The following protocol information is provided solely to describe how... research underlying the published report associated with the following article:
The following protocol information is provided solely to describe how the authors conducted the research underlying the published report associated with the following article: Abagovomab as Maintenance Therapy in Patients with Epithelial Ovarian Cancer (MIMOSA Study): A Phase III Trial of the AGO OVAR, COGI, GINECO, and GEICO on behalf of the MIMOSA Investigators Sabbatini, et al DOI: 10.1200/JCO.2012.46.4057 The information provided may not reflect the complete protocol or any previous amendments or modifications. As described in the Information for Contributors (http://jco.ascopubs.org/site/ifc/protocol.xhtml) only specific elements of the most recent version of the protocol are requested by JCO. The protocol information is not intended to replace good clinical judgment in selecting appropriate therapy and in determining drug doses, schedules, and dose modifications. The treating physician or other health care provider is responsible for determining the best treatment for the patient. ASCO and JCO assume no responsibility for any injury or damage to persons or property arising out of the use of these protocol materials or due to any errors or omissions. Individuals seeking additional information about the protocol are encouraged to consult with the corresponding author directly. MENARINI RICERCHE S.p.A. CLINICAL TRIAL PROTOCOL Sponsor Study Code: ABA-01 AGO Study Code: AGO-OVAR 10 BB-IND 10724 EuDRACT n°: 2006-002801-30 Phase of Clinical Research: II/III A RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED, MULTICENTRE TRIAL OF ABAGOVOMAB MAINTENANCE THERAPY IN PATIENTS WITH EPITHELIAL OVARIAN CANCER AFTER COMPLETE RESPONSE TO FIRST LINE CHEMOTHERAPY COORDINATING INVESTIGATOR: Prof. Jacobus Pfisterer Frauenklinik Universitätsklinikum D - 68167 Mannheim Germany Phone: +49 621 383 2386 Fax: +49 621 383 3814 USA CHAIR: Prof. Paul Sabbatini Memorial Sloan-Kettering Cancer Center New York, NY 10021 USA Phone: +1 212 639 6423 Fax: +1 212 639 8865 CONTRACT RESEARCH ORGANIZATION: Pharmaceutical Research Associates España, S.A.U. Avenida de Europa, 19 Edificio 1, 2ª Planta 28224 Pozuelo de Alarcón - Madrid (Spain) Phone: +34 91 708 1110 Fax: +34 91 708 1111 AGO-OVAR: Ovarian Cancer Study Group Wiesbaden Office Ludwig-Erhard Str. 100 D-65199 Wiesbaden Germany Phone: +49 611 433203 Fax: +49 611 433205 USA CO-CHAIR: Prof. Jonathan Berek Chair, COGI Department of Obstetrics and Gynecology Stanford, CA 94305-5317 USA Phone: +1 650 723 5533 Fax: +1 650 723 7737 SPONSOR: Menarini Ricerche S.p.A. Clinical Research Department Via Sette Santi 1 50131 Florence Italy Phone: +39 055 5680 9990 Fax: +39 055 5680 597 CONFIDENTIAL This document is a confidential communication of the sponsor. Acceptance of this document represents an agreement by the recipient that no unpublished information contained here will be published or disclosed without the Sponsor’s written authorisation, except that this document may be disclosed to appropriate Institutional Review Boards or Ethics Committees as long as they are requested to keep it confidential. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 1 of 66 SIGNATURE PAGE The signatories have read the protocol (ABA-01, version 1.0, dated 04 August 2006) carefully and agree to adhere to its provisions. Any changes to the protocol may only be made after consultation with Menarini Ricerche S.p.A and must be submitted to the appropriate Ethics Committee(s) or Institutional Review Board in the form of an Amendment. Signature Date COORDINATING INVESTIGATOR: _____________________ ______________ Prof. Jacobus Pfisterer, MD MENARINI RICERCHE S.p.A.: Corporate Director Clinical Research and Sponsor Representative _____________________ Angela Capriati, MD PhD Study Protocol ABA-01, Version 1.0, 4 August 2006 ______________ Page 2 of 66 INVESTIGATOR STATEMENT “My signature below verifies my agreement with the contents of this protocol (ABA-01, version 1.0, 18 July 2006) with regard to the execution of the study and the required documentation of data. I agree to comply with the protocol in its entirety and with the ICH guidelines for Good Clinical Practice.” Signature Date Principal Investigator: Please print name: Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 3 of 66 ABBREVIATIONS Ab1 Ab2 Ab3 ADCC ADR AE AGO OVAR ALT ANC AP ASCO AST BUN CA125 CEAC CHMP/EWP CI COGI CR CRF CRO CT CTC CV DBO DHHS DLT DMAP DSMB DSU EC ECG ECOG EU FDA FIGO GCP GMP GMSS Antibody that binds to a given TAA Anti-idiotypic antibody Anti-anti-idiotypic antibody Antibody-Dependent Cell-mediated Cytotoxicity Adverse Drug Reaction Adverse Event Arbeitsgemeinschaft Gynaekologische Onkologie studiengruppevarialkarzinom Alanine Transaminase Absolute Neutrophil Count Alkaline Phosphatase American Society of Clinical Oncology Aspartate Aminotransferase Blood Urea Nitrogen Cancer Antigen 125 Clinical event Adjudication Committee Committee for Medicinal Products for Human Use/Efficacy Working Party Confidence Intervals Cooperative Ovarian Cancer Group for Immunotherapy Complete Response Case Report Form Contract Research Organization Computerized Tomography Common Toxicity Criteria Curricula Vitae Double Blind Observation Department of Health and Human Services Dose Limiting Toxicity Data Monitoring Analysis Plan Data and Safety Monitoring Board Drug Safety Unit Ethics Committee Electrocardiogram Eastern Cooperative Oncology Group European Union Food and Drug Administration International Federation of Gynecology and Obstetrics Good Clinical Practice Good Manufacturing Practice Global Medical and Safety Service (PRA International) Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 4 of 66 GP γ-GT HAMA Hb HIPAA HIV HR IB ICH IM IND IP IRB ITT IV IVRS LDH Mab MITO NCI-CTC NMR NYHA OC125 OS PFS POC PR PS RFS SAE SAP SC SOP SUSAR TAA ULN WBC WMA General Practitioner γ-Glutamyl Transferase Human Anti Mouse Antibody Haemoglobin Health Insurance Portability and Accountability Act Human Immunodeficiency Virus Hazard Ratio Investigator’s Brochure International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Intramuscular Investigational New Drug Intraperitoneal Institutional Review Board Intent To Treat Intravenous Interactive Voice Recognition System Lactate Dehydrogenase Monoclonal antibody Multicenter Italian Trials in Ovarian cancer National Cancer Institute-Common Toxicity Criteria Nuclear Magnetic Resonance New York Heart Association Monoclonal antibody that binds to CA125 Overall Survival Progression Free Survival Proof-Of-Concept Partial Response Performance Status Recurrence Free Survival Serious Adverse Event Statistical Analysis Plan Subcutaneous Standard Operating Procedure Suspected Unexpected Serious Adverse Reaction Tumor associated antigen Upper Limit of Normal White Blood Cells World Medical Association Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 5 of 66 TABLE OF CONTENTS ABBREVIATIONS ..................................................................................................................................................... 4 1 PROTOCOL SYNOPSIS ................................................................................................................................ 9 2 INTRODUCTION ......................................................................................................................................... 19 3 2.1 THE INVESTIGATIONAL PRODUCT: ABAGOVOMAB......................................................................................20 2.2 CLINICAL EXPERIENCE WITH ABAGOVOMAB ..............................................................................................20 2.2.1 Phase Ib/II study - Proof of concept for specific immune response induced by Abagovomab and tolerability of repeated doses ............................................................................................................... 21 2.2.2 Phase I studies: influence of dose, route of administration and duration of treatment on the specific immune response induced by Abagovomab and its tolerability............................................................ 22 2.2.3 Summary of clinical experience with Abagovomab .............................................................................. 25 ETHICAL AND LEGAL ASPECTS ........................................................................................................... 26 3.1 GENERAL ASPECTS ......................................................................................................................................26 3.2 INDEPENDENT ETHICS COMMITTEE AND LEGAL REQUIREMENTS ................................................................26 3.3 SUBJECT INFORMATION AND INFORMED CONSENT ......................................................................................26 3.4 SUBJECT INSURANCE ...................................................................................................................................27 3.5 RECORD RETENTION ...................................................................................................................................28 3.6 CONFIDENTIALITY .......................................................................................................................................28 3.7 PROTOCOL ADHERENCE AND STUDY PROTOCOL AMENDMENTS .................................................................29 3.8 STUDY COMMENCEMENT ............................................................................................................................29 3.9 USE OF INFORMATION AND PUBLICATION ....................................................................................................30 4 QUALITY ASSURANCE ............................................................................................................................. 31 5 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURES................................................ 32 6 STUDY OBJECTIVES.................................................................................................................................. 34 7 INVESTIGATIONAL PLAN ....................................................................................................................... 35 7.1 OVERALL STUDY DESIGN AND PLAN DESCRIPTION ....................................................................................35 7.2 DISCUSSION OF STUDY DESIGN AND PLAN DESCRIPTION ............................................................................38 7.3 RANDOMIZATION ........................................................................................................................................39 7.4 STUDY POPULATION ....................................................................................................................................39 7.4.1 Number of subjects/centers................................................................................................................... 39 7.4.2 Inclusion Criteria ................................................................................................................................. 40 7.4.3 Exclusion criteria ................................................................................................................................. 40 7.4.4 Removal of subjects from therapy or assessment ................................................................................. 41 Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 6 of 66 7.5 7.5.1 Identity of Investigational Drugs .......................................................................................................... 41 7.5.2 Packaging............................................................................................................................................. 42 7.5.3 Labeling................................................................................................................................................ 42 7.5.4 Storage of Study Medication, Accountability and Dispensing.............................................................. 42 7.5.5 Schedule of Administration................................................................................................................... 43 7.5.6 Dose Adjustment and Modification ...................................................................................................... 43 7.5.7 Discontinuation of Treatment............................................................................................................... 43 7.5.8 Concomitant Treatments ...................................................................................................................... 44 7.6 STUDY PROCEDURES ...................................................................................................................................44 7.6.1 Efficacy and Safety Measurement Flowchart ....................................................................................... 44 7.6.2 Screening/Randomization..................................................................................................................... 46 7.6.3 Treatment and Double Blind Observation Period ................................................................................ 46 7.6.4 End of treatment and double blind observation period ........................................................................ 48 7.6.5 Overall survival follow-up.................................................................................................................... 48 7.7 EFFICACY AND SAFETY ASSESSMENT ..........................................................................................................48 7.7.1 Primary efficacy endpoint .................................................................................................................... 48 7.7.2 Secondary efficacy endpoints ............................................................................................................... 49 7.7.3 Safety Assessment ................................................................................................................................. 50 7.7.4 Monitoring of Adverse Events .............................................................................................................. 50 7.7.5 Breaking of Treatment Code................................................................................................................. 52 7.7.6 SAE Reporting ...................................................................................................................................... 52 7.7.7 24 - hour Medical Monitoring and SAE fax receipt ............................................................................. 53 7.8 8 TREATMENT ................................................................................................................................................41 STUDY COMMITTEES ...................................................................................................................................53 7.8.1 Steering Committee .............................................................................................................................. 54 7.8.2 Independent Clinical event Adjudication Committee (CEAC).............................................................. 54 7.8.3 Data and Safety Monitoring Board (DSMB) ........................................................................................ 54 7.8.4 Data Quality Management ................................................................................................................... 54 STATISTICAL METHODS ......................................................................................................................... 56 8.1 SAMPLE SIZE DETERMINATION ...................................................................................................................56 8.2 ANALYSIS POPULATIONS .............................................................................................................................56 8.3 ANALYSIS VARIABLES .................................................................................................................................57 8.3.1 Primary efficacy variable ..................................................................................................................... 57 8.3.2 Secondary efficacy variable: overall survival ...................................................................................... 58 8.3.3 Other secondary efficacy variables ...................................................................................................... 58 8.4 STATISTICAL ANALYSIS ..............................................................................................................................58 Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 7 of 66 8.4.1 Descriptive statistics............................................................................................................................. 58 8.4.2 Baseline analysis .................................................................................................................................. 59 8.4.3 Primary efficacy analysis ..................................................................................................................... 59 8.4.4 Sensitivity analysis of the primary variable.......................................................................................... 60 8.4.5 Secondary efficacy analysis.................................................................................................................. 60 8.4.6 Multiplicity issues................................................................................................................................. 60 8.4.7 Safety analysis ...................................................................................................................................... 60 8.4.8 Subgroup analysis ................................................................................................................................ 60 8.5 ON-STUDY AND PRE-STUDY CLOSURE ACTIVITIES .......................................................................................61 8.5.1 Protocol Violations and Blind Review.................................................................................................. 61 8.5.2 Data Monitoring................................................................................................................................... 61 8.5.3 Interim analysis .................................................................................................................................... 61 8.5.4 Stopping rules....................................................................................................................................... 61 8.5.5 DSMB analysis ..................................................................................................................................... 61 8.6 STATISTICAL ANALYSIS PLAN .....................................................................................................................62 9 REFERENCES .............................................................................................................................................. 63 10 APPENDICES................................................................................................................................................ 66 APPENDIX I Declaration of Helsinki APPENDIX II Subject Information and Informed Consent Form APPENDIX III Charter of Clinical Event Adjudication Committee (CEAC) APPENDIX IV Charter of Data Safety and Monitoring Board (DSMB) Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 8 of 66 < 1 PROTOCOL SYNOPSIS Study Title A randomized, double blind, placebo controlled, multicentre trial of Abagovomab maintenance therapy in patients with epithelial ovarian cancer after complete response to first line chemotherapy. Study Code Sponsor Code: ABA-01 BB-IND BB-IND 10724 EuDRACT No. EuDRACT No. 2006-002801-30 Study Drug Abagovomab: murine anti-idiotypic antibody against CA125 antigen. Clinical Phase Phase II/III. Duration of the study 48 months: estimated duration of double blind observation (DBO) period with start/end expected on 3Q 2006 / 3Q 2010. AGO Study Code: AGO-OVAR 10 After the end of DBO period, overall survival data will continue to be collected in an open fashion, for additional 5 years (i.e. up to 7 years from the randomization of the last patient). Objectives Primary objective: To evaluate the benefit in terms of recurrence free survival (RFS) of Abagovomab vs placebo as maintenance therapy after clinical complete response to debulking surgery and standard platinum/taxane 1st line chemotherapy. Secondary objectives: 1. to compare the effect of Abagovomab vs placebo in terms of overall survival (OS); 2. to evaluate the safety and tolerability of repeated doses of Abagovomab; 3. to evaluate the time course of immune response induced by repeated doses of Abagovomab, namely induction of Ab3 and HAMA; 4. to evaluate in a subset of approximately 10% of patients additional immunologic parameters (i.e. Ab1’ and CA125-specific T cell response). Study centers Approximately 120 centers distributed in Europe and USA. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 9 of 66 Study design Randomized, double blind, placebo controlled, multinational, multicentre study, with randomization 2:1 to abagovomab: placebo. Study Treatments/ Abagovomab verum 2mg/ml suspension for subcutaneous (SC) injection. Schedule and Route of Administration Abagovomab placebo suspension for SC injection. During the first 6 weeks of treatment (induction phase) patients will receive the study drug as 1 ml suspension by SC route every 2 weeks (i.e. at randomization and then at week 2, 4 and 6). Thereafter (maintenance phase), the study drug will be administered SC every 4 weeks until evidence of disease recurrence or up to 94 weeks (approximately 21 months) after the randomization of the last patient. Any additional anti-cancer therapy will not be allowed until evidence of disease recurrence. Number of patients 870 randomized patients, of which 580 in the Abagovomab arm and 290 in the placebo arm. Inclusion criteria At a maximum of 8 weeks after the last cycle of 1st line standard platinum/taxane chemotherapy, patients must fulfil all the following inclusion criteria to be eligible for entry into the study: Age ≥ 18 years; Properly executed written informed consent; History of histological and CA125 (> 35 U/ml) confirmed diagnosis of stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer; History of debulking surgery and standard platinum/taxane based non-investigational chemotherapy; Complete clinical response defined as: Normal physical examination; No symptoms suggestive of persistent cancer; No definite evidence of disease by computed tomography (CT) of the abdomen and pelvis within the previous 4 weeks; Negative chest x-ray (or chest CT scan) within the previous 4 weeks; Serum CA125 level < 35 U/ml. Adequate hematologic, renal and hepatic function: ANC >1.5 x 109/l; Platelets > 75 x 109/l; Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 10 of 66 Exclusion criteria Haemoglobin > 6.2 mmol/l (>9.9 mg/dl); Serum creatinine < 1.5 x ULN; Bilirubin < 1.5 x ULN; AST, ALT, AP < 2.5 x ULN. ECOG Performance Status (PS) < 2. Patients are ineligible to participate in the study, if any of the following criteria are present: any other invasive malignancies, with the exception of nonmelanoma skin cancer or cervical carcinoma in situ, within the last 5 years or whose previous cancer treatment contraindicates this protocol therapy; known active autoimmune disease requiring chronic treatment with immunosuppressive agents (e.g., rheumatoid arthritis, ulcerative colitis, etc.); known immune deficiency (e.g. HIV, hypogammaglobulinemia, etc.); known infection with hepatitis B, or hepatitis C; history of recent myocardial infarction (< 6 months) or decompensated heart failure (NYHA class > III); previous or concomitant use of any anti-cancer therapy other than the platinum-taxane 1st line chemotherapy; concomitant use of any other investigational agent; any prior investigational anti-cancer vaccine or monoclonal antibody; known allergy to murine proteins; any significant medical or psychiatric condition, drug or alcohol abuse that might prevent the patient from complying with all study procedures; clinically significant active infection; concomitant use of any immunosuppressive agent (e.g., steroids, cyclosporin, etc.); major surgery within the previous 2 weeks; radiotherapy within the previous 4 weeks; any significant toxicity from prior chemotherapy; unreliability or inability to follow protocol requirements. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 11 of 66 Study procedures Screening/Randomization Patients will be screened and randomized within a maximum of 8 weeks from the last cycle of standard platinum/taxane chemotherapy. Screening procedures (encompassing informed consent signature, verification of inclusion/exclusion criteria and baseline laboratory procedures, see attached flow chart of study schedule) should be completed within 2 weeks prior to randomizing eligible patients to Abagovomab or placebo (2:1 ratio). CT of abdomen and pelvis and chest X-ray must be performed within 4 weeks of randomization. The randomization will be stratified by the following baseline prognostic factors in order to preserve the randomization ratio within each stratum: Tumor size after debulking surgery (i.e. residual tumor < 1 cm; > 1 cm); FIGO stage (i.e. III; IV); Serum CA125 level after the first 3 cycles of chemotherapy (< 35 U/ml, > 35 U/ml). Treatment/Double blind Observation (DBO) period After randomization, patients will be visited for safety evaluation and will receive study treatment every 2 weeks for the first 4 doses (induction phase) and, starting from week 10 (end of induction/start of maintenance phase) every 4 weeks until the end of treatment, which will occur after 21 months from the randomization of the last patient. CT scan of abdomen and pelvis, and any other imaging techniques if needed, will be performed every 12 weeks, together with physical and gynecological examination for assessment of disease recurrence. Chest x-ray will be repeated every 24 weeks. Vital signs measurement and blood sampling for safety laboratory parameters will be performed at week 4, week 10, and then every 12 weeks. CA 125 assay will be performed at week 0 (i.e. the same day of the first Abagovomab administration), at week 10 and then every 12 weeks and results will be kept blinded until the end of double blind period. Blood sampling for immunologic evaluation will be performed at week 0, at week 10, and repeated at week 22, 58, and 94, and in any case at the final study visit (see below). Patients who remain on treatment until the end of DBO period will attend a final study visit for safety and efficacy 12 weeks after the last administered dose. In case of early treatment discontinuation patients will also attend a final study visit 12 weeks from the last administered dose (or within 4 weeks and without CT scan in case of treatment discontinuation for disease recurrence). All patients who early discontinued the study Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 12 of 66 treatment will continue to be monitored for safety and survival status by phone or mail (either directly or via the patient’s general practitioner - GP) every 12 weeks until the end of DBO period. Along the study all patients will have assessments scheduled at the same interval and frequency. End of treatment and End of DBO period Treatment administration will end 21 months after the randomization of the last patient and the DBO period of study will end 12 weeks later, i.e. 24 months after the randomization of the last patient. At that time all patients on treatment will undergo a final study visit, encompassing the same efficacy and safety assessments scheduled during the observation period. Patients who have prematurely discontinued study treatment will undergo the final visit as described above. Survival follow-up After the end of double blind period, survival data will continue to be collected in an open fashion by phone or mail (either directly or via the patient’s GP) every 3 months for 5 years (i.e. up to 7 years from the date of randomization of the last patient). Overall, based on a 2-year recruitment time, the individual observation period (double blind) for evaluation of recurrence free survival (RFS) will range from 2 up to 4 years, with a minimum treatment period of 21 months and a minimum observation period of 2 years. For survival, the expected individual follow-up period (double blind + open) will range from 7 to 9 years. Efficacy and assessments safety Efficacy: Physical and gynecological examination and CT scan of abdomen and pelvis will be obtained at screening (CT scan to be repeated if not performed in the previous 4 weeks prior to randomization), at week 10 (end of induction phase/start of maintenance phase) and then every 12 weeks, with the last assessment performed at the final study visit (without CT-scan if disease recurrence has been previously documented) Chest X-ray will be performed at screening (if not performed in the previous 4 weeks prior to randomization) and every 24 weeks and at the final study visit (not to be performed in case disease recurrence has been previously documented). CT scan can be performed at any time during the study if disease recurrence is suggested by physical examination or other clinical findings. Additional imaging techniques (e.g. NMR) may be performed if specifically requested by the Investigator to document disease recurrence. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 13 of 66 Immunologic tests (Ab3, HAMA) will be performed in all patients at week 0, and repeated at week 10 (end of induction phase/start of maintenance phase), and at week 22, 58 and 94 and in any case at the final study visit. At the same time points additional immunologic parameters will be measured in a subset of approximately 10% of patients. Serum CA125 must obtained in each patient during the screening procedure and will be used by the investigator to confirm the completeness of the clinical response. Serum CA125 will be also assayed at week 0, at week 10 and then every 12 weeks until the end of DBO period. All the CA125 assays obtained after the screening phase will be performed in a centralized lab facility independent from Sponsor and Investigators. The results of these CA125 assays will be kept blinded along the DBO period. Survival status will be collected along study conduct. After the DBO period or after early treatment discontinuation, survival data will continue to be collected in each patient every 12 weeks by phone or mail (either directly or via the patient’s GP) for additional 5 years (i.e. for 7 years after the date of randomization of the last patient). Safety: Before receiving any study treatment dose, patients will undergo a general medical visit for monitoring of adverse events and recording of any change in concomitant medication and ECOG performance status at week 0, and then every 2 weeks (induction phase) and every 4 weeks starting from week 10 (maintenance phase). Clinical laboratory tests and vital signs measurements will also be performed prior to dosing, at week 4, week 10 and then every 12 weeks, with the last assessment performed at the final study visit (12 weeks after last administered dose). For patients with premature treatment discontinuation a final study visit will be performed within 4 weeks (in case of discontinuation for disease recurrence) OR 12 weeks (any other reason) from last administered dose. Thereafter, safety will continue to be monitored every 12 weeks until completion of the DBO period by phone (or by visit at the center if deemed appropriate by the investigator) for collection of any adverse drug reactions. An independent Data and Safety Monitoring Board will review the safety data on a regular basis along study conduct. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 14 of 66 Study end points Efficacy Primary end point: Recurrence Free Survival (i.e. time from the date of randomization to documentation of disease recurrence or death from any cause). Disease recurrence is defined as the appearance of any lesion or development of tumor-related symptoms evaluated by medical examination and documented by CT scan. If the CT scan is not informative enough to document or to rule out the recurrence of disease, additional imaging techniques (e.g. NMR, etc) should be requested by the Investigator to document disease recurrence. Ultrasound documentation is not accepted per se as adequate documentation of disease recurrence. If any additional imaging technique leads to the diagnosis of recurrence, then the disease recurrence has to be considered as ‘documented’ even in the presence of a negative CT scan. In addition, the histologic or cytological documentation of disease recurrence can substitute imaging confirmation in case of pleural or peritoneal effusion. An independent Clinical Event Adjudication Committee (CEAC) will review all the imaging documentation and any pertinent clinical data in double blind condition, in order to assess the recurrence of the disease as well as the date of recurrence. The assessment of disease recurrence made by the CEAC will be used for the primary efficacy analysis, whereas the assessment made by the investigator will be used for clinical management of the patient. Secondary end points: Overall Survival (i.e. time from the date of randomization to all-cause death). Safety Incidence and severity of toxicity, recorded by the US-NCI Common Toxicity Criteria (CTC v.3). Immunologic evaluation Time course of Ab3 and HAMA levels. Time course of Ab1’ and CA125-specific T cell response (in a subset of approximately 10% patients). Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 15 of 66 Sample size A total number of 870 randomized patients (580 in the Abagovomab arm and 290 in the placebo arm) will provide more than 90% power in rejecting the null hypothesis of equality between Abagovomab and placebo on RFS according to the following assumptions: Median RFS for placebo arm = 18 months; Hazard ratio in RFS between Abagovomab and placebo = 1.33 (leading to an approximate benefit of 6 months of Abagovomab over placebo); Recruitment period = 24 months; Minimum follow-up for each patient = 24 months (i.e. average time on-study of 36 months); Significance level (α) = 5% (two-sided) Overall drop-out rate = 10% The expected number of recurrences to observe in the trial is 535 (338 in the Abagovomab arm and 197 in placebo arm). The sample size of 870 randomized patients will also provide more than 80% power for detecting the superiority of Abagovomab over placebo in the secondary end-point of overall survival (OS) according to the following assumptions: Median OS for placebo arm = 40 months; Hazard ratio in OS between Abagovomab and placebo = 1.30 (leading to an approximate benefit of 12 months of Abagovomab over placebo); Minimum follow-up for each patient = 84 months (i.e. average time of survival follow-up of 96 months); Significance level (α) = 5% (two-sided). No adjustment for multiplicity will be adopted due to the nature of the secondary analysis. Analysis population Safety Population: all patients receiving at least one study drug administration. ITT population: all patients randomized. Per Protocol population: all the patients of the ITT population excluding patients who experience major protocol violations prior to the documentation of ‘disease recurrence’, if any. Statistical analyses The primary analysis will answer to the primary trial objective by applying a Cox proportional hazard model having treatment as major covariate and adjusted by the three predefined prognostic stratification factors. The same model will be applied also for the evaluation of the secondary endpoint, OS, at the end of the survival follow-up. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 16 of 66 STUDY SCHEDULE SCREENING/ RANDOMIZATION TREATMENT/DOUBLE BLIND OBSERVATION PERIOD OPEN SURVIVAL Follow Up up to 2 yrs after last randomized pt 8 wks from last chemotherapy cycle Treatment Administration/Efficacy and Safety Assessment W-2 to W0* Abagovomab/placebo Inclusion/exclusion criteria Informed consent Demographics Medical history PS (ECOG) Physical and Gynecological examination Vital signs 12-lead ECG Haematology/Serum Chemistry/Urinalysis Serum CA125 marker CT scan (abdomen & pelvis) Chest X-ray HAMA, Ab3 tests Adverse Events Concomitant medication Survival status X X X X3 X X Induction Phase W0* W2 W4 W6 X X X X X X X X X X X X X5 X7 X Study Protocol ABA-01, Version 1.0, 4 August 2006 Maintenance Phase every 4 every 12 wks wks 2 X X W10 X X X Final Study Visit1 12 wks after last dose1 X X X X X X X X X X X X4 X4 X X X Monitored throughout the observation period9 10 10 10 10 10 X X X X X 11 Monitored throughout the observation period X4 X X7 X8 X4 X6 X7 X X9 10 X 11 X 10 X up to 7 yrs after last randomized pt Survival status every 12 wks Page 17 of 66 NOTE to the STUDY SCHEDULE * Week 0 corresponds to randomization and first administration of study treatment. 1 Final study visit for safety and efficacy corresponds to end of the double blind observation period (24 months after the last randomized patient and 12 weeks after the last administered dose) for regular end of treatment. In case of early treatment discontinuation, the final study visit will be performed 12 weeks after the last administered dose or within 4 weeks (and without CT scan and chest X-ray) in case of treatment discontinuation for disease recurrence. 2 Abagovomab or placebo will be administered every 4 weeks up to 94 weeks (approx. 21 month) after last randomized patient OR until disease recurrence is documented. 3 Including main tumor characteristics (e.g. histopathological grading, FIGO stage III/IV and III sub-categories [IIIA, IIIB, IIIC)], size f the residual tumor after surgery [0 cm, < 1cm, > 1cm]). 4 Samples will be collected but results of CA125 assay will be kept blinded until the end of DBO period. 5 CT scan to be done at screening if performed > 4 weeks prior to randomization. 6 CT scan to be repeated at final study visit only if disease recurrence has not been previously documented. 7 Chest X-Ray to be done at screening if performed > 4 weeks prior to randomization; to be repeated every 24 wks, and at final study visit (only if disease recurrence has not been previously documented). 8 ONLY at week 22, 58 and 94. 9 AE to be recorded at study center prior to each dose. In case of early treatment discontinuation (for disease recurrence or any other reason) adverse events will continue to be monitored by phone (or visit at center if deemed appropriate by the investigator) for collection of ADRs up to the end of the double blind observation period. 10 ONLY changes in concomitant medication from screening will be recorded. 11 In case of early treatment discontinuation (for reasons other than death) survival status will continue to be monitored in double blind condition by phone every 12 weeks up to the end of the double blind observation period, and then in open fashion during the survival follow up Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 18 of 66 2 INTRODUCTION Ovarian cancer is the sixth most common cancer in women, accounting for 204,572 new cases every year worldwide and it is the leading cause of gynecological cancer deaths in EU and in USA. In 2002, the incidences of ovarian cancer in Europe and USA were estimated at 63,467 and 22,491 new cases, respectively (Ferlay J et al, 2004). At the time of diagnosis, over 70% of patients present with advanced disease, which requires an aggressive therapeutic approach (surgery plus cytotoxic chemotherapy). The overall 5-year survival rate for patients with advanced stage disease is about 20-30% (Berek JS et al., 2003). The optimal management of patients with advanced ovarian cancer achieving a clinical complete response (CR) after surgery and first-line chemotherapy (platinum/taxane based) remains to be determined. Despite the good response rate reported after first line chemotherapy (up to 80%), the disease will recur in the majority of patients. Experimental administration of paclitaxel (12 vs 3 cycles) administered intravenously (IV) q28 days as maintenance therapy in women with clinical CR after 6 cycles of platinum/paclitaxel regimen led to a prolongation of progressionfree survival (PFS) (21 vs 28 months, after 3 cycles and 12 cycles, respectively) (Markman M et al., 2003). However, recent data shows no impact of this regimen on overall survival (Markman M et al., 2006). Similar findings were obtained from the Multicentre Italian Trials in Ovarian Cancer (MITO) group, where 4 cycles of topotecan, administered as maintenance therapy to patients responding to standard carboplatin and paclitaxel first-line therapy failed to demonstrate benefit in terms of progression free survival (PFS) (De Placido S et al., 2004). Alternative therapies (e.g. maintenance or consolidation therapy) that would delay or prevent recurrences after obtaining a CR, ideally with minimal toxicity and without adversely impacting the patients’ quality of life, are strongly needed (Ozols R, 2003; Sabbatini P et al., 2006). Among innovative strategies using immunologic approaches against tumor-associated antigens, Oregovomab (Mab-B43.13, Ovarex), a monoclonal antibody directed against the tumorassociated antigen (TAA) CA125 and currently in Phase III clinical development, demonstrated a significant prolongation of median time to relapse in comparison to placebo (24.0 vs 10.8 months); however benefit was obtained only in a population with ‘favourable prognostic factors,’ defined as optimal debulking surgery, a complete response to first-line chemotherapy, and a positive immune response to treatment (Berek JS et al., 2004). Clinical data to date with Abagovomab, a murine monoclonal anti-idiotypic antibody, able to induce an active response against the CA125 TAA, is promising and warrants a randomized trial to confirm efficacy. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 19 of 66 2.1 THE INVESTIGATIONAL PRODUCT: ABAGOVOMAB The active drug substance (Abagovomab) is a murine monoclonal antibody (MW 165-175 kDa) generated against the murine antibody OC125, which is able to recognize specifically the TAA CA125 and to induce an active immune response against it. Immunization of patients with Abagovomab demonstrated to induce an anti-anti-idiotypic immune response (Ab3) which leads to an anti-CA125 immune reaction (Wagner U et al., 2001). Since the high-molecular weight glycoprotein CA125 is detectable in more than 80% of patients with epithelial ovarian cancer, the therapeutic administration of a specific vaccine capable of inducing a sufficient immune response against CA125 represents a promising approach. The generated immune response can be considered in the context of the immune network hypothesis of Niels Jerne (Jerne NK, 1974). According to this theory, the anti-TAA antibody (Ab1) variable antigen-binding regions contain immunogenic idiotypic determinants that are able to induce the production of so-called antiidiotypic antibodies (Ab2). A subset of these antibodies is able to mimic functionally the original antigen. The immunization obtained by anti-idiotypic antibodies is expected to induce in the patient a specific humoral immune response (Ab3 and Ab1’) together with the cellular reaction directed against cells expressing the original TAA. The drug product is a white suspension for subcutaneous injection containing the anti-idiotypic antibody Abagovomab adsorbed onto aluminum hydroxide and suspended in a buffered and isotonic saline solution to adjust the pH to about 7.5. The drug product is free of any preservatives. It is provided in type I glass vials closed with a rubber stopper and an aluminum flip-off cap. The final product is manufactured according to GMP and relevant regulatory requirements for parenteral preparations. Abagovomab drug product is available in 2 mg/ml vials, with each dose to be administered as 1 ml suspension by subcutaneous route every two weeks during the induction phase (first four doses) and then every 4 weeks during the maintenance phase. Stability studies indicate that Abagovomab is stable at 2 °C to 8 °C for at least 6 months. 2.2 CLINICAL EXPERIENCE WITH ABAGOVOMAB The clinical development of Abagovomab went through three clinical studies, starting with a Phase Ib/II Proof of Concept (POC) study to demonstrate the safety of Abagovomab and its ability to stimulate a specific immunologic response, and followed by two Phase I clinical studies (one of these studies performed under IND in the USA) which evaluated the effect of different doses, routes of administration and duration of treatment on the safety and immune response, prior to selecting the optimal dose/schedule for the Phase II-III pivotal trial. The main results of the POC study have been previously published (Wagner U et al., 2001; Reinartz S et al., 2004). Results from the two Phase I studies are in press (Sabbatini P et al., 2006; Pfisterer J et al., 2006). A brief summary of the three studies is included. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 20 of 66 2.2.1 Phase Ib/II study - Proof of concept for specific immune response induced by Abagovomab and tolerability of repeated doses Study title: Anti-idiotype vaccine for patients with advanced ovarian carcinomas with the murine monoclonal anti-idiotype antibody Mab ACA125 (Anti-ID OC 125): determination of immunological therapy effects (Phase Ib/II) – Study Code DFG Wa 740/2-1 This was a Phase Ib/II, multicenter study to evaluate the safety and immunogenicity of repeated doses of Abagovomab in 119 patients with recurrent ovarian cancer, carcinoma of the fallopian tube, peritoneal carcinoma or with other CA125-positive malignant tumors. Patients were eligible for treatment if they had positive history of debulking surgery and previous platinumbased chemotherapy. Abagovomab was to be administered as a 1 ml suspension containing 2 mg of Abagovomab via intra-muscular (IM) route every 2 weeks for a total of 4 doses (induction Phase), followed by monthly doses until disease progression. Safety and efficacy (immune and clinical responses) of repeated Abagovomab vaccinations were the main study endpoints. The median overall survival was also assessed. The population recruited in this ‘first in human’ study was heterogeneous, particularly in terms of types and number of cycles of previous therapies, and therefore in terms of prognosis. Mean patient exposure to Abagovomab was 9.7 doses for a median of 4.9 months (range 0.554.8 months). Repeated 2 mg IM vaccinations were well-tolerated and no drug-related serious adverse events were reported. The most frequent drug-related adverse event (i.e. with drug relationship classified as any of the following: certain/definitely related, probable, possible and unknown/conditional unclassified) was local reaction at the injection site, reported in 13 patients (25 events). No serious allergic reactions could be detected within a follow up period of up to 56 months. A specific anti-anti-idiotypic antibody (Ab3) was induced in 68.1% of patients; antiCA125 antibodies (Ab1’) were induced in 50.4% of patients and an antibody-dependent cellmediated cytotoxicity (ADCC) was observed in the serum of 26.9% of patients. In terms of the scheduled doses, the results of the study suggested that a median of 4 induction bi-weekly doses was sufficient to induce detectable Ab3 titers. The monthly repeated administrations of Abagovomab were then able to maintain an elevated Ab3 titer, as depicted below. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 21 of 66 Serum Ab3 concentration in responding patients who received repeated monthly doses of Abagovomab (Phase I/II POC study results) 13 Natural logarithm of Ab3 titre (ng/ml) 12 11 10 9 Mean Median 8 7 6 5 4 3 2 1 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104 108 112 Weeks The median survival of all patients was 19.4 months (range 0.5-56.1 months). Notably, patients with an Ab3 response (Ab3+) showed a significantly longer survival (median 23.4 months) compared with patients without an immune response (Ab3-) (median 4.9 months) (p<0.001). It is also worth mentioning that Ab3 responders received more Abagovomab doses compared with the Ab3 non-responders (mean 12.3+9.5 vs. 4.3+2.1), with the ‘responding’ patients being in the study for a longer time. 2.2.2 Phase I studies: influence of dose, route of administration and duration of treatment on the specific immune response induced by Abagovomab and its tolerability Two studies have been performed: - Study title: Phase I trial of the monoclonal anti-idiotype antibody ACA125 in patients with epithelial ovarian, fallopian tube, or peritoneal cancer – Study Code ACA125-01 The aim of this open label, randomized study was to compare the safety and efficacy (in terms of immune response) of two different doses (0.2 mg and 2 mg as 1 ml solution) of Abagovomab, administered either by the intramuscular (IM) or the subcutaneous (SC) route, in order to evaluate any potential effect of the dose and/or the route of administration on the induction of an immune response. The trial was performed under IND in three centers in the USA including 44 patients (42 received study treatment) with stage II-IV epithelial ovarian cancer. Eligible patients received at least one platinum-based chemotherapy regimen before study entry and could have had asymptomatic residual disease or elevated CA125 or could have been in complete clinical remission. A total of six Abagovomab vaccinations were scheduled and given every two weeks, Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 22 of 66 for a total of 4 injections during the induction phase (week 0, 2, 4, 6), and then monthly for two additional injections (maintenance phase). Study endpoints were the safety of and immune response to Abagovomab in the four treatment groups (0.2mg IM, 0.2 SC, 2 mg IM, 2mg SC). All 42 randomized patients received at least one administration of Abagovomab (9 patients in the 0.2 mg IM group and 11 patients in each of the remaining groups). The total number of vaccinations administered per patient ranged from 2 to 6, with 66.7% of patients receiving the 6 scheduled vaccinations. The major reason for early treatment termination was disease progression. Thirty-three patients reached the fourth dose and underwent immunologic tests: in all patients, regardless of the treatment group, Ab3 titer was positive at the first evaluation point (week 10), with a further increase in titer in the subsequent follow-up samples collected up to 6 weeks after the last administered dose (see tabulated summary data). Ab3 titer (mg/mL) by dose and route of administration (Phase I study) 0.2 mg IM Pts 2.0 mg IM Median Pts 0.2 mg SC Median Pts Median 2.0 mg SC Pts Median Visit 6 (Week 10) 6 69.8 10 40.5 10 53.3 7 63.0 Follow-up 1 (Week 16) 4 330.0 7 246.3 10 209.1 5 474.0 Follow-up 2 (Week 20) 4 489.1 4 193.1 8 179.5 3 364.5 Statistical tests showed that there was no effect of the route of administration or of the administered dose on Ab3 or HAMA titer. The best overall response obtained in Ab3+ patients (n=33) was stable disease (12 patients, 36.4%). Overall, 42 patients were evaluable for safety. The most frequent drug-related adverse events were reported in the following numbers of patients: injection site reaction (n=15), myalgia (n=15), injection site pain (n=14), and pyrexia (n=7); all but one of these adverse events were reported as Grade 1-2 CTC severity (there was one injection site erythema that was graded 3-4). No drug- related serious adverse events were reported. The results of this study confirmed the good tolerability of the 2 mg dose, which had previously been associated with improved overall survival in the POC study. The immune response induced by the SC route as well as its tolerability was not statistically or clinically different from that with the IM route; this would favor the SC route for repeated, long-term administration for patient convenience. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 23 of 66 - Study Title: A Phase I trial of ACA125 in patients with recurrent epithelial ovarian fallopian tube or peritoneal cancer - Study code AGO OVAR 2.8 The aim of this open-label study was to collect additional data on the 2 mg SC dose of Abagovomab and to compare the Ab3 response following a short (6 doses) versus longer (9 doses) treatment duration. Abagovomab was given as a 2 mg dose SC in both treatment duration arms. To fulfil the inclusion criteria, patients must have received a second-line chemotherapy (after failure of a platinum-based first-line chemotherapy) within the last 6 weeks and have asymptomatic measurable disease, elevated CA125 or to be in complete clinical remission. Thirty-six patients with stage I-IV epithelial ovarian cancer were enrolled. In this study, 88.9% of patients in the “short-term” arm completed the planned 6 vaccinations, while 44.4% of patients in the “long-term” arm received all the planned 9 vaccinations; for both arms, the main reason for premature study termination was disease progression. Thirty-three of 36 patients were evaluable for the immune response (in the remaining three patients Ab3 titer was not measured because they prematurely went off study due to progressive disease [n=2] and death [n=1]). Ab3 resulted positive in all evaluable patients (100%), with a further increase in the Ab3 titer in the treatment arm exposed to 9 doses of Abagovomab (see tabulated summary data). Ab3 titer (µ µg/mL) following 2 mg SC at the end of induction and during maintenance period (Phase I study) End of induction Maintenance period Week 10 Week 14 Week 26 No. Pts* Median No.Pts* Median No. Pts* Median Short treatment (6 doses) 17 47.0 16 96.0 - - Long treatment (9 doses) 14 48.1 12 109.5 8 292.9 * Number of patients reaching the assessment time point No severe drug-related toxicity was recorded in either treatment group. The most frequent adverse events (mainly grade 1-2) were: anemia, leucopenia, neutropenia, injection site reactions, fatigue and nausea. Overall, the results of this second Phase I/II study confirmed the good tolerability of repeated administrations of Abagovomab and provided additional supporting evidence on the induction of an active immune response using the 2 mg dose and SC route of administration selected for the Phase III trial. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 24 of 66 2.2.3 Summary of clinical experience with Abagovomab In phase I/II studies, Abagovomab proved to be effective in generating a specific immune response (as expressed as Ab3) against CA125 positive cells. Antibody responses were associated with increased survival. Treatment with Abagovomab was well tolerated independently from the duration of treatment and route of administration (SC vs IM). The results of these studies support the dose/schedule selection (2 mg SC every 2 weeks for 4 injections followed by monthly maintenance injections) that will be used in this randomized, double blind, multicentre trial in which Abagovomab will be compared to placebo as maintenance therapy in stage III-IV ovarian cancer patients after completion of successful frontline therapy (surgery and standard platinum-taxane chemotherapy). Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 25 of 66 3 ETHICAL AND LEGAL ASPECTS 3.1 GENERAL ASPECTS This study will be carried out in compliance with the study protocol, the recommendations on biomedical research on human subjects of the current version of Declaration of Helsinki (Appendix I), ICH-Good Clinical Practice Guidelines and local ethical and legal requirements. Furthermore, the study will be conducted in compliance with the Sponsor and/or the appointed Contract Research Organization (CRO) SOPs. All clinical work conducted under this protocol is subject to Good Clinical Practice rules. This includes an inspection by the Sponsor, Sponsor’s representatives and/or relevant Regulatory Health Authority representatives at any time. All investigators must agree to the inspection of study-related records by the relevant Regulatory Health Authority representatives and/or the Sponsor representatives, which must be performed in accordance with national laws concerning personal data protection. 3.2 INDEPENDENT ETHICS COMMITTEE AND LEGAL REQUIREMENTS Before starting any study procedure in a center, the corresponding independent Ethics Committee (EC)/Institutional Review Board (IRB) has to approve the study conduct. For this purpose documents requested by the IRB/EC for reviewing the clinical study have to be submitted to the corresponding IRB/EC. In addition, all national legal requirements for the conduct of a clinical trial have to be followed prior to start of the study. The competent authority and the IRB/EC of the participating country will be informed about the end of the study or the premature study termination within the requested time period. 3.3 SUBJECT INFORMATION AND INFORMED CONSENT The subject will be informed of the following: purpose of the research; explanation of the trial treatment(s) and probability for random assignment to each treatment; explanation of the expected duration of subject’s participation; approximate number of subjects involved in the study; description of procedures to be followed (i.e., visits, physical exam, laboratory tests, chest x-ray, CT scan, etc.); subject’s responsibilities; identification of any procedures that are experimental; description of any reasonably foreseeable risks or discomforts to the subject; possibility of unforeseen risks; description of benefits to the subject or to others reasonably expected from research (including possibility of no benefits); explanation of the extent to which Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 26 of 66 confidentiality will be maintained allowing access to original medical records by appropriate regulatory agency, IRB/EC, Sponsor or representative and statement that if the records of the trial are published, the subject’s identity will remain confidential; disclosure of appropriate procedures or alternative treatments and their risks and benefits; for research involving more than minimal risk, an explanation to whether any compensation and an explanation as to whether any medical treatment are available if injury occurs; an explanation of whom to contact with questions regarding the research, subject’s rights, and study related injury; a statement addressing voluntary participation (i.e., subject may refuse to participate without penalty or loss of benefits, subject may discontinue without penalty or loss of benefits); a statement naming circumstances under which a subject may be discontinued without consent; additional costs to the subject (if any) that may result from participation in the study; the consequences of a subject’s decision to withdraw and procedures for orderly termination (i.e., notify site, return diary and unused drug, have appropriate safety assessments completed); statement explaining that the subject or legal representative will be informed in a timely manner if information becomes available that may affect the subject’s willingness to participate in the trial; statement that a signed and dated copy of the consent form will be given to the subject; informed consent will not include any language that causes the subject, or the subject’s legal representative to waive or to appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor, or their agents from liability for negligence; and that the consent does not contain any language that coerces the subject to participate or to continue to participate in the study. HIPAA requirements must be met and the HIPAA statement must be signed by the subject or subject’s legal representative. The investigator will inform the subjects about the subject’s insurance taken out by the Sponsor and any duties that may arise therefrom. A subject information sheet and informed consent form explaining all the above-mentioned items in detail must be approved by the IRB/EC; it will be submitted to the subject in the corresponding native languages and in accordance with local laws and regulations and must be signed and dated by the subject before any trial-related procedure may be performed. A template of the information sheet and informed consent is provided in Appendix II. The investigator must store the original of the signed consent form in the Investigator‘s File. Any revision to the subject information sheet and/or written informed consent form must receive the independent ethics committee approval prior to implementation. 3.4 SUBJECT INSURANCE For subjects participating in the study, Menarini Ricerche S.p.A. has stipulated an insurance policy in accordance with regulatory requirements. A copy of the insurance certificate will be provided to each investigator and will be filed in the Investigator’s File at the centers and in the Trial Master File. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 27 of 66 3.5 RECORD RETENTION All documentation pertaining to the study will be kept by Menarini Ricerche S.p.A. for the lifetime of the product. The final report, pertaining to this study, will be kept for additional five years. CRO will provide each Investigator with an Investigator’s Site File, which should be used to file the Investigator’s Brochure, protocol, drug accountability records, correspondence with the IRB/EC, concerned authorities, Sponsor and CRO, and other study-related documents. As required by International Conference of Harmonization GCP guidelines, the Investigator must keep patient’s file and essential documents (including the Investigator’s copy of the CRF, patients information and consent forms, drug accountability records and Patient Identification List) until at least two years after the last approval of a marketing application in an International Conference of Harmonization region; until there are no pending or contemplated marketing applications in an International Conference of Harmonization region, or at least two years have elapsed since the formal discontinuation of clinical development of the investigational product. In addition, the Investigator must make provision for the patient’s records to be kept for the same period of time. No data should be destroyed without the consent of the Sponsor. Menarini Ricerche S.p.A. will inform the Investigator in writing of the need for record retention and will notify the Investigator in writing when the trial related records are no longer needed. Patients' records and other original data will be archived according to the archiving regulations or facilities of the investigational sites. The original CRFs will be archived by Menarini Ricerche S.p.A. with the final report and all other documentation pertaining to the trial according to the Sponsor’s SOPs. 3.6 CONFIDENTIALITY By signing this study protocol, the investigator affirms that any information furnished by Menarini Ricerche S.p.A. and/or Sponsor’s representative pertaining to this study will be maintained in confidence, and that such information will be divulged to IRB/EC or regulatory authorities only under an appropriate understanding of confidentiality with such a committee or institution. In order to maintain the subjects’ confidentiality, identification of all patients data collected from the investigator will be by subject initials and study number. The investigator agrees that within local regulatory restrictions and ethical considerations, Menarini Ricerche S.p.A. or its representative or any regulatory agency may consult and/or copy study documents in order to verify data in the CRF. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 28 of 66 The Investigator or a designee will maintain a personal list of subject numbers and subject names (Subject Identification List) to enable records to be found at a later stage. The subjects’ medical records pertinent to the study will be reviewed by the study monitors of the Sponsor or CRO or representatives of Sponsor’s and/or regulatory authorities, to assure adequate source documentation, accuracy and completeness of CRFs. The review will be conducted in accordance with the Sponsor and/or CRO SOPs and with strict adherence to professional standards of confidentiality, GCP and the relevant data protection legislation. 3.7 PROTOCOL ADHERENCE AND STUDY PROTOCOL AMENDMENTS An amendment is a written description of change(s) to or formal clarification of a study protocol which may impact on the conduct of the clinical study, potential benefit of the clinical study, or may affect subject safety, including changes of study objectives, study design, subject population, sample size, study procedures, or significant administrative aspects. Such amendments will be agreed upon and approved in writing by the Principal Investigator, the Sponsor’s representatives and the appointed CRO. If those amendments are substantial and are likely to have an impact on the safety of the patients, the Sponsor they will be submitted for approval to IRB/EC and regulatory authority(ies) in the participating country(ies) with reason and contents of these amendments for revision and approval. If the IRB/EC approves the amendment and the competent authority has raised no reason for non-acceptance of the amendment, the clinical trial will be conducted following the amended protocol. Changes which have no significant impact on medical or scientific validity of the study will be agreed upon and approved in writing by the Principal Investigator, Menarini Ricerche S.p.A. and the appointed CRO, and the IRB/EC will be notified of this protocol amendment. Any revision of the protocol will be integrated in an updated study protocol. The Principal Investigator must ensure full compliance with the updated study protocol. 3.8 STUDY COMMENCEMENT Prior to enrolment of any subject into the study, the Investigator must provide Menarini Ricerche S.p.A. and the appointed CRO with the following documents: • Signed copy (original) of the IRB/EC approved protocol; • IRB Membership List/DHHS Number; • IRB Approval Document; • IRB/EC Statement of GCP Compliance; • Form FDA 1572 (Investigator’s Statement); • Financial Disclosure Form; Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 29 of 66 • Proof of Medical Licensure; • Curricula vitae (CV) of all personnel who take part in the study; • Name and location of the laboratory used for laboratory assays including laboratory certification number and date of certification; • List of Normal Values for laboratory tests; • Investigator Acknowledgement of IB and addenda; • Copy of the approved Informed Consent form by the EC; • HIPAA Authorization content, if applicable. 3.9 USE OF INFORMATION AND PUBLICATION All information concerning the study drug supplied by Menarini Ricerche S.p.A. in connection with this clinical study, and not previously published, is considered confidential and proprietary information. The information includes the Investigator’s Brochure, the Investigational Medicinal Product Dossier, the Clinical Protocol, Case Report Forms and assay methods. This confidential information shall remain the sole property of Menarini Ricerche S.p.A., shall not be disclosed to others without prior written consent from Menarini Ricerche S.p.A. and shall not be used except in the performance of this clinical study. The information developed during the conduct of this clinical study is also considered confidential and will be used by Menarini Ricerche S.p.A. in connection with the development of the study drug. The Investigator is obliged to provide Menarini Ricerche S.p.A. or its other designee with complete test results, all study data and access to all study records derived from this clinical study. A clinical study report covering clinical and statistical aspects will be prepared by Menarini Ricerche S.p.A. or its designee. Menarini Ricerche S.p.A. recognizes the importance of communicating medical study data and therefore encourages their publication in reputable scientific journals and at seminars or conferences. Once the clinical study report is prepared, an original manuscript on the study results will be written by the coordinating investigators. Besides the coordinating investigators, members of the Steering Committee will be co-authors. Principal investigators of each recruiting center with corresponding Institutions will be also listed in a separate appendix. Any results of medical investigations with the study drug and/or publication/lecture /manuscripts base thereon, shall be exchanged and discussed with Menarini Ricerche S.p.A. representatives 60 days prior to submission for publication or presentation. Due regards shall be given to Menarini Ricerche’s legitimate interests, e.g., manuscript authorship, obtaining optimal patent protection, coordinating with other ongoing studies in the same field, and protecting confidential data and information. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 30 of 66 4 QUALITY ASSURANCE Audits may be conducted by the Quality Assurance Unit of CRO or Menarini Ricerche S.p.A. and an inspection by the regulatory authorities may also be conducted. This is to ensure that the performance and the data generation are in compliance with International Conference of Harmonisation guidelines for GCP and CRO Quality Procedures. At investigational sites, the auditor and inspector should have direct access to facilities, laboratories, and all data (including source data) and documentation for inspection. Confidentiality of patient data will be maintained. All audits and inspections will be documented and kept on record. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 31 of 66 5 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURES Coordinating Investigator Prof. Jacobus Pfisterer Frauenklinik Universitätsklinikum Mannheim D - 68167 Mannheim (GERMANY) Phone: +49 621 383 2386 Fax: +49 621 383 3814 E-mail: [email protected] Sponsor Menarini Ricerche S.p.A. Clinical Research Via Sette Santi 1 50131 Firenze (ITALY) Phone: +39 055 56809990 Fax: +39 055 5680597 Clinical Research, Corporate Director and Sponsor’s Representative Angela Capriati, MD, PhD Clinical Research, Director Full Development Lorenzo Melani, MD, PhD E-mail: [email protected] Clinical Research Physician Monica Bertolotti, MD E-mail: [email protected] Biostatistician Giacomo Mordenti, Stat.D E-mail: [email protected] Data Manager Simona Scartoni, Stat.D E-mail: [email protected] Drug Safety Manager E-mail: [email protected] Joaquim Vallés Laboratorios Menarini, S.A. Clinical Research Alfons XII, 587 08918 Badalona (Barcelona), Spain E-mail: [email protected] Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 32 of 66 Quality Assurance Head of Quality Assurance Contract Research Organization Project Manager EU Project Manager NA Drug Safety Unit Research Toxicology Center S.p.A. Quality Assurance Unit Via Tito Speri 12 I-00040 Pomezia (ITALY) Maria Mercede Brunetti, Biol D E-mail: [email protected] Pharmaceutical Research Associates España, S.A.U. Avenida de Europa, 19 Edificio 1, 2ª Planta 28224 Pozuelo de Alarcón Madrid (SPAIN) Phone: +34 91 708 1110 Fax: +34 91 708 1111 Mario Aznar E-mail: [email protected] Wendy Kerby E-mail: [email protected] Melanie Weber Drug Safety Center Europe PRA International Dybamostrasse 13-15 D-68165 Mannheim Phone + 49 621 8782-252 Fax + 49 621 8782-181 Email: [email protected] Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 33 of 66 6 STUDY OBJECTIVES Primary objective: To evaluate the benefit in terms of recurrence free survival (RFS) of Abagovomab vs placebo as maintenance therapy after clinical complete response to debulking surgery and standard platinum/taxane 1st line chemotherapy. Secondary objectives: 1. to compare the effect of Abagovomab vs placebo in terms of overall survival (OS); 2. to evaluate the safety and tolerability of repeated doses of Abagovomab; 3. to evaluate the time course of immune response induced by repeated doses of Abagovomab, namely induction of Ab3 and HAMA; 4. to evaluate in a subset of approximately 10% patients additional immunologic parameters (e.g. Ab1’ and CA125-specific T cell response). Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 34 of 66 7 INVESTIGATIONAL PLAN 7.1 OVERALL STUDY DESIGN AND PLAN DESCRIPTION ABA-01 is a randomized, double blind, placebo controlled, multicentre study. Abagovomab or placebo (2:1 ratio) will be administered as maintenance therapy in patients with epithelial ovarian cancer (FIGO stage III-IV) in clinical complete response after the completion of front-line treatment (surgery plus standard platinum/taxane chemotherapy). Randomization of patients to study treatment should be completed within 8 weeks from the last administered cycle of chemotherapy. The 8 week-time lag is deemed as the most appropriate to fully benefit from a biological agent as maintenance therapy in patients in complete disease remission. The study will be conducted and evaluated in accordance with all relevant international and national guidelines and regulations on GCP/ICH and with ethical standards for human experimentation established by the Declaration of Helsinki (see Appendix I). Every patient must provide written informed consent to participate in the study. The study will be performed in about 120 study centers in Europe and in USA, with a projected average number of seven patients/center. The study will be performed in double blind condition with a survival follow-up performed in open-label conditions, as follows: the double blind observation (DBO) period of study spans from the randomization of the first patient up to 24 months after the randomization of the last patient, with a minimum and maximum individual observation period for the evaluation of RFS of 24 and 48 months, respectively. During the DBO period, study treatment will be administered from randomization up to 21 month after the randomization of the last patient or until a disease recurrence is documented. The open survival follow-up will start from the end of DBO period and will be continued for additional 5 years, i.e. up to 7 years from the randomization of the last patient. The overall study plan and main assumption are depicted in the study flow-chart. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 35 of 66 Study Flow Chart End of DBO period Last drug intake End of Survival Follow-up Last pt in 1st pt in 0 24 months 108 48 3 months Double blind treatment and observation period Open Survival follow-up STUDY ASSUMPTIONS Recruitment period (expected): 24 months Treatment period: from randomization until disease progression or up to 21 months after randomization of the last patient Final study visit 12 weeks after the last administered dose for patients who regularly completed the treatment or in case of early treatment discontinuation for reasons other than disease recurrence; 4 weeks after last administered dose in case of early treatment discontinuation for disease recurrence. 48 months (24 months for recruitment + 21 month of treatment + 3 months for final estudy visit) Overall double blind study period : Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 36 of 66 RFS Observation period (double blind): Survival follow up: max: 48 months min: 24 months mean: 36 months max: 108 months min: 84 months mean: 96 months At a maximum of 8 weeks from the completion of the last chemotherapy cycle, patients with clinically documented complete response and no definite radiographic evidence of disease on CT scan of abdomen and pelvis and negative chest X-say, obtained within the previous 4 weeks, will be screened for eligibility and those who will meet all the inclusion criteria and none of the exclusion criteria will be randomized. Serum CA125 must be obtained in each patient during the screening procedure and will be used by the investigator to confirm the completeness of the clinical response. Screening procedures must be completed within 2 weeks prior to randomization and will be considered as baseline assessments (the only exception being Ca 125 level and immunological parameters collected at time= 0 that are considered as baseline assessment). During the first 6 weeks of treatment (induction phase) patients will receive a subcutaneous (SC) administration of study drug every 2 weeks (i.e. at randomization and then at week 2, 4 and 6). Thereafter (maintenance phase, starting from week 10), the study drug will be administered SC every 4 weeks until evidence of disease recurrence or up 94 weeks (approximately 21 months) after the randomization of the last patient. CT scan will be performed at week 10 and thereafter every 12 weeks until completion of DBO period or until documentation of recurrence. Chest X-ray will be performed every 24 weeks until completion of DBO period or until documentation of recurrence. CA125 assay will be performed at week 0 and subsequently at the same time points of CT scan, but results will be kept blinded until the end of DBO period. Safety will be evaluated by monitoring adverse events every 4 weeks (prior to each study drug administration); in addition physical examination, laboratory safety tests and vital sign measurements will be performed at week 4, week 10, and every 12 weeks until the end of DBO period. In case of early treatment discontinuation for disease recurrence, complete safety assessment will be performed at the final study visit within 4 weeks after the last administered dose; after then, safety will continue to be monitored by phone (via patient or patient’s GP) every 12 weeks until the end of DBO period for collection of adverse drug reactions. Survival status will be collected along the double blind observation period (by phone in case of early treatment discontinuation for disease recurrence or any other cause). Survival will continue to be monitored every 12 weeks by phone (to patient or patient’s GP) during the survival follow up period (i.e. up to 7 years from the randomization of the last patient). Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 37 of 66 The induction of a specific immune response will be periodically assessed during the trial by measuring the Ab3 and HAMA titers in all patients who received at least 1 treatment dose, with the last assessment performed at the final study visit. Furthermore, in a subset of about 10% of patients, additional immunologic assays (i.e. CA125 specific antibodies Ab1’and analysis of CA125-specific T cell immune response) will also be performed (see § 7.7.2). This subset of patients will be selected mainly on the basis of logistic considerations (e.g. close proximity of study center with the central lab performing the assays). The minimum patient’s observation (double blind) period will be 24 months (mean expected observation follow-up equal to 36 months, considering a 2-year recruitment phase and a 2-year follow up from the randomization of the last patient). The minimum survival follow up (double blind + open) period will be 7 years. 7.2 DISCUSSION OF STUDY DESIGN AND PLAN DESCRIPTION The objective of this study is to confirm the benefit of Abagovomab on the Recurrence Free Survival (RFS) and the Overall Survival (OS) as compared to placebo in patients with stage III or IV ovarian cancer after debulking surgery and platinum/taxane first line chemotherapy. A time of up to 8 weeks between the end of chemotherapy and the start of Abagovomab vaccination is considered optimal to fully recover from any toxicity from previous chemotherapy and fully benefit from receiving a biological agent as maintenance of the complete remission status. The placebo controlled design will allow the double-blind evaluation of efficacy and safety of Abagovomab, while the 2:1 randomization design in favor of Abagovomab has been selected to give patients a greater chance to receive the active treatment and to collect safety information on a greater number of patients. The choice of the RFS as the primary endpoint is in line with the recent FDA guidelines (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, draft version, April 2005) for the clinical development of a non-cytotoxic maintenance anticancer therapy in the adjuvant setting after definitive treatments. Data on RFS will be collected blinded over a minimum of 2 years and up to 4 years after randomization. However, a much longer open follow-up period prolonged up to 5 years after completion of double blind observation period will allow for evaluation of OS as a secondary endpoint. The sample size and the study timelines give enough power to detect meaningful differences between Abagovomab and placebo both on RFS and on OS. Efficacy will be closely assessed by frequent clinical and instrumental (imaging) evaluation of the potential onset of recurrence over 2-4 years from the first drug administration, and by thorough monitoring of the survival status for 7-9 years. An independent Clinical Event Adjudication Committee (CEAC) will review all the imaging documentation and pertinent Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 38 of 66 clinical data in double blind condition, in order to assess the recurrence of the disease as well as the date of recurrence in the most objective fashion. The effect of Abagovomab treatment on the humoral and cellular immune response will be also evaluated, to explore the patient’s immune response and any impact on the clinical outcome. Safety will be assessed by close monitoring of adverse events during treatment up to the end of the DBO period, with the final assessment 12 weeks after the last administered dose. In case of treatment discontinuation for disease recurrence the final study visit is anticipated within 4 weeks after the last dose in order to avoid potential bias of the effects of subsequent therapies/disease recurrence status. Long-term safety follow-up data will be also collected in patients with premature treatment discontinuation by collecting adverse drug reactions every 12 weeks until completion of the DBO period. 7.3 RANDOMIZATION Eligible patients will be randomized, according to a central randomization procedure, by IVRS to receive Abagovomab or placebo in a 2: 1 ratio. The randomization list will be stratified according to the following baseline prognostic factors, without forcing the number of patients in each stratum:, in order to preserve the randomization ratio within each stratum. tumor size after debulking surgery (i.e. residual tumor < 1 cm; > 1 cm); FIGO stage (i.e. III; IV); serum CA125 level after the first 3 cycles of chemotherapy (< 35 U/ml, > 35 U/ml). The randomization list will be generated by an independent statistician using a validated computer program. The block size will not be disclosed to the investigators. IVRS will also be used for breaking the code in case the investigator deems necessary the unblinding of study treatment for safety reasons (see § 7.7.5). In any case, all the efforts will be done to provide a secure 24-hours available contact between the Investigator and the Sponsor or its designee to promptly document and explain any premature unblinding of the investigational product (see §7.7.7). 7.4 STUDY POPULATION 7.4.1 Number of subjects/centers A total of 870 patients will be randomized according to a 2:1 randomization ratio to Abagovomab or placebo. Assumptions for the sample size calculation are described in Section 8.1.1. The study will be conducted in about 120 study centers distributed in Europe and USA. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 39 of 66 7.4.2 Inclusion Criteria At a maximum of 8 weeks after the last cycle of first line standard platinum/taxane chemotherapy, patients must fulfil all the following inclusion criteria: 7.4.3 Age ≥ 18 years; Properly executed written informed consent; History of histological and CA125 confirmed diagnosis (CA125 > 35 U/ml) of stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer; History of debulking surgery and standard platinum/taxane based non-investigational chemotherapy; Complete clinical response defined as: Normal physical examination; No symptoms suggestive of persistent cancer; No definite evidence of disease by computed tomography (CT) of the abdomen and pelvis within the previous 4 weeks; Negative chest x-ray (or CT chest) within the previous 4 weeks; Serum CA125 level < 35 U/ml. Adequate haematologic, renal and hepatic function: ANC >1.5 x 109/l; Platelets > 75 x 109/l; Haemoglobin > 6.2 mmol/l (>9.9 mg/dl); Serum creatinine < 1.5 x ULN; Bilirubin < 1.5 x ULN; AST, ALT, AP < 2.5 x ULN. ECOG PS < 2. Exclusion criteria Patients are ineligible to participate to the study if any of the following criteria are met: Any other invasive malignancies, with the exception of non-melanoma skin cancer or cervical carcinoma in situ, within the last 5 years or whose previous cancer treatment contraindicates this protocol therapy; Known active autoimmune disease requiring chronic treatment with immunosuppressive agents (e.g., rheumatoid arthritis, ulcerative colitis, etc.); Known immune deficiency (e.g. HIV, hypogammaglobulinemia, etc.); Known infection with hepatitis B, or hepatitis C; History of recent myocardial infarction (< 6 months) or decompensated heart failure (NYHA class > III); Previous or concomitant use of any anti-cancer therapy other than the platinum-taxane first line chemotherapy; Concomitant use of any other investigational agent; Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 40 of 66 7.4.4 Any prior investigational anti-cancer vaccine or monoclonal antibody; Known allergy to murine proteins; Any significant medical or psychiatric condition, drug or alcohol abuse that might prevent the patient from complying with all study procedures; Clinically significant active infection; Concomitant use of any immunosuppressive agent (e.g., steroids, cyclosporin, etc.); Major surgery within the previous 2 weeks; Radiotherapy within the previous 4 weeks; Any significant toxicity from prior chemotherapy; Unreliability or inability to follow protocol requirements. Removal of subjects from therapy or assessment Subjects can withdraw consent for participation in the study at any time without prejudice. The investigator can withdraw a subject if, in his/her clinical judgement, it is in the best interest of the subject or if the subject cannot comply with the protocol. The subject will undergo a final study visit after withdrawal, the cause of which will be recorded in detail on the CRF. If the withdrawal of a subject resulted from an adverse event, this will be documented in accordance with procedures described under section “SAE Reporting”. Whenever possible, the tests and evaluations listed for the final study visit will be carried out. In addition, the time schedule for safety and overall survival follow-up should be maintained. NOTE: Subjects who will withdraw consent to participate to the study will be specifically asked to consent or not to be contacted/provide data on adverse drug reactions, if any, and survival status by phone or mail (either directly or via the patient’s GP). 7.5 TREATMENT The investigational medicinal product Abagovomab verum or placebo will be supplied by Berlin-Chemie AG, Glienicker Weg 125, D-12489 Berlin, Germany. The medication will be supplied directly by Berlin-Chemie AG to the centers or to authorized central warehouses within the participating countries. Manufacturing and distribution will be performed according to GMP requirements. 7.5.1 Identity of Investigational Drugs Abagovomab drug product is available in vials containing 2 mg Abagovomab as 1 ml suspension. The drug product is a white suspension for subcutaneous injection containing the anti-idiotypic antibody Abagovomab adsorbed onto aluminum hydroxide and suspended in a buffered and isotonic saline solution to adjust the pH to about 7.5. The drug product is free of any Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 41 of 66 preservatives. It is provided in type I glass vials closed with a rubber stopper and an aluminum flip-off cap. Stability studies indicate that Abagovomab drug product is stable at 2 to 8 °C for at least 6 months. 7.5.2 Packaging Study treatments will be packaged in individual treatment boxes. Each treatment box will bear an individual box number and will contain the following materials according to the IVRS packaging list: - eight vials with Abagovomab 2mg/ml suspension or Abagovomab placebo suspension (same packaging and volume) for SC injection and tear-off labels to be affixed on the CRF at the time of treatment administration to the patient; - leaflet with instructions. 7.5.3 Labeling Study medication will be labeled with the multilingual booklet labels including the appropriate local language according to the GMP/GCP-directives and local legal requirements, including, at least, the following information: study code; product name; individual box-number; dosage form, route of administration, quantity of dosage units; instructions for use; batch number, expiry date, storage conditions; ‘for clinical trial use only’; name, address, telephone number of the Sponsor 7.5.4 Storage of Study Medication, Accountability and Dispensing The investigational medicinal product will be supplied in carton boxes and stored at the hospital pharmacy in the secondary package at a temperature of 2 to 8 °C. The pharmacist will make an inventory and acknowledge receipt of all shipments of the study medication, checking also whether the expiry date allows the administration to the patients. At the investigator’s site the study medication will be stored in a separate, securely locked, limited-access storage area at a temperature of 2 to 8 °C, until it is dispensed to the subject. Investigators will be responsible for dispensing the study medication to the subjects; this will be documented on the appropriate CRF page. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 42 of 66 7.5.5 Schedule of Administration Abagovomab or placebo will be administered as 1 ml suspension by SC route (into buttocks, thighs, abdomen or arms) every 2 weeks during the induction phase (at randomization = week 0, and then at week 2, 4 and 6) and then every 4 weeks up to 21 months from the randomization of the last patient (approximately 94 weeks) or until disease recurrence. Sites may be rotated. 7.5.6 Dose Adjustment and Modification Dose reduction is not permitted. Patients are to be removed from the study in case of a Dose Limiting Toxicity (DLT). According to NCI- CTCAE (version 3.0) DLT is defined by: > Grade II allergic reaction (Grade II is defined as rush, flushing urticaria, dyspnea, or drug fever > 38 °C; Grade III is defined as symptomatic bronchospasm, with or without urticaria, requiring parenteral medications, allergy-related edema or angioedema, or hypotension; Grade IV is defined as anaphylaxis); > Grade II autoimmune reaction (Grade II is defined as evidence of autoimmune reaction involving a non-essential organ or function (e.g. hypothyroidism; Grade III is defined as reversible autoimmune reaction involving function of a major organ or other adverse event; Grade IV is defined as autoimmune reaction with life-threatening consequences); > Grade III hematologic or non-hematologic toxicity including fever (Grade III fever is > 40 °C for < 24 hours); > Grade III injection site reaction (Grade III is defined as ulceration, or necrosis that is severe or prolonged, or requiring surgery). Any patient with Grade II or greater toxicity has to be followed with appropriate safety assessments until resolution of the event(s). 7.5.7 Discontinuation of Treatment Treatment can be discontinued at any time if in the best interest of the patient or any of the following are observed: patient refusal; non-compliance of the patient with the protocol; physician judgment; DLT as defined above, or life-threatening SAE; documented disease recurrence. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 43 of 66 The Investigator is ultimately responsible for the safety and the well being of the patients and the patient may be withdrawn from the treatment at any time during the study if it is believed that the constraints of the study procedures are detrimental to the patient’s health. This event must be notified to the study monitor, the reason(s) of withdrawal should be documented in the CRF and follow-up should be reported. Patients who early discontinue the study treatment for disease recurrence will undergo a final study visit for safety and immunological evaluation within 4 weeks after the last treatment administration; in case treatment is early discontinued for reasons other than disease recurrence the final study visit will be performed 12 weeks after last treatment administration for efficacy, safety and immunological evaluation. For all patients with early treatment discontinuation, safety should be followed until the end of DBO period and survival status should be followed until the end of the open period unless consent is explicitly withdrawn from the patient. For patients who withdraw consent please refer also to the note under § 7.6.4. 7.5.8 Concomitant Treatments Patients are not allowed to receive concurrently any other clinical investigational drug, any other antineoplastic drug (including chemotherapy, hormonotherapy, immunotherapy) nor radiation therapy. The prophylactic use of corticosteroids is not allowed. Acetaminophen (or equivalent) and diphenhydramine (or equivalent) may be used at the discretion of the Investigator. The concomitant treatments must be recorded in the CRF. 7.6 STUDY PROCEDURES 7.6.1 Efficacy and Safety Measurement Flowchart The following observations and tests are to be performed and recorded on the CRF, as summarized in the attached study schedule table. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 44 of 66 STUDY SCHEDULE SCREENING/ RANDOMIZATION TREATMENT/DOUBLE BLIND OBSERVATION PERIOD OPEN SURVIVAL up to 2 yrs after last randomized pt Follow up 8 wks from last chemotherapy cycle Treatment/Efficacy and Safety assessment W-2 to W0* Abagovomab/placebo Inclusion/exclusion criteria Informed consent Demographics Medical history PS (ECOG) Physical and Gynecological examination Vital signs 12-lead ECG Haematology/Serum Chemistry/Urinalysis Serum CA125 marker CT scan (abdomen & pelvis) Chest X-ray HAMA, Ab3 tests Adverse Events Concomitant medication Survival status X X X X3 X X Induction Phase W0* W2 W4 W6 X X X X X X X X X X X X X5 X7 4 X X X X10 Final Study Visit1 Maintenance Phase every 4 every 12 wks wks 2 X X W10 X X X 12 wks after last dose1 X X X X X X X X X X X 4 4 X X X X X7 X X8 9 Monitored throughout the observation period X10 X10 X10 X10 X10 11 Monitored throughout the observation period up to 7 yrs after last randomized pt Survival status every 12 wks 4 X X6 X7 X X9 X10 X11 * Week 0 corresponds to randomization and first administration of study treatment. 1. Final study visit for safety and efficacy corresponds to end of the double blind observation period (24 months after the last randomized patient and 12 weeks after the last administered dose) for regular end of treatment. In case of early treatment discontinuation; the final study visit will be performed 12 weeks after the last administered dose or within 4 weeks (and without CT scan and chest X-ray) for treatment discontinuation due to disease recurrence. 2. Abagovomab or placebo up to 94 weeks after last randomized patient OR until disease recurrence is documented. 3. Including main tumor characteristics (e.g. histopathological grading, FIGO stage III/IV and III sub-categories [IIIA, IIIB, IIIC)], size f the residual tumor after surgery [0 cm, < 1cm, > 1cm]). 4. Samples will be collected but results of CA125 assay will be kept blinded until the end of DBO period. 5. CT scan to be done at screening if performed > 4 weeks prior to randomization. 6. CT scan to be repeated at final study visit only if disease recurrence has not been previously documented. 7. Chest X-Ray to be done at screening if performed > 4 weeks prior to randomization; to be repeated every 24 wks, and at final study visit (only if disease recurrence has not been previously documented). 8. ONLY at week 22, 58 and 94 9. AE to be recorded at study center prior to dosing. In case of early treatment discontinuation (for disease recurrence or any other reason) adverse events will continue to be monitored by phone (or visit at center if deemed appropriate by the investigator) for collection of ADRs up to the end of the double blind observation period. 10. ONLY changes in concomitant medication from screening will be recorded. 11. In case of early treatment discontinuation (for other reason other than death) survival status will continue to be monitored in double blind condition by phone every 12 weeks up to the end of the double blind observation period, and then in open fashion during the survival follow up. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 45 of 66 7.6.2 Screening/Randomization Screening and randomization by IVRS must be performed and completed within 8 weeks from the completion of the last cycle of standard platinum/taxane chemotherapy with documented clinical complete response. Patients who will meet all the inclusion and none of the exclusion criteria will be randomized through centralized IVRS as reported under § 7.3. At screening the following evaluations should be obtained within 2 weeks prior to randomization in order to be considered baseline assessments: Inclusion/exclusion criteria assessment; Written informed consent; Medical history (including main tumor characteristics, and previous and concomitant medications); General medical visit, including physical and gynecological examination; ECOG performance status; Vital signs (heart rate, arterial blood pressure); 12-lead ECG; Clinical laboratory tests (including hematology, serum chemistry, urinalysis); Serum CA125 level measurement. At screening the following evaluations should be obtained within 4 weeks prior to randomization (week 0) in order to be considered baseline assessments: Imaging exams: CT scan of the abdomen and pelvis and chest X-ray. NOTE: At the time of randomization, FIGO stage (III; IV) , CA 125 level after 3rd chemotherapy cycle (< 35 U/ml; > 35 U/ml) and residual tumor (< 1 cm; > 1 cm) after debulking surgery should be known in order to allow stratification by prognostic factors. 7.6.3 Treatment and Double Blind Observation Period After randomization, and during the first 6 weeks of treatment (induction phase) patients will receive at study center a SC administration of study drug every 2 weeks, i.e. at week 0 and then at week 2, 4 and 6. Thereafter (maintenance phase), the study drug will be administered at study center every 4 weeks until evidence of disease recurrence or up to 94 weeks (approximately 21 months) after the randomization of the last patient. Medical visit for recording of adverse events and change of concomitant medication, if any, and assessment of performance status will be performed prior to each dosing. Laboratory parameters for safety evaluation will be performed at week 4, at week 10 (end of induction/start of maintenance phase) and every 12 weeks until end of DBO. Blood sampling for CA125 assay and immune response will be performed at week 0, week 10 and every 12 weeks until end of DBO period. The assessment of disease recurrence will be performed at week 10 and every 12 weeks until end of DBO period. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 46 of 66 In particular, the following evaluations will be obtained: INDUCTION PHASE (week 0, and week 2, 4 and 6, prior to dosing) ECOG performance status; Recording of adverse events; Recording of change in concomitant medication. CA125 assay, HAMA and Ab3 antibodies (ONLY at week 0). Vital signs (heart rate, arterial blood pressure- ONLY at week 4); Clinical laboratory tests (including hematology, serum chemistry and urinalysis- ONLY at week 4). MAINTENANCE PHASE (week 10 until end of DBO period) Every 4 weeks ECOG performance status; Recording of adverse events; Recording of change in concomitant medication. Every 12 weeks General medical visit including physical and gynecological examination; Vital signs (heart rate, arterial blood pressure); Imaging exams: CT scan of abdomen and pelvis; Clinical laboratory tests (including hematology, serum chemistry and urinalysis); Serum CA125 level. Every 24 weeks chest X-ray. ONLY at week 10, 22, 58, 94 (and in all cases at final visit) Blood sampling for the immunologic tests All patients in the study will have assessments scheduled at the same interval and frequency, with the final efficacy and safety assessment (including all assessments listed above) to be performed at the end of the DBO period at the last study visit, i.e. 24 months after the randomization of the last patient and 12 weeks after the last scheduled dose in case of regular treatment termination. Patients with early treatment discontinuation will also attend the final study visit 12 weeks after the last administered dose, the only exception being patients with early treatment discontinuation Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 47 of 66 for disease recurrence who will attend the final visit within 4 weeks after the last administered dose. In all cases, patients who early discontinue treatment will continue to be monitored for safety (adverse reactions) and survival status by phone or mail (either directly or via the patient’s GP) every 12 weeks until the end of the DBO period. (NOTE: CT scan and chest X-ray will be performed at final study visit ONLY in case of early treatment discontinuation for reasons other than disease recurrence). 7.6.4 End of treatment and double blind observation period Treatment will end 21 months from the randomization of the last patient, and the DBO period will end 12 weeks after the last administered dose, i.e. 24 months from the randomization of the last patient. At that time all patients on study will undergo a final study visit, encompassing the same efficacy and safety assessments scheduled during the observation period (see § 7.6.3). 7.6.5 Overall survival follow-up After completion of DBO period, survival data will continue to be collected under open conditions by phone or mail (either directly to the patient or via the patient’s GP) every 3 months for additional 5 years (i.e. individual survival follow-up ranging from 7 to 9 years based on the time of randomization). Survival status should be followed in ALL patients, including those who prematurely terminate the study treatment, unless consent has been specifically withdrawn by the patient. 7.7 EFFICACY AND SAFETY ASSESSMENT 7.7.1 Primary efficacy endpoint The primary efficacy endpoint is the RFS (i.e. the time from the date of randomization to documented disease recurrence or death). Disease recurrence is defined as the appearance of any lesion or development of tumor-related symptoms evaluated by medical examination. Disease recurrence must be documented by CT scan. If the CT scan is not informative enough to document or to rule out the recurrence of disease, additional imaging techniques (e.g. NMR) should be requested by the Investigator to document disease recurrence. If any additional imaging technique leads to the diagnosis of recurrence, then the disease recurrence has to be considered as ‘documented’ even in the presence of a negative CT scan. In addition, the histologic or cytological documentation of disease recurrence can substitute imaging confirmation in case of pleural or peritoneal effusion. Ultrasound documentation is not accepted per se as adequate documentation of disease recurrence. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 48 of 66 Disease recurrence will be assessed every 12 weeks by physical examination (pelvic examination inclusive) and CT scan of abdomen and pelvis. Chest X-ray will be performed every 24 weeks. CT scan must be performed at any time during the study if disease recurrence is suggested by physical examination or other clinical findings. All images collected for the assessment of disease recurrence and all pertinent clinical data will be reviewed by an independent Clinical Event Adjudication Committee (CEAC) The CEAC will adjudicate the recurrence data and the relevant date of recurrence by reviewing all study images (i.e. CT scans and other images used by the Investigator for evaluating patient status) and clinical data deemed necessary for the adjudication. The rules and revision process of the CEAC are detailed in the CEAC charter (see Appendix III). The data adjudicated by the CEAC will be used for the primary analysis, whereas the assessment made by the Investigator will be used for clinical management of the patient. 7.7.2 Secondary efficacy endpoints Overall survival will be determined as the time from randomization to all-cause death. Survival status will be continuously assessed in all patients during DBO period and afterwards every 12 weeks up to 7 years from the randomization of the last patient by phone or mail (either directly to the patient or via the patient’s GP). Time course of immunologic parameters (HAMA, Ab3) will be assessed in all patients, by comparing levels at week 0, at the end of the induction (start of maintenance phase/ week 10) and at week 22, 58, and 94 weeks while on treatment and in case of treatment termination at 4 to 12 weeks after the last administered dose. Time course of additional immunologic parameters (CA125-specific antibodies (Ab1’) and CA125-specific T cell immune response) will be evaluated in a subset of about 10% of patients from centers who meet the criteria required for the collection/shipment of the blood samples (mainly close proximity to the central laboratory of immunological assay). All the immunologic tests will be performed according to published procedures (Wagner U. et al., 2001; Reinhartz S et al., 2004). All these assays will be performed at the Department of Clinical Pathology (Dr. Mosiello), RTC S.p.A., Pomezia, Italy, with the exception of the analysis of CA125-specific T cell immune response, which will be conducted at the Institute of Gynecology and Obstetrics of the University “Sacro Cuore”, Rome (Dr. Fattorossi). The results of all immunologic assays will be kept blinded along the double blind observation period. CA125 will be tested in each patient at week 0, week 10 and then repeated every 12 weeks until the end of the DBO period or up to disease recurrence. CA125 assay will be performed in a centralized lab facility independent from Sponsor and Investigators. Results of CA125 tests will be kept blinded along the DBO period. Since Abagovomab vaccination may interfere with the interpretation of CA125 assay results, CA125 will not be used to determine clinical relapse. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 49 of 66 7.7.3 Safety Assessment While on treatment, recording of adverse events and ECOG performance status evaluation will be done every 2 weeks during the induction phase and every 4 weeks during the maintenance phase prior to dosing. A complete safety assessment will be performed at week 4, week 10 and every 12 weeks thereafter until the end of DBO period, and it will include physical examination, vital signs measurements, ECOG performance status, monitoring of adverse events (see § 7.7.4), changes in concomitant medication and the following laboratory safety tests to be performed at the local laboratory: Hematology: Hb, WBC with differential count, platelets. Serum chemistry: total bilirubin, alkaline phosphatase, ALT, AST, total protein, albumin, Na+, K+, Cl-, γGT, LDH, glucose, BUN and creatinine. Creatinine clearance has to be determined (Cockroft-Gault method) in case of creatinine >1.5 x institutional ULN. Urinalysis: urine dipstick. Safety evaluation will be repeated at the final study visit, to be performed 12 weeks after the last administered dose or within 4 weeks in case of early treatment discontinuation for disease recurrence. 7.7.4 Monitoring of Adverse Events Adverse events will be collected at each visit prior to dosing, with the last assessment at the final study visit, and will be recorded in the appropriate section of the CRF. In case of early treatment discontinuation, the occurrence of adverse drug reactions, if any, will be monitored by phone (or general medical visit as deemed appropriate by the Investigator) every 12 weeks until the end of the DBO period. Adverse events will be classified according to the following definitions/criteria: Adverse Event (AE) Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. Adverse Drug Reaction (ADR) Any noxious and unintended responses to a medicinal product related to any dose should be considered an Adverse Drug Reaction. That means that a causal relationship between the product and the adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out. Serious Adverse Event (SAE) Any untoward medical occurrence that at any dose: - results in death; - is life-threatening; Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 50 of 66 NOTE: the term life-threatening in the definition of “serious” refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe. - requires hospitalization or prolongation of existing hospitalization; - results in persistent or significant disability/incapacity; - is a congenital anomaly/birth defect - is another medically important condition that may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the definition above. Expectedness AEs are expected when their nature, severity or outcome are consistent in the safety section of the Investigator’s Brochure. Causality criteria - “Certainly related”: an AE is considered certainly related to a drug when a clinical event, including a laboratory test abnormality, occurs in a plausible time relation to the administration of the drug, and which cannot be explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be clinically plausible. The event must be definitive pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if necessary. - “Probably related”: an AE is considered probably related to a drug when a clinical event, including a laboratory test abnormality, with a reasonable time relation to the administration of the drug, is unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information (AE reappearance after drug reintroduction) is not required to fulfil this definition. - “Possibly related”: an AE is considered possibly related to a drug when a clinical event, including a laboratory test abnormality, with a reasonable time relation to the administration of the drug, could also be explained by concurrent disease or other drugs or chemicals. Information on drug withdrawal (dechallenge) may be lacking or unclear. - “Unlikely related”: an AE is considered unlikely related to a drug when other drugs, chemicals or underlying disease provide plausible explanations and/or the temporal relation to the administration of the drug makes a causal relation improbable. - “Not related”: an AE is considered not related to the use of a drug in case of existence of a clear alternative explanation and/or unreasonable temporal relationship, and/or non plausibility. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 51 of 66 Grading criteria The criteria used for grading adverse events are the Common Toxicity Criteria (CTC v.3.0) of US-NCI. The highest severity grade reached in a given cycle should be reported in the CRF. All AEs must be followed-up until the AE has completely resolved, stabilized or the sequelae can be assessed by the Investigator. The results of additional diagnostic measures as the result of an AE, such as laboratory tests, ECG, imaging, must be available at site and provided at Sponsor’s request. 7.7.5 Breaking of Treatment Code The investigator always has the right to unblind the treatment code by contacting the IVRS if he or she thinks this knowledge is necessary to adequately treat the patient. Unblinding is a rare occurrence and should only be recommended for cases where the subject's treatment code must be known to offer adequate care for the patient’s immediate condition. Thus the treatment code should only be unblinded if the knowledge of whether the patient is receiving Abagovomab or placebo could be of benefit to the patient (for example, it should not be opened following the death of the patient). The reason for breaking the code will be always stated by the investigator. 7.7.6 SAE Reporting All SAEs occurring within 12 weeks after treatment discontinuation, whether or not related to study drug, must be reported to the Drug Safety Unit (DSU) by sending the CRF-AE recording pages by fax immediately and not later than within one calendar day, specifying the judgement on causal relationship between the SAE and the study medication. The Investigator must also fill in the “Serious Adverse Event” form. At the earliest possible date, preliminary reports should be followed by detailed reports and documentation that may be available, for example, hospital case records, autopsy reports, and/or other pertinent documents. Reports should be sent to the CRO Drug Safety Unit for the study: DSU contact : Melanie Weber Manager, Drug Safety Center Unit PRA International Dynamostrasse 13-15 D-68165 Mannheim (Germany) Phone + 49 621 8782-252 Fax +49-621-8782-181 Email: [email protected] The Investigator should not wait to receive additional information to fully document the event before notifying a SAE, though additional information may be requested. Where applicable, Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 52 of 66 information from relevant laboratory results, hospital case records and autopsy reports should be obtained. The Investigator is also required to submit follow-up reports to the DSU until the SAE has resolved or, in the case of permanent impairment, until the SAE stabilizes. In line with the revision of the Directive 2001/20/EC issued by the European Commission in April 2004, in order to avoid systematic unblinding and expedited reporting of events that have an impact on the efficacy endpoints, the Drug Safety Unit will assess the expectancy of all received drug-related SAEs on the basis of the consistency with Abagovomab Investigator’s Brochure. Moreover, all SAEs that can be clearly related to disease progression and/or to subsequent anticancer therapies as per Investigator’s judgement will be considered as expected, thus avoiding unblinding. Any SUSAR or any death during the study must be reported immediately, with the exception of death certainly due to disease recurrence and/or to subsequent therapies that do not require to be immediately notified. All SAEs that meet the criteria of serious unexpected ADRs will be reported to the relevant Regulatory Authority within the required timeframe, depending on the local regulations. Regulatory agencies will be notified as soon as possible but no later than 7 calendar days after the Sponsor’s first knowledge of fatal or life-threatening unexpected ADR and no later than 15 calendar days after the Sponsor’s first knowledge of the other serious unexpected ADRs. The Sponsor or its designee will also communicate all suspected non-fatal SUSARs in an expedited fashion to all concerned Investigators, who in turn will be instructed to report these events to their EC/IRB, when required and/or regulatory authorities. DSMB will review safety data on the ongoing trial on a regular basis and when necessary will recommend to the sponsor whether to continue, modify or terminate the trial. This procedure will be described in ad hoc DSMB Charter (Appendix IV). The DSMB opinion and recommendations will be timely submitted by the Sponsor or its designee to the involved Regulatory Authorities and Ethics Committees, as most appropriate. 7.7.7 24 - hour Medical Monitoring and SAE fax receipt A dedicated phone and/or pager number is provided to all investigators and clinical monitors participating in a clinical trial for a 24-hour telephone coverage. If the person on duty cannot receive the call immediately, a voice mailbox is activated and the call is returned as soon as possible. The CRO Global Medical and Safety Service (GMSS) has dedicated fax machines that work 24hours per day, but faxes are processed only during local office hours (Monday through Friday, excluding local public holidays). Faxes received outside of local business hours are processed during the next working day, with highest priority. The fax machines are also checked regularly during the weekend/holidays if there are 3 or more sequential non-working days. 7.8 STUDY COMMITTEES Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 53 of 66 A Steering Committee, an independent Clinical Event Adjudication Committee (CEAC), and a Data and Safety Monitoring Board (DSMB) will be established for the study. 7.8.1 Steering Committee The Steering Committee, consisting of the Coordinating Investigator and the national coordinators from participating countries, is entrusted to maintain the quality of the study conduct, the overall study co-ordination, to periodically assess the study progress and to address policy issues. The Committee chairperson will be responsible for communicating with the DSMB and the Sponsor. 7.8.2 Independent Clinical event Adjudication Committee (CEAC) An independent Clinical Event Adjudication Committee (CEAC), consisting of three independent radiologists and one oncologist (all blinded to patients’ treatment and local radiologist’s report), will review in double blind condition all CT scans for each patient, as well as other imaging records such as NMR and pertinent clinical data to adjudicate the presence of disease recurrence and the relevant date. The assessment of disease recurrence and date of recurrence made by the CEAC will be used for the primary analysis. Tumor measurements and response will not be evaluated in this protocol, since they are not study end-points. The structure, procedures and work-flow of the CEAC is described in details in a separate Charter (see Appendix III). 7.8.3 Data and Safety Monitoring Board (DSMB) The independent Data and Safety Monitoring Board (DSMB), consisting of five independent medical oncologists and one independent biostatistician, will conduct the monitoring of safety data during the course of the study and will periodically update the Sponsor and the Steering Committee. The duties of the DSMB, the adopted operational procedures as well as the frequency of meetings/teleconferences of the DSMB are described in the DSMB Charter (see Appendix IV). 7.8.4 Data Quality Management 7.8.4.1 Subject Records The Investigator will maintain individual subject records separate from the CRF. These records should include demographic data, medical history and other notes if appropriate. When the study is terminated all signed Informed Consent Forms should be archived in the Investigator’s File. 7.8.4.2 Case Report Forms Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 54 of 66 All the patient information collected during the study will be recorded in the CRFs identified by an unique code (e.g. subject screening number). It is the responsibility of the Investigator to ensure that the CRFs are properly and completely filled in. Every visit must be signed by the Investigator, attesting that the entered data have been verified. During the conduct of the clinical part of the study the CRF must be available and up-to-date so that they always reflect the latest observations on the subjects enrolled into the study. All original laboratory form as well as any original documentation pertinent to the study procedures must be available for review in each subject’s record. Entries shall be made in English language, legibly and in black ink using a ball-point pen. Corrections to the CRF must be made in a manner to not obscure the original entry, drawing a line through the original item, with Investigator’s initials and date. 7.8.4.3 Data Quality Control / Study Monitoring Study monitors, designated by the CRO, will be assigned to the investigational centers. During the periodic monitoring visits the CRF will be checked for completeness and consistency with the corresponding source data. The Investigator will offer the study monitors direct access to all subject documentation available in the Investigator’s files. 7.8.4.4 Clinical Data Management The subject data collected in the CRF will be entered into the study database after being verified. The database will be designed based on the CRF to allow the capture of all data contained in the CRF. Data entry will be performed using double data entry. Logical checks will be performed in order to solve data inconsistencies. A clear overview of all clinical data management activities (e.g. double data entry, storage, verification, correction, coding and retrieval) will be described in the Data Handling Manual. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 55 of 66 8 STATISTICAL METHODS 8.1 SAMPLE SIZE DETERMINATION At least 535 recurrences have to be observed during the trial in order to provide a power higher than 90% power in rejecting the null hypothesis of equality between Abagovomab and placebo on RFS according to the following assumptions: Median RFS for placebo arm = 18 months; Hazard ratio in RFS between Abagovomab and placebo = 1.33 (leading to an approximate benefit of 6 months of Abagovomab over placebo); Significance level (α) = 5% (two-sided) Overall drop-out rate = 10% A total number of 870 patients (580 in the Abagovomab arm and 290 in the placebo arm) recruited in 24 months should be followed for at least 24 months (i.e. average time on-study of 36 months) in order to observe the requested number of events. The study size will provide a power higher than 80% if the hazard ratio in RFS will remain higher than 1.28 or in case the median RFS for placebo arm will be lower than 29 months with the same hazard ratio between the groups. This sample size will also provide a power higher than 80% power for detecting the superiority of Abagovomab over placebo in the secondary end-point of overall survival on the basis of: Median OS for placebo arm = 40 months; Hazard ratio in OS between Abagovomab and placebo = 1.30 (leading to an approximate benefit of 12 months of Abagovomab over placebo); Minimum follow-up for each patient = 84 months (i.e. average time of survival follow-up of 96 months); Significance level (α) = 5% (two-sided). No adjustment for multiplicity will be adopted due to the nature of secondary analysis. 8.2 ANALYSIS POPULATIONS The following analysis populations will be considered in the statistical analysis: Safety population: all patients receiving at least one study drug administration; ITT population: all patients randomized; Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 56 of 66 Per protocol population: all the patients of the ITT population excluding patients who experienced major protocol violations before disease recurrence. 8.3 ANALYSIS VARIABLES 8.3.1 Primary efficacy variable The primary efficacy variable is Recurrence Free Survival (RFS) defined as time from randomization to the event of tumor recurrence (as determined by the Clinical Event Adjudication Committee- see Appendix III) or death from any cause. RFS will be calculated as follows: In case of event: RFS = event date – date of randomization + 1. In case of censored information: RFS = censored date – date of randomization + 1. Recurrence adjudication flow. The Clinical Event Adjudication Committee (CEAC) will adjudicate the recurrence data and the relevant dates by reviewing all patient study images (i.e. CT-scans and any other images used by the Investigator for evaluating patient status) and clinical data deemed necessary for the adjudication. The images will be archived digitally and read in a blinded fashion by the CEAC members. The image database will be compliant with regulatory guidelines. At the end of the adjudication process the committee will assign, for each patient, the presence or absence of recurrence and the recurrence date. For details of data flow and adjudication process see Appendix III: CEAC charter. Definition of event date. In case of adjudicated recurrence the event date will be the recurrence date as adjudicated by the CEAC. In case of CRF documented death from any cause in a patient with no adjudicated recurrence the event date will be the date of death. Censoring definition. The recurrence free survival time of a patient will be considered as censored in case of no event between randomization and individual study end, defined as one the following: premature treatment termination (before/without any subsequently adjudicated recurrence) for reasons other than death (e.g. patient drop out, investigator diagnosis of recurrence, etc). end of double blind observation period. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 57 of 66 Censoring date. In case of censoring, the censoring date is defined as the date of the last evaluable image assessed by the CEAC. 8.3.2 Secondary efficacy variable: overall survival The secondary efficacy variable is the Overall Survival (OS) calculated as: In case of all-cause death: OS = date of death – date of randomization + 1. In case of censored information not for drop-out: OS = In case of censored information for drop-out: OS = 8.3.3 date of end of observation period (i.e. study end / end of survival follow-up) – date of randomization + 1. Last date known alive – date of randomization + 1. Other secondary efficacy variables Remaining secondary efficacy variables will be the immune response parameters (Ab3; HAMA). 8.4 STATISTICAL ANALYSIS 8.4.1 Descriptive statistics All variables (including all generated and transformed variables) will be presented using appropriate descriptive statistics according to the variable nature: continuous variables: number of non missing observations, mean, standard deviation, minimum, median, maximum; categorical variables: number of non missing observations, absolute and relative frequency; time to event variables: number of non missing observations, number and percentage of censored observations, 1st quartile, median (and its 95% CI), 3rd quartile, Kaplan-Meier survival curves and event rates every three months, annualized mortality rate (i.e. number of events per 100 patient years of observation). The behavior over time of continuous variables will be analyzed by presenting descriptive statistics for each time point and the absolute and relative difference compared to baseline. The behavior over time of categorical data will be analyzed by presenting the descriptive statistics for each time point and the shift compared to baseline. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 58 of 66 All study data will be presented by treatment and by stratification factors within each relevant analysis population. 8.4.2 Baseline analysis Baseline patients’ characteristics will be analyzed by descriptive statistics. 8.4.3 Primary efficacy analysis Primary analysis will be run on RFS in the ITT analysis population. The superiority of Abagovomab over placebo will be claimed in case of rejection of the null hypothesis of equality (with observed HR favoring Abagovomab): H0: HRABAGOVOMAB / PLACEBO = 1 H1: HRABAGOVOMAB / PLACEBO ≠ 1 Due to the time-to-event nature of the primary efficacy variable, survival analysis techniques will be used. The clinical trial design includes a prospective stratification in randomization for balancing the trial arms for important variables that are highly likely to affect the trial’s primary efficacy variable. Covariate analyses will therefore be employed to adjust for variables that affect the outcome. For this reason a Cox proportional hazards model will be used for primary analysis and will have treatment as major covariate, adjusted only for the predefined prognostic stratification factors: FIGO stage (i.e. III; IV); tumor size after debulking surgery (i.e. residual tumor < 1 cm; > 1 cm); serum CA125 level after the first 3 cycles of chemotherapy (< 35 U/ml; > 35 U/ml). Analysis output will be the estimated hazard ratio, its 95% CI and the associated p-value for each covariate. As recommended in CPMP/EWP/2863/99, the covariates will enter the model as dichotomized variables. No additional covariates will be inserted in the primary model. No interaction terms will be included, since influence of the stratification factors on drug efficacy can be ruled out. The use of these three covariates is in accordance with ICH guideline E9 where it states “ If one or more factors are used to stratify the design, it is appropriate to account for those factors in the analysis”. The Cox proportional hazards model is a standard model used in failure time analysis. Compared to parametric analyses, its assumptions are fairly unspecified and will therefore yield robust estimates of the treatment effect. The model will be applied using the Efron approach for handling ties, since this approach is known to give a reasonable approximation of the exact likelihood in presence of ties. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 59 of 66 The Cox model relies on the assumption of proportional hazards. This assumption can be regarded as justified, since there are no clinical reasons for assuming that the efficacy of Abagovomab should change over time. Nevertheless this assumption will be examined using log-log plots of the event times. The primary hypothesis will be tested using the Wald test for the covariate treatment. The hazard ratio will be estimated as e β , where β̂ is the Maximum Likelihood (=ML) estimate of the treatment effect. Confidence intervals will be calculated using the asymptotic normality of the ˆ distribution of the ML estimate β̂ . The use of asymptotic distributions is justified due to the large sample size of the trial. 8.4.4 Sensitivity analysis of the primary variable Primary analysis results will be explored for sensitivity by an unstratified log-rank test for the influence of treatment, to assess if the results of the primary analysis are robust also in the absence of other covariates. 8.4.5 Secondary efficacy analysis Overall survival will be analyzed similarly to the primary analysis (of RFS) on the ITT population at the end of the survival follow-up. An exploratory analysis on OS will also be applied at the end of the double blind observation period. The time course of immune response parameters will be descriptively analyzed. 8.4.6 Multiplicity issues All the tests not included in the primary analysis are to be considered descriptive in nature since they are secondary or exploratory analyses and therefore will not be adjusted for multiplicity. 8.4.7 Safety analysis The number of patients reporting an adverse event and the number of adverse events will be summarized by treatment group on the Safety population. Separate sets of tables will be produced for adverse events by drug relationship, CTC toxicity grade and for those leading to treatment/study discontinuation. SAEs will be presented as described for AEs. The other safety parameters will be descriptively analyzed. Descriptive statistics will also be produced for assessment of compliance, extent of exposure and overall drug(s) administration. 8.4.8 Subgroup analysis The following subgroups derived from the ITT population will be investigated: FIGO stage (i.e. III, IV); Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 60 of 66 tumor size after debulking surgery (i.e. residual tumor < 1 cm; > 1 cm); serum CA125 level after the first 3 cycles of chemotherapy (< 35 U/ml, > 35 U/ml). In each subgroup the primary efficacy variable and overall survival will be analyzed according to the primary analysis. In addition an exploratory analysis on the interaction “treatment x subgroup” will be applied. 8.5 ON-STUDY AND PRE-STUDY CLOSURE ACTIVITIES 8.5.1 Protocol Violations and Blind Review Categories of protocol violations will be defined at the end of double blind observation period before study unblinding and will be integrated in the statistical analysis. A blind review meeting will take place in order to evaluate and accept the data management report, discuss remaining issues (outstanding queries, unresolved errors) and discuss the cases of major and minor protocol violations. After the blind review meeting has taken place and the database is considered cleaned, the database will be locked and unblinded. 8.5.2 Data Monitoring At regular times during the study conduct, the trial database will be transferred to the Sponsor in order to monitor the overall quality of the trial (e.g. highlight systematic protocol deviations, the consistency and the quality of data and the appropriateness of the design assumptions). The Sponsor will always receive and analyze the data under blinded conditions and will never have access, during the whole trial conduct, to unblinded information. Analyses will never deviate from these guidelines. 8.5.3 Interim analysis No interim analyses are planned for this trial. 8.5.4 Stopping rules No formal statistical stopping rule will be applied. 8.5.5 DSMB analysis At each meeting the DSMB will receive unblinded data on major safety parameters and on trial conduct issues (e.g. recruitment, baseline characteristics, eligibility rates etc.). At each meeting the DSMB can recommend early trial termination or study modification because of safety concerns, as details in the DSMB charter (see Appendix IV). Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 61 of 66 The DSMB can request additional unplanned unblinded analysis of primary outcome in case of major safety issues from the safety analysis. DSMB will therefore be able to monitor the trial in its completeness by analysing the overall risk/benefit of the trial results as necessitated by safety concerns if they arise. There is no planned interim efficacy analysis and the Sponsor will not receive the results of any efficacy analyses examined by the DSMB before the final study database lock except in the event of a recommendation to stop or seriously modify the protocol. In that event, due procedure will be discussed in advance with the DSMB and Regulatory Agencies. 8.6 STATISTICAL ANALYSIS PLAN The study statistical analysis plan (SAP) will be finalized prospectively, before the unblinding of the study treatment. The SAP will follow the protocol and indicate any deviations, but may also describe additional statistical analyses for efficacy and safety as required/described by the study committees. In addition, a Data Monitoring Analysis Plan (DMAP) for the DSMB will be finalized before the first DSMB data review meeting. The SAP will also detail the handling of missing, unused and spurious data. If major deviations from the original analyses will occur during the trial a protocol amendment will be inserted. No major deviations from the original analysis plan will take place after data unblinding. Minor deviations (e.g. not involving changes in the primary analysis) arising during the trial will be detailed only in the statistical analysis plan. All statistical analyses not prespecified and run after data unblinding will be considered additional/exploratory analyses. Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 62 of 66 9 REFERENCES Berek JS, Schultes BC, Nicodemus CF. Biologic and immunologic therapies for ovarian cancer. J Clin Oncol 2003; 21 (suppl): 168s-174s Berek JS, Taylor PT, Gordon A, Cunningham MJ, Finkler N, Orr J Jr, Rivkin S, Schultes BC, Whiteside TL, Nicodemus CF. Randomized, placebo-controlled study of oregovomab for consolidation of clinical remission in patients with advanced ovarian cancer. J Clin Oncol 2004; 22: 3507-3516 Cannistra SA. 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Clin Cancer Res 2001; 7: 1154-1162 Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 65 of 66 10 APPENDICES Study Protocol ABA-01, Version 1.0, 4 August 2006 Page 66 of 66 APPENDIX I DECLARATION OF HELSINKI ABA-01, Version 1.0, 4 August 2006 APPENDIX II SUBJECT INFORMATION AND INFORMED CONSENT FORM - TEMPLATE - ABA-01, Version 1.0, 4 August 2006 APPENDIX III CHARTER OF CLINICAL EVENT ADJUDICATION COMMITTEE (CEAC) ABA-01, Version 1.0, 4 August 2006 APPENDIX IV CHARTER OF DATA SAFETY AND MONITORING BOARD (DSMB) ABA-01, Version 1.0, 4 August 2006
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