Fludarabine-based conditioning for allogeneic marrow transplantations from unrelated donors in severe aplastic anemia (SAA): serious and unexpected adverse events in pre-defined cyclophosphamide (CY) done levels: results from BMT CTN Protocol # 0301. Presented at 53rd Annual ASH Meeting, San Diego, CA, December 2011. 2. Fludarabine-based conditioning for allogeneic marrow transplantation from unrelated donors in severe aplastic anemia: serious and unexpected adverse events in pre-defined cyclophosphamide dose levels. Poster presented at EBMT, Geneva, Switzerland, April 2012. Target Accrual = 81 patients Accrual per Month 5 BMT CTN #0301 Monthly Actual Accrual Projected Steady State Monthly Accrual Cumulative Accrual 90 80 70 4 60 50 3 40 2 30 20 1 10 0 0 51 Cumulative Accrual 6 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.1 Protocols Open to Accrual BMT CTN 0601 Protocol Number: BMT CTN 0601 Status: Open to Accrual Unrelated donor hematopoietic cell transplantation for children with severe sickle cell disease using a Title: reduced-intensity conditioning regimen Patients with severe sickle cell disease (SCD) have progressive perfusion-related vascular complications like stroke, acute chest syndrome, and vaso-occlusion-related pain. Both disease and therapy can cause morbidity and early mortality, especially when complications persist or progress despite supportive care measures. Allogeneic HCT can correct the hemoglobinopathy associated with SCD by engraftment of donor cells and is best performed in the pediatric population before irreversible organ damage has developed. Although excellent outcomes are reported in children with SCD following matched sibling donor HCT, this approach is rarely used because of (1) excess toxicities from standard myeloablative conditioning regimens; (2) absence of HLA-matched family donors; and (3) transplant-related morbidity and mortality, such as infection and GVHD. The rationale for this study derives from previous transplant Rationale: experience in patients with nonmalignant disorders, including hemoglobinopathies, with use of a reduced-intensity conditioning regimen comprised of alemtuzumab, fludarabine, and melphalan to support donor cell engraftment. The regimen was well tolerated, supported donor cell engraftment, and produced acceptable rates of graft rejection, transplant-related mortality, and GVHD. This Phase II trial will test the efficacy of bone marrow transplantation using this preparative regimen in children with severe complications of SCD without matched family donors. The protocol was developed in conjunction with sickle cell hematologists and incorporates detailed guidelines for prevention and treatment of SCD and transplant-related complications. To determine one-year event-free survival after unrelated donor bone marrow transplantation in Primary Objective: patients with SCD (death, disease recurrence, or graft rejection rates at one year will be used to measure this endpoint) To determine the effect of HCT on clinical and laboratory manifestations of SCD, including stroke; the incidence of other transplant-related outcomes, including overall survival, neutrophil and platelet recovery, grades II-IV and grades III-IV acute GVHD, chronic GVHD, hepatic veno-occlusive disease, Secondary Objectives: idiopathic pneumonia syndrome, central nervous system toxicity (reversible posterior leukoencephalopathy syndrome, hemorrhage, and seizures), neurocognitive dysfunction, cytomegalovirus infection, adenovirus infection, Epstein-Barr virus after transplant, lymphoproliferative disease, invasive fungal infection, donor chimerism, immune reconstitution, and health-related quality of life. Team Principals: Name: Email: Naynesh Kamani [email protected] Chairs: Shalini Shenoy [email protected] Officer: Mary Eapen [email protected] Coordinator: Iris Gersten [email protected] Medical Monitor: Angie Smith [email protected] Statistician: Brent Logan [email protected] Contract Rep: Nancy Poland [email protected] Additional Members: Email: Additional Members: Email: Joel Brochstein [email protected] Kirk Schultz [email protected] Shelly Carter [email protected] Paul Scott [email protected] Dennis Confer [email protected] Elliot Vichinsky [email protected] Michael DeBaun [email protected] Mark Walters [email protected] Nancy DiFronzo [email protected] Lolie Yu [email protected] Rebecca Drexler [email protected] PRC Approval Date: 08/13/2007 Allison King [email protected] DSMB Approval Date: 11/19/2007 Janet Kwiatkowski [email protected] Opened to Accrual: 06/27/2008 52 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.1 Protocols Open to Accrual Protocol Number: BMT CTN 0601 Richard Labotka John Levine Julie Panepinto Suhag Parikh Michael Pulsipher [email protected] [email protected] [email protected] [email protected] [email protected] Key Highlights: This study, known as the “SCURT” study (sickle cell unrelated transplantation), was activated on June 27, 2008. The trial was delayed because centers were not activated until enrollment of a first patient, to minimize activating too many centers for a study that targets only 45 patients. Currently, 2 Core and 16 PBMTC Centers are activated. In June 2010, the DSMB recommended an amendment to exclude cord blood grafts, due to an observed high graft failure rate after cord blood transplantation. Cord blood as a graft source was removed from Protocol Version 6. In addition, eligibility criteria were modified to increase the age limit to 19.75 years and include increased transcranial Doppler findings as a clinically significant neurological event. The amendment excluding cord blood grafts required centers to submit a revised protocol to their IRBs before continuing enrollment. Before this revision, 8 of 15 transplants used cord blood as the graft source. Not unexpectedly, accrual significantly slowed. The original accrual projections and completion were revised in April 2011 to address both the pause in enrollment required by these events and the anticipated decrease in the rate of future accrual since fewer patients would have an available graft source. In May 2011, the glomerular filtration rate requirement in the protocol was adjusted to include patients 16 years of age and older. In October 2011, the protocol was modified to ensure consistent HLA-matching criteria language. Reporting Period Update: The protocol was further amended in June 2012 (version 9.0) to reduce the targeted sample size to 30 bone marrow recipients and again in December 2012 to change the liver biopsy requirements from 30 days prior to initiation of alemtuzumab to 90 days prior. Publication: 1. Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one cohort from the Phase II study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Biology of Blood and Marrow Transplantation. Epub 2012 Feb 16. Closed to Enrollment: Revised Target Accrual: Total Accrual as of 3/31/13: Reporting Period Accrual: IND Number: Recent Version Released: N/A 30 BM recipients/ 8 CB 22 BM recipients/ 8 CB 6 N/A 12/19/2012 Target Accrual = 38 patients Accrual per Month 4 BMT CTN #0601 Monthly Actual Accrual Projected Steady State Monthly Accrual Cumulative Accrual 40 30 3 20 2 10 1 0 0 53 Cumulative Accrual 5 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.1 Protocols Open to Accrual BMT CTN 0702 Protocol Number: BMT CTN 0702 Status: Open to Accrual Title: A trial of single autologous transplant with or without consolidation therapy versus tandem autologous transplant with lenalidomide maintenance Rationale: The study compares three different treatment strategies that combine high-dose therapy and autologous stem cell rescue with novel anti-myeloma therapies. The hypothesis is that addition of novel agents will provide long-term disease control and survival equivalent to the effect of a second autologous transplant. The three strategies to be tested are autologous transplantation with high-dose melphalan followed by (1) second autologous transplantation with high-dose melphalan (followed by lenalidomide maintenance); (2) four cycles of bortezomib, lenalidomide and dexamethasone consolidation (followed by lenalidomide maintenance); or (3) lenalidomide maintenance alone. Primary Objective: To compare three-year progression-free survival among the three treatment arms. To compare response rates of very good partial remission or better; rates of complete remission conversion for patients not in complete remission at initiation of maintenance; overall survival; rates of Secondary Objectives: Grade 3 toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE); incidences of infections; treatment-related mortality rates; and rates of discontinuation of therapy. The study will also describe and compare quality-of-life in the three arms. Team Principals: Name Amrita Krishnan Chairs: George Somlo Edward Stadtmauer Officer: Marcelo Pasquini Courtney Nelson Coordinators: Connie Weaver Medical Monitor: Shannon Smiley Statistician: Shelly Carter Contract Rep: Nancy Poland Additional Members: Email Kenneth Anderson [email protected] Robert Schlossman [email protected] Angela Dispenzieri [email protected] [email protected] Rafael Fonseca [email protected] Nancy Geller Sergio Giralt [email protected] Phillip Greipp [email protected] Parameswaran Hari [email protected] John Koreth [email protected] Mary Horowitz [email protected] [email protected] Muzaffer Qazilbash Philip McCarthy [email protected] Key Highlights: Email [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] PRC Approval Date: DSMB Approval Date: Opened to Accrual: Closed to Enrollment: Target Accrual: Total Accrual as of 3/31/13: Reporting Period Accrual: IND Number: Current Version Released: Additional Members: William Merritt Heather Landau David Vesole 10/31/2008 03/18/2009 06/01/2010 N/A 750 600 243 104912 01/16/2013 Email [email protected] [email protected] [email protected] This trial is the follow-on study to BMT CTN 0102 and BMT CTN 0704/CALGB 100104 and is known as the STaMINA (Stem Cell Transplantation for Multiple Myeloma Incorporating Novel Agents) study. It was developed by a Multiple Myeloma Inter-Group Committee that included representatives from SWOG, CALGB, ECOG, and BMT CTN. The protocol was placed on the CTSU roster in March 2010. This is one of 54 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Protocol Number: 7.1 Protocols Open to Accrual BMT CTN 0702 the high-priority trials recommended during the 2007 State of the Science Symposium. It was identified as important to assess the role of post-transplantation treatment for myeloma in the era of novel agents. Reporting Period Update: Protocol Version 6 was released to centers on January 22, 2013, and requires lenalidomide to be mailed to patients through the RevAssist® for Study Participants Program. Version 6 of the protocol also allows for bortezomib to be administered subcutaneously and includes updated language and figures to provide clarity. As of March 2013, 22 Core Centers and 37 Affiliate Centers (23 through the CTSU) are activated for enrollment. 600 patients are enrolled on the trial, which is more than 3 months ahead of the projected accrual. Target Accrual = 750 patients BMT CTN #0702 Accrual per Month 30 800 Monthly Actual Accrual Projected Steady State Monthly Accrual Cumulative Accrual 700 600 25 500 20 400 15 300 10 200 5 100 0 0 55 Cumulative Accrual 35 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.1 Protocols Open to Accrual BMT CTN 0801 Protocol Number: BMT CTN 0801 Status: Open to Accrual Title: A Phase II/III randomized, multicenter trial comparing sirolimus plus prednisone and sirolimus/calcineurin inhibitor plus prednisone for the treatment of chronic GVHD Rationale: Standard immunosuppressive therapy for chronic GVHD using glucocorticoids ± calcineurin inhibitor has not changed for three decades, yet most patients respond inadequately and require at least 2 years of immunosuppressive therapy to achieve clinical tolerance. Protean and sometimes irreversible organ manifestations of chronic GVHD create a burden of symptoms that may negatively impact quality of life even after tolerance is achieved. New approaches are needed to improve early control of chronic GVHD and facilitate tolerance. The NIH Consensus Development Project for trials in chronic GVHD has primed the field for more rigorous evaluation of short-term clinical response endpoints. In parallel, a renewed understanding of regulatory T cells (Tregs) and their role in facilitating graft tolerance has generated enthusiasm for testing tolerance-induction strategies that do not impede the expansion of Tregs. Relevant to this, traditional calcineurin inhibitor-based therapy impedes Tregs. In contrast, therapies that facilitate Tregs, such as sirolimus have shown activity in steroid-refractory GVHD. This study compares early response rates to sirolimus plus prednisone against sirolimus plus calcineurin inhibitor plus prednisone. The intent is to enroll subjects either at the start of their initial therapy for chronic GVHD, or before their chronic GVHD is steroid refractory or chronically dependent on steroids and multiple immunosuppression therapy. Phase II study: To compare a treatment regimen that contains sirolimus without a calcineurin inhibitor, to a comparator regimen of sirolimus with a calcineurin inhibitor, with the goal of determining if sirolimus plus prednisone is a sufficiently promising treatment regimen for further comparison in the Phase III trial. Primary Objective: The primary hypothesis is that avoidance of a calcineurin inhibitor in the treatment of chronic GVHD might facilitate the development of tolerance and improve the GVHD response rates at 6 months and, ultimately, the 24 month complete response rates compared to immunosuppressive therapy regimens that contain a calcineurin inhibitor (the comparator arm, sirolimus plus calcineurin inhibitor plus prednisone). Secondary Objectives: Phase II study: To compare percent reductions in average daily dose of prednisone by 6 and 12 months; cumulative incidences of treatment failure at 1 year; prevalence of active symptomatic chronic GVHD at 1 and 2 years; cumulative incidences of discontinuation of all systemic immunosuppressive therapy at 1 and 2 years; overall and cancer progression-free survival at 1 and 2 years; candidate serum biomarkers of chronic GVHD at baseline, 2 months and 6 months. Phase III study: To compare percent reduction in average daily dose of prednisone at 6, 12, and 24 months; cumulative incidences of treatment failure at 1 and 2 years; prevalence of active symptomatic chronic GVHD at 1 and 2 years; cumulative incidence of discontinuation of all systemic immunosuppressive therapy at 1 and 2 years; overall and cancer progression-free survival at 1 and 2 years; candidate serum and urine biomarkers of chronic GVHD at baseline, 2 months and 6 months. The Phase II and Phase III studies will both evaluate NIH and other new response instruments in chronic GVHD. Team Principals: Name: Email: Mukta Arora [email protected] Chairs: Paul Carpenter [email protected] Officer: Marcelo Pasquini [email protected] Coordinator: Moira Lewis [email protected] Medical Monitor: Bipin Savani [email protected] Statistician: Brent Logan [email protected] Contract Reps: Pamela Budnick [email protected] Additional Members: Email: Amin Alousi [email protected] Javier Bolanos-Meade [email protected] Corey Cutler [email protected] 56 PRC Approval Date: DSMB Approval Date: Opened to Accrual: Closed to Enrollment: Target Accrual: Total Accrual as of 3/31/13: Reporting Period Accrual: IND Number: Current Version Released: Additional Members: Carrie Kitko Stephanie Lee 05/18/2009 09/17/2009 04/15/2010 N/A 110 (Phase II) 110 63 N/A 07/09/2012 Email: [email protected] [email protected] Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.1 Protocols Open to Accrual Protocol Number: BMT CTN 0801 Nancy DiFronzo Mary Horowitz David Jacobsohn Laura Johnston [email protected] [email protected] [email protected] [email protected] Pablo Parker Steven Pavletic Daniel Weisdorf [email protected] [email protected] [email protected] This study was rated as “high priority” at the 2007 State of the Science Symposium. The protocol was approved by the PRC in May 2009 and by the DSMB in September 2009. The study was activated April 15, 2010, after several centers received IRB approval. The BMT CTN 0801 trial was originally designed as two parallel but stand-alone studies of Sirolimus plus Prednisone, Sirolimus/Extracorporeal Photopheresis (ECP) plus Prednisone, and Sirolimus/Calcineurin Inhibitor. Key personnel from the Protocol Team met in June 2011 to address slow accrual (total of 31), particularly on the ECP study (n=6) of the Phase II component of the trial. Accrual initiatives included one-on-one calls with center’s PIs and development of an accrual thermometer and congratulatory emails to enrolling sites. Key Highlights: The team also discussed changes in the protocol, resulting in Protocol Version 5, which was released in September 2011. Eligibility criteria were broadened to allow standard risk patients at diagnosis, patients with 16 weeks of prior therapy, and patients of any weight. In addition, the ECP component of the trial was closed; centers that had been participating on the ECP study were encouraged to join the non-ECP study so that subjects across all centers will participate in just one Phase II study and be randomized to one experimental arm, Sirolimus + Prednisone, or the comparator arm, Sirolimus + Calcineurin Inhibitor + Prednisone. Since the BMT CTN 0801 trial was originally designed as two parallel but stand-alone studies, the DSMB determined that discontinuation of the ECP study would not compromise the scientific integrity of the trial. The Phase II study will proceed into the Phase III component if the experimental arm is more efficacious than the comparator arm. The study continues to address the important question regarding the removal of a calcineurin inhibitor for treatment of chronic GVHD. Target enrollment for the combined Phase II/III trial is 300 patients, 100 less than the original target. Twenty-eight Core Centers and 21 Affiliate Centers have been activated for enrollment. Fifteen additional centers are anticipated to participate in this trial. Accrual is close to projections. Accrual to the Phase II component of the study was completed at the end of this reporting period, and accrual to Phase III has commenced. Reporting Period The protocol was also amended (current version) with broadended eligibility criteria to allow newly diagnosed Update: patients to receive prednisone (or equivalent) for up to two weeks prior to enrollment/randomization, while the functional test (two minute walk, the grip test and Schirmer’s eye exam) became optional. The transition process from the Phase II portion to the Phase III portion was also clarified. Target Accrual = 110 patients (Phase II) BMT CTN #0801 10 120 Accrual per Month 8 Projected Steady State Monthly Accrual 100 Cumulative Accrual 80 6 60 4 40 2 20 0 0 57 Cumulative Accrual Monthly Actual Accrual Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.1 Protocols Open to Accrual BMT CTN 0803 Protocol Number: BMT CTN 0803 Status: Open to Accrual Title: High-dose chemotherapy with autologous stem cell rescue for aggressive B cell lymphoma and Hodgkin lymphoma in HIV-infected patients Rationale: Before effective anti-retroviral therapy, advances in and appreciation of the importance of antifungal and pneumocystis prophylaxis, and the availability of hematopoietic growth factors, high-dose chemotherapy with stem cell rescue was associated with fatal opportunistic infection in HIV patients. Several small studies suggest that high-dose chemotherapy with stem cell rescue is appropriate for patients with HIV and lymphoma and is often associated with long-term disease-free survival. However, many transplant guidelines exclude patients with HIV. As transplant studies to date have mainly been carried out in institutions with special expertise in HIV and transplant, there is some uncertainty as to whether the encouraging results in these smaller studies could be reproduced or improved upon in a multicenter setting. As with lymphoma patients without HIV, lymphoma relapse is the major cause of mortality in recent small studies of high-dose therapy with stem cell rescue. PET/CT imaging is emerging as an important tool for assessing disease responsiveness. If PET/CT were applied to lymphoma in HIV patients, it might be useful for identifying those patients most likely to benefit from high-dose therapy. PET/CT has not been systematically studied in HIV patients. However, there is literature characterizing fluorodeoxyglucose uptake in patients with HIV infection that raises concerns about extrapolating PET/CT findings in other populations to this population. Fluorodeoxyglucose uptake seems to be associated with the cellular response to the virus following initial infection, viral replication in lymphoid tissue, and immune reconstitution following the initiation of effective antiretroviral therapy. A second aim of the study is to systematically and prospectively assess the utility of PET/CT responses in identifying patients who would benefit from high-dose therapy. Primary Objective: To assess overall survival after autologous HCT for chemotherapy-sensitive aggressive B cell lymphoma or Hodgkin lymphoma in patients with HIV, using BEAM for pre-transplant conditioning. Secondary Objectives: Team Principals: Chairs: Officer: Coordinator: Medical Monitor: Statistician Contract Rep: Additional Members: Gorgun Akpek Robert Baiocchi Shelly Carter Steven Devine To evaluate time-to-progression, progression-free survival, complete remission (CR), and CR+PR (partial remission) proportion at day 100, time to progression after CR, lymphoma disease-free survival, time to hematopoietic recovery, hematologic function at day 100, toxicities, incidence of infections, treatment-related mortality, immunologic reconstitution, assessment of microbial gut translocation and assessment of DNA in blood (clonal Ig DNA in plasma, Epstein-Barr virus DNA in plasma and peripheral blood mononuclear cells) as tumor markers. Name: Email: Joseph Alvarnas [email protected] Richard Ambinder [email protected] Willis Navarro [email protected] Jason Thompson [email protected] Bipin Savani [email protected] Brent Logan [email protected] Pamela Budnick [email protected] Email: PRC Approval Date: 11/13/2009 [email protected] DSMB Approval Date: 01/05/2010 [email protected] Opened to Accrual: 07/12/2010 [email protected] Closed to Enrollment: N/A [email protected] Target Accrual: 40 58 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.1 Protocols Open to Accrual Protocol Number: Charles Flexner Stephen Forman Mary Horowitz Richard Jones Lawrence Kaplan Amrita Krishnan Richard Little Jennifer Le-Rademacher Alexandra Levine John Mellors 38 15 N/A 04/30/2010 Email: [email protected] [email protected] [email protected] [email protected] BMT CTN 0803 [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Total Accrual as of 3/31/13: Reporting Period Accrual: IND Number: Current Version Released: Additional Members: Ariela Noy Uday Popat Aruna Subramanian John Zaia The BMT CTN 0803 Protocol Team was formed in November 2008. In November 2009, the protocol received PRC approval, followed by DSMB approval in January 2010. It was released to centers for IRB submission in January 2010. On April 30, 2010, Protocol Version 2 was released to centers for IRB submission. The amendment removed the HIV reservoir ancillary study from the protocol. Key Highlights: Eleven Core, four affiliate and four AIDS Malignancy Consortium Centers are participating in the study, which opened to accrual in July 2010. Sixteen centers have enrolled 38 patients, and accrual is ahead of projections. The study is conducted in partnership with the AIDS Malignancy Consortium, an NCI-supported clinical trials group. Additional funding is provided by the NCI program for Non-AIDS-Defining Cancers. Reporting Period Update: Accrual has been steady throughout the year and is anticipated to close on time during the next reporting period. Target Accrual = 42 patients BMT CTN #0803 Accrual per Month 6 45 Monthly Actual Accrual Projected Steady State Monthly Accrual Cumulative Accraul 40 35 5 30 4 25 3 20 15 2 10 1 5 0 0 59 Cumulative Accrual 7 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.1 Protocols Open to Accrual BMT CTN 0804 / CALGB 100701 Protocol Number: BMT CTN 0804 / CALGB 100701 Status: Open to Accrual Title: Phase II study of reduced-intensity allogeneic stem cell transplant for high-risk chronic lymphocytic leukemia Rationale: Despite recent therapeutic advances that include monoclonal antibody therapy with alemtuzumab and rituximab in combination with chemotherapy, chronic lymphocytic leukemia (CLL) remains incurable with standard therapy. Although both autologous and allogeneic HCT have been attempted as definitive therapy, the role and optimal timing of transplantation in the treatment of CLL remain unclear. Recent attention has focused on allogeneic transplantation, given the demonstration of a robust graft-versus-leukemia effect in CLL. In an effort to expand the role of allogeneic transplantation to the age group affected by CLL, reduced-intensity conditioning allogeneic transplantation has been explored. Recent advances in understanding the biology of CLL include identifying prognostic factors that strongly predict outcomes, including overall survival. These factors include the gene mutation status of the IgVH gene, expression of CD38 and ZAP-70, and genetic abnormalities as assessed by fluorescence in situ hybridization. Among these genetic abnormalities, deletions of 17p and 11q account for 25% of presenting cases of CLL and are associated with median times to progression of only two years. These genetically-defined subsets are currently the subgroup of CLL patients with the poorest prognosis. Furthermore, patients with these genetic abnormalities respond to fludarabine-based regimens less well than others and manifest short response durations. Patients with these findings represent an excellent population in which to test the efficacy of upfront reduced-intensity allogeneic transplant, to determine whether this early intervention can favorably impact the natural history of the disease. Primary Objective: To determine if this treatment improves the current two-year rate of progression-free survival (PFS) in the early-disease cohort compared to historical controls, specifically assessing whether 2-year PFS ≥ 70% is achievable and whether two-year PFS ≤ 50% can be excluded. Secondary Objectives: To evaluate whether two-year current PFS ≥ 50% is achievable and two-year PFS ≤ 30% can be excluded in the advanced disease cohort; objective response rate; incidences of grades 2-4 and 3-4 acute GVHD; incidence of extensive chronic GVHD; incidences of transplant-related mortality at 100 days and one year; overall survival; donor chimerism for CD3+ cells at one and two years after transplantation; presence of donor antigen-specific T cell clones before and after withdrawal of immune suppression; relapse profiles of patients with T cell responses against CLL to those whose CLL cells that are not reactive; and to prospectively examine the impact of high-risk genomic features and immune-based single nucleotide polymorphisms on response, toxicity, and two-year PFS to reduced-intensity allogeneic HCT. Team Principals: Chair: Officer: Coordinator: Medical Monitor: Statistician: Statistician: Contract Rep: Name: Richard Maziarz Mary Horowitz Jason Thompson CALGB CALGB CALGB Nancy Poland Email: [email protected] [email protected] [email protected] [email protected] 60 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.1 Protocols Open to Accrual Protocol Number: BMT CTN 0804 / CALGB 100701 Additional Members: Edwin Alyea Allison Booth Michael Caligiuri Steven M. Devine John Gribben Vera Hars Michael Kelly Richard Larson Kouros Owzar Morgen Alexander-Young Email: [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Key Highlights: This study was rated as a “very high priority” at the 2007 State of the Science Symposium, and this protocol is a collaborative effort between CALGB and BMT CTN. CALGB patient accrual began February 15, 2010. BMT CTN opened the trial to enrollment on March 16, 2011. PRC Approval Date: DSMB Approval Date: Opened to Accrual: Closed to Enrollment: Target Accrual: Total Accrual as of 3/31/13: Reporting Period Accrual: IND Number: Recent Version Released: CALGB CALGB 03/16/2011 N/A 86 52 Total, 12 BMT CTN 23 Total, 7 BMT CTN N/A 1/15/2012 As of January 15, 2013, all registrations for CALGB and BMT CTN centers have moved to the CTSU Reporting Period Update: OPEN registration system. BMT CTN centers have enrolled 12 of the 52 patients on this trial, seven during this past reporting period. Target Accrual = 86 Accrual per Month 8 6 BMT CTN #0804/CALGB 100701 (BMT CTN accrual N = 12) Monthly Actual Accrual Projected Steady State Monthly Accrual Cumulative Accrual 60 50 CALGB opened this protocol in February 2010; enrollment started in January 2011. BMT CTN opened the trial to enrollment in March 2011. 40 30 4 20 2 10 0 0 61 Cumulative Accrual 10 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.1 Protocols Open to Accrual BMT CTN 0805 / SWOG 0805 Protocol Number: BMT CTN 0805 / SWOG 0805 Status: Open to Accrual Title: A Phase II study of combination of hyper-CVAD and dasatinib with or without allogeneic stem cell transplant in patients with Philadelphia chromosome positive and/or BCR-ABL positive acute lymphoblastic leukemia (ALL) (a BMT study). Rationale: The availability of targeted therapies of Philadelphia+ leukemia has improved outcomes of patients with these diseases. However, Philadelphia+ ALL still has a high risk of relapse. This study addresses the efficacy of two approaches; chemotherapy with the tyrosine kinase inhibitor dasatinib and allogeneic HCT, in achieving leukemia-free survival in patients with this disease. Primary Objective: To test whether the relapse-free survival after allogeneic HCT among Philadelphia+ and/or BCR-ABL gene+ ALL patients given an intensive short-term chemotherapy regimen of hyper-CVAD (cyclophosphamide, vincristine, adriamycin and dexamethasone) in combination with the tyrosine kinase inhibitor dasatinib is sufficiently high to warrant further investigation, and to test whether the continuous complete remission rate for previously untreated Philadelphia+ and/or BCR-ABL+ ALL patients given an intensive short-term chemotherapy regimen of hyper-CVAD in combination with the tyrosine kinase inhibitor dasatinib is sufficiently high to warrant Phase III investigation. To investigate, in a preliminary manner, the relative effectiveness of minimum residual disease detection using real-time quantitative polymerase chain reaction for BCR/ABL versus flow cytometry to predict the Secondary outcome of patients treated by the hyper-CVAD + dasatinib regimen and/or allogeneic stem cell transplant; Objectives: estimate the frequency and severity of toxicities of the intensive short-term chemotherapy regimen in these patients; and estimate the overall survival of all patients on the study. Team Principals: Name: Email: David Porter (BMT CTN) [email protected] Chairs: Farhad Ravandi (SWOG) [email protected] Officer: SWOG Amy Foley (BMT CTN) [email protected] Coordinators: Sandi Jo McMillan (SWOG) [email protected] Medical Monitor: SWOG Statistician(s): SWOG Contract Rep: Pamela Budnick [email protected] PRC Approval Date: SWOG Additional Email: Members: DSMB Approval Date: SWOG Stephen Forman [email protected] SWOG: 09/1/09 Opened to Accrual: CTSU: 8/9/10 Chul S Ha [email protected] Susan O’Brien [email protected] Closed to Accrual: N/A Jerald P Radich [email protected] Target Accrual: 85 Jeffrey YC Wong [email protected] Total Accrual as of 3/31/13: 74 Reporting Period Accrual: 46 IND Application Number: Held by SWOG This study was rated as a “very high priority” trial during the 2007 State of the Science Symposium; the collaborative study is led by SWOG with active involvement of BMT CTN and ECOG representatives on the Protocol Team. This protocol opened to accrual to SWOG centers in September 2009 and through the CTSU Key Highlights: in August 2010, where the study can be accessed by all BMT CTN centers. Several centers affiliated with both SWOG and BMT CTN are already participating on the study. The BMT CTN contributes to patient reimbursement for all patients on the transplant arm. 62 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.1 Protocols Open to Accrual Protocol Number: BMT CTN 0805 / SWOG 0805 One BMT CTN Core center was activated to participate on the study through the BMT CTN and enrolled Reporting Period one patient. Twelve other BMT CTN Core/Consortia centers are activated through SWOG or the CTSU and Update: have enrolled 38 total patients. Accrual is anticipated to be completed during the next reporting period. An accrual graph is not included because participation through the BMT CTN is limited. 63 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.1 Protocols Open to Accrual BMT CTN 0901 Protocol Number: BMT CTN 0901 Status: Open to Accrual Title: A randomized, multicenter Phase III study of allogeneic stem cell transplantation comparing regimen intensity in patients with myelodysplastic syndrome or acute myeloid leukemia Myelodysplastic syndrome (MDS) and AML are predominantly diseases of older patients. For patients with advanced or chemotherapy refractory disease, allogeneic HCT is currently the only strategy that offers a cure. Unfortunately, this modality is currently available only to a small proportion of patients. Many patients do not undergo HCT either because of advanced age, because no suitable donor is available, or because of unacceptable risks currently associated with HCT. Rationale: One major cause of mortality after HCT is toxicity from pre-transplant conditioning, which historically has included high, myeloablative doses of cytotoxic chemotherapy with or without radiation. In recent years, reduced-intensity conditioning regimens were introduced in an attempt to reduce non-relapse mortality so that HCT could be offered to patients who otherwise would not be considered candidates. The encouraging results of initial studies with these regimens are of particular interest for patients with MDS or AML diseases that increase in frequency with age, since older patients are at highest risk of severe complications from intensive conditioning. This study proposes a Phase III multicenter trial to compare outcomes with myeloablative and reducedintensity conditioning regimens in patients undergoing allogeneic HCT for MDS and AML. To compare 18-month overall survival between the two groups. The hypothesis to be tested is that reducing the intensity of the conditioning regimen will decrease treatment-related mortality without increasing relapse, so that overall survival will be improved. To compare disease-free survival rate after transplantation, rate of transplant-related mortality, hematologic recovery, kinetics of donor cell engraftment, incidence of graft failure, incidence and Secondary Objectives: severity of acute and chronic GVHD, immune reconstitution, quality of life, rates of infectious complications, rates of ≥ grade 3 toxicities according to CTCAE criteria, and quality of life. Team Principals: Name Email Mitchell Horwitz [email protected] Chairs: Bart Scott [email protected] Officer: Marcelo Pasquini [email protected] Coordinator: Iris Gersten [email protected] Medical Monitor: Bipin Savani [email protected] Statistician: Jennifer Le-Rademacher [email protected] Contract Rep: Renee Carby [email protected] Additional Members: Email PRC Approval Date: 07/23/2010 Shelly Carter [email protected] DSMB Approval Date: 09/15/2010 Joachim Deeg [email protected] Opened to Accrual: 06/2/2011 Steve Devine [email protected] Closed to Enrollment: N/A Nancy DiFronzo [email protected] Target Accrual: 356 Sergio Giralt [email protected] Total Accrual as of 3/31/2013: 147 Mary Horowitz [email protected] Reporting Period Accrual: 101 Eric Leifer [email protected] IND Number: N/A Brent Logan [email protected] Current Version Released: 03/06/2012 Richard Maziarz [email protected] Willis Navarro [email protected] Nancy Poland [email protected] Primary Objective: 64 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Protocol Number: BMT CTN 0901 David Porter Erica Warlick [email protected] [email protected] Key Highlights: 7.1 Protocols Open to Accrual The concept for this protocol was approved by the Steering Committee in October 2008 after being rated as a “high” priority at the 2007 State of the Science Symposium. The Protocol Team was formed in December 2008 and held its first meeting in March 2009. The protocol was approved by the PRC on June 23, 2010, and by the DSMB on September 15, 2010. It was activated on June 2, 2011, after several centers received IRB approval and identified potential patients. Eighteen Core and 15 Affiliate Centers have been activated, and 28 centers have enrolled patients to date. Version 3.0 of the protocol was released in March 2012; clarifications were added to patient eligibility criteria and donor age restriction was removed. Reporting Period Update: Accrual has remained above projections throughout the year. A protocol amendment (Version 4) will be submitted to the DSMB for review in April 2013. Changes will include allowance of serological typing on Class I alleles for related donors, drug dosage instruction clarification, and other minor updates. Target accrual = 356 patients BMT CTN #0901 12 200 Monthly Actual Accrual Projected Steady State Monthly Accrual Cumulative Accrual 150 10 8 100 6 4 50 2 0 0 65 Cumulative Accrual Accrual per Month 14 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.1 Protocols Open to Accrual BMT CTN 0903 Protocol Number: BMT CTN 0903 Status: Open to Accrual Title: Allogeneic hematopoietic cell transplant for hematological cancers and myelodysplastic syndromes in HIV-infected individuals Rationale: Survival in patients with HIV has improved dramatically with the advent of highly active antiretroviral therapy (HAART). Despite improvements in HIV infection-related survival, the risk of malignancies remains significant in patients with HIV infection. While non-Hodgkin lymphoma is an acquired immune deficiency (AIDS)-defining diagnosis, a comparison of a large cohort of HIV-infected patients to Surveillance, Epidemiology and End Results data demonstrates a significantly higher incidence of vaginal, Hodgkin lymphoma, liver, lung, melanoma, oropharyngeal, colorectal, renal cancers and leukemia in patients with HIV infection. Prior to the advent of HAART, the treatment of patients with malignancy in the setting of HIV infection was hamstrung by limited chemotherapy tolerance and complications due to opportunistic infection. Since the widespread availability of HAART, there have been significant improvements in the capacity to treat these patients in a fashion comparable to that of patients without HIV infection. This in turn has led to marked improvements in the outcomes of patients with malignancies in the setting of HIV infection. The prognosis for patients with AIDS-related lymphoma is dramatically different in the era of HAART therapy. In a comparison of treatment outcomes for patients treated before and after the advent of HAART, there is a statistically significant improvement in the overall survival of patients treated with HAART (p=0.002). While the International Prognostic Index remains a useful tool for estimating the prognosis of patients with AIDS-related non-Hodgkin lymphoma, the CD4 count of less than 100 per microliter has independent prognostic value for this group of patients. The impact of HAART therapy upon the immunological and functional status of patients with HIV infection has permitted the extension of aggressive therapeutic regimens to this patient population. HAART allows a significant portion of patients to reduce their viral load to undetectable levels and, therefore, tolerate far more aggressive therapeutic interventions than would have been possible previously. Primary Objective: To assess non-relapse morality at 100 days after allogeneic HCT. To analyze disease status at day 100 post HCT, time to hematopoietic recovery, chimerism at 30, 100, and 180 days, hematologic function at 100 and 180 days, infections, six-month overall survival, acute Secondary Objectives: and chronic GVHD, immunologic reconstitution at 8 weeks, 180 and 365 days and the impact of HCT on the HIV reservoir at day 100, 6 months, 1 year and 2 years post HCT. Team Principals: Chairs: Officer: Coordinator: Medical Monitor: Statistician: Contract Rep: Additional Members: Gorgun Akpek Robert Baiocchi Shelly Carter Steven Devine Charles Flexner Name: Joseph Alvarnas Richard Ambinder Willis Navarro Jason Thompson Tammy Kindwall-Keller (P) Jennifer Le Rademacher Pamela Budnick Email: [email protected] [email protected] [email protected] [email protected] [email protected] Email: [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] PRC Approval Date: 09/15/2010 DSMB Approval Date: 03/29/2011 Opened to Accrual: 5/11/2012 Closed to Enrollment: N/A Target Accrual: 15 Total Accrual as of 3/31/13: 5 66 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.1 Protocols Open to Accrual Protocol Number: Stephen Forman Mary Horowitz Rick Jones Amrita Krishnan Richard Little Alexandra Levine Brent Logan John Mellors BMT CTN 0903 [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Key Highlights: The protocol was approved by the PRC in September 2010 and by the DSMB in March 2011. Protocol Version 1 was released to centers in April 2011; however, due to the need for immediate protocol amendments, study activation was delayed. Protocol Version 2 was released on January 20, 2012, and the protocol opened to accrual on May 11, 2012. Like its sister study BMT CTN 0803, this trial is a partnership with the NCI-supported AIDS Malignancy Consortium. Additional funding will be provided by the NCI Cancer Therapy Evaluation Program for Non-AIDS-Defining Cancers. Reporting Period Update: Reporting Period Accrual: IND Number: Current Version Released: Additional Members: Ariela Noy Uday Popat Aruna Subramanian John Zaia 5 N/A 1/20/2012 Email: [email protected] [email protected] [email protected] [email protected] The study was opened this year. Accrual has been steady and continues ahead of schedule. Target accrual = 15 patients BMT CTN #0903 4 15 Monthly Actual Accrual Projected Steady State Monthly Accrual Cumulative Accrual 10 3 2 5 1 0 0 67 Cumulative Accrual Accrual per Month 5 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.1 Protocols Open to Accrual BMT CTN 1101 Protocol Number: BMT CTN 1101 Status: Open to Accrual Title: A multi-center Phase III randomized trial of reduced intensity conditioning and transplantation of double unrelated umbilical cord blood versus HLA-haploidentical related bone marrow for patients with hematologic malignancies Rationale: Reduced intensity conditioning (RIC) BMT has allowed older and less clinically fit patients to receive potentially curative treatment with allogeneic BMT for high risk or advanced hematological malignancies. Patients lacking an HLA-matched sibling may receive a graft from a suitably HLAmatched unrelated donor. However, up to a third of patients will not have an HLA-matched sibling or a suitably matched adult unrelated donor (i.e., no more than a mismatch at a single locus). Even when a suitably matched unrelated donor is identified, data from the NMDP indicate that a median of four months is required to complete searches that result in transplantation; thus some number of patients succumb to their disease while awaiting identification and evaluation of a suitably matched adult unrelated donor. Single or dual center studies have shown that partially HLA-mismatched related bone marrow and unrelated double umbilical cord blood are valuable sources of donor cells for RIC BMT, extending this treatment modality to patients who lack other donors. In order to study the reproducibility, and thus the wider applicability of these two alternative donor strategies, BMT CTN conducted two parallel multicenter prospective Phase II clinical trials. These two studies evaluated the safety and efficacy of related haplo-bone marrow (BMT CTN 0603) and double umbilical cord blood (BMT CTN 0604) transplantation after RIC. Both of these alternative donor approaches produced early results similar to that reported with unrelated donor, and even HLA-matched sibling, BMT. These data demonstrate not only the efficacy of both of these approaches but also that both can be safely exported from the single center setting. Both haplo-bone marrow and double umbilical cord blood grafts can be obtained rapidly for >90% of patients lacking an HLA-matched donor. Primary Objective: To compare progression-free-survival at two years post-randomization between patients who receive unrelated double cord blood unit transplantation versus HLA haploidentical related bone marrow transplantation. Secondary Objectives: To evaluate neutrophil recovery, graft failure, platelet recovery, donor cell engraftment, acute GVHD and chronic GVHD, overall survival, treatment-related mortality, infections, hospital admission and length of stay, health related quality of life, relapse/progression, and cost effectiveness. Team Principals: Chairs: Officer: Coordinator: Medical Monitor: Statistician: Contract Rep: Additional Members: Omar Aljitawi Joe Antin Karen Ballen Name Claudio Brunstein Ephraim Fuchs Paul O’Donnell Mary Eapen Kate Barowski Angie Smith Brent Logan Pam Budnick Email [email protected] [email protected] [email protected] Email [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] PRC Approval Date: DSMB Approval Date: Opened to Accrual: Closed to Enrollment: 68 10/22/2011 01/09/2012 06/19/2012 N/A Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.1 Protocols Open to Accrual Protocol Number: BMT CTN 1101 Javier Bolaños-Meade Shelly Carter Luciano Costa Corey Cutler Steve Devine Nancy DiFronzo Mary Horowitz Chatchada Karanes Elizabeth Rich [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Key Highlights: BMT CTN 1101 is a Phase III randomized follow-on study to the Phase II 0603 (haplo-bone marrow) study, which completed accrual in May 2010, and the 0604 (double umbilical cord blood) study, which completed accrual in March 2010. The protocol was approved by the PRC in October 2011 and by the DSMB in January 2012. Version 1 of the protocol was released to centers on February 27, 2012. Target Accrual: Total Accrual as of 03/31/13: Reporting Period Accrual: IND Number: Current Version Released: Additional Members: Liz Wagner John Wingard 410 11 11 N/A 11/20/2012 Email [email protected] [email protected] The study was opened to accrual June 19, 2012. Version 2.0 was released to centers on November 20, 2012. Significant changes included in this amendment were the separation of eligibility criteria into two components, eligibility criteria required prior to randomization and eligibility criteria Reporting Period Update: required prior to transplant, a revision of disease eligibility criteria. Additionally, the amendment included a new cost effectiveness companion study, funded by the NHLBI via an R01 grant obtained by Study Chair, Paul O’Donnell. Target accrual = 410 patients BMT CTN #1101 4 35 Monthly Actual Accrual Projected Steady State Monthly Accrual Cumulative Accrual 30 25 3 20 15 2 10 1 5 0 0 69 Cumulative Accrual Accrual per Month 5 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 This page intentionally left blank. 70 7.1 Protocols Open to Accrual Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual 7.2 Protocols that Completed Accrual BMT CTN Protocols that Completed Accrual (as of March 31, 2013) BMT CTN Protocol # 0101 0102 0201 0202 0302 0303 0401 0402 0403 0501 0502 / CALGB 100103 0603 0604 0701 0703/ SWOG 0410 0704 / CALGB 100104 / ECOG 100104 0802 0902 Protocol Title A randomized double-blind trial of fluconazole versus voriconazole for the prevention of invasive fungal infections in allogeneic blood and marrow transplant recipients A trial of tandem autologous stem cell transplants with or without post-second autologous transplant maintenance therapy versus single autologous stem cell transplant followed by matched sibling nonmyeloablative allogeneic stem cell transplant for patients with multiple myeloma A Phase III randomized, multicenter trial comparing G-CSF mobilized peripheral blood stem cell with marrow transplantation from HLA compatible unrelated donors Autologous versus non-myeloablative allogeneic HCT for patients with chemosensitive follicular non-Hodgkin lymphoma beyond first complete response or first partial response Initial systemic treatment of acute GVHD: A phase II randomized trial evaluating etanercept, mycophenolate mofetil, denileukin diftitox (Ontak), and pentostatin A single-arm, multicenter Phase II trial of transplants of HLA-matched, CD34+ enriched, T cell depleted peripheral blood stem cells isolated by the CliniMACS system in the treatment of patients with AML in first or second morphologic complete remission Phase III Rituxan/BEAM versus Bexxar/BEAM with autologous HCT for persistent or relapsed chemotherapy-sensitive diffuse large B cell non-Hodgkin lymphoma A Phase III randomized, multicenter trial comparing sirolimus/tacrolimus with tacrolimus/methotrexate as GVHD prophylaxis after HLA-matched, related peripheral blood stem cell transplantation A randomized double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor Enbrel (etanercept) for the treatment of acute noninfectious pulmonary dysfunction (idiopathic pneumonia syndrome) following allogeneic HCT Multicenter, open label, randomized trial comparing single versus double umbilical cord blood transplantation in pediatric patients with leukemia and myelodysplasia A Phase II study of allogeneic transplant for older patients with acute myeloid leukemia in first morphologic complete remission using a non-myeloablative preparative regimen A multicenter, Phase II trial of non-myeloablative conditioning and transplantation of partially HLAmismatched bone marrow for patients with hematologic malignancies A multicenter, Phase II trial of non-myeloablative conditioning and transplantation of umbilical cord blood from unrelated donors in patients with hematologic malignancies A Phase II trial of non-myeloablative allogeneic HCT in relapsed follicular non-Hodgkin lymphoma using related or unrelated donors beyond first complete response Tandem autologous stem cell transplantation for patients with primary progressive or recurrent Hodgkin disease (a BMT study), Phase II A Phase III, randomized, double-blind study of maintenance therapy with CC-5013 or placebo following autologous stem cell transplantation for multiple myeloma A multicenter randomized, double blind, Phase III trial evaluating corticosteroids with mycophenolate mofetil versus corticosteroids with placebo as initial systemic treatment of acute graft-versus-host disease A Phase III randomized, multicenter trial testing whether exercise or stress management improves functional status and symptoms of autologous and allogeneic HCT recipients 71 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual BMT CTN 0101 Protocol Number: BMT CTN 0101 Status: Closed to Accrual Title: A randomized double-blind trial of fluconazole versus voriconazole for the prevention of invasive fungal infections in allogeneic blood and marrow transplant recipients Rationale: Invasive fungal infections are a life-threatening complication of allogeneic HCT. Fluconazole prophylaxis has been found in randomized trials to be an effective prevention of invasive Candida infections. Invasive Aspergillus infections are a growing threat to transplant recipients; furthermore, treatment options are toxic, and outcomes are poor. Voriconazole is an extended-spectrum azole that is the most effective treatment for Aspergillosis. It may offer the potential for preventing Aspergillosis, but its toxicity may offset its benefit. New diagnostic tests, such as the galactomannan assay permit screening, and early detection of Aspergillus infection may lead to improved treatment outcomes. This trial compared two strategies to determine which was more effective in optimizing fungal-free survival: fluconazole prophylaxis plus a program of intensive screening including serial galactomannan testing versus voriconazole. Primary Objective: To compare the fungal-free survival rates between the two study arms through day 180. Secondary Objectives: Team Principals: Chairs: Officer: Coordinator: Medical Monitor: Statistician: Contract Rep: Additional Members: Nancy DiFronzo Nancy Geller Joanne Kurtzberg Brent Logan Kieren Marr Elizabeth Murphy Richard O'Reilly Trudy Small Key Highlights: To compare the frequencies of invasive fungal infection, time to invasive fungal infection, survival rate, duration of amphotericin B or caspofungin therapy for possible invasive fungal infection, time to neutrophil and platelet engraftment, time to and severity of acute and chronic GVHD, and adverse events and routine laboratory tests; additionally, the study was designed to include an exploratory analysis of the quantitative aspects of the galactomannan assay. Name: Thomas Walsh John Wingard Dennis Confer Iris Gersten Marcelo Pasquini Shelly Carter Pamela Budnick Email: [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] PRC Approval Date: 11/15/2002 Email: DSMB Approval Date: 01/22/2003 [email protected] Opened to Accrual: 12/01/2003 [email protected] Closed to Enrollment: 9/21/2006 [email protected] Evaluable for Primary Analysis: 09/2007 [email protected] Target Accrual: 600 [email protected] Total Accrual as of 3/31/13: 600 [email protected] Reporting Period Accrual: N/A [email protected] IDE Number: G020306 (closed prior to enrollment) [email protected] Last Version Released: 03/29/2006 The study experienced a delay from DSMB approval to study activation due to prolonged negotiations for drug acquisition and funding. Ultimately, an over-encapsulated blinded drug was secured, and the trial opened to accrual in December 2003. The study closed to accrual in September 2006 when 600 patients, as planned, were enrolled. Five transplant physicians from the Protocol Team assumed the role of Endpoint Review Committee and conducted an independent assessment of the major events of the primary and major secondary study endpoints. The Endpoint Review Committee spent considerable time checking and reconciling data, including a review of primary data documents to confirm diagnoses. 72 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual Protocol Number: BMT CTN 0101 Reporting Period Update: A secondary pharmacoeconomic analysis was performed, and the manuscript is in press. An additional secondary pharmacokinetic analysis of voriconazole concentrations in blood samples collected on Day 14 and 28 of therapy; at onset of serious suspected study drug toxicities; and at onset of possible, presumptive, probable or proven infection (prior to start of antifungal therapy) is in the process of being analyzed. Publications: 1. Design issues in a prospective randomized double-blinded trial of prophylaxis with fluconazole versus voriconazole after allogeneic hematopoietic cell transplantation. Clinical Infectious Disease. 2004 Oct 15;39 Suppl 4:S176-180. 2. Primary manuscript: Randomized double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood. 2010 Dec 9;116(24):5111-5118. Epub 2010 Sep 8. 3. Cost-effectiveness analysis of voriconazole compared with fluconazole for prevention of invasive fungal infection in patients receiving allogeneic hematopoietic cell transplants. American Journal of Health-System Pharmacy. [In Press] Presentation: 1. Results of a randomized, double-blind trial of fluconazole vs. voriconazole for the prevention of invasive fungal infections in 600 allogeneic blood and marrow transplant patients. Presentation: 49th Annual ASH Meeting, Atlanta, GA, December 2007. Target Accrual = 600 patients BMT CTN #0101 700 600 25 500 Accrual per Month 30 20 400 15 300 10 200 5 100 0 0 73 Cumulative Accrual 35 Monthly Actual Accrual Projected Steady State Monthly Accrual Cumulative Accrual Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual BMT CTN 0102 Protocol Number: BMT CTN 0102 Status: Closed to Accrual A trial of tandem autologous stem cell transplants with or without post-second autologous transplant maintenance therapy versus single autologous stem cell transplant followed by matched sibling nonmyeloablative allogeneic stem cell transplant for patients with multiple myeloma This study compared tandem autologous HCT (auto/auto) with autologous HCT followed by HLA-matched sibling allogeneic HCT with a nonmyeloablative conditioning regimen (auto/allo) in patients with multiple myeloma. Autologous HCT is widely accepted as a standard of care for patients with multiple myeloma. Allogeneic HCT offers a potential graft-versus-myeloma effect, and this study addressed whether it offers additional benefit compared with tandem autologous HCT. Additionally, the study evaluated the role of one-year maintenance therapy with thalidomide plus dexamethasone after tandem auto/auto HCT. Maintenance therapy after autologous HCT has demonstrated improvements in overall survival. To compare three-year progression-free survival between the two arms. Title: Rationale: Primary Objective: Secondary Objectives: Team Principals: Chairs: Officer: Coordinator: Medical Monitor: Statistician: Contract Rep: Additional Members: Nancy DiFronzo Stephen Forman Nancy Geller Sergio Giralt Elizabeth Murphy Edward Stadtmauer David Vesole John Wingard Key Highlights: To compare current myeloma-stable survival, three-year overall survival, and incidence of progression. Name Amrita Krishnan David Maloney Marcelo Pasquini Kristin Knust Marcelo Pasquini Brent Logan Pam Budnick Email [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] PRC Approval Date: DSMB Approval Date: Opened to Accrual: Closed to Enrollment: Evaluable for Primary Analysis: Target Accrual: Total Accrual as of 03/31/13: Reporting Period Accrual: IND Number: Last Version Released: Email [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] 11/15/2002 08/11/2003 11/15/2003 03/30/2007 04/2010 710 710 N/A 67956 05/15/2006 Accrual and analysis for this study were based on the anticipated number of standard-risk multiple myeloma patients with an available HLA-matched sibling donor. Statistical power required that 150 standard-risk patients be assigned to the autologous-allogeneic transplant arm. Enrollment would remain open until this goal was achieved, with concurrent enrollment of both standard-risk and high-risk patients, with and without HLA-matched sibling donors. When the protocol was developed, it was estimated that 500–750 total subjects would be required, as it was assumed that 20% to 30% of subjects would have available HLA-matched sibling donors. The study closed to enrollment on March 30, 2007, after 150 patients declared their intent to receive an allogeneic transplant. A total of 710 subjects were required to obtain 189 subjects with standard-risk disease biologically assigned to the autologous-allogeneic transplant arm. Patients were followed for three years after their second transplant. The Endpoint Review Committee formed in July 2008 after all patients completed maintenance therapy; the Committee conducted an independent assessment of the study’s primary and secondary endpoints. This preliminary review demonstrated many inconsistencies between the reported data and interpretation 74 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Protocol Number: 7.2 Protocols that Completed Accrual BMT CTN 0102 of disease response by transplant centers. Adjudication of such discrepancies was required, with source document review and consultation with the institutional PIs. The Endpoint Review Committee acknowledged the inherent difficulties in interpreting disease response in multiple myeloma, which suggests ongoing review of incoming data is preferred during active accrual for future myeloma clinical trials conducted by the BMT CTN. The Endpoint Review Committee completed review of all patients in June 2010. Reporting Period Update: Data are being reviewed for a secondary analysis of longer term follow-up. An abstract and manuscript are expected to be submitted with the next reporting period. Publications: 1. Correspondence: Tandem vs. single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and meta-analysis. 2. Design paper: Use of biological assignment in hematopoietic stem cell transplantation clinical trials. Clinical Trials. 2008;5(6):607-16. 3. Primary manuscript: Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a Phase 3 biological assignment trial. Lancet Oncology. 2011 Dec;12(13):1195-1203. [Epub 2011 Sep 29] Presentations: 1. Biologic assignment trials in hematopoietic stem cell transplantation (HCT): baseline characteristics of multiple myeloma patients in BMT CTN 0102 by treatment allocation according to donor availability. Presentation: 49th Annual ASH Meeting, Atlanta, GA, December 2007. 2. Tandem autologous hematopoietic stem cell transplants with or without maintenance therapy versus single autologous HCT followed by HLA matched sibling nonmyeloablative allogeneic HCT for patients with standard risk multiple myeloma: results from the BMT CTN 0102 Trial. Presented: 52nd Annual ASH Meeting, Orlando, FL, December 2010. 3. Tandem autologous HCT (auto-auto) versus single autologous HCT followed by HLA matched sibling nonmyeloablative allogeneic HCT (auto-allo) for patients with standard risk multiple myeloma: results from the BMT-CTN 0102 trial. Poster Presentation: 13th International Myeloma Workshop, Paris, France, May 2011. 4. Immunoglobulin free light chain (FLC) and heavy chain/light chain (HLC) assays – comparison with electrophoretic responses in multiple myeloma (MM): results of BMT CTN Protocol #0102. Poster Presentation: 53rd Annual ASH Meeting, San Diego, CA, December 2011. Target Accrual = 710 patients Accrual per Month 30 BMT CTN #0102 Monthly Actual Accrual Projected Steady State Monthly Accrual Cumulative Accrual 800 700 600 25 500 20 400 15 300 10 200 5 100 0 0 75 Cumulative Accrual 35 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual BMT CTN 0201 Protocol Number: BMT CTN 0201 Status: Closed to Accrual Title: A Phase III randomized, multicenter trial comparing G-CSF mobilized peripheral blood stem cell with marrow transplantation from HLA compatible unrelated donors Rationale: Many allogeneic marrow transplantation studies indicate that higher doses of marrow cells correlate with more robust hematopoietic engraftment and lower mortality from infectious complications. PBSCs collected after mobilization with G-CSF contain a larger number of CD34+ progenitors and total cells than bone marrow. These observations led to the hypothesis that transplantation of PBSC would lead to a lower mortality rate when compared with transplantation of marrow. PBSC grafts have a higher T cell content, predicting a possibly more powerful anti-leukemic effect. However, the higher T cell content of PBSC may also lead to an increased incidence and severity of acute and chronic GVHD. This concern is especially serious when the donor is unrelated to the recipient. This prospective, randomized, multicenter clinical trial of unrelated donor transplantation tested the hypothesis that transplantation of PBSC leads to similar patient survival compared to transplantation of marrow. To compare two-year survival probabilities between patients receiving PBSC versus marrow transplants from unrelated donors using an intent-to-treat analysis. Patients randomized to the two study arms and actually transplanted were compared for the following endpoints (patients who did not receive a transplant were excluded from these analyses): survival, incidences of neutrophil and platelet engraftment, graft failure, acute GVHD, chronic GVHD, time off immunosuppressive therapy, Secondary Objectives: relapse, infections, adverse events, immune reconstitution, and quality of life. Donors in each arm of the study were compared for time to return to baseline toxicity score, complete blood count and white blood count differential values after donation, and quality of life. Team Principals: Name Email Chair: Claudio Anasetti [email protected] Officer: Dennis Confer [email protected] Coordinator: Kristin Knust [email protected] Medical Monitor: Christopher Bredeson [email protected] Statistician: Brent Logan [email protected] Contract Rep: Nancy Poland [email protected] Additional Members Email PRC Approval Date: 05/05/2003 Paolo Anderlini [email protected] DSMB Approval Date: 09/04/2003 William Bensinger [email protected] Opened to Accrual: 01/20/2004 Shelly Carter [email protected] Closed to Enrollment: 10/16/2009 Nancy DiFronzo [email protected] Evaluable for Primary Analysis: 10/2011 Nancy Geller [email protected] Target Accrual: 550 Mary Horowitz [email protected] Total Accrual as of 3/31/13: 551 Stephanie Lee [email protected] Reporting Period Accrual: N/A Susan Leitman [email protected] IND Number: 6821 Scott Rowley [email protected] Last Version Released: 09/15/2006 Edmund Waller [email protected] Additional Member Email Daniel Weisdorf [email protected] John Wingard [email protected] Primary Objective: A total of 551 patients were enrolled on this study, which successfully closed to accrual on October 16, 2009. A total of 338 unrelated donors were also enrolled. Key Highlights: Overall accrual to the study was slower than projected. It was a difficult study due to the need for both donor and recipient consent, and donor refusal rates ranged from 25% to 30%. Activities implemented to enhance patient accrual included weekly Eligible Patient Notification emails to transplant centers; quarterly Trial Snapshot emails to centers, targeting high-accruing centers; coordinator and PI conference calls; presentations at the NMDP Council Meeting; a PI newsletter; and direct correspondence from the study PI and NMDP Medical Director. A total of 55 centers participated on the trial, which enrolled 551 recipients including 20 Canadian 76 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Protocol Number: 7.2 Protocols that Completed Accrual BMT CTN 0201 recipients. A coordinated effort involving transplant and donor centers and the NMDP Search Coordinating Unit made this study possible. It is the only study of its kind, and the BMT CTN is the only mechanism through which it could be accomplished. The Endpoint Review Committee was formed in January 2010 to review outcomes data and was completed in November 2011. The trial, through its ancillary laboratory studies, will also provide important information on multiple parameters of immune reconstitution and their correlation with clinical outcomes. Reporting Period Update: The primary manuscript was published in the New England Journal of Medicine during this period. A secondary analysis manuscript of the unrelated donor experience was submitted. Also, a secondary immune reconstitution analysis was presented at EBMT. Publication: 1. Primary manuscript: Peripheral-blood stem cells versus bone marrow from unrelated donors. New England Journal of Medicine. 2012 Oct 18;367(16):1487-96. Presentations: 1. Health-related quality-of-life among adult unrelated stem cell donors: a Blood and Marrow Transplant Clinical Trials Network randomized trial of marrow versus PBSC donation. Presented: 52nd Annual ASH Meeting, Orlando, FL, December 2010. 2. Increased incidence of chronic GVHD and no survival advantage with filgrastim-mobilized PBSCs compared to BM transplants from unrelated donors: results of BMT CTN Protocol #0201, a Phase III prospective randomized trial. Presented: 53rd Annual ASH Meeting, San Diego, CA, December 2011. 3. BMT CTN Protocol 0201 Results of a Phase III randomized multicenter trial of HLA compatible unrelated donor transplantation: G-CSF mobilized peripheral blood stem cells (PBSC) versus bone marrow. Presented: 53rd Annual ASH Meeting Plenary Session, December 2011. 4. Larger numbers of donor naïve CD8+ T-cells and plasmacytoid dendritic cell precursors in allogeneic BM grafts from unrelated donors are associated with improved survival: results from BMT CTN 0201. Presented: 53rd Annual ASH Meeting, San Diego, CA, December 2011. 5. Grade III - IV acute GvHD and treatment-related mortality are reduced among recipients of larger numbers of donor naïve CD8+ T-cells and plasmacytoid dendritic cell precursors in allogeneic BM grafts from unrelated donors: results from BMT CTN 0201. Presented: EBMT, April 2012. 6. Increased incidence of chronic GVHD and no survival advantage with filgrastim-mobilized PBSCs compared to BM transplants from unrelated donors: results of BMT CTN Protocol 0201, a Phase III, prospective, randomized trial. Presented: ASCO Annual Meeting, Chicago, IL, June 2012. Target Accrual = 550 patients BMT CTN #0201 20 600 Monthly Accrual Projected Steady State Monthly Accrual Cumulative Accrual 500 400 15 300 10 200 5 100 0 0 77 Cumulative Accrual Accrual per Month 25 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual BMT CTN 0202 Protocol Number: BMT CTN 0202 Status: Closed to Accrual (closed prematurely due to low enrollment) Title: Autologous versus nonmyeloablative allogeneic HCT for patients with chemosensitive follicular non-Hodgkin lymphoma beyond first complete response or first partial response Rationale: Follicular non-Hodgkin lymphoma is the second most common type of non-Hodgkin lymphoma in the United States. When treatment is indicated, most patients achieve a remission with initial chemotherapy, but patients with recurrent advanced follicular lymphoma have a median survival of only four to five years. At present, the optimal management of patients failing conventional therapy is unknown, with both autologous HCT and allogeneic HCT being offered to follicular lymphoma patients with recurrent disease. The results of several studies have shown improved disease-free survival with autologous HCT; one randomized study showing improved overall survival compared with conventional chemotherapy. Relapse remains the major cause of treatment failure. Allogeneic nonmyeloablative HCT is being explored with the goal of harnessing a graft-versuslymphoma effect and circumventing the significant upfront mortality associated with myeloablative HCT. Allogeneic nonmyeloablative HCT utilizes a less intensive preparative regimen and thus relies primarily on the immunotherapeutic effect of the allograft to confer antitumor activity rather than the cytoreductive effects of high-dose chemotherapy. Follicular lymphoma is an ideal disease in which to study the benefit of a graft-versus-lymphoma effect in a controlled trial against the other intensive approach of autologous HCT. Primary Objective: To compare three-year progression-free survival between the two treatment arms. Secondary Objectives: To compare three-year overall survival, time to progression, time to complete and partial response, time to off-study therapy, and incidence of infections and NCI CTCAE Version 3.0 Grade ≥ 3 toxicities. Secondary objectives for the nonmyeloablative allogeneic HCT recipients include the incidence and severity of acute and chronic GVHD and incidence of primary and secondary graft failure. Additional objectives are the efficacy of cyclophosphamide plus rituximab in vivo purging, the prediction of disease relapse by measurement of t(14;18) by quantitative polymerase chain reaction, and quality of life as measured by the SF-36 and the FACT-BMT. Team Principals: Chairs: Officer: Coordinator: Medical Monitor: Statistician: Contract Rep: Additional Members: Henry Chang David Maloney Elizabeth Murphy Auayporn Nadamanee Patrick Stiff Julie Vose Name Ginna Laport Robert Negrin Marcie Tomblyn Steve Wease Mary Eapen Marian Ewell Nancy Poland Email [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Email [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] PRC Approval Date: DSMB Approval Date: Opened to Accrual: Closed to Enrollment: Evaluable for Primary Analysis: Target Accrual: Total Accrual as of 03/31/13: Reporting Period Accrual: IND Number: 78 08/01/2003 03/01/2004 07/28/2004 03/02/2006 04/2009 480 30 N/A N/A Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Protocol Number: 7.2 Protocols that Completed Accrual BMT CTN 0202 Last Version Released: 01/17/2006 Key Highlights: When the study closed to accrual in March 2006, 22 patients were enrolled on the autologous HCT + rituximab arm and eight on the allogeneic HCT + rituximab arm. Discussions with BMT CTN and Cooperative Group investigators and analysis of the CIBMTR database led the Protocol Team to conclude that poor accrual on this trial came from low referrals of eligible patients by primary care oncologists. The Network continued to follow the enrolled patients for three-year survival and adverse events as recommended by the DSMB. (The last patient three-year survival follow-up finished on April 13, 2009.) Reporting Period Update: Important questions regarding the role of HCT for patients with follicular lymphoma must still be addressed. The NCI-funded Cooperative Group Transplant and Lymphoma Committee Chairs collaborated with the Network to design and implement a new trial with better feasibility (BMT CTN 0701, which opened on April 27, 2009, and completed accrual during this reporting period). Publication: 1. Autologous versus reduced intensity allogeneic hematopoietic cell transplantation for patients with chemosensitive follicular non-Hodgkin lymphoma beyond first complete response or first partial response. Biology of Blood and Marrow Transplantation. 2011 Jul;17(7):1051-7. Epub 2010 Nov 10. Presentation: 1. Autologous vs. reduced-intensity allogeneic hematopoietic cell transplantation for patients with follicular non-Hodgkin’s lymphoma beyond first complete response or first partial response. Abstract presented: ASCO Annual Meeting, Chicago, IL, May 2008. An accrual graph is not included due to premature study closure. 79 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual BMT CTN 0302 Protocol Number: BMT CTN 0302 Status: Closed to Accrual Title: Initial systemic treatment of acute GVHD: a Phase II randomized trial evaluating etanercept, mycophenolate mofetil, denileukin diftitox (Ontak), and pentostatin Rationale: Initial therapy of acute GVHD has limited efficacy. New agents that limit the morbidity and duration of steroid therapy are available for testing; however, they generally have only been tested in singleinstitution, uncontrolled trials. The purpose of this study was to test in a prospective, randomized Phase II parallel arm trial the use of four promising agents to manage acute GVHD in order to develop suitable data to initiate a formal follow-up Phase III trial. Primary Objective: To estimate the proportion of day 28 complete remissions for newly-diagnosed acute GVHD for each of these agents given in combination with corticosteroids. To determine the proportion of patients achieving a partial response, mixed response, and progression at day 28; proportion of patients with treatment failure (no response, progression, administration of additional therapy for GVHD, or mortality) by day 14; incidence of GVHD flares requiring increasing Secondary therapy before day 90; incidences of discontinuation of immune suppression without flare by days 90, Objectives: 180, and 270 after initiation of therapy; incidence of chronic GVHD by 9 months; overall survival at 6 and 9 months after initiation of therapy; incidences of systemic infections within three months of initiation of therapy; and incidence of Epstein-Barr virus-associated lymphoma. Team Principals: Name: Email: Chair: Daniel Weisdorf [email protected] Officer: Marcelo Pasquini [email protected] Coordinator: Maggie Wu [email protected] Medical Monitor: Mary Eapen [email protected] Statistician: Brent Logan [email protected] Contract Rep: Nancy Poland [email protected] Additional Members: Email: PRC Approval Date: 01/26/2004 Joseph Antin [email protected] DSMB Approval Date: 05/13/2004 Nelson Chao [email protected] Opened to Accrual: 08/25/2005 Nancy DiFronzo [email protected] Closed to Enrollment: 03/24/2008 James Ferrara [email protected] Evaluable for Primary Analysis: 12/2008 Vincent Ho [email protected] Target Accrual: 180 Mary Horowitz [email protected] Total Accrual as of 3/31/13: 180 Eric Leifer [email protected] Reporting Period Accrual: N/A John Levine [email protected] IND Number: 11726 Richard Nash [email protected] Last Version Released: 08/21/2007 Georgia Vogelsang [email protected] Key Highlights: Despite early concerns about slow accrual, the May 2006 amendment had a positive impact on the accrual rate, and the study was completed on March 24, 2008, with 180 patients enrolled as planned. That amendment involved four changes: (1) development of a second stratum (3-arm, balanced randomization with etanercept, pentostatin, and Ontak) for patients previously exposed to mycophenolate mofetil for GVHD prophylaxis; (2) enrollment of all patients with acute GVHD in whom the clinical decision to treat with corticosteroids was made at the participating center rather than to exclude those patients with upper gastrointestinal GVHD or limited skin diseases as the sole manifestations; (3) consent, enrollment, and randomization within 48 hours (previously 24) of initiating corticosteroid therapy; and (4) allowing enrollment of patients administered low-dose steroids for less 80 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Protocol Number: 7.2 Protocols that Completed Accrual BMT CTN 0302 than 7 days prior to enrollment. The DSMB approved formation of an Endpoint Review Committee (ERC) comprised of six transplant physicians from BMT CTN 0302 centers. All patients completed follow-up per protocol except two who were lost to follow up before nine months. The ERC reviewed the study data for each patient and results are published in a primary manuscript and secondary manuscripts. The results of the study suggested that mycophenolate mofetil was the most promising candidate for evaluation in a Phase III study. BMT CTN protocol 0802 was developed as a Phase III, randomized double blind, placebo controlled trial to evaluate the addition of mycophenolate mofetil vs. placebo to systemic corticosteroids as initial therapy for acute GVHD. Protocol 0802 was closed due to futility in November 2011. Reporting Period Update: A secondary analysis of lymphocyte phenotypes was published this year. This is the sixth BMT CTN 0302 manuscript to be published. Publications: 1. Optimal two-stage randomized Phase II clinical trials. Clinical Trials. 2005 Feb;2(1):5-12. 2. Etanercept, mycophenolate, denileukin or pentostatin plus corticosteroids for acute graft-versus-host disease, a randomized Phase II trial from the BMT CTN. Blood. 2009 Jul;114(3)511-517. Epub 2009 May 14. 3. Mycophenolate pharmacokinetics and association with response to acute graft-versus-host disease treatment from the BMT CTN. Biology and Blood and Marrow Transplantation. 2010 Mar;16(3)421429. 4. Graft-versus-host disease treatment: predictors of survival. Biology of Blood and Marrow Transplantation. 2010 Dec;16(12):1693-1699. Epub 2010 Jun 10. 5. Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a BMT CTN study. Blood. 2012 Apr 19;119(16)3854-3860. Epub 2012 Mar 1. 6. Lymphocyte phenotype during therapy for acute graft versus host disease: a brief report from BMT-CTN 0302. Biology of Blood and Marrow Transplantation. 2013 Mar;19(3)481-485. Epub 2012 Dec 11. Presentations: 1. A Phase II randomized trial evaluating etanercept, mycophenolate mofetil, denileukin diftitox and pentostatin in combination with corticosteroids in 180 patients with newly diagnosed acute graft vs. host disease. Abstract presented: 50th Annual ASH meeting, San Francisco, CA, December 2008. 2. GVHD biomarkers measured during treatment independently predict response to therapy and survival: a Blood and Marrow Transplant Clinical Trials Network study. Presented: EBMT Congress, Paris, France, April 2011. Target Accrual = 180 patients 13 12 11 10 9 8 7 6 5 4 3 2 1 0 Projected Steady State Monthly Accrual BMT CTN #0302 200 Cumulative Accrual 150 100 50 0 81 Cumulative Accrual Accrual per Month Monthly Actual Accrual Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual BMT CTN 0303 Protocol Number: BMT CTN 0303 Status: Closed to Accrual Title: A single-arm, multicenter Phase II trial of transplants of HLA-matched, CD34+ enriched, T cell depleted peripheral blood stem cells isolated by the CliniMACS system in the treatment of patients with AML in first or second morphologic complete remission Allogeneic blood or marrow transplantation is the treatment of choice for many patients with advanced AML in first or second complete remission because the graft-versus-leukemia effect limits the risk of relapse. However, transplantation of standard unmanipulated allografts is associated with a substantial risk of GVHD and other complications that limit the overall success of allogeneic HCT in this setting. Rationale: T cell depletion (TCD) has been used by many groups to mitigate the risk of GVHD. Effective TCD allows for the transplantation of allografts without the requirement for pharmacological GVHD prophylaxis. Retrospective data have suggested TCD is associated with higher risks of opportunistic infection, graft rejection and disease relapse, which have led some programs to abandon this technique despite the potential advantages over conventional allografting. Recently, several single-center trials employing novel TCD techniques report highly encouraging long-term results, particularly for patients with AML in first or second complete remission. Although the number of cases in each singlecenter series is limited, the consistency of the results suggests that the use of an effective technique for TCD together with an adequate cytoreductive regimen might yield transplant results superior to those achieved with unmodified grafts. BMT CTN 0303 was designed to evaluate the results of this approach in a multicenter trial. Primary Objective: To assess disease-free survival six months after transplant. Outcome measures to assess this endpoint were death or relapse. Secondary Objectives: To assess infusional toxicity, time to neutrophil and platelet engraftment, incidence and severity of acute and chronic GVHD, incidence of transplant-related mortality, incidence of Epstein-Barr virus after transplant, lymphoproliferative disorder, time to leukemia relapse, probability of survival and disease-free survival at 2 years, and the proportion of 6 5 grafts with both > 5 x 10 /kg CD34+ cells and < 1 x 10 /kg CD3 cells. Team Principals: Chairs: Officer: Coordinator: Medical Monitor: Statistician: Contract Rep: Additional Members: Chris Bredeson Nancy DiFronzo Stephen Forman Nancy Geller Hillard Lazarus Elizabeth Murphy Robert Soiffer Anthony Stein Roy Wu Key Highlights: Name Steve Devine Richard O’Reilly Marcelo Pasquini Kristin Knust Marcie Tomblyn Shelly Carter Nancy Poland Email [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] PRC Approval Date: DSMB Approval Date: Opened to Accrual: Closed to Enrollment: Evaluable for Primary Analysis: Target Accrual: Total Accrual as of 03/31/13: Reporting Period Accrual: IDE Number: Last Version Released: Email [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] 03/17/2004 10/15/2004 06/30/2005 12/24/2008 07/2009 45 47 N/A 11965 11/13/2006 There was a delay between PRC and DSMB approvals, due to a determination by the DSMB in April 2004 that safety data were required for donors and recipients. This required protocol resubmission to the DSMB. The long interval between DSMB approval and study activation was due to lengthy processing of an IDE. The protocol was submitted 82 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual Protocol Number: BMT CTN 0303 on September 30, 2004, to the FDA, which requested changes. It was ultimately approved by the FDA on December 28, 2004, and released to sites in January 2005. There was an additional delay in activation for training at sites by Miltenyi Biotec, Inc., and for preparation and submission of laboratory Standard Operating Procedures by each site. The study was opened to accrual on June 30, 2005. The study completed accrual in December 2008 with 47 patients enrolled. The Endpoint Review Committee completed an independent assessment of the primary and secondary endpoints of the study. Reporting Period Update: A secondary comparative analysis was published in the Journal of Clinical Oncology. A calcineurin inhibitor-free GVHD prophylaxis study proposal was approved by the Steering Committee as a follow-up to the BMT CTN 0303 study. A project team, including several 0303 investigators, has created a protocol and plans to apply for supplemental R01 funding during the upcoming reporting period. Publications: 1. Low risk of chronic graft-versus-host disease and relapse associated with T cell depleted peripheral blood stem cell transplantation for acute myeloid leukemia in first remission: results of the Blood and Marrow Transplant Clinical Trials Network Protocol 0303. Biology of Blood and Marrow Transplantation. 2011 Sep;17(9):1343-51. Epub 2011 Feb 12. 2. Characteristics of CliniMACS(®) System CD34-enriched T cell-depleted grafts in a multicenter trial for acute myeloid leukemia-Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0303. Biology of Blood and Marrow Transplantation. 2012 May;18(5):690-7. Epub 2011 Aug 26. 3. Comparative outcomes of donor graft CD34+ selection and immune suppressive therapy as graft-versus-host disease prophylaxis for patients with acute myeloid leukemia in complete remission undergoing HLA-matched sibling allogeneic hematopoietic cell transplantation. Journal of Clinical Oncology. 30(26):3194-3201, 2012. Presentations: 1. HLA-identical sibling-matched, CD34+ selected, T cell depleted peripheral blood stem cells following myeloablative conditioning for first or second remission acute myeloid leukemia, results of BMT CTN Protocol 0303. Presented: 51st Annual ASH Meeting, New Orleans, LA, December 2009. 2. Comparative effectiveness analysis of CD34+ selected, T cell depleted HLA-matched sibling grafts on allogeneic hematopoietic cell transplantation for patients with acute myeloid leukemia in complete remission. Poster presented: BMT Tandem Meetings, Orlando, FL, February 2010. 3. Characteristics of CD34-enriched products processed at multiple centers using the CliniMACS System - BMT CTN 0303. Abstract presented: Annual International Society for Cellular Therapy meeting, Philadelphia, PA, May 2010. Target Accrual = 45 patients BMT CTN #0303 Accrual per Month 5 50 Monthly Actual Accrual Projected Steady State Monthly Accrual Cumulative Accrual 45 40 35 4 30 3 25 20 2 15 10 1 5 0 0 83 Cumulative Accrual 6 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual BMT CTN 0401 Protocol Number: BMT CTN 0401 Status: Closed to Accrual Title: Phase III Rituxan/BEAM versus Bexxar/BEAM with autologous hematopoietic stem cell transplantation for persistent or relapsed chemotherapy-sensitive diffuse large B cell non-Hodgkin lymphoma Rationale: The protocol was designed to improve the long-term disease-free survival of patients with diffuse large B cell non-Hodgkin lymphoma by adding either an unlabelled or a radiolabelled anti-CD20 monoclonal antibody to high-dose chemotherapy and autologous HCT. Primary Objective: To compare progression-free survival after autologous HCT for chemotherapy-sensitive diffuse large B cell lymphoma using Rituxan/BEAM versus Bexxar/BEAM as a pre-transplant conditioning regimen. Secondary Objectives: To compare overall survival; time to progression; proportion of complete response and partial response at day 100; time to hematopoietic recovery; hematologic function; incidence of infection; maximum mucositis score by day 21; immune reconstitution; treatment-related mortality; and development of myelodysplasia, secondary acute myelogenous leukemia or abnormal cytogenetics. Team Principals: Chair: Officer: Coordinator: Medical Monitor: Statistician: Contract Rep: Additional Members: Linda Burns Dennis Confer Nancy DiFronzo Peter Holman John Koreth Eric Leifer William Merritt Elizabeth Murphy Oliver Press Edward Stadtmauer Name Julie Vose Marcie Tomblyn Steve Wease Eneida Nemecek Jennifer Le-Rademacher Pam Budnick Email [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Key Highlights: This study was activated on December 7, 2005; 37 centers enrolled patients on the trial. Although diffuse large B cell non-Hodgkin lymphoma is a common indication for autologous HCT, an increasing percentage of these procedures are performed in diverse community hospitals without academic programs, so only a few transplant centers have access to large numbers of eligible patients. To increase patient accrual, additional centers were recruited, and a collaboration with SWOG was developed. The study closed on July 17, 2009, after reaching its accrual goal of 224 patients. An Endpoint Review Committee was formed in April 2011, completing data review in June 2011 and submitting an abstract for ASH 2011. Email [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] PRC Approval Date: DSMB Approval Date: Opened to Accrual: Closed to Enrollment: Evaluable for Primary Analysis: Target Accrual: Total Accrual as of 03/31/13: Reporting Period Accrual: IND Number: Last Version Released: 84 09/24/2004 02/04/2005 12/07/2005 07/17/2009 07/2011 224 224 N/A 12520 01/14/2009 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual Protocol Number: BMT CTN 0401 Reporting Period Update: The primary manuscript was published in the Journal of Clinical Oncology. Publication: 1. Primary: Phase III randomized study of rituximab/carmustine, etoposide, cytarabine, and melphalan (BEAM) compared with Iodine-131 tositumomab/BEAM with autologous hematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: results from the BMT CTN 0401 Trial. Journal of Clinical Oncology. 2013 Mar 11. [Epub ahead of print] Presentation: 1. Randomized Phase III trial of 131Iodine-tositumomab (bexxar)/carmustine, etoposide, cytarabine, melphalan (BEAM) vs. rituximab/BEAM and autologous stem cell transplantation for relapsed diffuse large B-cell lymphoma (DLBCL): no difference in progression-free (PFS) or overall survival (OS). Abstract presentation: 53rd Annual ASH Meeting, San Diego, CA, December 2011. Target Accrual = 224 patients Accrual per Month 12 BMT CTN #0401 Monthly Actual Accrual Projected Steady State Monthly Accrual Cumulative Accrual 250 200 10 8 150 6 100 4 50 2 0 0 85 Cumulative Accrual 14 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual BMT CTN 0402 Protocol Number: BMT CTN 0402 Status: Closed to Accrual Title: A Phase III randomized, multicenter trial comparing sirolimus/tacrolimus with tacrolimus/methotrexate as GVHD prophylaxis after HLA-matched, related peripheral blood stem cell transplantation Rationale: GVHD is an important cause of treatment failure after allogeneic HCT. The results of Phase II studies suggest that acute GVHD prophylaxis with sirolimus and tacrolimus may provide better GVHD control and reduce transplant-related toxicity when compared with methotrexate and tacrolimus. This trial is designed to determine whether replacing methotrexate with sirolimus will improve GVHD-free survival and reduce transplant-related morbidity and mortality in HLA-identical sibling transplantation. Primary Objective: To compare day 114 grades II through IV acute GVHD-free survival rates between patients receiving sirolimus and tacrolimus with those receiving methotrexate and tacrolimus from the time of patient randomization, using an intent-to-treat analysis. Secondary Objectives: To compare time to neutrophil and platelet engraftment, incidence of grades III through IV acute GVHD, mucositis severity, time to first hospital discharge after transplantation, all infections, cytomegalovirus reactivation, thrombotic microangiopathy incidence, veno-occlusive disease during the first 100 days after transplantation, malignant disease relapse, and one-year relapse-free and overall survival rates. Team Principals: Name Email Joseph Antin [email protected] Corey Cutler [email protected] Officer: Coordinator: Medical Monitor: Statistician: Contract Rep: Additional Members: Sung Choi Nancy DiFronzo James Ferrara Nancy Geller Stephan Grupp Mary Horowitz Laura Johnston Eric Leifer Margaret MacMillan Philip McCarthy Elizabeth Murphy Marcelo Pasquini Kristin Knust Mary Eapen Brent Logan Pam Budnick Email [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] PRC Approval Date: 09/24/2004 DSMB Approval Date: 02/04/2005 Opened to Accrual: 11/20/2006 Closed to Enrollment: 10/26/2011 Target Accrual: 312 Total Accrual as of 03/31/13: 314 Reporting Period Accrual: N/A IND Number: N/A Last Version Released: 12/3/2010 Additional Members: Email Ryotaro Nakamura [email protected] David Porter [email protected] Key Highlights: Although this protocol was approved by the DSMB in a timely fashion, the Network agreed to delay activating the study for patient accrual until closure of BMT CTN 0101 to reduce potential competition for a similar patient population. Initial accrual to this study was slower than projected. Chairs: 86 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Protocol Number: 7.2 Protocols that Completed Accrual BMT CTN 0402 Discussion among the investigators led to a protocol amendment aimed at enhancing accrual. The amendment increased the maximum allowed cholesterol/triglyceride level at study entry to be ≤ 500 mg/dL. In addition, the requirement for donor toxicity assessments was removed, and the required assessment periods for mucositis were modified. Protocol Version 2 was approved by the DSMB and released to centers in June 2007 for IRB approval. On September 26, 2007, the veno-occlusive stopping guideline was crossed, and enrollment was suspended pending DSMB review. The DSMB approved re-opening the study on October 3, 2007, with exclusion of busulfan and cyclophosphamide pretransplantation conditioning regimens. The revised protocol was released to centers for IRB approval in November 2007. Some centers were unable to transition into a total body irradiation-based conditioning regimen in lieu of the busulfan regimen, and additional center participation was solicited. Since November 2007, overall enrollment increased. Version 4.0 of the protocol was released in December 2010 to allow patients whose primary disease was acute biphenotypic leukemia in first or subsequent remission. Twenty-six centers (13 Core and 13 Affiliate) participated on this trial. The study completed accrual in October 2011. The protocol team began the Endpoint Data Review in December 2011 for patients who had met the primary endpoint. Reporting Period Update: An absbtract was submitted and presented at the 2012 ASH meeting. The primary manuscript is in preparation. Presentation: 1. Tacrolimus/sirolimus vs. tacrolimus/methotrexate for GVHD prophylaxis after HLA-matched, related donor hematopoietic stem cell transplantation: Results of BMT CTN Trial 0402. Presented: Annual ASH Meeting, Atlanta, GA, December 2012. Target Accrual: 312 patients BMT CTN #0402 Accrual per Month 10 350 Monthly Actual Accrual Projected Steady State Monthly Accrual Cumulative Accrual 300 250 8 200 6 150 4 100 2 50 0 0 87 Cumulative Accrual 12 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual BMT CTN 0403 Protocol Number: BMT CTN 0403 Status: Closed to Accrual (closed prematurely due to low enrollment) Title: A randomized double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor Enbrel (etanercept) for the treatment of acute noninfectious pulmonary dysfunction (idiopathic pneumonia syndrome, IPS) following allogeneic cell transplantation Rationale: Despite significant advances in critical care medicine, IPS remains a frequently fatal complication following allogeneic HCT. Mortality in patients with IPS ranges from 60% to 80%, and the median time from diagnosis to death is 14 days. New therapeutic strategies are needed. Preclinical data reveal a significant role for tumor necrosis factor-α (TNF-α) in the development of experimental IPS, and the results of a pilot, dual-center clinical trial using etanercept, a TNF-α neutralizing agent, are encouraging. This randomized Phase III study is the culmination of several years of investigation. The central hypothesis is that cytokine dysregulation and TNF-α production significantly contribute to the development of IPS. Primary Objective: To determine the day 28 response rate following treatment with etanercept plus corticosteroids compared with placebo plus corticosteroids for patients with IPS after allogeneic HCT. (Response is defined as (1) survival at day 28; and (2) discontinuation of all supplemental oxygen support for more than 72 consecutive hours by day 28.) To evaluate response to therapy at day 56; overall mortality in patients with IPS; time to discontinuation of supplemental oxygen; and pro-inflammatory markers of pulmonary disease in both bronchoalveolar Secondary lavage fluid and plasma of patients with IPS. The last studies will correlate biologic and genetic markers of Objectives: inflammation with clinical response to therapy, and characterize plasma and bronchoalveolar lavage protein profiles to attempt to identify an inflammatory signature of the disease. Team Principals: Name: Email: Kenneth Cooke [email protected] Chairs: Gregory Yanik [email protected] Officer: Mary Horowitz [email protected] Coordinator: Steve Wease [email protected] Medical Monitor: Marcie Tomblyn [email protected] Statistician: Brent Logan [email protected] Contract Rep: Nancy Poland [email protected] Additional Members: Email: PRC Approval Date: 09/26/2005 Shelly Carter [email protected] DSMB Approval Date: 12/01/2005 Nancy DiFronzo [email protected] Opened to Accrual: 08/27/2007 Rebecca Drexler [email protected] Closed to Enrollment: 09/14/2011 James Ferrara [email protected] Target Accrual: 60 Sergio Giralt [email protected] Total Accrual as of 3/31/13: 37 Vincent Ho [email protected] Reporting Period Accrual: N/A Eric Leifer [email protected] IND Number: 11726 (Part of 0302 IND) David Madtes [email protected] Last Version Released: 6/2/2010 Elizabeth Murphy [email protected] Additional Member: Email: Robert Soiffer [email protected] Eric White [email protected] Daniel Weisdorf [email protected] Key Highlights: The study was activated August 27, 2007. A protocol amendment was released to centers in January 2008 that adjusted the eligibility criteria to include patients who developed IPS within 120 days after a donor leukocyte infusion, revised definitions of cytomegalovirus disease and infection, and revised study drug blinding logistics. An additional protocol amendment released in January 2009 extended eligibility to patients who develop IPS within 180 days post transplantation or post donor leukocyte infusion. Protocol 88 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Protocol Number: 7.2 Protocols that Completed Accrual BMT CTN 0403 Version 4 was released to centers in October 2009, relaxing the bronchoscopy requirements for participants less than 30 days post transplantation who were considered too medically unstable to undergo the bronchoscopy procedure. Protocol Version 5 was released to centers in June 2010, reducing the sample size from 120 patients (60 per arm) to 60 patients (30 per arm). Accrual continued to lag behind projections, despite the amendments. In April 2011, the DSMB approved the Protocol Team’s accrual plan for two interval assessments of enrollment; accrual of at least four patients from February 16, 2011, through July 1, 2011, (total of 38 patients) and/or nine patients from February 16, 2011, through October 1, 2011, (total of 43 patients). These accrual targets were not met, and the Protocol Team received DSMB approval to close the study on September 14, 2011. Reporting Period Update: The Endpoint Review Committee was formed and reviewed the study data from March to August 2012. After completion of data review, the study results were presented at the 2013 BMT Tandem Meetings. The primary manuscript is being written. Presentation: 1. Randomized, double blind, placebo-controlled trial of a TNF inhibitor (etanercept) for the treatment of idiopathic pneumonia syndrome after allogeneic stem cell transplant. A BMT CTN study. Presented: BMT Tandem Meetings, Salt Lake City, UT, February 2013. An accrual graph is not included due to premature study closure. 89 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual BMT CTN 0501 Protocol Number: BMT CTN 0501 Status: Closed to Accrual Title: Multicenter, open label, randomized trial comparing single versus double umbilical cord blood transplantation in pediatric patients with leukemia and myelodysplasia Rationale: Unrelated donor umbilical cord blood transplantation (UCBT) has increased access to transplant therapy for many patients without a fully matched adult donor. However, approximately 20% of patients undergoing UCBT fail to engraft in a timely manner (before day 42 post transplant). Engraftment and survival are highly dependent on the dose of cord blood cells delivered by the cord blood graft. Further, many cord blood units (CBUs) do not contain sufficient numbers of cells to provide an adequate cell dose, especially for larger patients. To address this problem, investigators at the University of Minnesota initiated pilot studies using two rather than one CBU in adults undergoing UCBT. Preliminary results of these studies were very encouraging, demonstrating increased rates of engraftment in patients transplanted with two CBUs. Interestingly, one CBU dominated during engraftment, although predictions of which CBU would dominate engraftment were not possible based on conventional criteria (e.g., cell dose or HLA matching). While initially developed as a strategy for patients for whom a single CBU of adequate cell number was not available, results raised the question of whether use of two CBUs to increase the dose beyond the minimum might improve UCBT outcomes. This study was conceived to test in a randomized, prospective, Phase III trial whether transplant outcomes were better with transplantation of one or two CBUs. It was designed for pediatric patients with hematologic malignancies because this was the only patient population where safe randomization would be possible, since single CBUs of adequate size are available for most children. Primary Objective: Secondary Objectives: Team Principals: Chairs: Officer: Coordinator: Medical Monitor: Statistician: Contract Rep: Additional Members: Colleen Delaney Nancy Geller Mary Horowitz Naynesh Kamani Eneida Nemecek Michael Pulsipher Andromachi Scaradavou Kirk Schultz Susan Staba To determine the efficacy of using two CBUs versus one; the primary endpoint is one-year survival rate. To compare disease-free survival, incidences of neutrophil and platelet engraftment, chimerism, acute GVHD, chronic GVHD, transplant-related mortality, infections, immune reconstitution, and relapse in patients randomized to the two study arms. Name: Email: Joanne Kurtzberg [email protected] John Wagner [email protected] Mary Eapen [email protected] Jason Thompson [email protected] Dianna Howard [email protected] Shelly Carter [email protected] Nancy Poland [email protected] Email: PRC Approval Date: 01/20/2006 [email protected] DSMB Approval Date: 04/24/2006 [email protected] Opened to Accrual: 10/16/2006 [email protected] Closed to Enrollment: 2/29/2012 [email protected] Target Accrual: 220 [email protected] Total Accrual as of 3/31/13: 224 [email protected] Reporting Period Accrual: N/A [email protected] IND Number: N/A [email protected] Last Version Released: 03/18/2010 [email protected] 90 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Protocol Number: Mike Verneris Donna Wall Key Highlights: 7.2 Protocols that Completed Accrual BMT CTN 0501 [email protected] [email protected] This trial received PRC approval in January 2006 and DSMB approval in April 2006. In September 2006, the protocol was amended to include patient registration procedures for COG. The study was activated October 16, 2006. Ten BMT CTN Core Centers and 38 COG Centers were activated for enrollment. Accrual on this study was completed in February 2012 with 224 patients enrolled. In April 2011, the DSMB approved the Protocol Team’s request to review blinded data on patients that have met the primary endpoint; this review process began in January 2012. The primary study results were presented at ASH, and the results compared to a previous cord blood transplantation (COBLT) study were presented at the BMT Tandem Meetings. The review Reporting Period Update: process will continue in April 2013 to complete review of all patients for the primary endpoint prior to submitting the primary manuscript for publication. 1. No survival advantage after double umbilical cord blood (UCB) compared to single UCB transplant in children with hematological malignancy: Results of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0501) randomized trial. Abstract presented: 54th Annual ASH Meeting, Atlanta, GA, December 2012. 2. Superior survival after single unit umbilical cord blood transplantation (UCBT) in children with hematological malignancies treated on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0501 relative to the cord blood transplantation (COBLT). Abstract presented: BMT Tandem Meetings, Salt Lake City, UT, February 2013. Presentations: Target Accrual = 220 patients 9 BMT CTN #0501 Monthly Actual Accrual Projected Steady State Monthly Accrual Cumulative Accrual Accrual per Month 8 250 200 7 6 150 5 4 100 3 2 50 1 0 0 91 Cumulative Accrual 10 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual BMT CTN 0502 / CALGB 100103 Protocol Number: BMT CTN 0502 / CALGB 100103 Status: Closed to Accrual Title: A Phase II study of allogeneic transplant for older patients with acute myeloid leukemia in first morphologic complete remission using a nonmyeloablative preparative regimen Rationale: The diagnosis of AML in older patients is associated with a very poor prognosis. For patients aged 60 or older receiving therapy for newly-diagnosed AML, the median survival is approximately seven months; the five-year survival rate has been <15% for the past three decades. The poor survival rate in this population is predominantly caused by de novo chemoresistance, which manifests in a substantially lower complete remission rate after induction chemotherapy and early relapse. Older patients with AML also have a significantly higher incidence of adverse prognostic and karyotypic features, which are associated with a worse outcome. Novel approaches are clearly warranted. One novel approach involves the use of blood cells from allogeneic donors. Recent retrospective data from multiple groups suggest that allogeneic HCT may yield durable remissions in older AML patients who, without a transplant, would have likely died of their leukemia. However, the risk of transplant-related complications in this patient group may be substantial; therefore, formal testing of this therapy in a prospective trial is logical and timely. This prospective trial is designed to evaluate the results of allogeneic HCT in patients aged 60 to 74 with AML in first remission. Primary Objective: To determine if allogeneic transplantation from an HLA-matched sibling or unrelated donor using a reduced-intensity preparative regimen results in two-year disease-free survival that is better than that reported in published trials evaluating standard chemotherapy among patients with AML in first complete remission who are older than 60 years of age. Secondary Objectives: To evaluate two-year actuarial risk of transplant-related mortality; acute and chronic GVHD and relapse rates; rate and extent of recovery of T and B cell number and function; time course of T cell, B cell, and myeloid progenitor chimerism following this preparative regimen; and pharmacokinetics of intravenous busulfan when used in a reduced-intensity preparative regimen in patients older than 60. Team Principals: Chairs: Officer: Coordinator: Medical Monitor: Statistician: Contract Rep: Additional Members: Trini Ajazi Morgen Alexander-Young Linda Bressler Shelly Carter Nancy DiFronzo Peggy Edwards Vera Hars Kathy Karas Kouros Owzar Elizabeth Rich Name Steven Devine Sergio Giralt Mary Horowitz Kate Barowski CALGB CALGB Nancy Poland Email [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Email [email protected] [email protected] [email protected] [email protected] [email protected] PRC Approval Date: DSMB Approval Date: Opened to Accrual: Target Accrual: Accrual as of 4/30/13: Reporting Period Accrual: IND Number: Last Version Released: Additional Members: 92 CALGB CALGB 08/29/2006 CALGB 01/29/2007 BMT CTN 136 total 132 Total 42 BMT CTN N/A N/A 12/15/2010 Email Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Protocol Number: BMT CTN 0502 / CALGB 100103 Debbie Sawyer Richard Schilsky [email protected] [email protected] 7.2 Protocols that Completed Accrual Mary Sherrel Roy Wu [email protected] [email protected] This protocol is a collaborative effort between CALGB and BMT CTN. CALGB patient accrual began August 29, 2006; the BMT CTN activated the study January 29, 2007. The study met its original accrual goal December 29, 2008. After DSMB review, the study was re-activated in November 2009 after NCI approved a CALGB amendment to increase the accrual goal to 136 to allow adequate numbers for separate analysis of related and unrelated donor transplantations. Key Highlights: The study closed to enrollment at both CALGB and BMT CTN sites on December 29, 2011, after enrolling 132 patients. Of the 132 patients enrolled directly through the BMT CTN, 41 were accrued by five Core Centers and three Affiliate Centers. An additional 72 of the 132 patients were accrued by six BMT CTN Core Centers that enrolled patients directly through CALGB. Reporting Period Update: Data review is being completed. An abstract for the study was presented at the December 2012 ASH meeting. The primary manuscript is being written. Presentation: 1. A Phase II study of allogeneic transplant for older patients with AML in first morphologic complete remission using a reduced intensity preparative regimen: results from CALGB 100103/BMT CTN 0502. Abstract presented: 54th Annual ASH Meeting, Atlanta, GA, December 2012. Target Accrual: 136 BMT CTN #0502/CALGB 100103 (BMT CTN accrual N = 41) Accrual per Month 6 45 Monthly Actual Accrual Projected Steady State Monthly Accrual Cumulative Accrual 40 35 5 30 4 25 3 20 15 2 Cumulative Accrual 7 10 1 * 0 5 0 * Note: This study completed accrual in December 2008 and reopened in November 2009 after it was amended to increase the accrual goal. 93 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual BMT CTN 0603 Protocol Number: BMT CTN 0603 Status: Closed to Accrual Title: A multicenter, Phase II trial of non-myeloablative conditioning and transplantation of partially HLAmismatched bone marrow for patients with hematologic malignancies Rationale: The purpose of this study was to validate, in a multicenter trial, the safety of a non-myeloablative HCT regimen for hematologic malignancies using partially HLA-mismatched related (haploidentical) donors. Preliminary results from two transplant centers suggest that this regimen, which incorporates high-dose, post-transplantation cyclophosphamide for GVHD prophylaxis, is associated with acceptably low rates of fatal graft rejection, acute and chronic GVHD, and opportunistic infection. The ultimate goal of this trial, and the parallel trial of umbilical cord blood transplantation after non-myeloablative conditioning (BMT CTN 0604), is to extend the availability of allogeneic HCT to patients who lack HLA-matched related or unrelated donors. If safety is established, this haploidentical regimen could be compared with umbilical cord blood and/or HLA-matched unrelated donor transplantation for specific disease entities. Primary Objective: To determine overall survival 180 days after HLA-haploidentical bone marrow transplantation using a non-myeloablative preparative regimen and post-transplantation cyclophosphamide To assess neutrophil and platelet recovery, graft failure, acute GVHD, chronic GVHD, incidence of Secondary Objectives: infection, treatment-related mortality, time to relapse/progression, overall survival time, and progression-free survival time Team Principals: Name: Email: Chair: Ephraim Fuchs [email protected] Officer: Mary Eapen [email protected] Coordinator: [email protected] Jason Thompson Medical Monitor: Shannon Smiley [email protected] Statistician: Shelly Carter [email protected] Contract Rep: Pamela Budnick [email protected] Additional Members: Email: PRC Approval Date: 12/21/2007 Claudio Anasetti [email protected] DSMB Approval Date: 06/06/2008 Karen Ballen [email protected] Opened to Accrual: 10/17/2008 Claudio Brunstein [email protected] Closed to Enrollment: 05/17/2010 Nancy DiFronzo [email protected] Evaluable for Primary Analysis: 12/2010 Mary Horowitz [email protected] Target Accrual: 50 Paul O'Donnell [email protected] Total Accrual as of 3/31/13: 55 John Wagner [email protected] Reporting Period Accrual: N/A IND Number: N/A Last Version Released: 01/28/2009 Key Highlights: A single Protocol Team was formed in December 2006 to develop both BMT CTN 0603 and 0604. Presentation to the DSMB for both protocols was delayed to allow competing protocols to near completion. The protocols were released to centers for IRB approval in summer 2008. Institutions participating in both protocols were required to submit allocation schemes or prioritization plans to avoid bias. These required approval by the Protocol Team before site activation. The BMT CTN 0603 protocol was activated on October 17, 2008. Eight Core Centers and nine Affiliate Centers enrolled a total of 55 patients on the trial. The study reached its targeted accrual goal and was closed to enrollment in May 2010, well ahead of projections. The Endpoint Review Committee formed in summer 2010 and conducted data review for all the primary and secondary endpoints of the study. 94 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual Protocol Number: BMT CTN 0603 Reporting Period Update: A secondary data review with all patients followed for two years is planned for spring 2013. The 0603/0604 Phase III follow-on study, BMT CTN 1101 (haplo-identical vs. double cord blood HCT) was released during this past year and is open for accrual. Publication: 1. Primary manuscript: Alternative donor transplantation: results of parallel Phase II trials using HLAmismatched related bone marrow or unrelated umbilical cord blood grafts. Blood. 2011 Jul 14;118(2):282-288. Epub 2011 Apr 28. Presentation: 1. Phase II trial of nonmyeloablative conditioning and transplantation of partially HLA-mismatched bone marrow for patients with hematologic malignancies: results of BMT CTN Protocol #0603. Abstract presented: BMT Tandem Meetings, Honolulu, HI, February 2011. Received a Best Abstract Award. Target Accrual = 50 patients BMT CTN #0603 60 7 50 Monthly Accrual 6 40 5 4 30 3 20 2 10 1 0 0 95 Cumulative Accrual 8 Monthly Actual Accrual Projected Steady State Monthly Accrual Cumulative Accrual Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual BMT CTN 0604 Protocol Number: BMT CTN 0604 Status: Closed to Accrual Title: A multicenter, Phase II trial of non-myeloablative conditioning and transplantation of umbilical cord blood from unrelated donors in patients with hematologic malignancies Rationale: Preliminary data from single transplant centers suggests that non-myeloablative umbilical cord blood transplantation with two units is a safe and valuable alternative for patients who lack a suitable related donor. The purpose of this study was to determine if the single center data can be reproduced in a multicenter setting. Primary Objective: To determine overall survival 180 days after double cord blood transplantation using a nonmyeloablative preparative regimen To assess neutrophil and platelet recovery, graft failure, acute GVHD, chronic GVHD, incidence of Secondary Objectives: infection, treatment-related mortality, time to relapse/progression, overall survival time, and progression-free survival time Team Principals: Name: Email: Chair: [email protected] Claudio Brunstein Officer: [email protected] Mary Eapen Coordinator: [email protected] Jason Thompson Medical Monitor: [email protected] Dianna Howard Statistician: [email protected] Shelly Carter Contract Rep: [email protected] Pamela Budnick Additional Members: Email: PRC Approval Date: 12/21/2007 Claudio Anasetti [email protected] DSMB Approval Date: 06/06/2008 Karen Ballen [email protected] Opened to Accrual: 12/23/2008 Nancy DiFronzo [email protected] Closed to Enrollment: 03/31/2010 Ephraim Fuchs [email protected] Target Accrual: 50 Mary Horowitz [email protected] Evaluable for Primary Analysis: 11/2010 Paul O'Donnell [email protected] Total Accrual as of3/31/13: 54 John Wagner [email protected] Reporting Period Accrual: N/A IND Number: N/A Last Version Released: 01/28/2009 Key Highlights: A single Protocol Team was formed in December 2006 to develop both BMT CTN 0603 and 0604. Presentation to the DSMB for 0603 and 0604 was delayed for competing protocols to near completion. The protocols were released to centers for IRB approval in summer 2008. Institutions participating in both protocols were required to submit allocation schemes or prioritization plans to avoid bias. These plans required approval by the Protocol Team before site activation. The 0604 protocol was activated on December 23, 2008. Eight Core Centers and eight Affiliate Centers enrolled a total of 54 patients on the trial. The protocol closed to enrollment in March 2010, well ahead of projections. In April 2010, the DSMB approved release of data to the Protocol Team in anticipation of submitting an abstract in October 2010. The Endpoint Review Committee formed in summer 2010 to review data for all of the primary and secondary endpoints of the study. Reporting Period Update: A secondary data review with all patients followed for two years is planned for spring 2013. The 0603/0604 Phase III follow-on study, BMT CTN 1101 (haplo-identical vs. double cord blood HCT) was released during this past year and is open for accrual. 96 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual Protocol Number: BMT CTN 0604 Publication: 1. Primary manuscript: Alternative donor transplantation: results of parallel Phase II trials using HLAmismatched related bone marrow or unrelated umbilical cord blood grafts. Blood. 2011 Jul 14;118(2):282-288. Epub 2011 Apr 28. Presentation: 1. Phase II trial of nonmyeloablative conditioning double umbilical cord blood transplantation from unrelated donors in patients with hematologic malignancies: results of Blood and Marrow Transplant Clinical Trials Network protocol 0604. Abstract presented: BMT Tandem Meetings, Honolulu, HI, February 2011. Target Accrual = 50 patients BMT CTN #0604 Monthly Accrual 7 60 Monthly Actual Accrual Projected Steady State Monthly Accrual Cumulative Accrual 50 6 40 5 4 30 3 20 2 10 1 0 0 97 Cumulative Accrual 8 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual BMT CTN 0701 Protocol Number: BMT CTN 0701 Status: Closed to Accrual Title: Allogeneic HCT using reduced-intensity conditioning for relapsed follicular cell non-Hodgkin lymphoma using related or unrelated donors Rationale: Follicular non-Hodgkin lymphoma is the second most common type of non-Hodgkin lymphoma in the United States. When treatment is indicated, most patients achieve remission with initial chemotherapy, but patients with recurrent advanced follicular lymphoma have a median survival of only four to five years. Numerous treatment options exist, including autologous and allogeneic HCT. Results of several studies using autologous HCT show improved disease-free survival, but relapse remains the predominant cause of treatment failure. High-dose chemo-radiotherapy with allogeneic HCT is sometimes offered with the goal of harnessing a graft-versus-lymphoma effect. Indeed, lower relapse rates are reported when compared with autologous HCT. However, high treatment-related mortality offsets any survival benefit this might confer. Reduced-intensity approaches to allogeneic HCT rely primarily on the immunotherapeutic effects of the allograft to confer anti-lymphoma activity rather than the cytoreductive effects of high-dose chemotherapy. The incorporation of lower doses of chemotherapy has resulted in lower treatmentrelated mortality and has thereby extended eligibility for allogeneic HCT to older patients who are unable to tolerate myeloablative regimens. Whether this approach offers substantial long-term diseasefree survival with good quality of life is uncertain. Primary Objective: To measure two-year progression-free survival after allogeneic HCT with a reduced-intensity pretransplant conditioning regimen of fludarabine, cyclophosphamide and rituximab. Secondary Objectives: To examine two-year overall survival; time to complete response and partial response; time to off-study therapy; incidences and severity of acute and chronic GVHD; treatment-related mortality; and incidences of primary and secondary graft failure; quality of life, as measured by the SF-36 and the FACT-BMT; and the ability to predict disease relapse by measuring t(14;18) using a quantitative polymerase chain reaction. Team Principals: Chair: Officer: Coordinator: Medical Monitor: Statistician: Contract Rep: Additional Members: Nancy DiFronzo Hillard Lazarus William Merritt Auayporn Nademanee Thomas Shea Liz Wagner Name: Ginna Laport Marcie Tomblyn Iris Gersten Gabrielle Meyers Brent Logan Nancy Poland Email: [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Key Highlights: Email: [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] PRC Approval Date: 04/01/2008 DSMB Approval Date: 05/20/2008 Opened to Accrual: 04/27/2009 Closed to Enrollment: 10/22/2012 Target Accrual: 65 Total Accrual as of 3/31/13: 65 Reporting Period Accrual: 14 IND Number: Exempt Last Version Released: 05/12/2011 The study was placed on the CTSU roster in February 2009 and endorsed by SWOG, CALGB, and ECOG. The study was activated on April 27, 2009, after several centers received IRB approval. Twelve Core Centers and 25 Affiliate Centers were activated for enrollment, 13 of which participated through the 98 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Protocol Number: 7.2 Protocols that Completed Accrual BMT CTN 0701 CTSU. Several initiatives were implemented to address slower-than-anticipated enrollment, including periodic study updates to transplant center PIs and Coordinators; template referral and insurance appeal letters to centers; a campaign to encourage all non-enrolling centers to enroll; and advertisements in CTSU, American Society of Blood and Marrow Transplant, Leukemia/Lymphoma Society, and Leukemia Research Foundation newsletters. Protocol Version 5 amendment was approved May 12, 2011. This amendment clarified the inclusion criteria to allow patients with stable follicular lymphoma to enroll if all lymph node masses are ≤ 3 cm and are smaller or unchanged in size to the most recent salvage regimen. Reporting Period Update: The study closed to accrual in October 2012 when 65 patients, as planned, were enrolled. The Endpoint Review Committee will begin reviewing data once the majority of patients have completed two year follow-up. Target Accrual = 65 patients BMT CTN #0701 10 70 Monthly Actual Accrual Projected Steady State Monthly Accrual 60 Cumulative Accrual 50 6 40 30 4 20 2 10 0 0 99 Cumulative Accrual Accrual per Month 8 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual BMT CTN 0703 / SWOG 0410 Protocol Number: BMT CTN 0703 / SWOG 0410 Status: Closed to Accrual Title: Tandem autologous stem cell transplantation for patients with primary progressive or recurrent Hodgkin disease (a BMT study), Phase II Hodgkin lymphoma (HL) comprises approximately 11% of all lymphomas in western countries and accounts for 15% of all cancers in young adults. Fortunately, nearly 80% of Hodgkin lymphoma patients are cured with frontline chemoradiotherapy. For patients with relapsed or refractory, chemosensitive disease, high-dose chemotherapy with autologous HCT is the standard of care and confers cure rates of 40% to 50%. Only about 25% of patients with poor-risk recurrent Hodgkin lymphoma (i.e., patients with symptoms, extranodal involvement, or chemorefractory disease at relapse) are cured. Rationale: The overall outcome of this poor-risk group might be improved if a minimal disease status could be achieved before conventional transplant. The result of a pilot study showed that high-dose melphalan with stem cell support is feasible as a salvage cytoreductive treatment. After achieving a minimal disease state or maximum debulking of the disease, a standard, defined conditioning regimen can be administered as "consolidation," followed by a second stem cell infusion. The tolerability of this very intensive regimen was encouraging; therefore, the pilot study is extending into a Phase II study in the Cooperative Group setting to further evaluate the efficacy of this approach. Primary Objective: To assess the two-year progression-free survival for patients with primary progressive or recurrent Hodgkin lymphoma treated with a tandem transplant program (two cycles of high-dose therapy with autologous stem cell rescue). Secondary Objectives: To evaluate the response rate and toxicity in patients with primary progressive or recurrent Hodgkin lymphoma treated with this regimen. Team Principals: Name: Email: Ginna Laport (BMT CTN) [email protected] Patrick Stiff (SWOG) [email protected] Eileen Smith (SWOG) [email protected] Marcie Tomblyn (BMT CTN) [email protected] Coordinator: Laura Devillier [email protected] Medical Monitor: SWOG Statistician: SWOG Contract Rep: Nancy Poland [email protected] Additional Members: Email: PRC Approval Date: N/A Gilbert Carrizales [email protected] DSMB Approval Date: N/A Jeri Jardine (SWOG) [email protected] Opened to Accrual: 10/15/2005 SWOG; 03/18/2008 BMT CTN Closed to Enrollment: 02/01/2009 Target Accrual: 85 Total Accrual as of 3/31/13: 9 BMT CTN, 89 SWOG Chairs: Officers: 100 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Protocol Number: 7.2 Protocols that Completed Accrual BMT CTN 0703 / SWOG 0410 Reporting Period Accrual: N/A IND Number: N/A Last Version Released: 11/07/2007 SWOG Key Highlights: This protocol was a collaborative effort between SWOG and BMT CTN. Six BMT CTN Core Centers enrolled patients. SWOG closed the study upon accrual completion on February 1, 2009. An analysis is being performed by SWOG, and the BMT CTN provided data as requested. Reporting Period Update: Results are anticipated to be published during the next reporting period. A graph is not displayed with this protocol, BMT CTN 0701 / SWOG 0410, due to limited BMT CTN accrual to the study during its 11 months of participation. 101 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual BMT CTN 0704 / CALGB 100104 / ECOG 100104 Protocol Number: BMT CTN 0704 / CALGB 100104 / ECOG 100104 Status: Closed to Accrual Title: A Phase III, randomized, double-blind study of maintenance therapy with CC-5013 or placebo following autologous stem cell transplantation for multiple myeloma Autologous HCT is a major component of standard, upfront therapy for multiple myeloma, resulting in major tumor reduction and improved response and survival rates. The majority of patients, however, will have disease progression or recurrence within two to three years after autologous HCT. No standard treatment to maintain response after autologous HCT exists. Rationale: Thalidomide has shown promise as a maintenance agent; however, patients may not tolerate prolonged administration of thalidomide and/or other agents, such as glucocorticoids. Lenalidomide (CC-5013), a derivative of thalidomide, may prove useful as a maintenance agent after single autologous HCT to prolong response to induction therapy. This agent does not cause major neurotoxicity, which is a limiting factor for prolonged thalidomide therapy. It is expected that CC-5013 toxicity will be low and lead to improved compliance with maintenance therapy. This Phase III, placebo-controlled study was designed to determine the importance of maintenance therapy for prolonging disease response and survival in these patients. Primary Objective: To compare the efficacy of lenalidomide and placebo as maintenance therapy after autologous HCT in terms of time to disease progression in patients with multiple myeloma. Secondary Objectives: To compare complete response rates, progression-free, and overall survival times and to determine the feasibility of long-term treatment with lenalidomide in these patients. Team Principals: Name: Kenneth Anderson (CALGB) Sergio Giralt (BMT CTN) Philip Greipp (ECOG) Philip McCarthy (CALGB) Marcelo Pasquini CALGB CALGB CALGB Nancy Poland Email: [email protected] [email protected] [email protected] [email protected] [email protected] Email: Opened to Accrual: [email protected] [email protected] [email protected] [email protected] [email protected] CALGB CALGB Closed to Enrollment: Total Accrual as of 3/31/13: Target Accrual: Reporting Period Accrual: Evaluable for Primary Analysis: IND Number: Last Version Released: Chairs: Officer: Coordinator: Medical Monitor: Statistician: Contract Rep: Additional Members: Martha Hering Michael Kelly William Merritt Lena Muwakki David Vesole PRC Approval: DSMB Approval: Key Highlights: [email protected] 12/15/2004 (CALGB) 05/15/2007 (BMT CTN) 07/02/2009 529 (172 BMT CTN) 40 BMT CTN; 533 total N/A 12/2009 N/A 06/15/2008 This CALGB-led, ECOG-endorsed trial opened in December 2004. It was designed to determine the importance of maintenance therapy with lenalidomide for prolonging disease response and survival in patients who have undergone HCT for treatment of multiple myeloma. Its target patient population overlapped with that of BMT CTN 0102, which opened in November 2003. The Multiple Myeloma Intergroup considered a follow-on trial to BMT CTN 0102 at that time, and the accrual difficulties of CALGB 100104 were discussed. Rather than open another competing trial, BMT CTN endorsed the CALGB trial and urged its centers to open the trial through local CALGB and ECOG mechanisms as soon as 0102 reached its enrollment target, which it did in May 2007. To allow BMT CTN centers that were not part of CALGB or ECOG to participate, the DCC worked with NCI to have 102 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Protocol Number: 7.2 Protocols that Completed Accrual BMT CTN 0704 / CALGB 100104 / ECOG 100104 the trial posted to the NCI Cancer Trials Support Unit roster. The BMT CTN Accrual Coordinator and other DCC staff worked with the CALGB Protocol Team to develop an accrual enhancement plan that included identifying and contacting centers with potentially large numbers of eligible patients, using the CIBMTR’s database of transplant activity. Webinars were also conducted to increase awareness of the trial. Network centers began accruing patients to this trial in summer 2007, and all of these strategies resulted in significant improvement (at least a doubling) in accrual. In December 2009, the CALGB Data and Safety Monitoring Board decided to release the trial results early, due to the significantly longer time to disease progression in patients who received lenalidomide maintenance than those receiving placebo. Timely completion of this trial answered an important question in post-transplant treatment in multiple myeloma, and led well into the Stem Cell Transplantation for Multiple Myeloma Incorporating Novel Agents (STaMINA) trial (BMT CTN 0702), which incorporates maintenance therapy in all treatment arms. This effort is a good example of how the BMT CTN has played a leadership role in developing and completing transplant trials by fostering collaboration on a national level. Reporting Period Update: The primary manuscript was published in the New England Journal of Medicine and was highlighted as a contributor to one of ASCO’s 17 Major Advances in Clinical Cancer Research in 2012. A secondary analysis of longer-term follow-up was conducted, and the abstract will be presented at the International Myeloma Workshop in April 2013. A subsequent publication is anticipated during the next reporting period. Publication: 1. Phase III study of lenalidomide versus placebo after HCT for multiple myeloma. New England Journal of Medicine. 2012 May 10;366(19):1770-81. Presentations: 1. Maximizing accrual to transplant trials in multiple myeloma, lessons from the BMT CTN, ECOG and CALGB. Presented: NCI ASCO Cancer Trials Accrual Symposium, Bethesda, MD, April 2020. 2. Phase III intergroup study of Lenalidomide versus placebo maintenance therapy following single autologous stem cell transplant for multiple myeloma: CALGB 100104. Presented: ASCO Annual Meeting, Chicago, IL, June 2010. 3. Phase III intergroup study of Lenalidomide versus placebo maintenance therapy following single autologous stem cell transplant for multiple myeloma: CALGB 100104. Presented: ASH Annual Meeting, Orlando, FL, December 2010. 4. Phase III intergroup study of Lenalidomide versus placebo maintenance therapy following single autologous stem cell transplant for multiple myeloma: CALGB ECOG BMT-CTN 100104. Presented: International Myeloma Workshop, Paris, France, May 2011. Target Accrual: 40 BMT CTN patients (actual 172); 533 total patients BMT CTN #0704 / CALGB 100104 30 Monthly Actual Accrual Cumulative Accrual 500 400 20 300 15 10 200 5 100 0 0 BMT CTN opened this study to accrual on May 15, 2007. 103 Cumulative Accrual Monthly Accrual 25 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual BMT CTN 0802 Protocol Number: BMT CTN 0802 Status: Closed to Accrual Title: A multicenter randomized, double blind, Phase III trial evaluating corticosteroids with mycophenolate mofetil versus corticosteroids with placebo as initial systemic treatment of acute graft-versus-host disease Rationale: Acute GVHD is one of the most common complications of allogeneic HCT, yet its therapy (the use of high doses of corticosteroids) has changed very little in the past 30 years. BMT CTN 0302 identified mycophenolate mofetil as a promising agent to test in combination with corticosteroids for acute GVHD treatment. This study is a Phase III, randomized, double-blind, placebo-controlled trial evaluating the addition of mycophenolate mofetil versus placebo to systemic corticosteroids as initial therapy for acute GVHD. Primary Objective: To estimate GVHD-free survival (acute or chronic) at day 56 after randomization without additional therapy. Secondary Objectives: To evaluate proportions of complete, partial, mixed response, no response and progression among surviving patients at day 14, 28 and 56; treatment failure (defined as no response, progression, administration of additional therapy for GVHD, or mortality) at day 14, 28, and 56; incidence of acute GVHD flare prior to day 90; and incidence of discontinuation of immune suppression without acute GVHD flare and without disease progression/ recurrence by days 56, 180, and 360 post therapy. Additional secondary endpoints include steroid dose at day 28 and 56 post randomization, incidence of topical/non-absorbable therapy given by day 56, incidence of chronic GVHD by 6 and 12 months post randomization, overall and GVHD-free survival at 6 and 12 months post randomization, incidences of systemic infections within 6 months of initiation of therapy, incidence of Epstein-Barr virus-associated lymphoproliferative disorder or reactivation requiring therapy, malignancy-free survival at 6 and 12 months post randomization, non-relapse mortality at 6 and 12 months, and change in patient-reported outcomes from enrollment to day 56. Team Principals: Chairs: Officer: Coordinator: Medical Monitor: Statistician: Contract Rep: Additional Members: Amin Alousi Joseph Antin Shelly Carter Nancy DiFronzo James Ferrara Eric Leifer John Levine Margaret MacMillan Paul Martin Marco Mielcarek Georgia Vogelsand Name Javier Bolaños-Meade Vincent Ho Mary Horowitz (temporary) Kate Barowski Dianna Howard Brent Logan Nancy Poland Email [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Email [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] PRC Approval Date: DSMB Approval Date: Opened to Accrual: Closed to Enrollment: Target Accrual: Total Accrual as of 3/31/13: Reporting Period Accrual: IND Number: Last Version Released: Additional Members: Liz Wagner Daniel Weisdorf 104 05/18/2009 06/30/2009 02/01/2010 11/14/2011 372 236 N/A N/A 01/31/2011 Email [email protected] [email protected] Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual Protocol Number: BMT CTN 0802 Key Highlights: BMT CTN 0802 is a follow-on study to the randomized Phase II 0302 study, which completed accrual and follow up in May 2008. The protocol was approved by the PRC in May 2009 and by the DSMB in June 2009. The study experienced a delay in its progress from DSMB approval to activation due to negotiations for drug acquisition. It was activated on February 1, 2010. The study was closed to enrollment on November 14, 2011 due to crossing a futility boundary. A total of 236 patients were enrolled from 36 centers. The endpoint review for this study began in March 2012. An absbtract was submitted and accepted Reporting Period Update: for oral presentation at the February 2013 BMT Tandem meetings. The primary manuscript will be written and submitted during the next reporting period. 1. A multi-center, randomized, double blind, Phase III clinical trial comparing steroids/placebo vs. steroids/mycophenolate mofetil as initial therapy for acute graft-versus-host disease. Blood and Marrow Transplant Clinical Trials Network Study 0802. Presented: BMT Tandem Meetings, Salt Lake City, UT, February 2013. Presentation: Target Accrual: 372 patients BMT CTN #0802 Accrual per Month 20 250 Monthly Actual Accrual Projected Steady State Monthly Accrual Cumulative Accrual 200 15 150 10 100 5 50 0 0 105 Cumulative Accrual 25 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual BMT CTN 0902 Protocol Number: BMT CTN 0902 Status: Closed to Accrual Title: A Phase III randomized, multicenter trial testing whether exercise or stress management improves functional status and symptoms of autologous and allogeneic HCT recipients Rationale: HCT patients experience numerous aversive symptoms (e.g., nausea, fatigue and sleep disturbance) accompanied by declines in physical and mental well-being. Although most longitudinal studies show return to baseline functioning for the majority of patients, it may take 6 to 12 months or longer to reach this goal. Clinical trials have shown that training in stress management techniques and participation in formal exercise programs each offered in isolation are effective in improving quality of life in patients receiving standard-dose chemotherapy and HCT. Review of these studies suggests that stress management interventions primarily improve mental health outcomes and nausea. The impact of exercise training interventions is more variable; most studies report physical health benefits, with some studies also reporting mental health benefits. Small studies suggest that combining stress management training and exercise are feasible and well tolerated, but whether the combination provides an additive or synergistic impact on quality-of-life outcomes has not been directly investigated. The purpose of this study is to test whether exercise or stress management training delivered to autologous and allogeneic HCT patients prior to transplantation can improve functional status and the transplantation experience. Primary Objective: To determine whether exercise or stress management improves self-reported physical and mental functioning compared to standard care at 100 days post transplant, using an intent-to-treat analysis Secondary Objectives: Team Principals: Chairs: Officer: Coordinator: Medical Monitor: Statistician: Contract Rep: Additional Members: Smita Bhatia Shelly Carter Nancy Geller Heather Jim Jennifer Le-Rademacher Navneet Majhail Douglas Rizzo To evaluate whether exercise or stress management improves physical and mental functioning compared to standard care at 100 days, limiting the analysis to patients who survive and provide a day 100 self-assessment (conditional analysis with main effects); physical and mental functioning among the four groups, limiting the analysis population to patients who provide a day 100 selfassessment; symptoms (fatigue, pain, sleep, nausea, cancer and treatment distress) at 100 days among patients who provide a day 100 self-assessment; the number of hospital days within the first 100 days; durability of effects by comparing functional status and symptoms at 6 months; and overall survival at 6 months. Name: Email: Paul Jacobsen [email protected] Stephanie Lee [email protected] Mary Horowitz [email protected] Laura Devillier [email protected] Gabrielle Meyers [email protected] Brent Logan [email protected] Pamela Budnick [email protected] Email: PRC Approval Date: 12/23/2009 [email protected] DSMB Approval Date: 03/18/2010 [email protected] Opened to Accrual: 01/03/2011 [email protected] Closed to Enrollment: 06/01/2012 [email protected] Target Accrual: 700 [email protected] Total Accrual as of 03/31/13: 711 [email protected] Reporting Period Accrual: 156 [email protected] IND Number: N/A 106 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.2 Protocols that Completed Accrual Protocol Number: Galen Switzer Karen Syrjala John Wingard BMT CTN 0902 [email protected] [email protected] [email protected] Key Highlights: This is the Network’s first trial examining quality of life as its primary endpoint. This trial was identified as one of 11 high-priority trials during the 2007 State of the Science Symposium. The protocol was approved by the PRC on December 23, 2009, and by the DSMB on March 18, 2010. The trial experienced a delay from DSMB approval to trial activation due to the time required to develop the patient materials for the study, including exercise and stress management videos and brochures. Patient materials were finalized in September 2010 and released to centers for IRB approval. The trial opened for enrollment on January 3, 2011, when the first center received IRB approval. Protocol Version 2 was released to centers on March 30, 2011; the amendment specified three new exclusion criteria. Last Version Released: Additional Member: William Wood 03/30/2011 Email: [email protected] Accrual was completed this year. Twenty-one centers enrolled a total of 711 patients on the trial, Reporting Period Update: resulting in completion of accrual 17 months earlier than projected. Endpoint review is underway with publication of results anticipated in the next reporting period. Target Accrual: 700 patients BMT CTN #0902 800 Monthly Actual Accrual Projected Steady State Monthly Accrual Cumulative Accrual Accrual per Month 600 500 400 300 200 100 0 107 Cumulative Accrual 700 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 This page intentionally left blank. 108 7.2 Protocols that Completed Accrual Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.3 Protocols Released to Centers 7.3 Protocols Released to Centers BMT CTN Protocols Released to Centers (as of March 31, 2013) BMT CTN Protocol # 1202 Protocol Title A prospective multicenter trial establishing a cohort of biologic samples collected prospectively as a shared biospecimen resource for future allogeneic HCT correlative studies evaluating biomarkers 109 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.3 Protocols Released to Centers BMT CTN 1202 Protocol Number: BMT CTN 1202 Status: Released to Centers Title: Prospective Multi-Center Cohort for the Evaluation of Biomarkers Predicting Risk of Complications and Mortality Following Allogeneic HCT Rationale: While HCT offers the only cure for many patients with malignant and non-malignant hematologic diseases, this treatment is associated with significant risks, leading to high rates of morbidity and mortality. There is a critical need for more effective prevention and treatment strategies for HCTassociated complications. The most serious of the latter include GVHD, cancer recurrence, organ toxicity and opportunistic infection. Although some clinical variables (e.g., recipient age, donorrecipient HLA mismatch) predict higher risk of some events (e.g., GVHD, infection), no diagnostic tests exist that reliably predict occurrence, severity or response to therapy of any of these complications. Recent compelling results from single center studies suggest that biomarkers can be identified that stratify patients into discrete risk groups for some outcomes and for overall mortality. However, these relatively small studies generally lack the statistical power or validation necessary to allow their results to be incorporated into practice. One key factor in the success of biomarker studies is the quality of clinical outcomes data that is linked to the specimens being analyzed. An adequate resource for these studies requires longitudinal sample collection integrated with longitudinal collection of comprehensive, standardized, high quality clinical data regarding complications, from onset to resolution, and regarding other clinical variables affecting risk of post-HCT outcomes. The goal of this protocol is to establish a cohort of biologic samples collected prospectively from patients treated in BMT CTN centers that will be a shared biospecimen resource for conducting future allogeneic HCT correlative studies. This resource is designed to allow genomic, proteomic and transcriptional data to be integrated with high quality clinical phenotype and outcomes data to identify risk factors for development and severity of acute GVHD, chronic GVHD, organ toxicity, relapse, mortality, infection and other clinically significant complications occurring after allogeneic HCT. Primary Objective: The goal of this protocol is to establish a cohort of biologic samples collected prospectively from patients treated in BMT CTN centers that will be a shared biospecimen resource for conducting future allogeneic HCT correlative studies. Secondary Objectives: Team Principals: Chairs: Officer: Coordinator: Medical Monitor: Statistician: Contract Rep: Additional Members: Asad Bashey Shelly Carter Dennis Confer James Ferrara Theresa Hahn Vincent Ho N/A Name: John Levine John Hansen Wael Saber Jason Thompson TBD Jennifer Le-Rademacher Renee Carby Email: [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Email: [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] PRC Approval Date: DSMB Approval Date: Opened to Accrual: Closed to Enrollment: Target Accrual: Total Accrual as of 3/31/13: Reporting Period Accrual: 110 11/19/2012 12/17/12 TBD N/A 1500 N/A N/A Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 7.3 Protocols Released to Centers Protocol Number: BMT CTN 1202 Mary Horowitz Alan Howard Leslie Kean Eric Leifer Phillip McCarthy Bill Merritt Miguel-Angel Perales [email protected] [email protected] [email protected] [email protected] Key Highlights: The BMT CTN 1202 Protocol Team was formed in March 2012. Reporting Period Update: In November 2012, the protocol received PRC approval, followed by DSMB approval in December 2012. It was released to centers for IRB submission in January 2013 and is anticipated to open to accrual in spring 2013. Several members of the protocol team also played a significant role in the development of a DCC-lead R24 application for funding opportunity to extend the research scope of the BMT CTN 1202 study, furthering the potential impact of this national resource. A final NHLBI determination of funding is expected within the next two to three months. IND Number: Current Version Released: Additional Members: Stefanie Sarantopoulos [email protected] Steve Spellman [email protected] Elizabeth Wagner [email protected] 111 N/A 1/4/2013 Email: [email protected] [email protected] [email protected] Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 This page intentionally left blank. 112 7.3 Protocols Released to Centers Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment A: Data and Coordinating Center Organizational Structure Attachment A: Data and Coordinating Center Organizational Structure The EMMES Corporation Shelly Carter, ScD DCC Co-Principal Investigator Peter Dawson, PhD Adam Mendizabal, MS Yanli Wang, MS Maggie Wu, MS Statisticians Erica Anderson, MA Kate Barowski Laura Devillier Moira Lewis, MPH Courtney Nelson Alyssa Ramirez Jason Thompson, MS Connie Weaver Protocol Coordinators Linda Johnson Sandi Sykes Admin Coordinators Michelle LaMotteo Rus Maxwell Programmer / Analysts Iris Gersten, MS Project Director Kristin Knust, MS Mary Magliocco Ravi Sinani Sunny Verma Data Systems Coordinators Alan Ramnath Regulatory Coordinator Jeanette Carreras, MPH Brent Logan, PhD Jennifer Le-Rademacher, PhD Waleska Perez, MPH Biostatisticians Angela Soriano Steve Wease, MPH Integrity Coordinators Cara Brown, RN, MN Cynthia Couture, RN Protocol Monitors NMDP / CIBMTR Minneapolis Dennis Confer, MD ^ DCC Co-Principal Investigator Sue Lorenz Business Manager Rebecca Drexler Senior Manager, Prospective Research Stephen Spellman, MBS Director, Immunobiology & Observational Research Cheryl Reiter Administrative Asst Leslie Bellamy Administrative Asst Alan Howard, PhD Principal Immunobiology Research Specialist Kavita Bhavsar BMT CTN Data Coordinator Amy Foley, MA BMT CTN Project Manager Mita Desai Data Entry Coordinator NMDP Support Services TBD AE Coordinator KEY ^ * CIBMTR Milwaukee Mary Horowitz, MD, MS ^ DCC Principal Investigator ^ * Mary Eapen, MD ^ * Marcelo Pasquini, MD ^ * Wael Saber, MD ^ * Willis Navarro, MD * Christopher Bredeson, MD * Dianna Howard, MD * Tammy Kindwall-Keller, MD * Gabrielle Meyers, MD * Eneida Nemecek, MD * Bipin Savani, MD * Shannon Smiley, MD * Angie Smith, MD ^ * Marcie Tomblyn, MD EMMES Corporation, Rockville, MD CIBMTR, Milwaukee, WI CIBMTR/NMDP, Minneapolis, MN Various Locations Protocol Officer Medical Monitor Brian Lindberg, JD Senior VP & General Counsel Bruce Schmaltz Director, Finance / Controller Elizabeth Murphy, EdD, RN VP, Patient Services Nancy Poland, MA Sr Mgr, Contracts & Procurement Gina Graves Sr Manager / Asst Controller Ellen Denzen, MS Sr Manager, Health Services Research Pam Budnick Renee Carby, MS Kiila Lee Scott Westre Contract Representatives Kevin Weber Gov’t Cost Analyst, Clinical Trials Heather Moore, MPH, CHES Program Specialist Anh Vorarath Supervisor, Gov’t Accounting Lensa Idossa Program Analyst Susanne Lahti Paralegal Tom Switzer Senior Buyer 113 Stephanie Waldvogel Immunobiology Research Specialist Paula Washington Bookkeeper, Gov’t Accounting Peggy Schmidt Cost Accountant, Gov’t Accounting Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment B: Core and Affiliate Centers Attachment B: Core and Affiliation Centers Attachment B1: Core Centers Baylor College of Medicine Methodist Hospital, Houston, TX Principal Investigator: Catherine Bollard, MD Case Western Reserve University (Consortium) Ireland Cancer Center, Cleveland, OH Principal Investigator: Hillard Lazarus, MD Consortium Centers: Oregon Health Sciences University, Portland, OR. Principal Investigator: Richard Maziarz, MD Cleveland Clinic. Principal Investigator: Matthew Kalaycio, MD City of Hope National Medical Center Duarte, CA Principal Investigator: Stephen Forman, MD Dana-Farber/Partners Cancer Care (Consortium) Boston, MA Principal Investigator: Joseph Antin, MD Consortium Centers: Brigham & Women’s Hospital, Massachusetts General Hospital and Boston Children’s Hospital, Boston, MA. Principal Investigator: Joseph Antin, MD Duke University Medical Center Durham, NC Principal Investigator: Joanne Kurtzberg, MD Fred Hutchinson Cancer Research Center Seattle, WA Principal Investigator: Frederick Appelbaum, MD H. Lee Moffitt Cancer Center Tampa, FL Principal Investigator: Claudio Anasetti, MD Johns Hopkins University Oncology Center Baltimore, MD Principal Investigator: Richard Jones, MD 114 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment B: Core and Affiliate Centers Memorial Sloan-Kettering Cancer Center New York, NY Principal Investigator: Sergio Giralt, MD (Steering Committee Immediate Past Chair) Northside Hospital Atlanta Atlanta, GA Principal Investigator: Asad Bashey, MD Ohio State University Comprehensive Cancer Center (Consortium) Columbus, OH Principal Investigator: Steven Devine, MD Consortium Centers: Roswell Park Cancer Institute, Buffalo, NY. Principal Investigators: Philip McCarthy, MD and Theresa Hahn, PhD University of North Carolina, Chapel Hill, NC. Principal Investigator: Thomas Shea, MD University of California, San Francisco. Principal Investigator: Lloyd Damon, MD Medical College of Virginia Hospital / Virginia Commonwealth University Medical Center, Richmond, VA. Principal Investigator: John McCarty, MD Pediatric Blood and Marrow Transplant Consortium Primary Children’s Medical Center/University of Utah, Salt Lake City, UT Principal Investigator: Michael Pulsipher, MD Stanford Hospital and Clinics Stanford, CA Principal Investigator: Ginna Laport, MD (Steering Committee Chair) University of Florida College of Medicine (Consortium) Gainesville, FL Principal Investigator: John Wingard, MD Consortium Center: Emory University, Atlanta, GA. Principal Investigator: Edmund Waller, MD, PhD University of Michigan Medical Center Ann Arbor, MI Principal Investigator: James Ferrara, MD 115 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment B: Core and Affiliate Centers University of Minnesota Minneapolis, MN Principal Investigator: Daniel Weisdorf, MD University of Nebraska Medical Center (Consortium) Omaha, NE Principal Investigator: Julie Vose, MD Consortium Center: University of Kansas Medical Center, Kansas City, KS. Principal Investigator: Joseph McGuirk, DO University of Pennsylvania Hospital Philadelphia, PA Principal Investigator: Edward Stadtmauer, MD University of Texas MD Anderson Cancer Center Houston, TX Principal Investigator: Richard Champlin, MD Washington University St. Louis, MO Principal Investigator: Peter Westervelt, MD 116 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment B: Core and Affiliate Centers Attachment B2: Affiliate Centers Advocate Lutheran General Hospital, Park Ridge, IL All Children's Hospital, St Petersburg, FL Arizona Cancer Center/University of Arizona, Tucson, AZ Avera Hematology & Transplant Center, Sioux Falls, SD Banner Research Institute, Sun City, AZ Baylor University Medical Center, Waco, TX Beth Israel Deaconess Medical Center, Boston, MA British Columbia Children's Hospital, Vancouver, Canada Cancer Centers of the Carolinas, Greenville, SC Cancer Institute of New Jersey/Robert Wood Johnson University, New Brunswick, NJ CancerCare Manitoba BMT Program, Canada Cedars-Sinai Medical Center, West Hollywood, CA Centre Hopital Affilie Enfant-Jesus, Quebec, Canada Children's Healthcare of Atlanta, Atlanta, GA Children’s Hospital at Oakland, Oakland, CA Children's Hospital at Westmead, Australia Children's Hospital Los Angeles, Los Angeles, CA Children's Hospital of Denver, Denver, CO Children's Hospital of New Orleans, New Orleans, LA Children's Hospital of Philadelphia, Philadelphia, PA Children's Medical Center of Dallas, Dallas, TX Children's Mercy Hospital and Clinics, Kansas City, MO Children’s National Medical Center, Washington, DC Christiana Care Health System, Wilmington, DE Colorado Blood Cancer Institute, Denver, CO Columbia River Oncology Program, Portland, OR Cook Children's Medical Center, Fort Worth, TX DeKalb Medical Center, Lithonia, GA Florida Hospital Cancer Institute, Orlando, FL Fox Chase - Temple University BMT Program, Philadelphia, PA Geisinger Medical Center, Danville, PA Georgia Health Sciences University, Augusta, GA Hackensack University Medical Center (Adult and Pediatric), Hackensack, NJ Hamilton Health Sciences, Ontario, Canada Henry Ford Health System, Detroit, MI Hopital Maisonneuve Rosemont, Montreal, Canada Hopital Sainte-Justine, Montreal, Canada 117 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment B: Core and Affiliate Centers Hopital Saint-Louis, France Indiana BMT Clinics, Beech Grove, IN Indiana University Medical Center/Riley Hospital, Indianapolis, IN Intermountain BMT Program, Salt Lake City, UT Jewish Hospital BMT Program, Cincinnati, OH Kansas City Cancer Centers, Kansas City, MO Kapi'olani Medical Center for Women and Children – University of Hawaii, Honolulu, HI Karmanos Cancer Institute/Children's Hospital of Michigan, Detroit, MI Lahey Clinic, Burlington, MA Louisiana State University Health Sciences Center, Baton Rouge, LA Loyola University Medical Center, Chicago, IL Mayo Clinic, Phoenix, AZ Medical College of Wisconsin (Adult and Pediatric), Milwaukee, WI Medical University of South Carolina (Adult and Pediatric), Charleston, SC Montefiore Medical Center, New York, NY Mount Sinai Medical Center, New York, NY National Cancer Institute – NIH, Bethesda, MD Nationwide Children's Hospital, Columbus, OH Nemours Children’s Clinic, Jacksonville, FL New York Medical College, Valhalla, NY North Shore University Hospital, Manhasset, NY Ottawa Hospital, Canada Penn State College of Medicine - The Milton S. Hershey Medical Center, Hershey, PA Phoenix Children's Hospital, Phoenix, AZ Providence Portland Medical Center, Portland, OR Queen Elizabeth II Health Sciences Centre – Halifax, Canada Rush University Medical Center, Chicago, IL Sarah Cannon BMT Program, Nashville, TN St. Louis University, St. Louis, MO St. Lukes Mountain States Tumor Institute, Boise, ID SUNY Upstate Medical University, Syracuse, NY Sydney Children's Hospital, Australia Texas Transplant Institute (Adult and Pediatric), San Antonio, TX Thompson Cancer Survival Center, Knoxville, TN Tom Baker Cancer Centre-Calgary, Canada Tufts Medical Center, Boston, MA University of California Los Angeles-Center for Clinical AIDS Research and Education, Los Angeles, CA University of California San Diego Medical Center, San Diego, CA University of Alabama at Birmingham, Birmingham, AL 118 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment B: Core and Affiliate Centers University of California Davis Medical Center, Sacramento, CA University of Chicago, Chicago, IL University of Illinois at Urbana-Champaign, Champaign, IL University of Iowa Hospitals and Clinics, Iowa City, IA University of Kentucky, Lexington, KY University of Louisville/Kosair Children's Hospital, Louisville, KY University of Maryland Medical Systems - Greenebaum Cancer Center, Baltimore, MD University of Massachusetts/Memorial Medical Center, Worcester, MA University of Miami, Miami, FL University of Mississippi Medical Center, Jackson, MI University of Oklahoma Medical Center, Norman, OK University of Pittsburgh Cancer Institute, Pittsburgh, PA University of Rochester Medical Center (Adults and Pediatric), Rochester, NY University of Texas Southwestern Medical Center, Dallas, TX University of Toronto - Princess Margaret Hospital, Canada University of Wisconsin Hospital & Clinics, Madison, WI Utah BMT/University of Utah Medical School, Salt Lake City, UT Tennessee Valley Healthcare, Nashville, TN Vancouver General Hospital, Canada Vanderbilt University Medical Center (Adult and Pediatric), Nashville, TN Wake Forest University Health Sciences, Winston-Salem, NC Washington University / St. Louis Children’s Hospital, St. Louis, MO Weill Cornell Medical College/New York Presbyterian Hospital, New York, NY West Virginia University Hospital, Morgantown, WV Wichita Community Clinical Oncology Program, Wichita, KS Yale University School of Medicine/Yale-New Haven Hospital, New Haven, CT 119 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment C: Publications, Abstracts, and Presentations Attachment C: Publications, Abstracts, and Presentations Attachment C1: Publications Number Protocol Number Publication PMCID 2004 1 Wingard JR. Design issues in a prospective randomized doubleblinded trial of prophylaxis with fluconazole versus voriconazole after allogeneic hematopoietic cell transplantation. Clinical Infectious Disease. 2004 Oct 15;39 Suppl 4:S176-180. BMT CTN 0101 N/A (pre-dates PMCID requirements) BMT CTN 0302 N/A (pre-dates PMCID requirements) N/A (pre-dates PMCID requirements) 2005 2 3 Logan BR. Optimal two-stage randomized Phase II clinical trials. Clinical Trials. 2005 Jan 01;2(1):5-12. Ho VT, Cutler C, Carter S, Martin P, Adams R, Horowitz M, Ferrara J, Soiffer R and Giralt S. BMT CTN Toxicity Committee consensus summary, thrombotic microangiopathy after hematopoietic stem cell transplantation. Biology of Blood and Marrow Transplantation. 2005 Aug 01;11(8):571-575. N/A Network publication 2007 4 5 Weisdorf D, Carter S, Confer D, Ferrara J and Horowitz M. BMT CTN: Addressing unanswered questions. Biology of Blood and Marrow Transplantation. 2007 Mar 01;13(3):257-62; discussion 255-256. N/A Network publication Ferrara J, Anasetti C, Stadtmauer E, Antin J, Wingard J, Lee SJ, Levine J, Schultz K, Appelbaum F, Negrin R, Giralt S, Bredeson C, Heslop H and Horowitz M. BMT CTN State of the Science Symposium 2007. Biology of Blood and Marrow Transplantation. 2007 Nov 01;13:12681285. N/A Network publication N/A (pre-dates PMCID requirements) N/A (pre-dates PMCID requirements) 2008 6 Logan B, Leifer E, Bredeson C, Horowitz M, Ewell M, Carter S and Geller N. Use of biological assignment in hematopoietic stem cell transplantation clinical trials. Clinical Trials. 2008 Jan 01;5(6):607616. 120 BMT CTN 0102 PMC2671015 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment C: Publications, Abstracts, and Presentations Number Publication 7 Cutler C, Stevenson K, Kim HT, Richardson P, Ho VT, Linden E, Revta C, Ebert R, Warren D, Choi S, Koreth J, Armand P, Alyea E, Carter S, Horowitz M, Antin JH, Soiffer R. Sirolimus is associated with venoocclusive disease of the liver after myeloablative allogeneic stem cell transplantation. Blood. 2008 Dec 01;112(12):4425-4431. Epub 2008 Sep 5. Protocol Number BMT CTN 0402 PMCID PMC2597119 2009 BMT CTN 0302 PRIMARY MANUSCRIPT PMC2713466 BMT CTN 0102 N/A Author reply BMT CTN 0302 PMC3104501 10 Jacobson PA, Huang J, Wu J, Kim M, Logan B, Alousi A, Grimley M, Bolaños-Meade J, Ho V, Levine JE, Weisdorf D. Mycophenolate pharmacokinetics and association with response to acute GVHD treatment from the BMT CTN. Biology of Blood and Marrow Transplantation. 2010 Mar 01;16(3):421-429. BMT CTN 0302 PMC2955996 11 Levine JE, Logan B, Wu J, Alousi AM, Ho V, Bolaños-Meade J, Weisdorf D, On behalf of the BMT CTN. Graft-versus-host disease treatment: predictors of survival. Biology of Blood and Marrow Transplantation. 2010 Dec 01;16(12):1693-1699. Epub 2010 Jun 9. BMT CTN 0101 PRIMARY MANUSCRIPT PMC3012532 12 Wingard JR, Carter SL, Walsh TJ, Kurtzberg J, Small TN, Baden LR, Gersten ID, Mendizabal AM, Leather HL, Confer DL, Maziarz RT, Stadtmauer EA, Bolaños-Meade J, Brown J, Dipersio JF, Boeckh M, Marr KA; BMT CTN. Randomized double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood. 2010 Dec 09;116(24):5111-8. Epub 2010 Sep 8. 8 9 Alousi A, Weisdorf D, Logan B, Bolaños-Meade J, Carter S, DiFronzo N, Pasquini M, Goldstein S, Ho V, Hayes-Lattin B, Wingard J, Horowitz M and Levine J. Etanercept, mycophenolate, denileukin or pentostatin plus corticosteroids for acute GVHD: A randomized Phase II trial from the BMT CTN. Blood. 2009 Jul 16;114(3):511-517. Epub 2009 May 14. Giralt S, Vesole DH, Somlo G, Krishnan A, Stadtmauer E, McCarthy P, Pasquini MC, BMT CTN Multiple Myeloma Working Group. Re: Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: A systematic review and meta-analysis. Journal of the National Cancer Institute. 2009 Jul 01;101(13):964; author reply 966-967. Epub 2009 Jun 17. [Comment on: Journal of the National Cancer Institute 101(2):100-106, 2009]. 2010 121 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment C: Publications, Abstracts, and Presentations Protocol Number BMT CTN 0301 PMC3053041 BMT CTN 0202 PRIMARY MANUSCRIPT PMC3114272 [Available on 2012/7/1] 14 Tomblyn MR, Ewell M, Bredeson C, Kahl BS, Goodman SA, Horowitz MM, Vose JM, Negrin RS and Laport GG. Autologous versus reduced intensity allogeneic hematopoietic cell transplantation for patients with chemosensitive follicular non-Hodgkin lymphoma beyond first complete response or first partial response. Biology of Blood and Marrow Transplantation. 2011 Jul 01;17(7):1051-1057. Epub 2010 Nov 10. N/A Network publication PMC Journal – In Process 15 Horwitz EM, Horowitz MM, DiFronzo NL, Kohn DB, Heslop HE, BMT CTN State of the Science Cell and Gene Therapy Committee. Guidance for developing Phase II cell therapy trial proposals for consideration by the BMT CTN. Biology of Blood and Marrow Transplantation. 2011 Feb 01;17(2):192-196. Epub 2010 Dec 21. BMT CTN 0303 PRIMARY MANUSCRIPT PMC3150599 [Available on 2012/9/1] N/A Network publication PMC3048197 BMT CTN 0603 / BMT CTN 0604 PRIMARY MANUSCRIPT PMC3138683 [Available on 2012/7/14] Number Publication 13 Pulsipher MA, Young NS, Tolar J, Risitano AM, Deeg HJ, Anderlini P, Calado R, Kojima S, Eapen M, Harris R, Scheinberg P, Savage S, Maciejewski JP, Tiu RV, DiFronzo N, Horowitz MM, Antin JH. Optimization of therapy for severe aplastic anemia based on clinical, biological and treatment response parameters: conclusions of an international working group on severe aplastic anemia convened by the BMT CTN, March 2010. Biology of Blood and Marrow Transplantation. 2011 Mar 01;17(3):291-299. Epub 2010 Oct 27. PMCID 2011 16 17 18 Devine SM, Carter S, Soiffer RJ, Pasquini MC, Hari PN, Stein A, Lazarus HM, Linker C, Stadtmauer EA, Alyea EP 3rd, Keever-Taylor CA, O'Reilly RJ. Low risk of chronic graft-versus-host disease and relapse associated with T cell depleted peripheral blood stem cell transplantation for acute myeloid leukemia in first remission: results of the BMT CTN protocol 0303. Biology of Blood and Marrow Transplantation. 2011 Sep 01;17(9):1343-51. Epub 2011 Feb 12. Kohn DB, Dotti G, Brentjens R, Savoldo B, Jensen M, Cooper LJ, June C, Rosenberg S, Sadelain M and Heslop HE. CARs on track in the clinic: workshop of the BMT CTN sub-committee on cell and gene therapy. Molecular Therapy. 2011 Mar 01; 19(3): 432-438. Epub 2011 Mar 1. Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J, Devine SM, Wingard JR, Aljitawi OS, Cutler CS, Jagasia MH, Ballen KK, Eapen M, O'Donnell PV. Alternative donor transplantation: results of parallel Phase II trials using HLA-mismatched related bone marrow or unrelated umbilical cord blood grafts. Blood. 2011 Jul 14;118(2):282288. Epub 2011 Apr 28. 122 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment C: Publications, Abstracts, and Presentations Protocol Number N/A Network publication Number Publication PMCID 19 Denzen EM, Burton Santibáñez ME, Moore H, Foley A, Gersten I, Gurgol G, Majhail NS, Spellecy R, Horowitz MM, Murphy EA. Easy-toread informed consent forms for hematopoietic cell transplantation clinical trials. Biology of Blood and Marrow Transplantation. 2012 Feb 01;18(2):183–189. Epub 2011 Jul 30. BMT CTN 0303 PMC Journal – In Process 20 Keever-Taylor CA, Devine SM, Soiffer RJ, Mendizabal A, Carter S, Pasquini MC, Hari PN, Stein A, Lazarus HM, Linker C, Goldstein SC, Stadtmauer EA, O'Reilly RJ. Characteristics of CliniMACS(®) System CD34-enriched T cell-depleted grafts in a multicenter trial for acute myeloid leukemia-BMT CTN Protocol 0303. Biology of Blood and Marrow Transplantation. 2012 May 01;18(5):690-7. Epub 2011 Aug 26. BMT CTN 0102 PRIMARY MANUSCRIPT PMC3611089 [Available on 2013/3/29] 21 Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea E 3rd, Antin JH, Comenzo R, Goodman S, Hari P, Laport G, Qazilbash MH, Rowley S, Sahebi F, Somlo G, Vogl DT, Weisdorf D, Ewell M, Wu J, Geller NL, Horowitz MM, Giralt S, Maloney DG. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a Phase 3 biological assignment trial. Lancet Oncology. 2011 Dec 01;12(13):1195-1203. Epub 2011 Sep 29. BMT CTN 0601 PMC3618440 [Available on 2013/8/1] 22 Kamani NR, Walters MC, Carter S, Aquino V, Brochstein JA, Chaudhury S, Eapen M, Freed BM, Grimley M, Levine JE, Logan B, Moore T, Panepinto J, Parikh S, Pulsipher MA, Sande J, Schultz KR, Spellman S, Shenoy S. Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one cohort from the Phase II study from the BMT CTN. Biology of Blood and Marrow Transplantation. 2012 Aug 01;18(8):1265-1272. Epub 2012 Feb 16. BMT CTN 0302 23 Levine J, Logan BR, Wu J, Alousi AM, Bolaños-Meade J, Ferrara JLM, Ho VT, Weisdorf DJ, Paczesny S. Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a BMT CTN study. Blood. 2012 Apr 19;119(16):3854-3860. Epub 2012 Mar 1. PMC3335389 [Available on 2013/4/19] BMT CTN 0301 PMC Journal – In Process 24 Tolar J, Deeg HJ, Arai S, Horwitz M, Antin JH, McCarty J, Adams R, Ewell M, Leifer E, Gersten I, Carter S, Horowitz MM, Nakamura R, Pulsipher MA, Difronzo NL, Confer D, Eapen M, Anderlini P. Fludarabine-based conditioning for marrow transplantation from unrelated donors in severe aplastic anemia: early results of a cyclophosphamide dose deescalation study show life-threatening adverse events at predefined cyclophosphamide dose levels.Biology of Blood and Marrow Transplantation. 2012 July 01; 18(7):1007-1011. Epub 2012 Apr 30. PMC3242929 [Available on 2013/2/1] 2012 123 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment C: Publications, Abstracts, and Presentations Protocol Number BMT CTN 0704 / CALGB 100104 / ECOG 100104 PRIMARY MANUSCRIPT Number Publication PMCID 25 McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, Giralt S, Stadtmauer EA, Weisdorf DJ, Vij R, Moreb JS, Callander NS, Van Besien K, Gentile T, Isola L, Maziarz RT, Gabriel DA, Bashey A, Landau H, Martin T, Qazilbash MH, Levitan D, McClune B, Schlossman R, Hars V, Postiglione J, Jiang C, Bennett E, Barry S, Bressler L, Kelly M, Sexton M, Rosenbaum C, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM, Anderson KC, Linker C. Phase III study of lenalidomide versus placebo after HCT for multiple myeloma. New England Journal of Medicine. 2012 May 10; 366(19):1770-1781. BMT CTN 0303 PMC Journal – In Process 26 Pasquini M, Devine S, Mendizabal A, Baden L, Wingard J, Lazarus H, Appelbaum F, Keever-Taylor C, Horowitz M, Carter S, O’Reilly R, Soiffer R. Comparative outcomes of donor graft CD34+ selection and immune suppressive therapy as graft-versus-host disease prophylaxis for patients with acute myeloid leukemia in complete remission undergoing HLA-matched sibling allogeneic hematopoietic cell transplantation. Journal of Clinical Oncology. 2012 Sep 10;30(26):3194-3201. Epub 2012 Aug 6. BMT CTN 0201 PRIMARY MANUSCRIPT PMC Journal – In Process 27 Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR, Cutler CS, Westervelt P, Woolfrey A, Couban S, Ehninger G, Johnston L, Maziarz RT, Pulsipher MA, Porter DL, Mineishi S, McCarty JM, Khan SP, Anderlini P, Bensinger WI, Leitman SF, Rowley SD, Bredeson C, Carter SL, Horowitz MM, Confer DL; Blood and Marrow Transplant Clinical Trials Network. Peripheral blood stem cells versus bone marrow from unrelated donors. New England Journal of Medicine. 2012 Oct 18;367(16):1487-1496. BMT CTN 0302 PMC Journal – In Process 28 Bolanos-Meade J, Wu J, Logan BR, Levine JE, Ho VT, Alousi AM, Weisdorf DJ, Luznik L. Lymphocyte phenotype during therapy for acute graft versus host disease: a brief report from BMT-CTN 0302. Biology of Blood and Marrow Transplantation. 2013 Mar 01;19(3):481-485. Epub 2012 Dec 11. BMT CTN 0401 PRIMARY MANUSCRIPT PMC Journal – In Process PMC Journal – In Process 2013 29 Vose JM, Carter S, Burns LJ, Ayala E, Press O, Moskowitz CH, Stadtmauer EA, Mineshi S, Ambinder RF, Fenske TS, Horowitz MM, Fisher RI, Tomblyn M. Phase III randomized study of rituximab/carmustine, etoposide, cytarabine, melphalan (BEAM) compared with 131-Iodine tositumomab/BEAM with autologous stem cell transplantation for relapsed diffuse large B-Cell lymphoma: results from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0401 trial. Journal of Clinical Oncology. 2013 Mar 11 [Epub ahead of print] 124 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment C: Publications, Abstracts, and Presentations Number Publication 30 Giralt S, McCarthy PL, Anderson KC, Carter SL, Richardson PG, Rajkumar SV, Laport GG, Stadtmauer EA, Pasquini MC, Horowitz MM. Anatomy of a successful practice-changing study: a Blood and Marrow Transplant Clinical Trials Network-National Cancer Institute Cooperative Group Collaboration. Biology of Blood and Marrow Transplantation. [In press] 31 Mauskopf J, Chirila C, Graham J, Gersten I, Mullins D, Maziarz R, Baden L, Bolanos-Meade J, Brown J, Walsh T, Horowitz M, Kurtzberg J, Marr K and Wingard J. Cost-effectiveness analysis of voriconazole compared With fluconazole for prevention of invasive fungal infection in patients receiving allogeneic hematopoietic cell transplants. American Journal Health-System Pharmacy. [In press] 125 Protocol Number BMT CTN 0704 / CALGB 100104 / ECOG 100104 BMT CTN 0101 PMCID PMC Journal – In Process PMC Journal – In Process Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment C: Publications, Abstracts, and Presentations Attachment C2: Abstracts and Presentations Number Meeting/Presentation Protocol Number 2007 1 Pasquini M, Ewell M, Stadtmauer E, Bredeson C, Alyea E, Stockerl-Goldstein K, Krishnan A, Shebi F, Rowley S, Maloney D, Vesole D, Horowitz M, Carter S, Geller N, Giralt S. Biologic assignment trials in hematopoietic stem cell transplantation: baseline characteristics of multiple myeloma patients in BMT CTN 0102 by treatment allocation according to donor availability. Presented: 49th Annual ASH Meeting, Atlanta, GA, December 2007 BMT CTN 0102 2 Wingard J, Carter S, Walsh T, Kurtzberg J, Small T, Gersten I, Mendizabal A, Leather H, Confer D, Baden L, Maziarz R, Stadtmauer E, Bolaños-Meade J, Brown J, DiPersio J, Boeckh M, Marr K. Results of a randomized, double-blind trial of fluconazole versus voriconazole for the prevention of invasive fungal infections in 600 allogeneic blood and marrow transplant patients. Presented: 49th Annual ASH Meeting, Atlanta, GA, December 2007 BMT CTN 0101 2008 3 Laport G, Bredeson C, Tomblyn MR, Kahl BS, Goodman SA, Ewell M, Klein J, Horowitz MM, Vose JM, Negrin RS. Autologous versus reduced-intensity allogeneic hematopoietic cell transplantation for patients with follicular non-Hodgkin lymphoma beyond first complete response or first partial response (abstract). Presented: ASCO Annual Meeting, Chicago, IL, May-June, 2008 BMT CTN 0202 4 Alousi A, Weisdorf D, Logan B, Bolaños-Meade J, Goldstein S, Ho V, Hayes-Lattin B, Wingard J, Horowitz M, Levine J. BMT CTN 0302, a Phase II randomized trial evaluating etanercept, mycophenolate mofetil, denileukin diftitox and pentostatin in combination with corticosteroids in 180 patients with newly diagnosed acute GVHD (abstract). Presented: 50th Annual ASH Meeting, San Francisco, CA, December 2008 BMT CTN 0302 2009 5 Devine S, Soiffer R, Carter S, Pasquini M, Hari P, Devore S, Stein A, Lazarus H, Linker C, Goldstein S, Keever-Taylor C and O’Reilly R. HLA-identical sibling-matched, CD34+ selected, T cell depleted peripheral blood stem cells following myeloablative conditioning for first or second remission acute myeloid leukemia, results of BMT CTN Protocol 0303. Presented: 51st Annual ASH Meeting, New Orleans, LA, December 2009 BMT CTN 0303 2010 6 Pasquini M, Devine S, Mendizabal A, Baden L, Wingard J, Lazarus H, Appelbaum F, Keever-Taylor C, O'Reilly R and Soiffer R. Comparative effectiveness analysis of CD34+ selected, T cell depleted HLA-matched sibling grafts on allogeneic hematopoietic cell transplantation for patients with acute myeloid leukemia in complete remission (poster). Presented: BMT Tandem Meetings, Orlando, FL, February 2010 126 BMT CTN 0303 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Number Attachment C: Publications, Abstracts, and Presentations Meeting/Presentation Protocol Number 7 Gurgol C, Foley A, Belt P, Denzen E, Duffy S, Gallagher C, Grodman C, Horowitz M, Confer D, Carter S, on behalf of the BMT CTN Sponsored by NHLBI and NCI. Developing materials for transplant centers to share BMT CTN clinical trial results with their patients, a pilot study (poster). Presented: NCI ASCO Cancer Trials Accrual Symposium, Bethesda, MD, April 2010 N/A Network publication 8 Foley A, Horowitz M, Confer D, Carter S on behalf of the BMT CTN, sponsored by NHLBI and NCI. Development of an accrual assessment tool for BMT CTN transplant trials, a proactive approach (poster). Presented: NCI ASCO Cancer Trials Accrual Symposium, Bethesda, MD, April 2010 N/A Network publication 9 Pasquini M, Foley A, Carter S, Confer D, Horowitz M, Gurgol C, Giralt S, Schilsky R, McCarthy P on behalf of the Cancer and Leukemia Group B and the Blood and Marrow Transplant Clinical Trial Network. Maximizing accrual to transplant trials in multiple myeloma, lessons from the BMT CTN, Eastern Cooperative Oncology Group, and Cancer and Leukemia Group B Collaboration (poster). Presented: NCI ASCO Cancer Trials Accrual Symposium, Bethesda, MD, April 2010 BMT CTN 0704 / CALGB 100104 / ECOG 100104 10 Keever-Taylor C, Devine SM, Soiffer RJ, Carter SL, Pasquini MC, Hari P, Stein A, Lazarus HM, Linker C, Goldstein S, O’Reilly RJ on behalf of the BMT CTN. Characteristics of CD34enriched products processed at multiple centers using the CliniMacs System - BMT CTN 0303. Presented: 16th Annual International Society for Cellular Therapy Meeting, Philadelphia, PA, May 2010 BMT CTN 0303 11 McCarthy PL, Owzar K, Anderson KC, Hofmeister CC, Hassoun H, Hurd DD, Stadtmauer EA, Giralt S, Hars V, Linker CA. Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous stem cell transplant for multiple myeloma: BMT CTN 0704 / CALGB 100104 / ECOG 100104. Presented: ASCO Annual Meeting, Chicago, IL, June 2010 BMT CTN 0704 / CALGB 100104 / ECOG 100104 12 McCarthy PL, Owzar K, Anderson K, Hofmeister CC, Hurd DD, Hassoun H, Giralt S, Stadtmauer EA, Richardson PG, Weisdorf DJ, Vij R, Moreb JS, Callander N, Van Besien K, Gentile T, Isola L, Maziarz RT, Gabriel DA, Bashey A, Landau H, Martin T, Oazilbash MH, Levitan D, McClune B, Hars V, Postiglione J, Jiang C, Bennett E, Barry SS, Bressler L, Kelly M, Sexton M, Rosenbaum C, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM, Linker C. Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous hematopoietic stem cell transplantation for multiple myeloma: BMT CTN 0704 / CALGB 100104 / ECOG 100104 (oral). Presented: 52nd Annual ASH Meeting, Orlando, FL, December 2010 BMT CTN 0704 / CALGB 100104 / ECOG 100104 13 Krishnan A, Pasquini MC, Ewell M, Stadtmauer EA, Alyea EP, Antin JA, Comenzo RL, Goodman S, Hari P, Negrin R, Qazilbash MH, Rowley SD, Sahebi F, Somlo G, Vesole DH, Vogl DT, Weisdorf DJ, Geller N, Horowitz MM, Giralt S and Maloney DG. Tandem autologous hematopoietic stem cell transplants with or without maintenance therapy versus single autologous HCT followed by HLA matched sibling non-myeloablative allogeneic HCT for patients with standard risk multiple myeloma: results from the BMT CTN 0102 Trial. Presented: 52nd Annual ASH Meeting, Orlando, FL, December 2010 127 BMT CTN 0102 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment C: Publications, Abstracts, and Presentations Protocol Number Number Meeting/Presentation 14 Stadtmauer EA, Krishnan A, Pasquini MC, Ewell M, Alyea EP, Antin JH, Castro-Malaspina H, Kassim AA, Negrin R, Qazilbash MH, Rizzo JD, Rowley SD, Sahebi F, Somlo G, Vesole DH, Vogl DT, Weisdorf DJ, Geller N, Horowitz MM, Maloney DG, Giralt S. Tandem autologous stem cell transplants with or without maintenance therapy versus single autologous transplant followed by HLA-matched sibling non-myeloablative allogeneic stem cell transplant for patients with high risk multiple myeloma: Results from the BMT CTN 0102 Trial. Presented: 52nd Annual ASH Meeting, Orlando, FL, December 2010 BMT CTN 0102 15 Switzer GE, Harrington D, Haagenson MD, Drexler R, Foley A, Confer DL, Bishop M, Anderlini P, Rowley SD, Leitman S, Anasetti C, Wingard Jr. Health-related quality-of-life among adult unrelated stem cell donors: a BMT CTN randomized trial of marrow versus stem cell donation. Presented: 52nd Annual ASH Meeting, Orlando, FL, December 2010 BMT CTN 0201 2011 16 Fuchs EJ, Wu J, Carter S, Brunstein C, Costa L, Wingard J, Jagasia M, D’Elia J, Eapen M, O’Donnell PV. Phase II trial of non-myeloablative conditioning and transplantation of partially HLA-mismatched bone marrow for patients with hematologic malignancies: results of BMT CTN Protocol #0603. Presented: BMT Tandem Meetings, Honolulu, HI, February 2011 *Received a Best Abstract Award BMT CTN 0603 17 Brunstein CG, Carter S, Fuchs EJ, Karanes C, Devine S, Cutler C, Ballen KK, Thompson J, O'Donnell PV, Eapen M. Phase II trial of non-myeloablative conditioning double umbilical cord blood transplantation from unrelated donors in patients with hematologic malignancies: results of BMT CTN Protocol 0604. Presented: BMT Tandem Meetings, Honolulu, HI, February 2011 BMT CTN 0604 18 Levine JE, Logan BR, Wu J, Alousi AM, Bolaños-Meade J, Ho VT, Weisdorf DJ, Paczesny S. GVHD biomarkers measured during treatment independently predict response to therapy and survival: a BMT CTN study. Presented: European Group for Blood and Marrow Transplantation Congress, Paris, France, April 2011 BMT CTN 0302 19 McCarthy P, Owzar K, Anderson K, Hofmeister C, Richardson P, Hassoun H, Stadtmauer E, Giralt S, Hurd D, Hars V, Jiang C, Postiglione J, Bressler L, Devine S, Linker C. Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous stem cell transplant for multiple myeloma: BMT CTN 0704 / CALGB 100104 / ECOG 100104. Presented: 13th International Myeloma Workshop, Paris, France, May 2011 BMT CTN 0704 / CALGB 100104 / ECOG 100104 20 Krishnan A, Pasquini M, Logan B, Stadtmauer EA, Alyea III E, Antin J, Comenzo R, Goodman S, Hari P, Negrin R, Qazilbash M, Rowley S, Sahebi F, Somlo G, Vesole D, Vogl D, Weisdorf D, Wu J, Geller N, Horowitz MM, Giralt S, and Maloney D. Tandem autologous HCT (auto-auto) versus single autologous HCT followed by HLA matched sibling non-myeloablative allogeneic HCT (auto-allo) for patients with standard risk multiple myeloma: results from the BMT-CTN 0102 Trial. Poster presented: 13th International Myeloma Workshop, Paris, France, May 2011 BMT CTN 0102 128 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Number Attachment C: Publications, Abstracts, and Presentations Meeting/Presentation Protocol Number 21 Hari P, Pasquini M, Logan B, Stadtmauer E, Krishnan A, Howard A, Alvi S, Harding S, Carter S, Rajkumar V, Alyea E, Qazilbash M, LaPort G, Maloney D, Giralt S, Vesole D. Immunoglobulin free light chain and heavy chain/light chain assays – comparison with electrophoretic responses in multiple myeloma: results of BMT CTN Protocol #0102. Presented: 53rd Annual ASH Meeting, San Diego, CA, December 2011 BMT CTN 0102 22 Anasetti C, Logan B, Lee SJ, Waller EK, Weisdorf D, Wingard JR, Cutler C, Westervelt P, Woolfrey A, Couban S, Johnston L, Maziarz R, Pulsipher M, Anderlini P, Bensinger W, Leitman S, Rowley SD, Carter SL, Horowitz MM, Confer DL. Increased incidence of chronic graft-versus-host disease and no survival advantage with filgrastim-mobilized peripheral blood stem cells compared to bone marrow transplants from unrelated donors: Results of BMT CTN Protocol #0201, a Phase III prospective randomized trial. Presented: 53rd Annual ASH Meeting, San Diego, CA, December 2011 [Plenary Session] BMT CTN 0201 23 Waller EK, Harris WAC, Devine S, Porter DL, Mineishi S, McCarty JM, Gonzalez CE, Spitzer TR, Krijanovski OI, Linenberger ML, Woolfrey A, Howard A, Gurgol C, Logan BR, Confer DL, Anasetti C. Larger numbers of donor naïve CD8+ T-cells and plasmacytoid dendritic cell precursors in allogeneic Bone marrow grafts from unrelated donors are associated with improved survival: results from BMT CTN #0201. Presented: 53rd Annual ASH Meeting, San Diego, CA, December 2011 BMT CTN 0201 24 Tolar J, Deeg HJ, Arai S, Horwitz M, Antin JH, McCarty J, Adams R, Eapen M, Ewell M, Leifer E, Gersten I, Carter SL, Horowitz MM, Confer D, Nakamura R, Pulsipher MA, DiFronzo N, Anderlini P. Fludarabine-based conditioning for allogeneic marrow transplantation from unrelated donors in severe aplastic anemia: serious and unexpected adverse events in pre-defined cyclophosphamide dose levels: results from BMT CTN protocol #0301. Presented: 53rd Annual ASH Meeting, San Diego, CA, December 2011 BMT CTN 0301 25 Vose JM, Carter SL, Burns L , Ayala E, Press O, Moskowitz C, Stadtmauer E, Mineshi S, Ambinder R, Fenske T, Horowitz M, Tomblyn M. Randomized Phase III trial of 131IodineTositumomab (Bexxar)/Carmustine, Etoposide, Cytarabine, Melphalan (BEAM) versus Rituximab/BEAM and autologous stem cell transplantation for relapsed diffuse large B cell lymphoma: no difference in progression-free or overall survival. Presented: 53rd Annual ASH Meeting, San Diego, CA, December 2011 BMT CTN 0401 26 Spellecy R, Denzen E, Burton Santibáñez M, Moore H, Foley A, Gersten I, Gurgol C, Horowitz M, Majhail N, Murphy E. Informed consent: improving the form and the process. Presented: Public Responsibility in Medicine and Research, National Harbor, MD, December 2011 129 N/A Network publication Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Number Attachment C: Publications, Abstracts, and Presentations Meeting/Presentation Protocol Number 2012 27 Waller EK, Harris WA, Devine S, Porter DL, Ferrara J, McCarty JM, Gonzalez CE, Spitzer TR, Krijanovski OI, Howard A, Gurgol C, Logan BR, Confer DL, Anasetti C. Grade III-IV acute GVHD and treatment-related mortality are reduced among recipients of larger numbers of donor naïve CD8+ T-cells and plasmacytoid dendritic cell precursors in allogeneic bone marrow grafts from unrelated donors: results from BMT CTN 0201. Presented: 38th Annual European Group for Blood and Marrow Transplantation Congress, Geneva, Switzerland, April 2012 BMT CTN 0201 28 Anderlini P, Tolar J, Deeg HJ, Arai S, Horwitz M, Antin JH, McCarty JM, Adams RH, Ewell M, Leifer E, Gersten I, Carter SL, Horowitz MM, Confer DL, Nakamura R, Pulsipher M, DiFronzo NL, Eapen M. Fludarabine-based conditioning for allogeneic marrow transplantation from unrelated donors in severe aplastic anaemia: serious and unexpected adverse events in pre-defined cyclophosphamide dose levels. Poster presented: 38th Annual European Group for Blood and Marrow Transplantation Congress, Geneva, Switzerland, April 2012 BMT CTN 0301 29 Crann ME, Mendizabal AM, Gersten ID, and Carter SL. Adverse event reporting for hematopoietic cell transplantation. Poster presented: Society for Clinical Trials Annual Meeting, Miami, FL, May 2012 30 Anasetti C, Logan B, Lee SJ, Waller EK, Weisdorf D, Wingard JR, Cutler C, Westervelt P, Woolfrey A, Couban S, Johnston L, Maziarz R, Pulsipher M, Anderlini P, Bensinger W, Leitman S, Rowley SD, Carter SL, Horowitz MM, Confer DL. Increased incidence of chronic graft-versus-host disease and no survival advantage with filgrastim-mobilized peripheral blood stem cells compared to bone marrow transplants from unrelated donors: results of BMT CTN Protocol #0201, a Phase III prospective randomized trial. Presented: ASCO Annual Meeting (ASCO/ASH Joint Session), Chicago, IL, June 2012 BMT CTN 0201 31 Cutler C, Logan BR, Nakamura R, Johnston L, Choi SW, Porter DL, Hogan WJ, Pasquini MC, MacMillan ML, Wingard JR, Waller EK, Grupp SA,McCarthy PL, Wu J, Hu Z, Carter SL, Horowitz MM, Antin JH. Tacrolimus/sirolimus vs. tacrolimus/methotrexate for graft-vs.-host disease prophylaxis after HLA-matched, related donor hematopoietic stem cell transplantation: results of Bone Marrow Transplant Clinical Trials Network 0402. Presented: 54th Annual ASH Annual Meeting, Atlanta, GA, December 2012 BMT CTN 0402 32 Wagner JE, Eapen M, Carter SL, Haut P, Perez E, Schultz K, Thompson J, Wall D, Kurtzberg J. No survival advantage after double umbilical cord blood (UCB) compared to single UCB transplant in children with hematological malignancy: results of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0501) randomized trial. Presented: 54th Annual ASH Annual Meeting, Atlanta, GA, December 2012 BMT CTN 0501 130 N/A Network publication Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment C: Publications, Abstracts, and Presentations Number Meeting/Presentation 33 Devine SM, Owzar K, Blum W, DeAngelo DJ, Stone RM, Hsu JW, Champlin R, Chen YA, Vij R, Slack JL, Soiffer RJ, Larson RA, Shea TC, Hars V, Bennett E, Spangle S, Giralt SA, Carter SL, Horowitz MM, Linker C, Alyea EP. A Phase II study of allogeneic transplantation for older patients with AML in first complete remission using a reduced intensity conditioning regimen: results from CALGB 100103/BMT CTN 0502. Presented: 54th Annual ASH Annual Meeting, Atlanta, GA, December 2012 Protocol Number BMT CTN 0502 / CALGB 100103 2013 34 Yanik D, Ho VT, Horowitz MM, Weisdorf DJ, Logan BR, Wu J , Soiffer RJ, Wingard JR, Levine JE, Ferrara JL, Giralt SA, White E, Carter SL, DiFronzo N, Cooke KR. Randomized, double blind, placebo-controlled trial of a TNF inhibitor (etanercept) for the treatment of idiopathic pneumonia syndrome (IPS) after allogeneic stem cell transplant (SCT), a Blood and Marrow Transplant Clinical Trials Network (BMT CTN) study. Presented: BMT Tandem Meetings, Salt Lake City, UT, February 2013 BMT CTN 0403 35 Kurtzberg J, Carter SL, Mendizabal A, Wall DA, Schultz KR, Kernan NA, Eapen M, Wagner JE. Superior survival after single unit umbilical cord blood transplantation (UCBT) in children with hematological malignancies treated on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0501 relative to the cord blood transplantation (COBLT). Presented: BMT Tandem Meetings, Salt Lake City, UT, February 2013 BMT CTN 0501 36 Bolaños-Meade J , Logan BR, Alousi AM, Antin JH, Barowski K, Carter SL, Hexner EO, Horowitz MM, Levine JE, MacMillan ML, Martin PJ, Nakamura R, Pasquini MC, Weisdorf DJ, Westervelt P, Ho VT. A multi-center, randomized, double blind, Phase III clinical trial comparing steroids/placebo vs. steroids/mycophenolate mofetil as initial therapy for acute graft-versus-host disease, Blood and Marrow Transplant Clinical Trials Network Study 0802. Presented: BMT Tandem Meetings, Salt Lake City, UT, February 2013 BMT CTN 0802 37 McCarthy P, Owzar K, Hofmeister C, Richardson P, Hassoun H, Stadtmauer E, Giralt S, Hurd D, Qazilbash M, McClune B, Pasquini M, Hars V, Jiang C, Postiglione J, Kelly M, Bressler L, Devine S, Anderson K, Linker C. Analysis of overall survival (OS) in the context of cross-over from placebo to lenalidomide and the incidence of second primary malignancies (SPM) in the Phase III study of lenalidomide versus placebo maintenance therapy following autologous stem cell transplant (ASCT) for multiple myeloma (MM), CALGB (Alliance) ECOG, BMT CTN 100104. To be presented: 14th International Myeloma Workshop, Kyoto, Japan April 2013 BMT CTN 0704 / CALGB 100104 / ECOG 100104 131 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment D: Committee Rosters Attachment D: Committee Rosters Committee Chairs are bolded. Attachment D1: Steering Committee Core Center Principal Investigators Center Claudio Anasetti, MD H. Lee Moffitt Cancer Center, Tampa, FL Joseph Antin, MD Dana-Farber Cancer Institute, Boston, MA *Frederick Appelbaum, MD (Chair-Elect) Fred Hutchinson Cancer Research Center, Seattle, WA Asad Bashey, MD Northside Hospital, Atlanta, GA Catherine Bollard, MD Baylor College of Medicine, Houston, TX Richard Champlin, MD MD Anderson Cancer Center, Houston, TX Steven Devine, MD (Vice-Chair) Ohio State University, Columbus, OH James Ferrara, MD University of Michigan, Ann Arbor, MI Stephen Forman, MD City of Hope National Medical Center, Duarte, CA Sergio Giralt, MD Memorial Sloan-Kettering Cancer Center, New York, NY Richard Jones, MD Johns Hopkins University, Baltimore, MD Joanne Kurtzberg, MD Duke University, Durham, NC *Ginna Laport, MD (Chair) Stanford University, Stanford, CA Hillard Lazarus, MD Case Western Reserve University, Cleveland, OH Michael Pulsipher, MD University of Utah, Salt Lake City, UT Edward Stadtmauer, MD University of Pennsylvania, PA Julie Vose, MD University of Nebraska, Omaha, NE Daniel Weisdorf, MD University of Minnesota, Fairfield, MN Peter Westervelt, MD Washington University, St. Louis, MO John Wingard, MD University of Florida, Gainesville, FL Cooperative Group Representatives Alliance: Steven Devine, MD SWOG: Patrick Stiff, MD COG: Stephan Grupp, MD, PhD ECOG: Hillard Lazarus, MD Center Ohio State University, Columbus, OH Loyola University, Chicago, IL Children’s Hospital of Philadelphia, PA Case Western Reserve University, Cleveland, OH Affiliate Center Representatives Henry Fung, MD Parameswaran Hari, MD, MS Voravit Ratanatharathorn, MD Center Rush University, Chicago, IL Medical College of Wisconsin, Milwaukee, WI Karmanos Cancer Institute, Detroit, MI 132 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 DCC Principal Investigators *Shelly Carter, ScD (Co-PI) *Dennis Confer, MD (Co-PI) *Mary Horowitz, MD, MS (PI) Organization The EMMES Corporation, Rockville, MD NMDP, Minneapolis, MN CIBMTR, Milwaukee, WI NHLBI and NCI Project Officers *Nancy DiFronzo, PhD *William Merritt, PhD *Elizabeth Wagner, MPH *Roy Wu, PhD Attachment D: Committee Rosters Organization National Heart, Lung, and Blood Institute, NIH, Bethesda, MD National Cancer Institute, NIH, Bethesda, MD National Heart, Lung, and Blood Institute, NIH, Bethesda, MD National Cancer Institute, NIH, Bethesda, MD The Executive Committee is a subcommittee of the Steering Committee. Individuals who serve on the Executive Committee are identified by an asterisk (*). 133 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment D: Committee Rosters Attachment D2: Publications, Abstracts & Presentations Committee Name Organization Term Expiration Joseph Antin ([email protected]) Dana-Farber Cancer Institute Boston, MA 2015 Edward Stadtmauer (co-chair) ([email protected]) University of Pennsylvania Philadelphia, PA 2015 Mark Litzow ([email protected]) Mayo Clinic Rochester, MN 2014 Peter Westervelt ([email protected]) Washington University School of Medicine St. Louis, MO 2014 Mort Cowan ([email protected]) University of California San Francisco Medical Center San Francisco, CA 2013 John Wingard (co-chair) ([email protected]) Shands HealthCare & University of Florida Gainesville, FL 2013 Shelly Carter (ex-officio) ([email protected]) The EMMES Corporation Rockville, MD - Dennis Confer (ex-officio) ([email protected]) NMDP Minneapolis, MN - Nancy Geller (ex-officio) ([email protected]) National Heart, Lung, and Blood Institute, NIH Bethesda, MD - Mary Horowitz (ex-officio) ([email protected]) CIBMTR Milwaukee, WI - Nancy Poland (ex-officio) ([email protected]) CIBMTR Minneapolis, MN - Roy Wu (ex-officio) ([email protected]) National Cancer Institute, NIH Bethesda, MD - 134 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment D: Committee Rosters Attachment D3: Biomarkers Committee Name Organization Term Expiration Edward Agura ([email protected]) Baylor University Dallas, TX 2015 Philip McCarthy (chair) ([email protected]) Roswell Park Cancer Institute Buffalo, NY 2015 Joseph Pidala ([email protected]) H. Lee Moffitt Cancer Center Tampa, FL 2015 Jerald Radich ([email protected]) Fred Hutchinson Cancer Research Center Seattle, WA 2014 James Ferrara ([email protected]) University of Michigan Medical School Ann Arbor, MI 2013 Marcel van de Brink ([email protected]) Memorial Sloan-Kettering Cancer Center New York, NY 2013 Shelly Carter (ex-officio) ([email protected]) The EMMES Corporation Rockville, MD - Dennis Confer (ex-officio) ([email protected]) NMDP Minneapolis, MN - Nancy DiFronzo (ex-officio) ([email protected]) National Heart, Lung, and Blood Institute, NIH Bethesda, MD - John Hansen (ex-officio) ([email protected] ) Fred Hutchinson Cancer Research Center Seattle, WA - Alan Howard (ex-officio) ([email protected]) CIBMTR Minneapolis, MN - John Levine (ex-officio) ([email protected]) University of Michigan Ann Arbor, MI - William Merritt (ex-officio) ([email protected]) National Cancer Institute, NIH Bethesda, MD - Marcelo Pasquini (ex-officio) ([email protected]) CIBMTR Milwaukee, WI - 135 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment D: Committee Rosters Attachment D4: Clinical Research Associates Committee Name Organization Term Expiration Stacey Brown ([email protected]) Northside Hospital Atlanta, GA 2015 Michael Gates ([email protected]) All Children’s Hospital St. Petersburg, FL 2015 Romelia May ([email protected]) Baylor College Houston, TX 2015 Alex Stentz ([email protected]) Oregon Health Sciences University Portland, OR 2015 Shawnda Tench ([email protected]) Cleveland Clinic Cleveland, OH 2015 Terry Furlong ([email protected]) Fred Hutchinson Cancer Research Center Seattle, WA 2014 Gwen Konsler ([email protected]) University of North Carolina at Chapel Hill School of Medicine Chapel Hill, NC 2014 Andrea Ortega ([email protected]) Hackensack University Medical Center Hackensack, NJ 2014 Laura Hancock ([email protected]) Cure Search for Children’s Cancer Bethesda, MD 2013 Bertha Villa ([email protected]) Stanford University Palo Alto, CA 2013 Shelly Carter (ex-officio) ([email protected]) The EMMES Corporation Rockville, MD - Cynthia Couture (ex-officio) ([email protected]) The EMMES Corporation Rockville, MD - Nancy DiFronzo (ex-officio) ([email protected]) National Heart, Lung, and Blood Institute, NIH Bethesda, MD - Mary Magliocco (chair) (ex-officio) ([email protected]) The EMMES Corporation Rockville, MD - Connie Weaver (ex-officio) ([email protected]) The EMMES Corporation Rockville, MD - 136 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment D: Committee Rosters Attachment D5: Pharmacy Committee Name Organization Term Expiration John Rogosheske (chair) ([email protected]) Fairview Health Services Minneapolis, MN 2015 Jamie Shapiro ([email protected]) H. Lee Moffitt Cancer Center Tampa, FL 2015 Kristan Augustin ([email protected]) Barnes-Jewish Hospital St. Louis, MO 2014 Celalettin Ustun ([email protected]) University of Minnesota Medical Center Minneapolis, MN 2014 Alison Gulbis ([email protected]) University of Texas MD Anderson Cancer Center Houston, TX 2013 Ashley Morris ([email protected]) Duke University Durham, NC 2013 Dennis Confer (ex-officio) ([email protected]) NMDP Minneapolis, MN - Iris Gersten (ex-officio) ([email protected]) The EMMES Corporation Rockville, MD - 137 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment D: Committee Rosters Attachment D6: Special Populations (Pediatrics/Human Subjects) Committee Name Organization Term Expiration Partow Kebriaei ([email protected]) M.D. Anderson Cancer Center Houston, TX 2015 Carrie Kitko ([email protected]) University of Michigan Ann Arbor, MI 2015 Mark Walters ([email protected]) Children’s Hospital and Research Center Oakland Oakland, CA 2015 John Horan ([email protected]) Children’s Healthcare of Atlanta Atlanta, GA 2014 Michael Nieder ([email protected]) H Lee Moffitt Cancer Center Tampa, FL 2014 William Wood ([email protected]) University of North Carolina at Chapel Hill School of Medicine Chapel Hill, NC 2014 Ginna Laport (non-peds) ([email protected]) Stanford University School of Medicine Palo Alto, CA 2013 Alison Loren ([email protected]) University of Pennsylvania Medical Center Philadelphia, PA 2013 Michael Pulsipher (chair) ([email protected]) University of Utah Primary Children’s Medical Center Salt Lake City, UT 2013 Shelly Carter (ex-officio) ([email protected]) The EMMES Corporation Rockville, MD - Nancy DiFronzo (ex-officio) ([email protected]) National Heart, Lung, and Blood Institute, NIH Bethesda, MD - Mary Horowitz (ex-officio) ([email protected]) CIBMTR Milwaukee, WI - Brent Logan (ex-officio) ([email protected]) CIBMTR Milwaukee, WI - 138 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment D: Committee Rosters Attachment D7: Toxicity and Supportive Care Committee Name Organization Term Expiration Richard Maziarz (chair) ([email protected]) Oregon Health Sciences University Portland, OR 2015 John McCarty ([email protected]) Virginia Commonwealth University Richmond, VA 2015 Angela Smith ([email protected]) University of Minnesota Minneapolis, MN 2015 Kenneth Cooke University Hospitals Case Medical Center ([email protected]) Cleveland, OH 2014 Jeffrey Schriber ([email protected]) Phoenix, AZ 2014 Mohamed Sorror ([email protected]) Fred Hutchinson Cancer Research Center Seattle, WA 2014 Javier Bolaños-Meade ([email protected]) Johns Hopkins Hospital Baltimore, MD 2013 David Porter ([email protected]) University of Pennsyvania Health System Philadelphia, PA 2013 Trudy Small ([email protected]) Memorial Sloan-Kettering Cancer Center New York, NY 2013 Shelly Carter (ex-officio) ([email protected]) The EMMES Corporation Rockville, MD - Mary Horowitz (ex-officio) ([email protected]) CIBMTR Milwaukee, WI - 139 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment E: Center Performance Report Attachment E: Center Performance Report CENTER PERFORMANCE REPORT Center Name: Date of Evaluation: January 1, 2013 ADMINISTRATIVE ACTIVITY Items # Protocol N % Protocol Chairs or Co-chairs 3 Protocol Team members Protocol Team conf call participation2 in 2012 /=% Steering Comm Chair/Chair-elect/Past-chair in 2012 % Steering Comm meeting/call participation in 2012 % Notes: 1 Total N for all sites and all protocols. 2 Percentages for call are calculated based on the protocols that the center is one of the chairs/members. 3 ― means not applicable or not calculated. Protocol Team Conference Call Participation in 2012 Protocol Total # Calls # Calls Participated (%) 0301 0401 0402 Total 140 Total N1 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment E: Center Performance Report ACTIVATION AND ENROLLMENT PROTOCOL # Protocol activated # Accrual in 2012 Projected Accrual in 20121 (%2) 0301 0402 0403 0501 0601 0701 0702 0801 0802 0803 0804 0805 141 # Days to consent preview1 # Days to activation # Days from activation to 1st patient Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 PROTOCOL # Protocol activated # Accrual in 2012 Attachment E: Center Performance Report Projected Accrual in 20121 (%2) # Days to consent preview1 # Days to activation N_Total= (/=%) [85%] Median_Overall= Median_Recent= [56] Median_Overall= Median_Recent= [180] # Days from activation to 1st patient 0901 0902 0903 1101 Total/Overall N_Total= N_Recent= [4] N_Total= Median_Overall= Median_Recent= [56] Notes: 1 Protocols that have closed accrual before Jan 1, 2011, are not included in this table. 2 % is the actual accrual total over projected accrual total (including only protocols “activated”). If projected accrual number not available, the actual accrual number was used as projected number. 3 N_Recent means N only counts the protocols opened within the preceding 4 years (the evaluated year plus 3 previous years). Median_Recent means median only counts the protocols opened within the preceding 4 years. 4 5 for row “Protocol activated” means site is not participating the study. for other rows mean not activated yet or not applicable or information not available. Targets are in “[ ]”. 142 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment E: Center Performance Report DATA QUALITY PROTOCOL # # Accrual in total Data audit error rate (%) # Protocol deviations in 2012 (% of enrolled patients) 0102 0201 0301 0303 0401 0402 0403 0501 0601 0603 0604 0701 0702 0801 0802 143 # Required forms # Forms > 30 days overdue Forms > 30 days overdue/Patient Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 PROTOCOL # # Accrual in total Data audit error rate (%) Attachment E: Center Performance Report # Protocol deviations in 2012 (% of enrolled patients) # Required forms # Forms > 30 days overdue Forms > 30 days overdue/Patient 0803 0901 0902 0903 1101 Total/Overall [2%] (%) [2%] [5] Notes: 1 Protocols that have finished following up patients before Jan 1, 2011, are not included in this table. Protocols that EMMES do not monitor data quality are not included. 2 for row “# Accrual” means site is not participating the study or not activated yet. for row “Data audit error rate” means there were no data audit performed within the preceding 3 years. for other rows means not applicable due to no patients. 3 Targets are in “[ ]”. CIBMTR REPORT FORM COMPLIANCE # BMT CTN Patients # Patients Registered with CIBMTR (%) # CIBMTR Report Forms Due (%) # CIBMTR Report Forms Received (%) (%) 144 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment E: Center Performance Report LABORATORY EVALUATION COMPLIANCE Protocol # Lab Compliance 0102 0201 0401 0402 0403 0501 0601 0701 0702 0801 0802 0803 0901 Center Overall Evaluation Annual Center Performance Report Rating Note: AC means acceptable. MA means marginally acceptable. NA means not acceptable. 145 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment E: Center Performance Report CENTER PERFORMANCE RATING Score Administrative Accrual Activation and Enrollment Data Quality Laboratory Compliance Overall Assessment 146 Rating Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment F: Center Performance Rating Attachment F: Center Performance Rating Administrative Activity Accrual max=10 points Outstanding (10 points) Holds Steering Committee Chair, Past-Chair or Chair- Elect position OR Protocol Team Chair + > 70% of team calls participation Acceptable (3-9 points) % Call Participation × 10 Needs Improvement (0 points) Attends < 33% of Protocol Team calls max=60 points Outstanding (60 points) Activation and Enrollment max=10 points # protocols activated within preceding 4 years [4] # days to consent preview [56] Accrues more than 24 patients and meets ≥ 100% of projected accrual OR Enrolls > 48 patients Acceptable (40-59 points) Score = (Actual/Projected) x 60 then adjust for maximum For centers enrolling 20 or more patients, can get a maximum score of 60; for centers enrolling < 20 patients, can only get a maximum of 45 points even if meeting or exceeding projections Needs Improvement (<40 points) Score < 40 points For centers enrolling < 18 patients, can only get a maximum of 10 points even if meeting or exceeding projections Outstanding (10 points) Meets 4 of 4 metrics Acceptable (5 points) Meets 2-3 of 4 metrics Needs Improvement (0 points) Meets < 2 of 4 metrics # days to activation [180] # days activation to 1st patient [56] Data Quality Data audit error rate [2%] max=10 points Outstanding (10 points) % protocol deviations [2%] Meets 4 of 4 metrics Acceptable (5 points) Meets 2-3 of 4 metrics Needs Improvement (0 points) Meets < 2 of 4 metrics Forms >30 days past due per patient [5] CIBMTR form compliance [90%] 147 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment F: Center Performance Rating Outstanding (10 points) OS Average compliance percentage for all participating protocols Acceptable (3.0-8.0 points) AA - Above Average 7.5; AC - Acceptable 5.0 Evaluated by Alan Howard Needs Improvement (0-3 points) UN – Unacceptable; MA - Marginally Acceptable 2.5 Outstanding > 90 points Acceptable 60 – 90 points Needs Improvement < 60 points; center required to submit action plan Laboratory Compliance Overall Assessment max=10 points max=100 points 148 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment G: Total Accrual by Month Attachment G: Total Accrual by Month 149 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment H: Accrual Plan Assessment <CTN #>: <CTN Study Short Name> PI(s): Coordinator: Total accrual: Accrual period: Anticipated study activation date: Number participating BMT CTN core sites: Projected BMT CTN core site annual accrual: Optimal number of sites: Number of affiliate sites to recruit: Identified affiliate sites based on CIBMTR registry data: Cooperative or special interest group collaboration: Cooperative/special interest group contacts: Anticipated accrual barriers: 1. 2. 3. Competing protocols: Competing treatment preference/bias: Recruitment focus: Participating sites Patient Referring MD Yes / No Yes / No Yes / No Via coop/special interest group Yes / No Other: Yes / No Associated conferences/meetings: Additional notes: 150 Attachment H: Accrual Plan Assessment Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment I: Review Checklist Attachment I: Review Checklist Protocol # _____________ BMT CTN Reviewer Checklist * Please provide an explanation/comments for all questions answered “NO” I. Background and Rationale 1. The background information included in this protocol is up to date, complete and relevant to the study. 2. The objective of this trial is clearly stated in the background. 3. The protocol synopsis is consistent with the information in the protocol. 4. Comments II. Study Design 1. Eligibility is inclusive and will not lead to slow accrual. 2. Inclusion Criteria-Comments: Rating Scale YES NO YES YES NO NO YES NO YES YES NO NO YES NO YES NO 3. Exclusion Criteria-Comments: 4. The description of the study treatment is unambiguous and sufficiently detailed. 5. The description of the study treatment will not cause undue conflicts with institutional guidelines for supportive care. 6. The study treatment and procedures are appropriately described. III. Study Endpoints: 1. Are there any concerns with the primary endpoints of the study? If yes, please explain: 151 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment I: Review Checklist 2. Are there any concerns with the secondary endpoints of the study? If yes, please explain: IV. Patient Evaluation 1. The patient evaluations are clear, easy to follow and include tests that are standard of care and will not likely result in an excessive reporting burden. 2. Please list any evaluations that you think could be omitted without compromising the integrity of the study: V. Statistical Considerations 1. Sample Size-Comments 2. Power Calculations-Comments 3. Stopping Guidelines-Comments 152 YES NO YES NO Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment I: Review Checklist 4. General Statistical Considerations-Comments VI. Informed Consent 1. The Informed Consent is written at a 6th grade reading level. 2. The Informed Consent is concise and comprehensible. 3. The Informed Consent clearly outlines the risks associated with the trial. VII. Ancillary Studies 1. Do you have any issues about the type of ancillary studies that are being requested? If yes, please explain: 2. Do you have any issues with the frequency of which the ancillary studies are being requested? If yes, please explain: VIII.Overall Assessment of Protocol 1. This trial is ready for PRC submission and does not require any additional revisions. 2. Are there any additional issues related to this protocol that need to be addressed? If yes, please explain: 153 YES YES YES NO NO NO YES NO YES NO YES YES NO NO Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment I: Review Checklist IX. Participation Would you consider participating in this study? If not, please explain why. YES X. Additional Comments Name and date of the person completing this form ____________________________ PLEASE PRINT 154 NO Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment J: Terms and Abbreviations Attachment J: Terms and Abbreviations Term / Abbreviation AIDS ALL AML ASCO ASH BEAM BMT BMT CTN acquired immunodeficiency syndrome acute lymphoblastic leukemia acute myelogenous leukemia American Society of Clinical oncology American Society of Hematology carmustine (BCNU), etoposide, cytarabine, and melphalan bone marrow transplant / transplantation Blood and Marrow Transplant Clinical Trials Network (also “the Network”) CALGB Cancer and Acute Leukemia Group B (member Alliance for Clinical Trials in Oncology) CBMTG CBU CIBMTR CIR CLL CNI COG CR CTCAE CTSU CVAD DCC DSMB EBMT ECOG ECP FACT FDA G-CSF GVHD HAART HCT HIV HLA IDE IND IPS IRB MCW MDS Canadian Blood and Marrow Transplant Group cord blood unit Center for International Blood and Marrow Transplant Research CIBMTR Immunobiology Research chronic lymphocytic leukemia calcineurin inhibitor Children’s Oncology Group complete remission common terminology criteria for adverse events Cancer Trials Support Unit cyclophosphamide, vincristine, adriamycin and dexamethasone Data and Coordinating Center Data and Safety Monitoring Board European Group for Blood and Marrow Transplantation Eastern Cooperative Oncology Group extracorporeal photophoresis Foundation for the Accreditation of Cellular Therapy Food and Drug Administration granulocyte-colony stimulating factor graft-versus-host disease highly-active antiretroviral therapy hematopoietic stem cell transplantation human immunodeficiency virus human leukocyte antigen investigational new device investigational new drug idiopathic pneumonia syndrome Institutional Review Board Medical College of Wisconsin myelodysplastic syndrome Definition 155 Blood and Marrow Transplant Clinical Trials Network Progress Report 2013 Attachment J: Terms and Abbreviations Term / Abbreviation NCI NHL NHLBI NIAID NIH NMDP PBMC PBMTC PBSC PFS PI PRC RIC SCD SCURT National Cancer Institute non-Hodgkin lymphoma National Heart, Lung, and Blood Institute National Institute of Allergy and Infectious Diseases National Institutes of Health National Marrow Donor Program peripheral blood mononuclear cell Pediatric Blood and Marrow Transplant Consortium peripheral blood stem cell progression-free survival principal investigator protocol review committee reduced-intensity conditioning sickle cell disease Sickle Cell Unrelated Transplantation; BMT CTN Protocol 0601 STaMINA Stem Cell Transplantation for Multiple Myeloma Incorporating Novel Agents; BMT CTN Protocol 0702 TCD TNF Tregs TRM UCBT T cell depletion tumor necrosis factor regulator T cells transplant-related mortality umbilical cord blood transplantation Definition 156
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