CLINICAL INVESTIGATION PLAN
HEPAR-trial CCMO NL25956.041.08 METC 08-450 CLINICAL INVESTIGATION PLAN Radioactive holmium microspheres for the treatment of patients with non-resectable liver metastases of mixed origin; a single center, interventional, non-randomized, open label, safety study. Authors: B.A. Zonnenberg, MD PhD M.A.A.J. van den Bosch, MD PhD T.B. Bosma, CRC trainee W. Bult, Reg. Ph. M.G.E.H. Lam, MD PhD J.F.W. Nijsen, PhD A.D. van het Schip, PhD M.A.D. Vente, DVM PhD T.C. de Wit, PhD Final version: 28 Date: April 29, 2011 © University Medical Center Utrecht Final version 28, 29-04-2011 Page 1 of 45 HEPAR-trial CCMO NL25956.041.08 METC 08-450 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE Principal investigator B.A. Zonnenberg, medical oncologist UMC Utrecht Department of Internal Medicine Division of Internal Medicine and Dermatology E 02.222 P.O. Box 85500 NL-3508 GA UTRECHT Tel.: +31 88 75 56680, #1154 Investigators M.A.A.J. van den Bosch, interventional 1 radiologist 2 W.P.Th.M. Mali, interventional radiologist 3 M.G.E.H. Lam, nuclear medicine physician 4 I.H.M. Borel Rinkes, oncological surgeon UMC Utrecht P.O. Box 85500 NL-3508 GA UTRECHT Division of Radiology, Radiotherapy and Nuclear Medicine: 1 Department of Radiology E 01.132 Tel.: +31 88 75 6689 2 Department of Radiology E 01.132 Tel.: +31 88 75 6689, #1070 3 Department of Nuclear Medicine E 02.222 Tel.: +31 88 75 57779, #3705 Division of Surgical Specialisms: Department of Surgery G 04.228 Tel.: +31 88 75 58072, #1219 4 Production manager J.F.W Nijsen, assistant professor UMC Utrecht Department of Radiology and Nuclear Medicine Division of Radiology, Radiotherapy and Nuclear Medicine E 02.222 P.O. Box 85500 NL-3508 GA UTRECHT Tel.: +31 88 75 56676 Sponsor M. Hendriks, medical manager UMC Utrecht Division of Radiology, Radiotherapy and Nuclear Medicine E 01.335 P.O. Box 85500 NL-3508 GA UTRECHT Tel.: +31 88 75 56689 © University Medical Center Utrecht Final version 28, 29-04-2011 Page 2 of 45 HEPAR-trial CCMO NL25956.041.08 METC 08-450 Independent physician Dr. G.D. Valk, internist-endocrinologist UMC Utrecht Department of Endocrinology Division of Internal Medicine and Dermatology C 02.222 P.O. Box 85500 NL-3508 GA UTRECHT Tel.: +31 88 75 56304 Study Coordinator T.B. Bosma, trainee Clinical Research Coordinator UMC Utrecht Trial bureau Radiology, Radiotherapy and Nuclear Medicine Division of Radiology, Radiotherapy and Nuclear Medicine E 02.222 P.O. Box 85500 NL-3508 GA UTRECHT Tel.: +31 88 75 51321, #1081 Laboratory sites J. den Hartog, manager laboratory UMC Utrecht Department Laboratory of Clinical Chemistry and Haematology Division of Laboratory and Pharmacy G03.550 P.O. Box 85500 NL-3508 GA UTRECHT Tel.: +31 88 75 58669 Tel. secr.: +31 88 75 57604 / 57612, #4351 Pharmacy W. Meulenhoff, pharmacist UMC Utrecht Department Pharmacy Division of Laboratory and Pharmacy D.00.218 P.O. Box 85500 NL-3508 GA UTRECHT Tel.: +31 88 75 56089, #1004 Monitor K. Groot, Clinical Research Associate Julius Clinical Research B.V. J.F. Kennedylaan 101 NL-3981 GB BUNNIK Tel.: +31 30 656 91 25 Mob.: +31 6 3805 99 72 © University Medical Center Utrecht Final version 28, 29-04-2011 Page 3 of 45 HEPAR-trial CCMO NL25956.041.08 METC 08-450 PROTOCOL SIGNATURE SHEET Name Signature Date Head of Division M. Hendriks, Medical Manager, Division Radiology, Radiotherapy and Nuclear Medicine Principal Investigator B.A. Zonnenberg, medical oncologist Department of Internal Medicine Division of Internal Medicine and Dermatology © University Medical Center Utrecht Final version 28, 29-04-2011 Page 4 of 45 HEPAR-trial CCMO NL25956.041.08 METC 08-450 TABLE OF CONTENTS INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE....................................... 2 PROTOCOL SIGNATURE SHEET........................................................................................ 4 LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS................................................ 8 SUMMARY...........................................................................................................................10 1. INTRODUCTION AND RATIONALE.............................................................................12 2. OBJECTIVES ...............................................................................................................14 3. STUDY DESIGN...........................................................................................................14 4. STUDY POPULATION .................................................................................................16 4.1 Inclusion criteria ....................................................................................................16 4.2 Exclusion criteria...................................................................................................16 5. TREATMENT OF PATIENTS........................................................................................18 5.1 Schedule of procedures ........................................................................................18 5.2 Study procedures..................................................................................................19 5.2.1 Screening......................................................................................................19 5.2.2 Visit 1 (week 0)..............................................................................................19 5.2.3 Visit 2 (week 1-2)...........................................................................................20 5.2.4 Visit 3 (week 2-3)...........................................................................................21 5.2.5 Visit 4-7 (week 3-6) .......................................................................................21 5.2.6 Visit 8 (week 7)..............................................................................................21 5.2.7 Visit 9-13 (week 8-12) ...................................................................................21 5.2.8 Visit 14 (week 13; final visit) ..........................................................................22 5.3 Holmium content ...................................................................................................22 5.4 Laboratory examinations.......................................................................................22 5.5 Radiation exposure rate ........................................................................................22 5.6 Use of co-medication ............................................................................................22 5.7 Escape medication................................................................................................23 6. INVESTIGATIONAL MEDICAL DEVICE.......................................................................24 6.1 Name and description of investigational medical product ......................................24 6.2 Animal studies.......................................................................................................24 6.3 Clinical studies ......................................................................................................24 6.4 Summary of known and potential risks and benefits..............................................24 6.4.1 Potential risks................................................................................................24 6.4.2 Potential benefits...........................................................................................24 6.5 Dose .....................................................................................................................25 6.6 Accountability of radioactive device.......................................................................26 7. SAFETY PROFILE .......................................................................................................28 7.1 General.................................................................................................................28 7.1.1 Fatigue ..........................................................................................................28 7.1.2 Fever.............................................................................................................28 7.1.3 Abdominal pain .............................................................................................28 7.1.4 Gastrointestinal toxicity .................................................................................28 7.1.5 Tumor Lysis Syndrome..................................................................................28 7.1.6 Radiation hepatitis.........................................................................................28 © University Medical Center Utrecht Final version 28, 29-04-2011 Page 5 of 45 HEPAR-trial CCMO NL25956.041.08 METC 08-450 7.1.7 Veno oclussive disease .................................................................................29 7.1.8 Carcinoid crisis..............................................................................................29 7.2 Technique related .................................................................................................29 7.2.1 Peptic Ulceration ...........................................................................................29 7.2.2 Pancreatitis ...................................................................................................29 7.2.3 Radiation Pneumonitis ..................................................................................29 7.2.4 Radiation induced cholecystitis......................................................................29 7.2.5 Aneurysma Spurium/Haematoma..................................................................30 7.2.6 Infection/inflammation of the arterial puncture wound....................................30 7.2.7 Iatrogenic arterial dissection..........................................................................30 7.2.8 Contrast induced renal insufficiency ..............................................................30 8. METHODS....................................................................................................................31 8.1 Study endpoints ....................................................................................................31 8.1.1 Primary study endpoint..................................................................................31 8.1.2 Secondary study endpoints ...........................................................................31 8.2 Withdrawal of individual patients ...........................................................................31 8.2.1 Replacement of withdrawn patients...............................................................32 8.3 Premature termination of the study .......................................................................32 8.3.1 Definition of Radiation Dose Limiting Toxicity (RDLT) ...................................32 8.3.2 Determination of MTRD.................................................................................32 8.4 Independent Data Monitoring Committee (IDMC)..................................................32 9. SAFETY REPORTING .................................................................................................34 9.1 Section 10 WMO event .........................................................................................34 9.2 Adverse events and adverse device effects ..........................................................34 9.3 Serious adverse events.........................................................................................34 9.4 Suspected unexpected serious adverse reactions (SUSAR) .................................34 9.5 Documentation......................................................................................................35 9.5.1 Intensity.........................................................................................................35 9.5.2 Treatment relationship...................................................................................35 9.6 Follow-up of adverse events .................................................................................36 10. STATISTICAL ANALYSIS.........................................................................................37 11. ETHICALCONSIDERATIONS...................................................................................37 11.1 Regulation statement ............................................................................................37 11.1.1 Obligations of the investigator .......................................................................37 11.2 Recruitment and consent ......................................................................................37 11.2.1 Consent.........................................................................................................37 11.3 Benefits and risks assessment, group relatedness................................................38 11.3.1 Benefits .........................................................................................................38 11.3.2 Risks .............................................................................................................38 11.4 Confidentiality .......................................................................................................38 11.5 Financing ..............................................................................................................38 11.6 Compensation for injury ........................................................................................38 11.7 Incentives..............................................................................................................38 12. ADMINISTRATIVE ASPECTS AND PUBLICATION .................................................39 12.1 Case Report Forms...............................................................................................39 12.1.1 Completing CRF’s .........................................................................................39 12.1.2 Corrections to CRF’s .....................................................................................39 12.2 Source document verification ................................................................................39 12.3 Monitoring .............................................................................................................40 12.4 Amendments.........................................................................................................40 © University Medical Center Utrecht Final version 28, 29-04-2011 Page 6 of 45 HEPAR-trial 12.5 12.6 12.7 12.8 13. CCMO NL25956.041.08 METC 08-450 Annual progress report..........................................................................................40 Annual safety report ..............................................................................................40 End of study report................................................................................................41 Publication policy ..................................................................................................41 REFERENCE LIST ...................................................................................................42 Appendices Appendix I Appendix II Appendix III Appendix IV Appendix V Appendix VI Appendix VII Appendix VIII Appendix IX Appendix X Declaration of Helsinki CTCAE v3.0 WHO Performance status RECIST-criteria Laboratory parameters, normal values CBO-directive “Richtlijn Voorzorgsmaatregelen bij jodiumhoudende contrastmiddelen”, page 23-26 EORTC questionnaire QLQ-C30 with colorectal liver metastases module QLQ-LMC21 Patient Information Informed Consent Form Summary preclinical investigations © University Medical Center Utrecht Final version 28, 29-04-2011 Page 7 of 45 HEPAR-trial CCMO NL25956.041.08 METC 08-450 LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS 166 HoPLLA-MS 5-FU/LV 90 Y-MS µg µmol ABR AE ALT ANC AST AR CA CBO CCMO CRF CRP CT CTCAE CV DSMB e.g. ECG EORTC EU EudraCT FAS GBq GCP GMP Gy h HCC IB IC ICH IDMC IEC IMDD IU i.v. keV kg km L LDH MBq METC holmium-166 loaded poly(L-lactic acid) microspheres 5-fluorouracil in combination with leucovorin yttrium-90 microspheres microgram micromole ABR form (General Assessment and Registration form) is the application form that is required for submission to the accredited Ethics Committee (in Dutch: ABR = Algemene Beoordeling en Registratie) Adverse Event alanine aminotransferase absolute neutrophil count aspartate aminotransferase Adverse Reaction Competent Authority Quality institute for Healthcare Central Committee on Research Involving Human Subjects Case Record Form C-reactive protein Computed Tomography Common Terminology Criteria for Adverse Events Curriculum Vitae Data Safety Monitoring Board exemlpi gratia Electrocardiogram European Organization for Research and Treatment of Cancer European Union European drug regulatory affairs Clinical Trials Full Analysis Set Giga Becquerel Good Clinical Practice Good Manufacturing Practice Gray hour(s) hepatocellular carcinoma Investigator’s Brochure Informed Consent International Conference on Harmonization Independent Data Monitoring Committee Independent Ethics Committee Investigational Medical Device Dossier International Units intravenous kilo electron volt kilogram kilometer liter Lactate dehydrogenase Mega Becquerel Medical research ethics committee (MREC) (in Dutch: Medisch Ethische ToetsingsCommissie (METC)) © University Medical Center Utrecht Final version 28, 29-04-2011 Page 8 of 45 HEPAR-trial MeV mg ml MRI MTRD NCI NSAIDs NYHA PPS PET PI PT PTC PTT QOL RDLT RECIST RID ROI SAE SDV SGOT SGPT SOP SPC SPECT SVC Sponsor SUSAR t Tc-MAA TLS ULN UMC VEGF Vx2 Wbp WHO WMO CCMO NL25956.041.08 METC 08-450 mega electron volt Milligram Millilitre Magnetic Resonance Imaging Maximum Tolerated Radiation Dose National Cancer Institute Non-Steroidal Anti-Inflammatory Drugs New York Heart Association Per Protocol Set Positron Emission Tomography Principal Investigator prothrombin time Protocol partial thromboplastin time Quality of Life Radiation Dose Limiting Toxicity Response Evaluation Criteria in Solid Tumors Reactor Institute Delft Region of Interest Serious Adverse Event source data verification Serum glutamate oxaloacetate transaminase serum glutamate pyruvate transaminase Standard Operating Procedure Summary of Product Characteristics (in Dutch: officiële productinfomatie IB1-tekst) Single Photon Emission Computed Tomography Superior vena cava The sponsor is the party that commissions the organisation or performance of the research, for example a pharmaceutical company, academic hospital, scientific organisation or investigator. A party that provides funding for a study but does not commission it is not regarded as the sponsor, but referred to as a subsidising party. Suspected Unexpected Serious Adverse Reaction time Technetrium macroaggregates Tumor Lysis Syndrome Upper Limit of Normal University Medical Center (in Dutch: Universitair Medisch Centrum) Vascular Endothelial Growth Factor virus induced papilloma in rabbits liver Personal Data Protection Act (in Dutch: Wet bescherming persoonsgevens) World Health Organization Medical Research Involving Human Subjects Act (in Dutch: Wet Medischwetenschappelijk Onderzoek met mensen © University Medical Center Utrecht Final version 28, 29-04-2011 Page 9 of 45 HEPAR-trial CCMO NL25956.041.08 METC 08-450 SUMMARY Acronym Rationale Objective Study design Study population Intervention Study endpoints Duration of treatment Methodology Number of study centers Adverse events Inclusion period © University Medical Center Utrecht Final version 28, 29-04-2011 Holmium Embolization Particles for Arterial RadioTherapy – HEPAR-trial A significant need for new treatment options for dominant liver metastases is recognized, because survival of patients with unresectable liver disease is poor. The preclinical phase of studies with 166 Ho-PLLA-MS has been successfully completed and now clinical studies for evaluation of safety and efficacy are warranted. Primary objective: To establish the safety and toxicity profile of treatment with 166Ho-PLLA-MS. Secondary objectives: • To evaluate tumor response. • To evaluate biodistribution. • To evaluate performance status. • To evaluate Quality of Life (QOL). • To compare Tc-MAA-scan with 166 Ho-PLLA-MS safety dose scan. Interventional, treatment, non-randomized, open label uncontrolled, safety study. 15 to 24 patients, male and female aged 18 years and over with dominant liver metastases. All histologies are acceptable, provided no standard therapeutic options are available, such as chemotherapy and surgery. 166 Ho-PLLA-MS will be administered via a catheter during angiography. Primary endpoint: Safety and toxicity profile of treatment with 166 Ho-PLLA-MS. Secondary endpoints: • Tumor response. • Biodistribution. • Performance status. • Quality of Life. • Comparison of Tc-MAA-scan and 166 Ho-PLLA-MS safety dose scan. The study consists of a screening period of approximately 2 weeks followed by a treatment period of approximately 14 weeks. Cohorts of 3 successive patients will be treated with 4 dose levels of 166Ho-PLLA-MS. If a RDLT occurs the cohort will be increased to 6 patients. If at least 2 patients out of 6 have a RDLT, then the MTRD is reached. Single Center (UMC Utrecht). All adverse events will be recorded throughout the study. May 2009 – November 2010. Page 10 of 45 HEPAR-trial CCMO NL25956.041.08 METC 08-450 Analysis Interim analysis will be performed after every 3 patients. Full analysis will be performed after the last patient’s last visit. The primary endpoint will be evaluated in FAS. The secondary endpoints will be evaluated in FAS and PPS. Manufacturers of the medical device 165Ho-PLLA-MS are manufactured by the radionuclide pharmacy of the UMC Utrecht, The Netherlands. 165 Ho-PLLA-MS are neutron activated by the Reactor Instituut Delft, The Netherlands. 166 Ho-PLLA-MS are prepared by the radionuclide pharmacy of the UMC Utrecht, The Netherlands. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 11 of 45 HEPAR-trial 1. CCMO NL25956.041.08 METC 08-450 INTRODUCTION AND RATIONALE Primary liver cancer (hepatocellular carcinoma, cholangiocarcinoma) is the sixth most common cancer, worldwide. The incidence rate is over 600,000 new cases each year and the mortality rate is almost as high. Five-year survival rates are only 3-5% because the majority of patients is not eligible for surgical resection (partial hepatectomy or orthotopic liver transplantation) [1, 2]. Systemic chemotherapy has proven ineffective in HCC. However, the recently introduced sorafenib, an oral multikinase inhibitor, offers a survival benefit of several months [3]. The liver is also the most common site of metastatic spread. As many as 50% of all patients with a primary malignancy will in due course develop hepatic metastases. Metastases confined to the liver most commonly, but not exclusively, occurs from colorectal carcinoma, of which the incidence is very high as well [4]. Each year worldwide approximately one million people develop cancer of the large bowel (colorectal carcinoma) [1]. The primary tumor is in general resectable but unfortunately in 25% of cases the cancer will have spread to the liver at the time of diagnosis whereas in due time more than 50% of patients will develop hepatic metastases [5, 6]. Subtotal hepatic resection is the treatment of choice, yet only 20-30% of patients are eligible for surgical resection of the liver metastases [7]. If resection is performed with curative intent a 33% 5-year survival is reported [8]. For several decades, standard first-line chemotherapy for colorectal cancer has consisted of 5-fluorouracil in combination with leucovorin (5-FU/LV). Nowadays, oxaliplatin or irinotecan is added to 5-FU/LV which has improved median survival from 12 to 20 months [9, 10]. Typically, long-term survival for patients with unresectable metastatic disease remains less than 5% [6]. The use of anti-angiogenic drugs has further improved the prognosis of these patients. The Vascular Endothelial Growth Factor (VEGF) antibody bevacizumab is now considered standard treatment with 5-FU and oxaliplatin containing combinations. Median survival is now considered to be about two years with this triple combination [11-13] Therefore, a significant need for new treatment options is recognized. One novel treatment modality is yttrium-90 radioembolization which consists of injecting beta-particle emitting yttrium-90 loaded (glass or resin) microspheres into the hepatic artery using a catheter. The clinical results of this form of internal radiation therapy are promising [14, 15]. It has been reported in literature that the administration of yttrium-90 microspheres (90Y-MS) along with chemotherapy (5-FU/LV) more than doubled survival with no difference in quality of life compared to chemotherapy alone [16]. It is not known if this is also the case with the use of the triple regimen (bevacizumab, oxaliplatin and 5-FU). Although 90Y-MS therapy is evermore used and considered a safe and effective treatment option for patients with liver dominant disease, these microspheres have a major drawback: following administration the actual biodistribution cannot be accurately visualized [17]. For this reason, holmium-166 loaded poly(L-lactic acid) microspheres (166Ho-PLLA-MS) have been developed [18, 19] at the Department of Radiology and Nuclear Medicine of the University Medical Center (UMC) Utrecht. Like yttrium-90, holmium-166 emits high-energy beta particles that can eradicate tumors but they also emit gamma radiation which allows for nuclear imaging. Visualization of the microspheres is possible. This is very useful for several reasons. Prior to administration of the therapeutic dose a small scout dose of 166Ho-PLLA-MS can be instilled to predict the distribution of the therapeutic dose. Also, quantitative analysis of the nuclear scans would allow assessment of the radiation dose delivered on both the tumor(s) and the normal liver (dosimetry) [20]. In addition, since holmium is highly paramagnetic it can be visualized using magnetic resonance imaging (MRI). Quantitative analysis of these MRI scans is possible as well and especially useful for medium- and longterm monitoring of the intrahepatic behavior of the microspheres [21, 22]. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 12 of 45 HEPAR-trial CCMO NL25956.041.08 METC 08-450 The pharmaceutical quality of the 166Ho-PLLA-MS has been thoroughly investigated and proven to be satisfactory [23-25]. Several animal studies have been conducted to investigate the intrahepatic distribution (ratio tumor:normal liver), the toxicity profile/biocompatibility of the 166Ho-PLLA-MS, safety of the administration procedure, and efficacy of these particles. A non-survival biodistribution study in rats was performed in which it was demonstrated that the 166 Ho-PLLA-MS deposition was restricted to the liver and that in the tumorous tissue the radioactivity concentration was six times higher than in the non-target tissue [26]. To demonstrate that 166Ho-PLLA-MS injected into the hepatic artery have a tumoricidal effect, an efficacy study in Vx2 carcinoma bearing rabbits was performed. In all animals that were treated with 166Ho-PLLA-MS tumor growth was arrested and necrosis set in [27]. In a rat study, in order to show that 166Ho-PLLA-MS are biocompatible, rods composed of (decayed) 166 Ho-PLLA-MS were implanted into the liver and the animals were terminated between 3 days and 18 months post implantation during which time no biochemical or clinical side effects were observed [28]. Finally, an extensive toxicity study in healthy pigs was conducted [29]. Five animals were administered (non-radioactive) 165Ho-PLLA-MS and in 13 animals (radioactive) 166Ho-PLLA-MS were instilled into the hepatic artery. The animals were injected with 166Ho-PLLA-MS in amounts of radioactivity corresponding with very high absorbed liver doses. Just very mild side effects were seen: slight and transitory inappetence and somnolence, which may well have been associated with the anesthetic and analgesic agents that had been given and not necessarily with the microsphere ‘treatment’. A very important adverse event (AE) which had occurred in two animals (166Ho-PLLA-MS) was inadvertent deposition of 166Ho-PLLA-MS into the so-called gastroduodenal artery with consequent radioembolization of the gastric wall. To avoid this type of complication, in analogy to what is already customary in yttrium-90 therapy, selected vessels in patients will be occluded by coiling prior to administration of 166Ho-PLLA-MS [30, 31]. The preclinical phase has been successfully completed and now clinical studies for evaluation of safety and efficacy are warranted. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 13 of 45 HEPAR-trial 2. CCMO NL25956.041.08 METC 08-450 OBJECTIVES In this safety study a new device will be investigated, namely radioactive holmium microspheres for microbrachytherapy for the treatment of liver malignancies. In a group of 15 to 24 patients, treated with increasing amounts of radioactive microspheres, the device will be investigated on safety. Primary objective: • To establish the safety and toxicity profile of treatment with 166Ho-PLLA-MS. Secondary objectives: • To evaluate tumor response. • To evaluate biodistribution. • To evaluate performance status. • To evaluate Quality of Life (QOL). • To compare Tc-MAA-scan with 166Ho-PLLA-MS safety dose scan 3. STUDY DESIGN Study type Study design Study start date Estimated study completion date Interventional Treatment, safety study, non-randomized, open label, medical device* May 2009 November 2010 This single centre study will be conducted in a minimum of 15 and a maximum of 24 patients with liver metastases for whom no standard surgical or chemotherapeutic options will be available. A standard dose escalation protocol with four cohorts will be used. Consecutive patients will be treated in cohorts of 3 with identical amounts of 600 mg microspheres, where the last cohort will consist of at least 6 patients. The first three cohorts will be extended when toxicity is observed ( see 8.3.2). The specific activity will be increased by adapting irradiation time in the nuclear reactor. The first cohort will be treated with a dose of 1.3 GBq/kg (liver weight). The second cohort will be treated with a dose of 2.5 GBq/kg (liver weight). The third cohort will be treated with a dose of 3.8 GBq/kg (liver weight) and the fourth cohort will be treated with a dose of 5.0 GBq/kg (liver weight). See for dose calculation chapter 6.5. * Regarding the method of administration (through a catheter inside the hepatic artery), invivo characteristics (no release of radionuclide) and mechanism of action (local irradiation of the tumor) 166Ho-PLLA-MS is comparable to the two 90Y-MS products, either resin based (SIR-Spheres) or glass based (TheraSphere), which are currently applied clinically and are commercially available. The main difference and therefore main expected improvement compared to the 90Y-MS is in the use of the radionuclide 166Ho to irradiate the tumor. In contrast to 90Y, 166Ho can be visualised both by SPECT and MRI, which is important to accurately detect biodistribution and perform dosimetric calculations. The shorter half-life of 166 Ho (26.8 h vs. 64.2 h for 90Y) also is an advantage, since high doserates on the tumor can be achieved. Both commercially available 90Y-MS products are approved by the FDA and EMEA as a medical device. According to the FDA ((http://www.fda.gov/cdrh/devadvice/312.html) a medical device is defined as: "an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is: © University Medical Center Utrecht Final version 28, 29-04-2011 Page 14 of 45 HEPAR-trial CCMO NL25956.041.08 METC 08-450 recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them, intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of it's primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes." This definition provides a clear distinction between a medical device and other FDA regulated products such as drugs. If the primary intended use of the product is achieved through chemical action or by being metabolized by the body, the product is usually a drug. According to this definition and by analogy with the 90Y-MS we consider the 166Ho-PLLAMS as a medical device. The Dutch medicine evaluation board (College ter Beoordeling van Geneesmiddelen) has discussed this issue (13 July 2007) and concluded that the microspheres are to be considered as a medical device (see IMDD Appendix 1). © University Medical Center Utrecht Final version 28, 29-04-2011 Page 15 of 45 HEPAR-trial 4. CCMO NL25956.041.08 METC 08-450 STUDY POPULATION The study will include patients with dominant liver metastases. All histologies are acceptable, provided no standard therapeutic options are available, such as chemotherapy and surgery. 4.1 Inclusion criteria Patients meeting the following criteria may enter the study: 1. Patients must have given written informed consent. 2. Female or male aged 18 years and over. 3. Confirmed histological diagnosis of metastatic malignancy with dominant liver metastases without standard therapeutic options for treatment including chemotherapy or surgery. Dominant liver metastases are defined (according to the Response Evaluation Criteria in Solid Tumors (RECIST) methodology, see Appendix IV) as the diameter of all metastases in the liver must be more than 200% of the sum of the diameters of all soft tissue lesions outside the liver. 4. Life expectancy of 12 weeks or longer. 5. World Health Organisation (WHO) Performance status 0-2 (see Appendix III). 6. One or more measurable lesions at least 10 mm in the longest diameter by spiral Computed Tomography (CT) scan (5 mm slice thickness) according to the RECIST criteria. 7. Negative pregnancy test for women of childbearing potential. 4.2 Exclusion criteria Patients meeting any of the following criteria cannot enter the study: 1. Brain metastases or spinal cord compression, unless irradiated at least 4 weeks prior to the date of the experimental treatment and stable without steroid treatment for at least 1 week. 2. Radiation therapy within the last 4 weeks before the start of study therapy. 3. The last dose of prior chemotherapy has been received less than 4 weeks prior the start of study therapy. 4. Major surgery within 4 weeks, or incompletely healed surgical incision before starting study therapy. 5. Any unresolved toxicity greater than National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE version 3.0, see Appendix II) grade 2 from previous anti-cancer therapy. 6. Serum bilirubin > 1.5 x Upper Limit of Normal (ULN). 7. Serum creatinine > 185 µmol/L. 8. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) > 5 x ULN. 9. Leukocytes < 4.0 109/l and/or platelet count < 150 109/l. 10. Significant cardiac event (e.g. myocardial infarction, superior vena cava (SVC) syndrome, New York Heart Association (NYHA) classification of heart disease ≥2 within 3 months before entry, or presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia. 11. Pregnancy or breast feeding (women of child-bearing potential). 12. Comorbidity with a grave prognosis (estimated survival <3 months) and/or worse then the basic disease for which the patients will be included in the study. 13. Patients with abnormalities of the bile ducts (such as stents) with a increased chance of infections of the bile ducts. 14. Patients suffering from diseases with a increased chance of liver toxicity, such as primary biliairy cirrhosis or xeroderma pigmentosum. 15. Patients suffering from psychic disorders that make a comprehensive judgement impossible, such as psychosis, hallucinations and/or depression. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 16 of 45 HEPAR-trial 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. CCMO NL25956.041.08 METC 08-450 Patients who are declared incompetent. Previous enrolment in the present study or previous treatment with radioembolization. Treated with an investigational agent within 42 days prior to starting study treatment. Female patients who are not using an acceptable method of contraception (oral contraceptives, barrier methods, approved contraceptive implant, long-term injectable contraception, intrauterine device or tubal ligation) OR are less than 1 year postmenopausal or surgically sterile during their participation in this study (from the time they sign the consent form) to prevent pregnancy. Male patients who are not surgically sterile or do not use an acceptable method of contraception during their participation in this study (from the time they sign the consent form) to prevent pregnancy in a partner. Evidence of portal hypertension, splenomegaly or ascites. Body weight over 150 kg. Active hepatitis (B and/or C). Liver weight > 3 kg (determined by software using CT data). Allergy for i.v. contrast used (Visipaque®). MRI contra-indications: severe claustrophobia, metal shrapnel, implanted pacemaker and/or neurostimulators. Patients who have arterial variations that will not allow whole liver treatment. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 17 of 45 HEPAR-trial CCMO NL25956.041.08 METC 08-450 5. TREATMENT OF PATIENTS 5.1 Schedule of procedures Procedures Screening Informed consent X In-/exclusion X Demographic data X Medical/surgical and medication history Physical exam, vital signs and WHO performance status Treatment and follow-up period W0 W1 W2 W3 W4 X X X X W5 W6 W7 W8 W9 X X X X X W10 W11 W12 W13 X X X X X X Pregnancy test (urine) X X X X EORTC Questionnaire X X X CT scan X X X MRI scan X PET scan* X X4 Angiography X Pre-safety dose of Tc-99m-MAA X Safety dose of X X X X X X X 166 Ho-PLLA-MS Therapeutic dose of 166 Ho-PLLA-MS X Ho-excretion (blood samples + 48 h urine) X X1 Scintigraphy Radiation exposure rate X2 X3 X ECG X Laboratory examination type A** X X X Laboratory examination type B** X X X X X Laboratory examination type C** Monitoring of (S)AE’s + concomitant med. X X X X X X X X X X X X X X X X X X X X * Positron Emission Tomography (PET) will only be performed in FDG-avid tumors. ** Laboratory examination type A (blood), B (blood) and C (blood and urine) see table 2: Laboratory parameters for safety. 1. Tc-99m-MAA scintigraphy 2. Safety scintigraphy 3. Post treatment scintigraphy 4. Non-contrast enhanced MRI of a limited duration Table 1: Schedule of study procedures © University Medical Center Utrecht Final version 28, 29-04-2011 Page 18 of 45 X X HEPAR-trial Laboratory examination Type A (blood) CCMO NL25956.041.08 METC 08-450 Parameters Hematology Coagulation profile Serum chemistry Type B (blood) Hematology Serum chemistry Type C (blood and urine) Holmium content Leukocytes, erythrocytes, hemoglobin (Hb), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), differential leukocyte count (neutrophils, lymphocytes, monocytes, eosinophils, basophils) and platelet count. Reagent-independent prothrombin ratio PT/PTT. If PT and/or PTT are out of range, Thrombin time (TT) will be automatically measured. Activated partial thromboplastin time (APTT). Creatinine, total bilirubin, alkaline phosphatase, SGPT/ALT, SGOT/AST, γGT, glucose, chloride, calcium, potassium, sodium, total protein, albumin, bicarbonate, urea, magnesium, phosphorus, ammonia, LDH, CRP and relevant tumor markers. Total: 10 ml Leukocytes, erythrocytes, hemoglobin (Hb), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), differential leukocyte count (neutrophils, lymphocytes, monocytes, eosinophils, basophils) and platelet count. Creatinine, total bilirubin, alkaline phosphatase, SGPT/ALT, SGOT/AST, γGT, glucose, albumin, ammonia, LDH and CRP. Total: 4 ml Holmium content. Total blood: 4.5 ml Table 2: Laboratory parameters for safety. 5.2 Study procedures 5.2.1 Screening The screening visit will take place at the outpatient clinic within 14 days prior to the fist angiography. During this visit the following procedures must be documented and reviewed as a part of the screening process: • Informed Consent. • Inclusion and exclusion criteria. • Demographic data. • Medical and surgical history. • Previous and ongoing medications (within the last 3 months). • Physical examination including height and weight. • Vital signs, including blood pressure (after at least 3 minutes sitting), pulse and temperature. • WHO performance assessment. • CT, MRI and Positron Emission Tomography (PET) scan (scans should be performed within 2 weeks prior to the first angiography). Positron Emission Tomography (PET) will only be performed in FDG-avid tumors. • ECG. • Laboratory examination type A (blood). 5.2.2 Visit 1 (week 0) Patients will be hospitalized on the evening before the day of angiography. They will be discharged approximately 24 hours after the intervention unless complications will occur. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 19 of 45 HEPAR-trial CCMO NL25956.041.08 METC 08-450 During this visit the following procedures must be documented and reviewed as a part of the study: • Inclusion and exclusion criteria. • Physical examination and vital signs (blood pressure, pulse and temperature). • Pregnancy test for women of childbearing age. • WHO performance assessment. • Concomitant medication. • Monitoring of occurrence of (serious) adverse events. • Laboratory examination type A (blood). On day 0 the patient is subjected to an angiography of the upper abdominal vessels. At least the celiac trunk and upper mesenteric artery are visualised. Followed by coiling of relevant (aberrant) vessels, especially branches of the celiac axis supplying the organs. This procedure will be performed by a skilled and trained interventional radiologist*. The catheter is introduced using the Seldinger technique. Prior to the procedure the patient is offered a tranquilizer. Premedication consists of proton pump inhibitors (pantoprazol 1 dd 40 mg), starting at the day of the intervention. Proton pump inhibitors are prescribed to the patients to be used until the end of the follow up. * The attending intervention-radiologist, after finishing his residency in Radiology, stayed for an additional 2 year training in interventional radiology at Stanford University Medical Center (USA) and AMC Amsterdam. In the USA he was for the first time exposed to Y90 radioembolization. He performed additional supervised radioembolizations in the University Hospital in Gent. Currently, he performs these radioembolizations on a routine basis in the UMC Utrecht. After successful angiography and coiling of relevant vasculature a dose of Tc-99m-MAA will be administered. The patient is subjected to scintigraphy to determine the distribution. Both planar imaging of the thorax and abdomen will be performed, as well as Single Photon Emission Computed Tomography (SPECT) of abdomen. Images will be evaluated qualitatively and quantitatively. Excessive extrahepatic deposition of activity is a contraindication for administration of the therapeutic dose. ROI (region of interest) analysis will be used to calculate lung shunting. Lung shunting should not exceed 20% of the dose Tc-99mMAA. If the amount of lung shunting can not be reduced using standard radiological interventional techniques to decrease lung shunting under 20%, the patient will not be eligible to receive a safety and therapeutic dose of 166Ho-PLLA-MS. 5.2.3 Visit 2 (week 1-2) The second intervention takes place around 1 week after the first intervention but no longer than 2 weeks after. Patients will be hospitalized on the evening before the day of treatment. They will be discharged approximately 48 hours after the intervention unless complications will occur. During this visit the following procedures must be documented and reviewed as a part of the study: • Inclusion and exclusion criteria. • Physical examination and vital signs (blood pressure, pulse and temperature). • WHO performance assessment. • Concomitant medication. • Monitoring of occurrence of (serious) adverse events. • Collecting of 48 hours urine for holmium content. • Laboratory examination type A and C (blood and urine). • Radiation exposure rate. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 20 of 45 HEPAR-trial CCMO NL25956.041.08 METC 08-450 Prior to the procedure the patient is offered a tranquilizer. An experienced interventional radiologist will administer the safety dose of 166Ho-PLLA-MS through a catheter inside the hepatic artery at the position as planned during the first intervention. In order to detect inadvertent administration to the lungs or other (upper abdominal organs) a scintigraphy will be performed after administration of the safety dose of 166HoPLLA-MS to assess the distribution. Both planar imaging of the thorax and abdomen will be performed, as well as SPECT of the abdomen. When the amount of lung shunting does not exceed 20% of the safety dose of 166HoPLLA-MS, the therapeutic dose of 166HoPLLA-MS will be administered. In order to obtain detailed information on the distribution of the 166Ho-PLLA-MS an MRI will be performed both after the safety dose and the therapeutic dose. The MRI after the safety dose will be a non-contrast enhanced MRI of limited duration. The amount of radioactivity administered to the patient is determined by the study protocol (see chapter 6.5). An experienced nuclear physician will assist the radiologist during administration. 5.2.4 Visit 3 (week 2-3) This visit will take place at the outpatient clinic. During this visit the following procedures must be documented and reviewed as a part of the study: • Physical examination and vital signs (blood pressure, pulse and temperature). • WHO performance assessment. • Concomitant medication. • Monitoring of occurrence of (serious) adverse events. • Laboratory examination type B (blood). • A post treatment scintigraphy (scan will be acquired when the administered dose will have decayed to approximately 500 MBq, which will take around 4 days, depending on the administered dose). • A MRI will also be performed. 5.2.5 Visit 4-7 (week 3-6) These visits will take place at the outpatient clinic. During these visits the following procedures must be documented and reviewed as a part of the study: • Physical examination and vital signs (blood pressure, pulse and temperature). • WHO performance assessment. • Concomitant medication. • Monitoring of occurrence of (serious) adverse events. • Laboratory examination type B (blood). 5.2.6 Visit 8 (week 7) This visit will take place at the outpatient clinic. During this visit the following procedures must be documented and reviewed as a part of the study: • Physical examination and vital signs (blood pressure, pulse and temperature). • WHO performance assessment. • Concomitant medication. • Monitoring of occurrence of (serious) adverse events. • Laboratory examination type A and C (blood and urine). • CT and PET scan. 5.2.7 Visit 9-13 (week 8-12) These visits will take place at the outpatient clinic. During these visits the following procedures must be documented and reviewed as a part of the study: © University Medical Center Utrecht Final version 28, 29-04-2011 Page 21 of 45 HEPAR-trial • • • • • 5.2.8 CCMO NL25956.041.08 METC 08-450 Physical examination and vital signs (blood pressure, pulse and temperature). WHO performance assessment. Concomitant medication. Monitoring of occurrence of (serious) adverse events. Laboratory examination type B (blood). Visit 14 (week 13; final visit) This visit will take place at the outpatient clinic. During this visit the following procedures must be documented and reviewed as a part of the study: • Physical examination and vital signs (blood pressure, pulse and temperature). • WHO performance assessment. • Concomitant medication. • Monitoring of occurrence of (serious) adverse events. • Laboratory examination type A and C (blood and urine). • CT, MRI and PET scan. 5.3 Holmium content Pooled urine samples will be collected in week 1 from 0-3 hours, 3-6 hours, 6-24 hours and 24-48 hours following 166Ho-PLLA-MS administration. In week 7 and week 13 pooled 24 hours urine will be collected (Laboratory examination type C, see tables 1 and 2). The date and time of the start and the end of the collection period, the volume and whether the collection was complete or not, will be noted in the Case Record Form (CRF). Measurement of holmium content in urine and blood will be performed. The data and the time of measurement and the results will be reported in the CRF. During the hospitalization in week 1 (at t = 0, 3, 6, 24 and 48 hours following 166Ho-PLLA-MS administration) and the outpatient clinic visits in week 7 and week 13 blood will be drawn for measuring the holmium content in the blood. 5.4 Laboratory examinations Blood samples for safety parameters will be taken using an indwelling canula or by single vein puncture. During the follow-up visits with the investigator, blood samples for safety parameters will be drawn by a research nurse and delivered to the Laboratory of Clinical Chemistry and Haematology (see table 2). 5.5 Radiation exposure rate During the hospitalization in week 1 the radiation exposure rate will be measured at t = 0, 3, 6, 24 and 48 hours from 1 meter distance (see table 1). 5.6 Use of co-medication All patients that are eligible for the experimental treatment will receive proton pump inhibitors (pantoprazol 1 dd 40 mg) starting the day before the catheterisation, which will be continued until the end of the follow-up. During the vascular intervention the patient will receive heparin (1000 IU/ml in saline, up to 2500 IU), to avoid the formation of thromboembolism during the intervention. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 22 of 45 HEPAR-trial CCMO NL25956.041.08 METC 08-450 The vascular intervention will be performed under x-ray guidance. To be able to visualise the blood vessels during the procedure, a non-ionogenic x-ray contrast agent (jodixanol, Visipaque®) will be administered to the patient. Should women of childbearing age require microsphere therapy, non-pregnancy needs to be ascertained prior to treatment. Therefore, proper contraceptive measures should be used, such as the birth control pill. 5.7 Escape medication Patients will receive oral analgesics (paracetamol up to 4000 mg/24h) for relief of fever and pain after the administration of microspheres. To reduce nausea and vomiting, patients will receive anti-emetics (ondansetron up to 3 dd 8 mg) during the first 24 hours after administration of microspheres. In the case of persisting nausea, metoclopramide (up to 300 mg/24h) will be used. Patients suffering from diarrhoea will receive loperamide (up to 16 mg/24h). The vascular contrast agent jodixanol (Visipaque®) can cause renal insufficiency in poorly hydrated patients. Therefore, all patients will be hydrated according to the CBO-directive. This consists of 1.5 l NaCl 0.9% prior and post angiography. Inadvertent shunting of microspheres to organs such as the lungs, stomach and gall bladder is associated with serious side effects. To reduce toxicity of the radioactive microspheres in this case, amifostine (Ethyol® , up to 200 mg i.v./m2 for 7 days) can be administered. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 23 of 45 HEPAR-trial 6. INVESTIGATIONAL MEDICAL DEVICE 6.1 Name and description of investigational medical product CCMO NL25956.041.08 METC 08-450 The device under investigation comprises radioactive particles dedicated for treatment of hepatic malignancies. The particles, called microspheres, contain the radionuclide holmium166, which emits gamma rays (81 keV) and high-energy (1.8 MeV) beta particles. The beta particles are responsible for the therapeutic effect of the device, the gamma ray can be used for nuclear imaging purposes. Liver metastases are preferably supplied by the hepatic artery. This selective vascularisation allows the use of the hepatic artery for selective administration to the metastases without compromising hepatic flow by the portal vein. The microspheres are locally administered by means of selective catheterisation of the hepatic artery by a trained intervention radiologist. 6.2 Animal studies Several animal studies have been performed with 166Ho-PLLA-MS. These studies were aimed to get insight into the toxic effect, the method/technique of administration, efficacy, safety and in vivo stability of the microspheres. The studies have been performed on rats, rabbits, and pigs. The animal studies showed promising and positive results. An overview and summary of the animal studies performed is given in Appendix X and the Investigational Medical Device Dossier (IMDD, page 14, 18 and Appendix 6). 6.3 Clinical studies This study will be the first clinical study to be performed with this medical device. 166 Ho-PLLA-MS and 90Y-MS are applied in a similar fashion (administration into the hepatic artery using a catheter) and can therefore be compared. A description of comparative studies is given in the IMDD (page 16 and 17). 6.4 Summary of known and potential risks and benefits 6.4.1 Potential risks Based on the literature on 90Y-MS and animal studies on 166Ho-PLLA-MS, it is expected that, if the 166Ho-PLLA-MS are administered correctly, the risk of complications is low. However, it has been described in the literature that, due to excessive radiation doses delivered to the liver parenchyma, “radiation hepatitis” is known to occur [16, 32]. This veno-occlusive disease can usually be managed by steroid treatment but in some cases will result in fulminant liver failure. However, the incidence of this complication is very low. There is also the risk of known side effects (see chapter 7). 6.4.2 Potential benefits The data and information provided in the IMDD demonstrates that the 166Ho-PLLA-MS are suitable for therapy due to their radiotherapeutic and safety properties (see IMDD chapter 2.1.2 and chapter 4.4). The radioactive therapeutic dosage can be adjusted per patient based on liver weight (see IMDD chapter 5.2). In short, the use of radioactive microspheres administered intra-arterially as radionuclide therapy for liver malignancies can overcome disadvantages of external beam radiation, which is limited by the radiosensitivity of healthy liver tissue. Microspheres have the potential to provide treatment to previously untreatable patients. The preclinical data of 166Ho-PLLAMS presented in this dossier provide a rational basis for further clinical investigations. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 24 of 45 HEPAR-trial 6.5 CCMO NL25956.041.08 METC 08-450 Dose The amount of 166Ho radioactivity (A) that must be administered to a patient to deliver the desired absorbed liver dose can be calculated according to the following formula [29]: AHo166 (MBq)/LW (kg) = Liver Dose (Gy)/15.87 x 10 -3(J/MBq) = Liver Dose (Gy) x 63 (MBq/J) where LW is the liver weight of the patient which may be determined using CT, MRI or ultrasound scans. The calculated dose is based on the assumption that all administered activity will be equally distributed over the whole liver. This is not a realistic assumption but a rather conservative and safe approach. Using this approach, only mild adverse events were encountered in healthy pigs treated with calculated whole liver doses up to 150 Gy [29]. The administered activity will show heterogeneous distribution over the liver enabling regeneration of relatively spared liver tissue. In this study 4 dose levels were chosen (calculated whole liver doses of 20 Gy, 40 Gy, 60 Gy and 80 Gy). This allows for a conservative approach while delivering therapeutic doses to all patients at the same time. In the matrix “Dose (Gy) and activity (MBq) relation of holmium-166 treatment” examples of amounts of activity for typical liver weights are given for the four investigated cohorts: 1.3 GBq/kg (liver weight), 2.5 GBq/kg (liver weight), 3.8 GBq/kg (liver weight) and 5.0 GBq/kg (liver weight). A maximum of 15.1 GBq will be given to the maximum treated liver weight (inclusive the tumour tissue) of 3 kg. The amounts of 166Ho radioactivity are calculated with the above described formula. Dose (Gy) and activity (MBq) relation of holmium-166 treatment Liver dose (Gy) 10 20 30 40 50 60 70 80 1 A (MBq) 630 1260 1890 2520 3150 3780 4410 5040 1.5 A (MBq) 945 1890 2835 3780 4725 5670 6615 7560 LW (kg) 2 A (MBq) 1260 2520 3780 5040 6300 7560 8820 10080 2.5 A (MBq) 1575 3150 4725 6300 7875 9450 11025 12600 3 A (MBq) 1890 3780 5670 7560 9450 11340 13230 15120 4 dose cohorts: 1.3 GBq/kg; 2.5 GBq/kg (40 Gy); 3.8 GBq/kg (60Gy) and 5.0 GBq/kg (80Gy) Matrix 1: Dose (Gy) and activity (MBq) relation of holmium-166 treatment © University Medical Center Utrecht Final version 28, 29-04-2011 Page 25 of 45 HEPAR-trial 6.6 CCMO NL25956.041.08 METC 08-450 Accountability of radioactive device The following flowchart demonstrates the route from preparation to disposition of the radioactive device 166Ho-PLLA-MS. 1. 2. 3. Preparation of 165 Ho-PLLA-MS Neutron activation of 165Ho-PLLA-MS (Radionuclide pharmacy) (RID Delft) 6. 5. Preparation of Ho-PLLA-MS for patient administration 166 (Radionuclide pharmacy) 4. Disposition of radioactivity Measurement of radioactivity left in administration materials (Radionuclide pharmacy) (Radionuclide pharmacy) Administration of Ho-PLLA-MS to patient 166 (Interventional suite Radiology dept.) Figure 1: 166Ho-PLLA-MS flowchart, route from preparation to disposition. Step 1 – Preparation of 165Ho-PLLA-MS is carried out in the Good Manufacturing Practice (GMP) facility (room E.02.4.11) of the radionuclide pharmacy of the UMC Utrecht. After passing quality control, batches of 165Ho-PLLA-MS are stored in the radionuclide pharmacy at room temperature in room E.02.422 in a vacuum dessicator. Before neutron activation patient dose vials are given a unique identification number with a permanent marker that is resistant to neutron irradiation. A complete description of the preparation, labelling and release of 165Ho-PLLA-MS is given in the IMDD (page 9-11, Appendix 2 and 3, PTC-01 and PTC-02). Step 2 – Neutron activation is carried out in the Reactor Instituut Delft (RID). A complete description of neutron activation is given in the IMDD (page 12, Appendix 4 and 7 and PTC-04). Step 3 – Preparation of 166Ho-PLLA-MS for patient administration is carried out in the GMP facility (room E.02.4.11) of the radionuclide pharmacy of the UMC Utrecht. A complete description of the preparation of 166Ho-PLLA-MS is given in the IMDD (Appendix 4, PTC-01 and PTC-05). Step 4 – Administration of 166Ho-PLLA-MS to the patient is carried out in the interventional suite of the Radiology department. A complete description of the method of administration of 166Ho-PLLA-MS is given in the IMDD (page 19). © University Medical Center Utrecht Final version 28, 29-04-2011 Page 26 of 45 HEPAR-trial CCMO NL25956.041.08 METC 08-450 Step 5 – Measurement of radioactivity left in the administration materials is carried out in the GMP facility (room E.02.4.11) of the radionuclide pharmacy of the UMC Utrecht. Measurement is performed to calculate the net activity administered to the patient. Step 6 – Disposition of radioactivity is carried out in room E.00.2.19. A complete description of the disposition of radioactivity is given in the IMDD (PTC.300.02). © University Medical Center Utrecht Final version 28, 29-04-2011 Page 27 of 45 HEPAR-trial 7. CCMO NL25956.041.08 METC 08-450 SAFETY PROFILE The following effects are expected based on literature on treatment with 90Y-MS [14, 33-36]. A similar safety profile is expected for 166Ho-PLLA-MS. The safety profile is divided in general and technique related effects. 7.1 General When the patient is treated with the proper technique, without excessive radiation to any organ, the common adverse events after receiving radioactive microspheres are fever, abdominal pain, nausea, vomiting, diarrhoea and fatigue. An abnormality of liver function tests is likely to occur. This may be up to grade 3 or 4 (CTCAE vs 3) in the case of AST/SGOT, ALT/SGPT, γGT, ALP and LDH, without direct clinical relevance. In general these effects are transient [31]. 7.1.1 Fatigue Fatigue is often observed in patients. In general it does not exceed grade 2. 7.1.2 Fever Fever can be observed immediately after the embolization (post-embolization syndrome) or later in the follow-up. This can last for one week. The occurrence of fever later in the followup may be caused by the development of hepatic abscesses. 7.1.3 Abdominal pain Right upper quadrant abdominal pain is frequently observed in patients undergoing radioembolization, but easily managed by outpatient medication. 7.1.4 Gastrointestinal toxicity Nausea, vomiting, or both may be controlled with anti-emetic therapy. Ondansetron (up to 3 dd 8 mg) is recommended the first 24 hours after the administration. Subsequently, metoclopramide (up to 300 mg/24h) can be prescribed. Diarrhoea should be treated with adequate doses of loperamide (up to 16 mg/24h). 7.1.5 Tumor Lysis Syndrome A major complication but very rare complication is a Tumor Lysis Syndrome (TLS). This is caused by rapid necrosis of the tumor. Laboratory tests show a high serum LDH, high uric acid, high serum potassium, high phosphate and low serum calcium. In patients with solid tumors this side effect is extremely rare. Supportive care including fluids is recommended. 7.1.6 Radiation hepatitis The frequency of radiation hepatitis is very uncommon in radioembolization due to the inhomogeneous distribution that may be anticipated. There is no specific therapy for this particular side effect. In case hepatic insufficiency occurs only the use of high doses of lactulose and, if appropriate, assessing brain pressure and relieving increased brain pressure might be beneficial. Hepatic insufficiency may occur in < 1% of all treated patients. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 28 of 45 HEPAR-trial 7.1.7 CCMO NL25956.041.08 METC 08-450 Veno oclussive disease Veno occlusive disease (VOD) may occur by radiation damage to the portal veins. This is caused by activation of the coagulation system probably by enodothelial damage. Anticoagulants such as low molecular heparin (Fraxiparin in therapeutic dosages) have been shown to be beneficial. 7.1.8 Carcinoid crisis In cases patients with neuroendocrine tumours receive this experimental treatment the release of neuroendocrine factors may give rise to the so called ‘carcinoid syndrome’. This consists of high blood pressure , flushing and diarrhoea. This syndrome can be prevented to some extent with octreotide (300 µg i.v./24h). 7.2 Technique related The following effects are directly related to inadvertent deposition of the microspheres in organs other than the liver, and should therefore be classified as technique related: In case significant amounts of the dose of the 166Ho-PLLA-MS are deposited outside the liver the potential toxicity may be decreased by starting treatment with the radiation scavenger amifostine (up to 200 mg i.v./m2 for 7 days). It is imperative to start this treatment as soon as possible. 7.2.1 Peptic Ulceration A peptic ulcer may occur in < 10% of all treated patients. The development of acute peptic ulceration is suggested by the symptoms of ulcer disease and diagnosed by endoscopy. If this were to occur the patient should be treated using best standard practice, including pain relief, gastric acid blocking drugs and intravenous fluids (pantoprazol i.v. up to 80 mg). Treatment is the same as for any cause of peptic ulceration. 7.2.2 Pancreatitis Pancreatitis may occur in 1% of all treated patients. The post treatment nuclear scan will determine if the microspheres have lodged in the pancreas or other organs, but additional tests such as serum amylase are also indicated if pancreatitis is suspected. If this were to occur the patient should be treated using best standard practice, including pain relief, and intravenous fluids (pantoprazol i.v. up to 80 mg). 7.2.3 Radiation Pneumonitis High levels of implanted radiation and/or excessive shunting to the lung may lead to radiation pneumonitis. This may be suspected if patients develop a non-productive cough several days or weeks after the implantation of the microspheres and is diagnosed by chest X-ray. Patients should be treated with systemic corticosteroids (1 mg/kg/day) and supportive care until the condition has subsided. 7.2.4 Radiation induced cholecystitis A rare complication is a radiation induced cholecystitis, which may occur in 1-2 % of all treated patients. This side effect can be expected a few weeks after the intervention. Complaints are local pain in the liver area, sometimes colicky in nature, elevated bilirubin values and an increased CRP. Treatment may consist of a cholecystectomy. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 29 of 45 HEPAR-trial 7.2.5 CCMO NL25956.041.08 METC 08-450 Aneurysma Spurium/Haematoma As a complication of arterial catheterization in the groin a false aneurysm may develop within a few days after the procedure. This can be suspected because of local pain and a swelling in the groin. It can be visualized by ultrasound. If this aneurysm is becoming very large and threatens or causes skin necrosis, or is expanding rapidly as it may be infected, surgical management should be performed. In most cases ultrasound-guided compression will be effective. Ultrasound-guided injection of bovine thrombin is also very successful [37]. In rare cases, pseudoaneurysms less than 2 cm can be managed conservatively and monitored by serial imaging to confirm spontaneous resolution. In case a hematoma is diagnosed this will resolve spontaneously. 7.2.6 Infection/inflammation of the arterial puncture wound As a complication of arterial catheterization in the groin an infection/inflammation of the arterial puncture wound may develop. Adequate antibacterial treatment will be provided to resolve this. 7.2.7 Iatrogenic arterial dissection If a dissection of an (abdominal) artery is suspected, this can be managed in general by medical treatment (such as lowering of the blood pressure). But if the dissection ruptures, immediate surgery should be performed. Depending on the size of the lesion and the affected vessel an embolization may be performed. 7.2.8 Contrast induced renal insufficiency Although the frequency of contrast-induced renal insufficiency has decreased by the use of non-ionogenic contrast, care should be taken to hydrate the patient adequately. Particularly in patients with an impaired food intake and or diabetes mellitus this will require also adequate hydration (> 2 l of fluid/24 h) prior to both angiographic procedures. If renal insuffiency develops, patients will complain about asthenia, vomiting may occur and edeme can be observed. The diagnosis is made by laboratory testing. Rehydration is generally sufficient. Care should be taken to prevent hyperkalemia to avoid cardiac rhythm abnormalities. To prevent nefrotoxicity, patients will be pre- and posthydrated according to the CBO-directive “Richtlijn Voorzorgsmaatregelen bij jodiumhoudende contrastmiddelen”, page 23-26 (see Appendix VI). © University Medical Center Utrecht Final version 28, 29-04-2011 Page 30 of 45 HEPAR-trial 8. METHODS 8.1 Study endpoints 8.1.1 Primary study endpoint CCMO NL25956.041.08 METC 08-450 To establish the safety and toxicity profile of treatment with 166Ho-PLLA-MS. This profile will be established using CTCAE (incl. SAE) methodology (CTCAE vs 3). The profile will be used to determine the Maximum Tolerated Radiation Dose (MTRD, see chapter 8.3.2). 8.1.2 • • • • • 8.2 Secondary study endpoints To evaluate tumor response: CT of the liver will be used to quantify tumor response in time according to Response Criteria in Solid Tumor (RECIST) guidelines. Tumor size will be assessed on the porto-venous phase of the dynamic contrast-enhanced CTimages. At fixed intervals in time (6 and 12 weeks after treatment), the largest liver lesions are selected, to a maximum of five, and the maximum diameter in axial plane is measured. The sum of the maximum diameter of the lesions is recorded. Complete Response (CR): disappearance of all lesions, confirmed at 6 weeks Partial Response (PR): ≥ 30% decrease in the sum of the longest diameters of target lesions, with the baseline measurements taken as reference, confirmed at 6 weeks Stable Disease (SD): <30% decrease and <20% increase Progressive Disease (PD): ≥20% increase in the sum of the longest diameters of target lesions, with the baseline measurements taken as reference or appearance of new lesions To assess changes in tumor viability a PET-scan will be performed. Antitumoral effect will also be assessed by relevant tumor markers (e.g. CEA for colorectal carcinoma, AFP for hepatoma and Chromogranine A for neuroendocrine tumors) responses. Tumor marker changes will be expressed as a percentage of the pre-treatment values. To evaluate biodistribution using CT, quantitative SPECT and MRI, blood analysis and urinalysis. To evaluate performance status using WHO performance status criteria. To evaluate QOL using EORTC questionnaire QLQ-C30 with colorectal liver metastases module QLQ-LMC21 (see Appendix VII). To compare Tc-MAA-scan with 166Ho-PLLA-MS safety dose scan using hepatic scintigraphy, both planar and SPECT. Withdrawal of individual patients Patients can leave the study at any time for any reason if they wish to do so without any consequences for treatment or care. The investigator can decide to withdraw a patient from the study for urgent medical reasons. Patients may be withdrawn from the study if: • A serious adverse event occurs. Patients will be withdrawn from the study if: • The investigator considers it in the best interest of the patient that he/she be withdrawn. • The patient withdraws consent. • The patient is unable to comply with the protocol procedures © University Medical Center Utrecht Final version 28, 29-04-2011 Page 31 of 45 HEPAR-trial CCMO NL25956.041.08 METC 08-450 The date and reason for withdrawal must be recorded. If the patient withdraws consent after the therapeutic dose of 166Ho-PLLA-MS has been administered, the patient will be advised to agree to follow-up safety investigations. In case of a serious adverse event a follow-up visit will be arranged by the investigator. 8.2.1 Replacement of withdrawn patients All patients registered in the study will be accounted for. Patients who do not receive the active compound will be replaced by another patient at the same dose level, in order to allow at least adequate assessment of the toxicity of 3 patients in a particular dose group. All patients that received the experimental treatment will be available for the toxicity assessment, regardless if they completed the 12 weeks of follow-up. If patients did not complete the full 12 weeks of follow-up, they will be replaced. 8.3 Premature termination of the study 8.3.1 Definition of Radiation Dose Limiting Toxicity (RDLT) Any of the following events which are considered possibly or probably related to the administration of 166Ho-PLLA-MS will be considered a RDLT during the 12 weeks follow-up period: • • • • • • Grade 3-4 neutropenic infection (ANC < 1.0 x 109/L) with fever > 38.3°C, Grade 4 neutropenia lasting > 7 days, Grade 4 thrombocytopenia (platelet count < 25.0 x109/L), Grade 3 thrombocytopenia lasting for > 7 days, Any other grade 3 or 4 toxicity (excluding expected AST/SGOT, ALT/SGPT, γGT, ALP and LDH elevation, elevated bilirubin and lymphocytopenia) possibly related to study device, using NCI CTCAE v3.0. Any life threatening event possibly related to the study device. Disease progression will not be considered to be RDLT. 8.3.2 Determination of MTRD If no RDLT is observed, the next cohort of 3 patients will be treated at the next radiation dose level. If 1 patient with RDLT is observed in a particular cohort, it will be extended to maximally 6 patients. If 2 or more patients in a particular cohort suffer from RDLT, the study will be terminated because the endpoint e.g. the MTRD is reached. The dose level prior to the toxic radiation dose will become the recommended dose for efficacy studies (the MTRD). If an event is classified as grade 3 or 4 administration technique related, the patient will be replaced. If administration related RDLT occurs in 2 out of 6 consecutive patients (33%), the study will be suspended. This will be reported to the METC. 8.4 Independent Data Monitoring Committee (IDMC) An IDMC is established. The IDMC is an external independent group including the following members: • • Dr. J.M.H. de Klerk, Meander Medical Center Amersfoort; a nuclear physician with specific experience in radionuclide therapy and dosimetry. Dr. O.M. van Delden, Academisch Medisch Centrum Amsterdam; a interventionradiologist with specific experience in oncological patients and embolization therapy. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 32 of 45 HEPAR-trial • • CCMO NL25956.041.08 METC 08-450 Dr. B. Oldenburg, Universitair Medisch Centrum Utrecht; a gastro-enterologist with specific experience in oncological patients with liver metastases. Prof. Dr. K.C.B. Roes, Universitair Medisch Centrum Utrecht; a biostatistician. The members have no conflict of interest with the sponsor because they are not involved in the study, nor are they receiving funds. The IDMC will perform a safety review after every three patients. The IDMC will receive reports on a regular basis on all SAEs reported for this trial. The IDMC will work according to Standard Operating Procedures (SOPs). Recruitment will not be interrupted unless otherwise requested by the Chairman of the IDMC. The responsibilities of the IDMC include: • minimize the exposure of patients to an unsafe therapy or dose • make recommendations for changes in study processes where appropriate • advise on the need for dose adjustments because of safety issues • endorse continuation of the study • inform the METC in case of unexpected toxicity and/or when the well being of the subjects is jeopardized © University Medical Center Utrecht Final version 28, 29-04-2011 Page 33 of 45 HEPAR-trial 9. SAFETY REPORTING 9.1 Section 10 WMO event CCMO NL25956.041.08 METC 08-450 In accordance to section 10, subsection 1, of the WMO, the investigator will inform the patients and the reviewing accredited METC if anything occurs, on the basis of which it appears that the disadvantages of participation may be significantly greater than was foreseen in the research proposal. The study will be suspended pending further review by the METC, except insofar as suspension would jeopardise the patients’ health. The investigator will take care that all patients are kept informed. 9.2 Adverse events and adverse device effects Adverse events are defined as any undesirable experience occurring to a patient during a clinical trial, whether or not considered related to the investigational medical device. All adverse events reported spontaneously by the patient or observed by the investigator or his staff will be recorded. An adverse device effect occurs when there is a causal relationship between the device and an adverse event. 9.3 Serious adverse events A serious adverse event is any untoward medical occurrence or effect that at any dose results in death; - is life threatening (at the time of the event); - requires hospitalisation or prolongation of existing inpatients’ hospitalisation; - results in persistent or significant disability or incapacity; - is a congenital anomaly or birth defect; - is a new event of the trial likely to affect the safety of the patients, such as an unexpected outcome of an adverse reaction, lack of efficacy of a medical device used for the treatment of a life threatening disease, major safety finding from a newly completed animal study, etc. All SAEs will be reported to the accredited METC that approved the protocol, according to the requirements of that METC. 9.4 Suspected unexpected serious adverse reactions (SUSAR) Adverse reactions are all untoward and unintended responses to an investigational product related to any dose administered. Unexpected adverse reactions are adverse reactions, of which the nature, or severity, is not consistent with the applicable product information. The sponsor will report expedited the following SUSARs to the METC: − SUSARs that have arisen in the clinical trial that was assessed by the METC; − SUSARs that have arisen in other clinical trial of the same sponsor and with the same medical product, and that could have consequences for the safety of the patients involved in the clinical trial that was assessed by the METC. The remaining SUSARs are recorded in an overview list (line-listing) that will be submitted once every half year to the METC. This line-listing provides an overview of all SUSARs from the study medicine, accompanied by a brief report highlighting the main points of concern. The sponsor will report expedited all SUSARs to the competent authority, the Medicine Evaluation Board and the competent authorities in other Member States. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 34 of 45 HEPAR-trial CCMO NL25956.041.08 METC 08-450 The expedited reporting will occur not later than 15 days after the sponsor has first knowledge of the adverse reactions. For fatal or life threatening cases the term will be maximal 7 days for a preliminary report with another 8 days for completion of the report. 9.5 Documentation Attention is to be paid to the occurrence of AEs at all stages of the examination. Thus, the patient should be closely observed by the investigator both during and after the treatment. The recording phase for AEs will start with the first study drug administration and will end the last day of the follow-up period. AEs related to hematological or renal toxicity which are still present at the end of the follow-up period will be followed up until complete resolution as assessed by the investigator. Any adverse events have to be documented in detail as indicated on the CRF. The following information is required: • The date and time of onset of any AEs • The duration (the entire duration of an event or symptom, calculated from date of onset and date of end) • The maximum intensity (mild, moderate or severe; for definitions, see below). • The drug relationship of the AE to the investigational product (for definitions, see below) • Any study drug action taken and any other action taken by the investigator to resolve the adverse events (entered in free text) • The outcome of the adverse event (recovered completely, recovered with residual effects, continuing). • An assessment of the seriousness of the event will be made by the investigator. 9.5.1 Intensity Toxicities listed in the NCI CTCAE v3.0 are graded on a scale of 0 to 4. If a specific adverse event is not included in the toxicity scale, the investigator is to classify its intensity according to the following definitions: Intensity Mild Definition The patient is aware of signs or symptoms, but they are easily tolerated. Usually does not require additional therapy or discontinuation of study treatment. Moderate The signs and symptoms are sufficient to restrict, but do not prevent usual activity; possibly requires additional therapy but usually does not require discontinuation of study treatment. Severe The patient is unable to perform usual activities and usually requires discontinuation of study treatment. Table 3: Intensity grading of AE’s not described in NCI CTCAE v3.0 9.5.2 Treatment relationship The investigator will be asked whether an AE is related to the administration of 166Ho-PLLAMS, or whether he is not capable to define a clear relationship to the study device. The investigator will also be asked whether an AE is related to inadvertent deposition of the microspheres in organs other than the liver, and should therefore be classified as technique related. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 35 of 45 HEPAR-trial Categories None Unlikely Possible Probable Definite CCMO NL25956.041.08 METC 08-450 Definition The time course between administration of 166Ho-PLLA-MS and occurrence or worsening of the adverse event rules out a causal relationship and/or another cause is confirmed and no indication of involvement of 166HoPLLA-MS in the occurrence/worsening of the adverse event exists. The time course between administration of 166Ho-PLLA-MS and occurrence or worsening of the adverse event makes a causal relationship unlikely and/or the known effects of 166Ho-PLLA-MS or of the substance class provide no indication of involvement in occurrence/worsening of the adverse event and another cause adequately explaining the adverse event is known and/or regarding the occurrence/worsening of the adverse event a plausible causal chain may be deduced from the known effects of 166Ho-PLLA-MS or the substance class, but another cause is much more probable and/or another cause is confirmed and involvement of 166Ho-PLLA-MS in the occurrence/worsening of the adverse event is unlikely. Regarding the occurrence/worsening of the adverse event, a plausible causal chain may be deduced from the pharmacological properties of 166 Ho-PLLA-MS or the substance class, but another cause just as likely to be involved is also known or although the physical properties of 166Ho-PLLA-MS or the substance class provide no indication of involvement in the occurrence/worsening of the adverse event, no other cause gives adequate explanation The physical properties of 166Ho-PLLA-MS or of the substance class and/or the course of the adverse event after dechallenge and, if applicable, after rechallenge and/or specific tests suggest involvement of 166Ho-PLLA-MS in the occurrence/worsening of the adverse event, although another cause cannot be ruled out. The physical properties of 166Ho-PLLA-MS or of the substance class and the course of the adverse event after dechallenge and, if applicable, after rechallenge and specific tests indicate involvement of 166Ho-PLLA-MS in the occurrence/worsening of the adverse event and no indication of other causes exists. The available information is not sufficient for causality assessment. Unclassified [only used for SAE] Table 4: categories of treatment relationship of AE’s 9.6 Follow-up of adverse events All adverse events will be followed until they have abated, or until a stable situation has been reached. Depending on the event, follow up may require additional tests or medical procedures as indicated, and/or referral to the general physician or a medical specialist. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 36 of 45 HEPAR-trial 10. CCMO NL25956.041.08 METC 08-450 STATISTICAL ANALYSIS Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) will be calculated for each quantitative variable; frequency counts by category will be made for each qualitative variable. Interim analysis will be performed after every 3 patients. Inclusion of patients in the next cohort will be performed if the IDMC has scrutinized the toxicity data and gave permission to proceed. Two sets of study data will be evaluated: the primary endpoint will be evaluated in the Full Analysis Set (FAS). The FAS is defined as the set of data generated from the included patients who received at least the safety dose. The secondary endpoints will be evaluated in both FAS and Per Protocol Set (PPS). The PPS is defined as the set of data generated from the included patients who complied with the protocol. 11. ETHICALCONSIDERATIONS 11.1 Regulation statement The study will be conducted according to the principles of the Declaration of Helsinki (version 9.10.2004) (see Appendix I) and in accordance with the Medical Research Involving Human Patients Act (WMO), the requirements of International Conference on Harmonization - Good Clinical Practice (ICH-GCP) and this protocol. The protocol is submitted to the Independent Ethics Committee (IEC) and to the Radiation Protection Committee of the UMC Utrecht. The study will not start until written approval of the IEC of the UMC Utrecht has been received by the investigator. 11.1.1 Obligations of the investigator An updated copy of the curriculum vitae of each investigator and co-investigator will be provided to the ethics committee. For the purpose of ensuring compliance with GCP and regulatory guidelines, Health Authorities may conduct a site audit or an inspection. By signing this protocol the investigator agrees to allow regulatory agencies to have direct access to the study records for review. 11.2 Recruitment and consent Patients with liver metastases will be referred, after analysis for surgical metastasectomy, by the department of Surgery to the Principal Investigator (PI). The PI will inform every patient and obtain their informed consent. 11.2.1 Consent Before enrollment into the study the PI will inform every patient, verbally and in writing (Appendix VIII) about the nature of the study, its purpose, procedures, expected duration and the benefits and risks involved in study participation. Each patient will be given the opportunity to ask questions and will be informed about the right to withdraw from the study at any time without prejudice. Patients must be given adequate opportunity (at least 48 hours) to read the information and enquire about details of the study before consent is given. Patients will have to voluntary sign and date a written informed consent statement before participation (Appendix IX). The informed consent statement will be signed and dated by the PI, or by a person delegated with this responsibility by the PI. The patient will receive a copy of the signed consent statement. This will include use of the acquired data for regulatory approval and product information. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 37 of 45 HEPAR-trial 11.3 Benefits and risks assessment, group relatedness 11.3.1 Benefits CCMO NL25956.041.08 METC 08-450 It is anticipated that treatment with radioactive microspheres will reduce tumor size and will improve quality of life as known from literature from yttrium-90 [38-40]. It is anticipated that the gamma emission of the radioactive Holmium will improve the safety of the procedure. Also the difference in specific activity of 166Ho-PLLA-MS compared to the currently available yttrium-90 may improve therapeutic results. Participation in this study may possibly produce useful scientific data for the future. Regular medical check-ups during the study can be seen as an additional benefit. The number of visits (15) is comparable to a standard chemotherapy protocol. However, the scheduling is different. There are 10 more visits in comparison to treatment with 90Y-MS, which is a regular in the UMC Utrecht since the beginning of 2009. The treatment with 90Y-MS is considered the standard treatment in Europe. 11.3.2 Risks Apart from the angiographic procedures and device related toxicity as described in chapter 7, standard radiological and nuclear procedures are also used that may have their inherent side effects. For the frequent blood sampling an indwelling cannula may be used and this may be accompanied by mild bruising and also, in rare cases, by transient inflammation of the vessel wall. After initial irritation, the presence of an indwelling cannula is usually painless and hardly noticeable. The same applies to single vein punctures for blood sampling. When needed, the use of a urethral catheter may also cause infection. The total amount of blood withdrawn during the study will be up to 100 ml (normal blood donation: 500 ml). 11.4 Confidentiality All persons involved in the study agree to keep confidential any information pertaining to the patient’s identity which becomes known to them in the course of the study. 11.5 Financing This academic study is investigator driven; the investigators are employed solely by the UMC Utrecht, a conflict of interest will not arise. 11.6 Compensation for injury Injury directly related to participation in this study will be covered by the existing insurance of the UMC Utrecht. Investigators and appropriate staff will be indemnified by the UMC Utrecht for liability for study induced injury. 11.7 Incentives The patients will receive compensation for travelling expenses; € 0.28/km and a ticket for free parking. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 38 of 45 HEPAR-trial CCMO NL25956.041.08 METC 08-450 12. ADMINISTRATIVE ASPECTS AND PUBLICATION 12.1 Case Report Forms CRF’s will be provided by the UMC Utrecht. The CRF will be completed by the Clinical Research Coordinator and Research Nurse. 12.1.1 Completing CRF’s It is the responsibility of each investigator to ensure that the CRF’s are legible, correct and complete. All relevant questions must be answered and no empty data blocks should exist. However, in a situation where it is unavoidable that data cannot be entered, this should be indicated in the CRF by entering the following in the relevant field: ND NK NA - not done not known not available (i.e. test done but result not available) or not applicable The signature at the end of each CRF by the principal investigator, investigator or authorized co-investigator will serve as confirmation that the information recorded is complete, accurate and has not been falsified. 12.1.2 Corrections to CRF’s Errors, changes and/or additions entered on original CRF’s must be corrected by drawn in a single line through the incorrect entry and writing the new entry as close to the original as possible so as to leave the correct entry legible. If necessary the reason for the change must be given. The correction must be initialed and dated by the authorized person making the change. 12.2 Source document verification For the purpose of this study, the ‘source documents’ are defined as the patient’s hospital medical records, clinician note’s, laboratory print outs, digital and hard copies of imaging, memos, electronic data, etc. The Clinical Research Coordinator will require direct access to the source documents in order to verify CRF entries. As an absolute minimum, the source documents must include: • A record that the patient has participated in a clinical trial, by study title, protocol number, patient identification code and date of entry in the study (e.g. by signed Informed Consent Form). • Evidence that the patient satisfied all inclusion and exclusion criteria. • A record of the doses and dates of administration of the investigational drugs • A record of the safety parameters • A record of the uptake and excretion data • A record of concomitant medications • Hard copies of relevant imaging • A record of all adverse events. Entries in the patient’s source documents must be signed and dated according to usual hospital procedure. After completion of the study the completed patient files will be stored in the hospital archives and maintained for a minimum of 15 years. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 39 of 45 HEPAR-trial 12.3 CCMO NL25956.041.08 METC 08-450 Monitoring On-site monitoring (by UMC Utrecht: Division Julius Centrum) will be applied in order to assure the quality and validity of the research data. Monitors will perform source data verification (SDV) on the research data by comparing the data entered into the CRF with the available source documentation in the regular patient records. A complete check will be performed on • • • • • • Informed Consent Forms (availability and correctness) Verification of existence and identity of the participant In- & Exclusion criteria Reporting and follow-up of AEs / SAEs / SARs / SUSARs Primary and Secondary Endpoints 166 Ho-PLLA-MS accountability In addition to the complete check on the above mentioned items, a random sample of the other research data will be checked. The random sample will be selected from the completed CRFs prior to a monitoring visit. Over the course of the study, the random sample will be spread to include; • >50% of the participants at least once • all types of visits at least once If the quality of the data in the random sample is insufficient, the monitor will inform the principal investigator and additional monitoring will be applied. A monitoring report will be made after each visit and kept in the Study Master File. 12.4 Amendments Amendments are changes made to the clinical investigation plan after a favourable opinion by the METC of the UMC Utrecht has been obtained. All amendments will be notified to the METC that gave the favourable opinion. 12.5 Annual progress report The sponsor/investigator will submit a summary of the progress of the trial to the METC once a year. Information will be provided on the date of inclusion of the first patient, numbers of patients included and numbers of patients that have completed the trial, serious adverse events/ serious adverse reactions, other problems, and amendments. 12.6 Annual safety report The annual safety report may be combined with the annual progress report. In addition to the expedited reporting of SUSARs, the principal investigator will submit, once a year throughout the clinical trial, a safety report to the METC, competent authority, Medicine Evaluation Board and competent authorities of the concerned Member States. This safety report consists of: • a list of all suspected (unexpected or expected) serious adverse reactions, along with an aggregated summary table of all reported serious adverse reactions, ordered by organ system, per study; • a report concerning the safety of the patients, consisting of a complete safety analysis and an evaluation of the balance between the efficacy and the harmfulness of the medicine under investigation. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 40 of 45 HEPAR-trial 12.7 CCMO NL25956.041.08 METC 08-450 End of study report The investigator will notify the METC of the end of the study within a period of 8 weeks. The end of the study is defined as the last patient’s last visit. In case the study is ended prematurely, the investigator will notify the METC, including the reasons for the premature termination. Within one year after the end of the study, the investigator/sponsor will submit a final study report with the results of the study, including any publications/abstracts of the study, to the accredited METC. 12.8 Publication policy Any publication of the study results will be considered as a collaborative effort between the investigators and appropriate personnel. Authorship shall be determined by mutual consent. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 41 of 45 HEPAR-trial 13. CCMO NL25956.041.08 METC 08-450 REFERENCE LIST 1. Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002. Ca Cancer J Clin 2005;55(2):74-108. 2. 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Coldwell D, Kennedy A: Treatment of hepatic metastases from breast cancer with Yttrium-90 SIR-Spheres radioembolization. Society of Interventional Radiology 2005;Annual meeting, New Orleans, LA. 36. Goin J, Dancey JE, Roberts C: Comparison of post-embolization syndrome in the treatment of patients with unresectable hepatocellular carcinoma: Trans-catheter arterial chemo-embolization versus yttrium glass microspheres. World J Nucl Med 2004;3:49-56. 37. Webber GW, Jang J, Gustavson S, Olin JW: Contemporary management of postcatheterization pseudoaneurysms. Circulation 2007;115(20):2666-2674. 38. Van den Eynde M, Flamen P, El Nakadi I, Liberale G, Delatte P, Larsimont D, Hendlisz A: Inducing resectability of chemotherapy refractory colorectal liver metastasis by radioembolization with yttrium-90 microspheres. Clin Nucl Med 2008;33(10):697-699. 39. Vente MAD, Wondergem M, van der Tweel I, van den Bosch MAAJ, Zonnenberg BA, Lam MGEH, van het Schip AD, Nijsen JFW: Yttrium-90 microsphere radioembolization for the treatment of liver malignancies: a structured meta-analysis. Eur Radiol 2008. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 44 of 45 HEPAR-trial CCMO NL25956.041.08 METC 08-450 40. Sato KT, Lewandowski RJ, Mulcahy MF, Atassi B, Ryu RK, Gates VL, Nemcek AA, Jr., Barakat O, Benson A, III, Mandal R, Talamonti M, Wong CY, Miller FH, Newman SB, Shaw JM, Thurston KG, Omary RA, Salem R: Unresectable chemorefractory liver metastases: radioembolization with 90Y microspheres--safety, efficacy, and survival. Radiology 2008;247(2):507-515. © University Medical Center Utrecht Final version 28, 29-04-2011 Page 45 of 45
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