SIRveNIB: Selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma

Transcription

1 The following protocol information is provided solely to describe how the authors conducted the research underlying the published report associated with the following article: SIRveNIB: Selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma Chow, et al DOI: /JCO The information provided may not reflect the complete protocol or any previous amendments or modifications. As described in the Author Center ( only specific elements of the most recent version of the protocol are requested by JCO. The protocol information is not intended to replace good clinical judgment in selecting appropriate therapy and in determining drug doses, schedules, and dose modifications. The treating physician or other health care provider is responsible for determining the best treatment for the patient. ASCO and JCO assume no responsibility for any injury or damage to persons or property arising out of the use of these protocol materials or due to any errors or omissions. Individuals seeking additional information about the protocol are encouraged to consult with the corresponding author directly.

2 Asia-Pacific Hepatocellular Carcinoma Trials Group Protocol AHCC06 PHASE III MULTI CENTRE OPEN LABEL RANDOMIZED CONTROLLED TRIAL OF SELECTIVE INTERNAL RADIATION THERAPY (SIRT) VERSUS SORAFENIB IN LOCALLY ADVANCED HEPATOCELLULAR CARCINOMA (SIRveNIB) 21 January 2014 Confidential This protocol is intended for use by collaborators of this study. It is otherwise available for information only. No part of this protocol may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system. Page 1 of 106

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4 PHASE III MULTI CENTRE OPEN LABEL RANDOMIZED CONTROLLED TRIAL OF SELECTIVE INTERNAL RADIATION THERAPY (SIRT) VERSUS SORAFENIB IN LOCALLY ADVANCED HEPATOCELLULAR CARCINOMA (SIRveNIB) Protocol Chair : Pierce KH Chow FRCSE PhD Department of General Surgery Singapore General Hospital, Outram Road Singapore Tel: Fax: pierce.chow.k.h@sgh.com.sg pierce.chow@duke-nus.edu.sg Page 3 of 106

5 Steering Committee Pierce KH Chow FRCSE PhD Department of General Surgery Singapore General Hospital, Outram Road Singapore Tel: Fax: Soo Khee Chee FRACS MD Dept of Surgical Oncology National Cancer Centre 11 Hospital Drive Singapore Tel: Fax: Choo Su Pin MBBS MRCP Department of Medical Oncology National Cancer Centre 11 Hospital Drive Singapore Tel: Fax: choosupin@nccs.com.sg Thng Choon Hua MBBS FRCR Department of Oncology Radiology National Cancer Centre 11 Hospital Drive Singapore Tel: Fax: dditch@nccs.com.sg Tan Say Beng PhD Duke-NUS Graduate Medical School Singapore 8 College Road Singapore Tel: Fax: saybeng.tan@duke-nus.edu.sg Albert Low Su Chong MBBS FRCR Department of Diagnostic Radiology Singapore General Hospital, Outram Road Singapore Tel: Fax: albert.low.s.c@sgh.com.sg Page 4 of 106

6 Cheow Peng Chung MBBS, MMEd FRCS FAMS Department of General Surgery Singapore General Hospital, Outram Road Singapore Tel: Fax: Anthony Goh Soon Whatt MBBS MSc Department of Nuclear Medicine Singapore General Hospital, Outram Road Singapore Tel: Fax: anthony.goh.s.w@sgh.com.sg Tay Kiang Hiong MBBS FRCR Department of Diagnostic Radiology Singapore General Hospital, Outram Road Singapore Tel: Fax: tay.kiang.hiong@sgh.com.sg Richard Hoau Gong Lo MBBS FRCR Department of Diagnostic Radiology Singapore General Hospital, Outram Road Singapore Tel: Fax: richard.lo.h.g@sgh.com.sg Brian Goh Kim Poh MBBS, MRCS, MMed, MSc, FRCS Department of General Surgery Singapore General Hospital, Outram Road Singapore Tel: Fax: bsgkp@hotmail.com Wong Jen San MB ChB, MRCS, MMed, FRCS, FAMS, MSc Department of General Surgery Singapore General Hospital, Outram Road Singapore Tel: Fax: wong.jen.san@sgh.com.sg Page 5 of 106

7 David Ng MBBS, MRCP, FAMS Department of Nuclear Medicine Singapore General Hospital, Outram Road Singapore Tel: Fax: david.ng.c.e@sgh.com.sg Page 6 of 106

8 Participating Centres: Brunei Kenneth Kok Yuh Yuen MBChB FRCS FRCSEd FAMS FACS Department of Surgery The Brunei Cancer Centre Jerudong Park BG3122 Brunei Darussalam Tel: Ext 2295 Fax: Hong Kong Ronnie Poon MBBS MS PhD FHKAM(Surg) FCSHK FRCS(Edin) FACS Department of Surgery Queen Mary Hospital, 102 Pokfulam Road, Hong Kong Tel: Fax: Indonesia L.A Lesmana MD PhD SpPD-KGEH FACP FACG Department of Medicine University of Indonesia, Jakarta Universitas Indonesia Kampus UI Depok 16424, Indonesia Tel: , Fax: llesmana@cbn.net.id Tjakra Wibawa Manuaba MD MPH Division of Surgical Oncology Department of General Surgery, School of Medicine University of Udayana, Rumah Sakit Sanglah Denpasar, Bali, Indonesia Tel: Fax: wibawa@denpasar.idola.net.id Korea Hyun-Ki Yoon MD PhD Department of Radiology Asan Medical Center Pungnap-2 Dong, Songpa-Gu, Seoul , Korea Page 7 of 106

9 Tel: Fax: Yun-Hwan Kim MD Department of Abdominal Radiology Korea University Anam Hospital Anam-Dong 5-Ga Seongbuk-Gu, Seoul , Korea Tel: Fax: yhkku@kumc.or.kr Ho-Seong Han MD PhD Seoul National University Bundang Hospital 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do , Korea Tel: Fax: hanhs@snubh.org Jong-Yun Won MD PhD Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seongsanno, , Seodaemun-gu, Seoul, Korea Tel: Fax: jywon@yuhs.ac Si-Hyun Bae MD PhD Department of Internal Medicine Seoul St. Mary s Hospital Catholic University Medical College #505 Banpo-Dong, Seocho-Gu, Seoul, , Korea Tel: , 6020, 2073 (Liver Clinic) Tel: (Out-Patient) Fax: baesh@catholic.ac.kr Malaysia T. Aloysius Raj MBBS MD DMRT MS (Gen) Department of Oncology Penang Adventist Hospital Page 8 of 106

10 465, Burma Road, Pulau Pinang, Malaysia Tel: Fax: Mongolia Dr. Ariunaa Khasbazar National Cancer Center of Mongolia The Chemotherapy Department Bayan-Zurkh District Nam Yan Ju Street, P.O. Box: Ulaanbaatar, Mongolia Tel: Fax: Myanmar Khin Maung Win MBBS M.Med.Sc MRCP FRCP Department, Department of Hepatology Yangon GI & Liver Centre , 30th Street (Upper Block), Pabedan Township 11141, Yangon, Myanmar Tel: , Fax: New Zealand Adam Bartlett MBChB FRACS Hepatoma Interest Group, Auckland City Hospital 2 Park Road, Grafton, Auckland 1023, New Zealand Tel: Fax: AdamB@adhb.govt.nz Philippines Rolley Rey Lobo MD Davao Doctors Hospital Room 505, Medical Tower, Davao Doctors Hospital Quirino Street, Davao City, Philippines Tel: , , to 223 Fax: rrlobo8@yahoo.com Catherine SC Teh, MD, FPCS, FPSGS, FPALES Hepatobiliary Pancreatic Surgery Surgical Oncology Minimally Invasive Surgery Makati Medical Center Page 9 of 106

11 No. 2 Amorsolo St. Legaspi Village, Makati City, Philippines, 1229 Tel: drcteh@me.com Ian Homer Y. Cua, MD, FPCP, FPSG, FPSDE St. Luke's Medical Center Center for Liver Diseases 279 E. Rodriguez Sr. Blvd. Quezon City, Philippines 1102 Tel: Fax: iancuamd@gmail.com Janus Ong, MD, MPH The Medical City Ortigas Avenue, Pasig City, Metro Manila Philippines. Tel: loc janong@mac.com Singapore Cheow Peng Chung MBBS, MMEd FRCS FAMS Department of General Surgery Singapore General Hospital, Outram Road Singapore Tel: Fax: gsucpc@sgh.com.sg Choo Su Pin MBBS MRCP Department of Medical Oncology National Cancer Centre 11 Hospital Drive Singapore Tel: Fax: choosupin@nccs.com.sg Dr. Tan T'zu Jen MD Department of General Surgery Khoo Teck Puat Hospital 90 Yishun Central Singapore Tel: Fax: tan.tzu.jen@alexandrahealth.com.sg Page 10 of 106

12 Chang Kin Yong Stephen MBBS MRCSEd MMed FRCS Hepatobiliary & Pancreatic Surgery National University Hospital 5 Lower Kent Ridge Road Singapore Tel: Fax: cfscky@nus.edu.sg Taiwan Chien-Fu Hung MD Radiology Department Chang Gung Memorial Hospital No. 5 Fu-Hsing Street. Kuei Shan Hsiang, Taoyuan Hsien, Taiwan Tel: hcf5514@adm.cgmh.org.tw Po-Chin Liang MD Radiology Department National Taiwan University Hospital No.7, Chung Shan S. Rd., Taipei 100, Taiwan Tel: Fax: e510012@yahoo.com.tw Rheun-Chuan Lee MD Radiology Department Taipei Veterans General Hospital No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan Tel: rclee8888@gmail.com Peng Cheng Yuan MD PhD China Medical University Hospital No.2, Yuh-Der Road Taichung 404, Taiwan Tel: ext cypeng@mail.cmuh.org.tw Chen Chao Long MD Kaohsiung Chang Gung Memorial Hospital 123 Ta-Pei Road, Niao-Sung Hsiang Kaohsiung Hsien 833, Taiwan Tel: clchen@cgmh.org.tw Page 11 of 106

13 Thailand This investigator-initiated study is supported by: Chanisa Chotipanich MD National Cyclotron and PET Centre Nuclear Medicine Department Chulabhorn Hospital, 54 Khamphang Phet 6 Talad Bankane Laksi, Bangkok, Thailand Tel: ext 1211/ Chanisa.ja@gmail.com 1. National Medical Research Council, Singapore 2. Sirtex Technology Pty. Ltd. Page 12 of 106

14 TABLE OF CONTENTS 1. GENERAL INFORMATION...16 Contact Details Independent Data and Safety Monitoring Committee Summary of Key Changes Protocol Version 5 to STUDY SYNOPSIS STUDY OBJECTIVES Primary Objective Secondary Objectives INVESTIGATOR APPROVAL AND AGREEMENT STUDY PRODUCTS SIR-Spheres Product Description Mode of Action Form and Stability Regulatory Status Singapore Australia USA European Union Sorafenib Product Description PRELIMINARY INVESTIGATIONS AND JUSTIFICATION FOR THE STUDY Hepatocellular Carcinoma Current Treatment Options Surgical Resection Liver Transplantation Trans-catheter Arterial Chemo-Embolisation (TACE) Selective Internal Radiation Therapy (SIRT) Justification for this Study STUDY DESIGN AND PATIENT ELIGIBILITY Patient Eligibility Inclusion Criteria Exclusion Criteria STUDY ENTRY AND RANDOMISATION Patient Screening Patient Informed Consent Patient Stratification Study Entry and Patient Randomisation SCREENING / BASELINE ASSESSMENTS Clinical Assessment Haematological and Biochemical Investigations Radiological and Nuclear Medicine Investigations CT Scan of the Chest, Abdomen, Pelvis Baseline Assessment of Patient Suitability for Selective Internal Radiation Therapy (ONLY for patients randomised to SIRT-arm) Visceral and Hepatic Angiogram Tc-99m MAA Lung Shunt Study Exclusion Criteria specific to patients randomised to SIRT-arm Page 13 of 106

15 10. TREATMENT PLAN Treatment Arm A: Sorafenib Precautions Duration of Treatment Sorafenib Dose and Schedule Modifications Dose Modification of Sorafenib for Skin Toxicity Cessation of Sorafenib Therapy Treatment Arm B: SIR-Spheres Calculation of Body Surface Area Calculation of Percent Tumour Involvement Calculation of Percent Lung Shunting Administration of SIR-Spheres Measurement of Residual SIR-Spheres Activity Post-Treatment Non-Protocol Chemotherapy Supportive (Non-Protocol) Treatment Concomitant Medications SERIAL STUDY ASESSMENTS Study Assessments Study Calendar Notes to Study Plan Window Period Study Flow Chart Visit Schedule During Protocol Therapy...55 Post Study Conclusion RESPONSE ASSESSMENT Overall Survival Tumour Response RECIST Guidelines Response Criteria Best Overall Response Tumour Response Rate Disease Control Rate Time to Disease Progression Progression-Free Survival Progression-Free Survival Overall Progression-Free Survival in the Liver Health-related Quality of Life Toxicity and Safety Post-study HCC Treatment STATISTICAL CONSIDERATIONS AND METHODOLOGY Statistical Analysis DEVIATIONS/AMENDMENTS of the study protocol Deviations from the Study Protocol Amendments to the Study Protocol Early Stopping Due to Toxicity REGULATORY & REPORTING REQUIREMENTS Definitions Adverse Event Serious Adverse Event...64 Page 14 of 106

16 15. Unexpected Adverse Drug Reaction Study Safety Recording Sorafenib SIR-Spheres General Exceptions Safety Reporting Pregnancy During the Study ETHICAL CONSIDERATIONS Informed Consent Confidentiality Changes to Final Study Protocol PUBLICATION POLICY ADMINISTRATIVE PROCEDURES Site Initiation Visit Investigator File Monitoring of the Study Quality Assurance Study Funding Study Completion BIBLIOGRAPHY...70 APPENDIX 1 ECOG Performance Status (Definitions)...76 APPENDIX 2 Child-Pugh-Turcotte Prognostic Criteria...76 APPENDIX 3 HCC Staging Classifications...77 APPENDIX 4 SIR-Sphere Package Insert...79 APPENDIX 5 Technique for Administration of SIR-Spheres...81 APPENDIX 6 Nuclear Medicine Tc-99m MAA Lung Shunt Study...84 APPENDIX 7 SIR-Spheres Radiation Absorbed Dose/Activity Calculation Procedure 85 APPENDIX 8 Example SIR-Spheres Radiation Absorbed Dose/Activity Calculation 87 APPENDIX 9 SIR-Spheres Administered Activity Calculation Tables...88 APPENDIX 10 Consumer Medicine Information For Sorafenib...92 APPENDIX 11 NCI CTC Version 4.02 Recommendation for Grading of Acute and Subacute Toxicity...96 APPENDIX 12 EQ-5D Quality Of Life Questionnaire...97 APPENDIX 13 CT Image Acquisition Guidelines APPENDIX 14 World Medical Association Declaration of Helsinki APPENDIX 15 Abbreviations Page 15 of 106

17 1. GENERAL INFORMATION 1.1 Contact Details Trial Principal Investigator: Pierce KH Chow FRCSE PhD Department of General Surgery Singapore General Hospital, Outram Road Singapore Tel: Fax: Study Diagnostic Radiologists: Thng Choon Hua MBBS FRCR Department of Oncology Radiology National Cancer Centre 11 Hospital Drive Singapore Tel: Fax: Kwek Jin Wei Department of Oncology Radiology National Cancer Centre 11 Hospital Drive Singapore Tel: Fax: James Khoo Department of Oncology Radiology National Cancer Centre 11 Hospital Drive Singapore Tel: Fax: Patrick Teo Department of Oncology Radiology National Cancer Centre 11 Hospital Drive Singapore Tel: Fax: Page 16 of 106

18 Juliana Ho Department of Oncology Radiology National Cancer Centre 11 Hospital Drive Singapore Tel: Fax: Study Interventional Radiologists: Tay Kiang Hiong MBBS FRCR Department of Diagnostic Radiology Singapore General Hospital Outram Road Singapore Tel: Fax: Richard Hoau Gong Lo MBBS FRCR Department of Diagnostic Radiology Singapore General Hospital Outram Road Singapore Tel: Fax: Tan Bien Soo MBBS FRCR FAMS Department of Radiology Singapore General Hospital Outram Road Singapore Tel: Fax: tan.bien.soo@sgh.com.sg Study Medical Oncologists: Choo Su Pin MBBS MRCP Department of Medical Oncology National Cancer Centre 11 Hospital Drive Singapore Tel: Fax: choosupin@nccs.com.sg Page 17 of 106

19 Study Nuclear Medicine Physicians: Anthony Goh Soon Whatt MBBS MSc FAMS Department of Nuclear Medicine Singapore General Hospital, Outram Road Singapore Tel: Fax: anthony.goh.s.w@sgh.com.sg David Ng MBBS, MRCP, FAMS Department of Nuclear Medicine Singapore General Hospital, Outram Road Singapore Tel: Fax: david.ng.c.e@sgh.com.sg Study Pharmacist: Ng Hui Cheng BPharm National Cancer Centre Oncology Pharmacy Level 3 11, Hospital Drive Singapore Phone: Fax: phmnhc@nccs.com.sg Trial Project Management & Trial Coordination: Singapore Clinical Research Institute Pte Ltd (SCRI) 31 Biopolis Way Nanos #02-01 Singapore Phone: Fax: Project Manager: Sophie Moss sophie.moss@scri.edu.sg (65) Trial Statistician: Mihir Gandhi mihir.gandhi@scri.edu.sg (65) Data Manager: Su Jie jie.su@scri.edu.sg (65) Page 18 of 106

20 Independent Data and Safety Monitoring Committee An independent Data and Safety Monitoring Committee (DSMC) have been appointed to advice the Steering Committee on safety and ethical aspects of the trial. DMC Chairman: DMC Members: Dr Thomas W. T. Leung Associate Director and Honorary Consultant Comprehensive Oncology Centre Hong Kong Sanatorium and Hospital 2 Happy Valley, Hong Kong, China thomaswtleung@hksh.com Professor David Machin Emeritus Professor of Clinical Statistics University of Leicester, UK Emeritus Professor of Clinical Trials Research, University of Sheffield, UK dm113@leicester.ac.uk Prof Bruno Sangro Director of the Hepatology Unit Department of Internal Medicine at the University Hospital of Navarra Pamplona, Spain bsangro@unav.es Page 19 of 106

21 Summary of Key Changes Protocol Version 5 to 6. Please note the table below summarises only key changes. For a full list of tracked changes, please refer to the separate amendment summary sheet provided by SCRI. Section Number Summary of Amendments Treatment Plan Pre-defined dose levels for sorafenib specified at the start of the Sorafenib Dose and Schedule Modifications section. - Dose delay and dose modification tables 10.1 A - C no longer specify reduced dosage, but rather to reduce one dose level. This is more appropriate in cases where patients may experience multiple AEs of different types and may already be on a reduced dose. - At the discretion of the investigator, the dose may be re-escalated to 400 mg po bid after the resolution of the adverse event. - For patients who require a dose reduction for grade 3 rash or hand-foot skin reaction, the dose of study drug may be increased to the starting dose after 28 days of therapy has been administered at the reduced dose without the appearance of rash or hand-foot skin reaction grade 1. - Table 10.1 E, column header dose for next cycle updated to dose at reintroduction as cycles are not applicable to this study Serial Study Assessments 1 - Addition of a week 2 toxicity assessment for sorafenib patients, to review drug-related toxicity and delay/modify dose accordingly. 1 - EQ5D to be done at all visits. If the patient is unable to visit the clinic in person the EQ5D may be administered over the telephone instead. - Clarification on scheduling of visits all visits to be scheduled from the date of randomization (reference date). 1 Safety Reporting Update to SIRT safety reporting timelines. All adverse events for subjects in the SIRT arm will be recorded from the time of signing the Informed Consent Form until 30 days post SIRT regardless of causality, and for a further 5 months thereafter if judged by the investigator to be causally related (definitely, probably or possibly) to SIRT or Sir-spheres (or until commencement of next alternative therapy, whichever is earlier). If the adverse event is a SIRT related toxicity, follow-up will continue until resolution. Safety reporting timelines for sorafenib remain unchanged. Reporting of pregnancy also to apply to pregnancies following the administration of the investigational product to the father. The outcome of the pregnancy should be followed to term. Page 20 of 106

22 2. STUDY SYNOPSIS This study is a multi-centre, open-label, randomised controlled trial that will compare the impact of selective internal radiation therapy (SIRT) using SIR-Spheres yttrium-90 microspheres versus sorafenib on overall survival in patients with locally advanced hepatocellular carcinoma (HCC). Page 21 of 106

23 3. STUDY OBJECTIVES This study will evaluate the efficacy of selective internal radiation therapy (SIRT) using SIR-Spheres yttrium-90 microspheres compared to sorafenib in the treatment of patients with locally advanced primary hepatocellular carcinoma (HCC). 3.1 Primary Objective The primary objective of this study is to assess the efficacy of SIRT as compared with sorafenib in patients with locally advanced liver cancer in terms of overall survival (OS). 3.2 Secondary Objectives To compare SIRT with sorafenib for: Tumour response rate at the end of the study o Disease control rate at the end of the study Time to disease progression Progression free survival overall Progression free survival in the liver Health related quality of life assessed by EQ-5D over the study period Toxicity and safety Liver resection rate Liver transplantation rate Page 22 of 106

24 4. INVESTIGATOR APPROVAL AND AGREEMENT I have read and understand the requirements of this study protocol entitled Phase III Multi Centre Open Label Randomized Controlled Trial of Selective Internal Radiation Therapy (SIRT) versus Sorafenib in Locally Advanced Hepatocellular Carcinoma (SIRveNIB). I agree to treat all patients entered in this study as per the study protocol and as per applicable local regulations and ICH Guideline for Good Clinical Practice. I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described clinical study and to maintain the appropriate records and documentation required. I will ensure that all staff participating in this study will be appropriately trained and informed of their responsibilities and obligations in relation to this study. I will ensure mechanisms are in place to ensure that site staffs receive the appropriate information throughout the study. Principal (Site) Investigator: Investigator Printed Name Signature: Date: (DD-MMM-YYYY) On behalf of: Institution and Address: Page 23 of 106

25 5. STUDY PRODUCTS 5.1 SIR-Spheres Product Description SIR-Spheres consist of biocompatible resin microspheres containing yttrium-90, with a size between 20 and 60 microns in diameter. Yttrium-90 is a high-energy pure beta-emitting isotope with no primary gamma emission. The maximum energy of the beta particles is 2.27MeV, with a mean of 0.93MeV. The maximum range of emissions in tissue is 11mm, with a mean of 2.5mm. The half-life of yttrium-90 is 64.1 hours. In clinical use which requires the isotope to decay to infinity, 94% of the radiation is delivered in 11 days leaving only background radiation with no therapeutic value. SIR-Spheres microspheres themselves are a permanent implant and each device is intended for single patient use. Each device consists of sufficient microspheres to provide 3.0GBq (+/-10% at calibration) at the time and date of calibration (as shown on the label). The SIR-Spheres are suspended in sterile water for injection. Each vial of 3.0GBq is dispatched in a volume of 5ml (microspheres and water together). This allows the required tumour activity to be manipulated as a volume Mode of Action Brachytherapy refers to the procedure of physically implanting permanent radiation sources into, next to, or through malignant tumours. Its history dates back to the discovery of radiation and since then has become established as an effective treatment modality in many organs. The most common applications for brachytherapy today involve prostate, uterine cervix, and head and neck malignancies. The key principle of brachytherapy involves the delivery of tumourcidal doses of radiation to the malignant tumour, but as a result of rapid radiation dose fall-off, minimal damage to adjacent normal tissues. Currently, only a few specialized centers are able to place radiation sources manually into the liver, either percutaneously or via open laparotomy. A more convenient and broadly applicable technique utilizes yttrium-90 microspheres, which takes advantage of the unique vascular anatomy of the liver to preferentially implant hepatic tumours via selective hepatic arterial embolization. This process is referred to as selective internal radiation therapy or SIRT. It has long been established that the liver s arterial system supplies % of the blood to liver tumours (primary and metastatic); however, the normal liver derives nearly all of its blood flow from the parallel portal venous system. In addition, tumours form a dense arterial network with up to 200 times more vessels in plexi around tumours, compared to the normal liver tissues immediately nearby. This combination of vascular structure and local tumour feeding vessel concentration has led to the discovery that SIR-Spheres released into the hepatic artery will preferentially accumulate in the periphery of tumours in at least a 3:1, up to 20:1 ratio compared to normal liver (Kennedy, 2004; Campbell, 2000; Fox, 1991). Thus, the therapeutic index is favourable, in a manner similar to other brachytherapy approaches, e.g. prostate seed brachytherapy. The diameter of SIR-Spheres enables them to become implanted in the tumour microvasculature, but they are too large to pass through the end arterioles into the hepatic sinusoids, which have a restrictive diameter of 8 10 microns. Only if arterial-venous fistulae in the tumour are Page 24 of 106

26 present with diameters of >30 microns, could SIR-Spheres pass into the next capillary bed, in the lung. The active moiety, yttrium-90 is a pure beta emitter which has an energy deposition and dose rate close to that of external beam radiotherapy, yet the effective range is under 3mm from the microsphere itself. 5. Form and Stability SIR-Spheres do not exhibit pharmacodynamics in the classic sense, but induce cell damage by emitting beta radiation. Once implanted, this device remains within the vasculature of hepatic tumours, with small amounts within the vasculature of normal liver parenchyma. The device is not phagocytised, nor does it dissolve or degrade after implantation. High dose radiation emitted from the device is cytocidal to cells within the range of the radiation. After the yttrium-90 has decayed, the non-radioactive microspheres remain intact and are not removed from the body. SIR-Spheres have the potential to interact with other cytotoxic agents and are typically administered concomitantly with either systemic or loco-regional chemotherapeutic agents. This interaction may be exploited to the benefit of the patient, in that there can be an additive toxicity on tumour cells, which can enhance the tumour cell kill rate. This interaction can also lead to additive toxicity on non-tumourous cells. 5. Regulatory Status SIR-Spheres are regulated as a medical device product, based on international and US Food and Drug Administration definitions of devices, and are classified as a sealed source brachytherapy device Singapore SIR-Spheres have been regulated as a Radioactive Material by the Centre of Radiation Protection Nuclear Science of the National Environment Agency since July 2005, used for: the treatment of patients with advance non-operable liver cancer Australia SIR-Spheres were listed on the TGA Australian Register of Therapeutic Goods (ARTG) on 27 Feb, 1998 as a medical device in accordance with the Therapeutic Goods Act 1989, under AUSTL No and subsequently as an included active implantable medical device (AIMD) in Jan 2008 under ARTG with the following intended purpose: Intended for the treatment of inoperable liver cancer USA SIR-Spheres were approved by the US FDA as a Class III medical device product via PMA P in March 2002 for: the treatment of unresectable metastatic liver tumours from primary colorectal cancer together with adjuvant intra-hepatic artery chemotherapy (IHAC) of FUDR (Floxuridine) European Union SIR-Spheres were approved in the European Union in October 2002 as an active implantable medical device under the Active Implantable Medical Device (AIMD) Page 25 of 106

27 Directive (90/385/EEC), indicated for: the treatment of primary and secondary (metastatic) liver cancer. 5.2 Sorafenib Product Description Conventional chemotherapy has not demonstrated efficacy in the treatment of patients with HCC in any randomized controlled trials. Sorafenib (Bayer HealthCare AG, Leverkusen, Germany) is an orally administered multi-targeted kinase inhibitor targeting several serine/threonine and receptor tyrosine kinases. It acts as an inhibitor of signal transduction, thus preventing tumour cell proliferation and angiogenesis via its effects on the RAF/MEK/ERK pathway. Data from a pivotal phase III, international, multi-center, randomized, double blind, placebo-controlled trial of sorafenib in patients with unresectable HCC have been published in 2008 (Llovet 2008). In this study, overall survival was the primary endpoint and a total of 602 patients were randomized; 299 to sorafenib 400 mg twice daily and 303 to matching placebo. The trial was stopped for efficacy following a pre-specified second interim analysis for survival and demonstrated a statistically significant advantage for sorafenib over placebo for overall survival (OS) and time to disease progression (TTP). The median OS was 10.7 months (95% CI months) for Sorafenib versus 7.9 months (95% CI months for placebo (HR: 0.69; p = ) and median TTP was 5.5 months (95% CI months) for sorafenib versus 2.8 months (95% CI months for placebo (HR: 0.58; p = ). Page 26 of 106

28 6. PRELIMINARY INVESTIGATIONS AND JUSTIFICATION FOR THE STUDY 6.1 Hepatocellular Carcinoma Primary hepatocellular carcinoma (HCC) is the fifth most common cancer in the world (El-Serag HB and Rudolph KL 2007), and the third most common cause of cancer related death (Llovet, 2003). Primary HCC is estimated to occur at a global rate of more than 1 million new cases annually, with an increasing incidence rate (El Serag, 1999) and predominance in developing countries. Approximately % of all HCC are in Asia where it is an important public health concern (McGlynn KA et al 2001). Approximately 25% of HCC may benefit from proven ablative therapies that are potentially curative such as surgical resection or radio-frequency ablation (Llovet JM et al 2004, Hung H 2005, Poon D et al 2009). Most patients with primary HCC are diagnosed at intermediate to advanced stages of their disease, for which no generally accepted standard therapy exists (Llovet, 2003).For these patients, options are limited and the prognosis is poor (Pawarode A et al 2000, Chow PK et al 2002). The only systemic therapy proven to confer survival advantage to these patients is Sorafenib (Nowak AK et al 2004, Llovet JM et al 2008, Cheng AL et al 2009). In the absence of active therapy, median survival in unresectable HCC is 3 6 months, actuarial survival is 31% at one year, 8% at two years, and <3% at three years in the USA (SEER). Primary HCC generally leads to death as a consequence of local tumour growth, tissue destruction and liver dysfunction, rather than as a result of widespread extra-hepatic disease. 6.2 Current Treatment Options Surgical Resection Surgical resection of the affected portion of the liver offers the best chance for disease-free survival. Unfortunately, most patients with HCC have tumours that are not amenable to surgical resection (multi-focal disease) or have other medical contraindications to surgery (limited hepatic reserve related to cirrhosis or chronic hepatitis) (Kassianides 1987). Overall, fewer than 15% of patients with HCC are suitable surgical candidates Liver Transplantation Orthotopic liver transplantation is also an option for some patients who meet the specific criteria for a liver transplant. However, the majority of patients with locally advanced disease do not fulfil transplant criteria and access to this alternative is typically limited by donor availability. Furthermore, patients with advanced HCC receiving liver transplants experience a significantly high recurrence rate (80% at 3 years for patients with advanced stage disease) (Marco-Alvarez 1996, Mazzafero 1996, Selby 1995, Gores 1993) Trans-catheter Arterial Chemo-Embolisation (TACE) Page 27 of 106

29 Trans-catheter arterial chemo-embolisation (TACE) combines the intra-arterial delivery of chemotherapy together with embolisation via a hepatic artery branch. Due to the importance of achieving local tumour control, TACE has become a widely used therapy when surgical resection is not an option. Chemotherapy inhibits HCC tumour cells, while embolisation deprives the tumour cells of blood-derived oxygen and nutrients. Attempts to quantify and compare the therapeutic benefits of TACE have been hampered by the heterogeneity of institution-specific procedures, combining different chemotherapeutic drugs, embolising agents and administration schedules (Venook 1994, Nerenstone 1987, Ramming 1983). Most early published studies were non-randomised comparisons and found survival in the order of 50% at one-year and 20% at two years (Carr 2002). More recently, randomised controlled trials have demonstrated encouraging rates of tumour shrinkage (Llovet 2002, Lo 2002). TACE is usually well tolerated as long as cirrhosis is not severe. In patients with cirrhosis, TACE can cause severe liver damage; approximately 80% of patients with HCC have some form of cirrhosis. TACE is typically associated with significant local side effects including a characteristic post- embolisation syndrome comprising fatigue, abdominal pain, nausea and fever in 80% of patients. Serious complications occur in around 5% of cases, and 30-day post-treatment mortality is approximately 2%. TACE is usually indicated for only approximately 10 15% of patients with unresectable HCC fulfilling the following criteria: A single large tumour (although complications are more frequent when largest diameter > 10 cm), or multiple tumours (but patients with very extensive disease are likely to have a poor response). Preserved liver function (serum bilirubin < 3.0 mg/dl, albumin > 2.8 g/dl). No portal vein (or branch) infiltration or thrombosis. For those patients with unresectable HCC who do not fulfill these criteria, no generally accepted treatment option of proven efficacy exists at present. 6.3 Selective Internal Radiation Therapy (SIRT) Yttrium-90 labelled microspheres of various compositions have been used extensively for the treatment of hepatic malignancy, including HCC dating back to the 1960s. This application includes the use of SIR-Spheres which have been studied previously in various Asian and Western patient populations. The earliest study of SIR-Spheres in patients with HCC (Lau et al 1994) was a phase I/II study in 18 patients from Hong Kong with unresectable HCC (median tumour size 13cm; range 4 20cm) including some with recurrent disease (2; 11%) or cirrhosis (Childs B: 2; 11%). This study demonstrated that in those patients receiving an adequate tumour radiation dose (>120Gy) median survival was significantly longer (55.9 weeks) compared to those patients who received a lower tumour radiation dose (<120Gy) which conferred a median survival of 26.2 weeks (p = 0.005). Furthermore, the objective response rate by CT for patients receiving a tumour dose >120 Gy was 87.5% with a further 12.5% of patients achieving static disease, equating to a disease control rate of 100%. AFP levels Page 28 of 106

30 dropped by >50% in all 10 patients (100%) who had an elevated AFP pre-sirt (>300 mg/ml), and dropped by >80% in 8 patients (80%). The tumour marker serum ferritin dropped by >50% in all 8 patients (100%) who did not have an elevated AFP level pre-sirt (<300 mg/ml). The investigators on this first study of SIR-Spheres in HCC concluded that SIR-Spheres appeared to be safe, with the treatment being well tolerated without major complications and that tumour response is dose related with a tumour recommended dose of >120 Gy. In the next prospective study conducted in Hong Kong using SIR-Spheres in 71 patients with unresectable HCC, including 28% who had relapsed after surgical resection (Lau et al 1998), median overall survival was 9.4 months ( 46.4 months), with no significant difference in survival between the 20 patients with post-operative recurrence and the 51 patients receiving SIRT as a first-line therapy (8.6 months vs. 9.4 months; p = 0.941). Partial response was obtained in 19 patients (27%) by CT imaging, minor response or stable disease in 46 (65%), and progressive disease in only 6 (8%), either due to new intra-hepatic lesions (3) or distant metastases (3). In this study, down-staging to resection occurred in 4 patients (6%), with 2 patients showing complete histological remission and confirmed CR and only occasional viable tumour cells in the necrotic centres of the other 2 resected tumours. AFP dropped post-sirt by a median of 94% (20 99+%) in all 46 patients (100%) who had an elevated AFP pre-sirt, with a CR in 10 (22%) by normalisation of AFP levels, and a PR in 31 (67%) by >50% drop in AFP. Importantly 83% of patients were reported to have experienced no side effects, 17% had post-embolisation symptoms and 14% experienced only a low-grade fever, which contrasts significantly with the higher rate of post-embolization syndrome assosciated with TACE. The investigators on this study concluded that SIRT therapy is effective in selected cases of unresectable HCC, is well tolerated and can convert non-resectable tumours to resectable ones through down-staging. They also noted that the rapid fall in tumour markers post-sirt in most patients is not commonly observed with other treatment modalities, and that the median survival achieved by this group of patients was encouraging. The first comprehensive European experience in the use of SIR-Spheres for the treatment of patients with inoperable primary HCC (Sangro et al 2006) recorded data from every patient considered for SIRT for the treatment of HCC at a single institution as a prospective study. Patients were considered for SIRT provided that they had an unequivocal diagnosis of HCC that could not be treated by surgical resection, liver transplantation, or percutaneous therapies (radiofrequency ablation or alcohol injection). Patients received no further anti-neoplastic therapy. Overall, 28 patients were evaluated for SIRT therapy in a single institution. Four patients (14.2%) were excluded from treatment for various reasons, including excessive lung shunting, inappropriate portal venous flow and pre-treatment investigations that indicated an excessive risk of non-targeted delivery of microspheres to extra-hepatic structures. Of 24 patients receiving SIRT, 11 patients had progressed after TACE therapy and the remaining 13 patients received SIRT as first-line therapy. Among 21 patients evaluable for response using RECIST criteria, a reduction in size of target lesions was observed in all but one patient. When considering only target lesions, disease control rate and response rate were 100% and 23.8%, respectively. Overall, best response rate was stable Page 29 of 106

31 disease or partial response in 88% of patients using RECIST criteria and median overall survival was 7 months (95% CI, 2 12 months), and 1-year actuarial survival rate was 30%. The investigators on this study concluded that SIRT may be an alternative to embolizing treatments such as TACE and TAE, which are typically delivered as a series of sequential treatments and may produce significant side effects, including post-embolization syndrome, cholecysitis, acute renal failure, and a decline in liver function. In comparison, from this European experience SIRT typically required a 24 hour admission and most patients experienced no side effects after being discharged. The investigators also concluded that SIRT can be a valuable treatment modality for patients with tumours invading the portal vein and preserved liver function, a subset of patient for whom no effective therapy can presently be offered. An updated analysis of the institution s experience in 72 patients with unresectable advanced HCC (Inarrairaegui et al 2009), mostly complicated by cirrhosis (79%), tumour size (median volume: 222ml), portal vein involvement (22%), >5 nodules (49%) and poor prognosis (BCLC B 61%, BCLC C 29% revealed that the median survival was 12 months and was significantly prolonged in patients with 5 nodules compared to those with >5 nodules (22 vs. 8 months; p = 0.001). Furthermore, of 19 patients with 1 2 nodules, 5 (26%) were down-sized to resection (3 patients; all alive; 2 recurrence-free at 3 and 27 months post-surgery) or transplantation (2 patients, both alive and recurrence-free at 16 and 24 months post-transplant). In a recently reported single-center, prospective, longitudinal cohort study (Salem et al 2009) the long term outcomes from SIRT therapy in patients with HCC (n = 291) were reported with the intention of gaining insights into which patients appear to potentially benefit from therapy. Toxicities were recorded using the Common Terminology Criteria version 3.0 and response rate and time to progression (TTP) were determined using World Health Organization (WHO) and European Association for the Study of the Liver (EASL) guidelines. Survival by stage was assessed and univariate/multivariate analyses were performed. In this study a total of 526 SIRT treatments were administered (mean ; range 1 5). Toxicities included fatigue (57%), pain (23%), and nausea/vomiting (20%), and 19% exhibited grade 3/4 bilirubin toxicity. The 30-day mortality rate was 3%. Response rates were 42% and 57% based on WHO and EASL criteria, respectively and the overall TTP was 7.9 months (95% confidence interval, ). Survival times differed between patients with Child Pugh A and B disease (A, 17.2 months; B, 7.7 months; p = 0.002). Patients with Child Pugh B disease who had portal vein thrombosis (PVT) survived 5.6 months (95% confidence interval, months). Baseline age; sex; performance status; presence of portal hypertension; tumour distribution; levels of bilirubin, albumin, and alpha-fetoprotein; and WHO/EASL response rate predicted survival. The investigators concluded that in properly selected patients, SIRT can be used safely with encouraging survival. They also concluded that patients with Child Pugh A disease, with or without PVT, benefited most from SIRT treatment. Patients with Child-Pugh B disease without PVT or metastases also benefitted from SIRT therapy. Patients with Child Pugh B disease who had PVT had poor outcomes. TTP and overall survival varied by patient stage at baseline. The authors recommended that these data could be used to design future SIRT trials in patients with HCC. Page 30 of 106

32 In summary, selective internal radiation therapy (SIRT) using SIR-Spheres is a promising treatment for well selected patients with unresectable HCC. Survival appears to be similar to that reported in the literature for TACE. When compared to palliative care, SIRT shows a significant increase in overall survival. SIRT appears to have the potential to improve quality of life and tumour response while at the same time offering patients the possibility of longer term cure via surgical resection or transplantation. 6.4 Justification for this Study Existing Knowledge and Gaps: In the group of patients with advanced HCC but with good underlying liver function (Child-Pugh A), Sorafenib confers a median survival of 10.7 month in Western patients and 6.2 months in Asian patients (Llovet JM et al 2008, Cheng AL et al 2009). Efficacious systemic therapy is important to the subset of patients with HCC with extra-hepatic metastases and in this group Sorafenib, confers a median survival of 5.7 months (Kang YK et al 2008). In the larger group of patients with locally advanced HCC however, the benefits of Sorafenib over efficacious loco-regional ablative therapy is unclear. This is of critical importance as HCC is a fast growing locally aggressive disease that frequently causes patient demise before the development of extra-hepatic metastases. Thus the response of loco-regional disease to first-line therapy determines survival in this group of patients. Currently the most commonly used therapy in this group of patients worldwide is trans-arterial delivered loco-regional ablative therapy. Of the 2 commonly used forms of loco-regional ablative therapies, Selective Internal Radiation Therapy (SIRT) has higher efficacy over Transarterial Chemo-Embolisation (TACE) (Lewandowski RJ et al 2009, Salem R et al 2009, Lau WY et al 1994). Clinical Significance and long-term impact: In locally advanced HCC without portal vein thrombosis (PVT), the reported median survival for patients treated with Sorafenib and SIRT are 14.3 months and 19.4 months respectively. In the group of patients with locally advanced HCC and PVT the reported difference in median survival is even wider at 4.4 months and 15.9 months for Sorafenib and SIRT respectively ((Kang YK et al 2008, Lewandowski RJ et al 2009, Salem R et al 2009, Lau WY et al 1994, Sangro B et al 2009). While Sorafenib has bene shown in phase III trials to be superior to placebo in the treatment of advanced HCC, sorafenib has never been compared to SIRT for locally advanced disease in a randomised controlled trial (RCT). A definitive RCT comparing the 2 most promising therapies in locally-advanced HCC will impact on outcomes in a large number of patients and change clinical practice. This will also pave the way for future trials in combined modality therapies in HCC. Page 31 of 106

33 7. STUDY DESIGN AND PATIENT ELIGIBILITY This study is an investigator-initiated multi-centre study conducted by the Asia Pacific Hepatocellular Carcinoma Trials Group (AHCC) that will enroll patients in an open label phase III trial. The trial will assess the impact of Selective Internal Radiation Therapy (SIRT) compared to sorafenib on overall survival in the treatment of patients with locally advanced hepatocellular carcinoma (HCC). The AHCC is an established multi-center trials group with its data center at the Singapore Clinical Research Institute (SCRI) ( ). This study will recruit a minimum of 360 patients from a minimum of 15 sites. Study null hypothesis: There is no difference in overall survival between patients receiving SIRT and those receiving sorafenib therapy. The study is structured so that patients with locally advanced HCC, who satisfy the study eligibility criteria, will be randomised to receive either: Treatment Arm A: Oral Sorafenib therapy at a dose of 400 mg b.i.d until disease progression, no further response, complete regression or unacceptable toxicity or Treatment Arm B: A single administration of SIR-Spheres into the liver targeted at HCC in the liver by the trans-arterial route. Eligibility criteria Locally advanced HCC Not amenable to curative treatment Randomisation 1:1 Stratified by - Institutions - Branch PVT n=360 Sorafenib 400mg b.i.d. SIR-Spheres Primary Endpoint Overall survival Secondary Endpoints Tumour response rate Disease control rate Time To Disease Progression Progression free survival overall Progression free survival in the liver Health Related Quality of Life Toxicity and Safety Liver resection rate Liver transplantation rate Patients in this multi-center trial will receive SIR-Spheres therapy at designated regional centers in the Asia-Pacific, the main center being at the Singapore General Hospital. Page 32 of 106

34 Sorafenib will be administered at individual trial centers within the multi-center trials group. The logistics of getting overseas patients to Singapore to receive SIR-Sphere therapy and be monitored subsequently (> 1 week later) at their native trial centers have been successfully carried out in a previously completed multi-center trial of the AHCC trials group (AHCC05) ( 7.1 Patient Eligibility 1. Patients must have an unequivocal diagnosis of HCC in the liver based on: a) Histology consistent with HCC and its histological variants such as poorly differentiated HCC and sacomatoid HCC OR b) Space occupying lesion of the liver demonstrated by CT scan (non-dynamic) or MRI (non-dynamic) and either: Serum alpha-feto protein level of at least 400 mcg/l or Dense homogenous lipiodol retention OR c) Nodule larger than 1 cm with imaging appearances typical of HCC (i.e., hypervascular in the arterial phase with hypodensity in the portal venous or delayed phase), on 4-phase (unenhanced, arterial, portal venous and delayed phases) multi-dector CT scan or 4-phase dynamic contrast enhanced MRI in a cirrhotic liver. All radiology images in this multi-center trial will be centrally reviewed by trial radiologists in Singapore. CT and MRI scans will be stored in portable media and couriered to Singapore where response to therapy will also be determined. 2. The HCC must not be amendable to potentially curative treatment modalities, such as surgical resection, immediate liver transplantation or optimal percutaneous radio-frequency ablation as determined by the center. 3. The disease must be locally advanced as defined by BCLC (B) intermediate stage or BCLC (C) advanced stage without extra-hepatic disease i.e. vascular invasion and tumor thrombus is eligible EXCEPT when there is complete portal vein occlusion. (Appendix 3) 7.2 Inclusion Criteria Patients must fulfil all of the following criteria in order to be eligible for this study: (a) Locally advanced HCC (as defined above) without extra-hepatic metastases. Page 33 of 106

35 (b) Willing, able and mentally competent to provide written informed consent prior to any testing undertaken for this study protocol, including screening tests and evaluations that are not considered to be part of the subject's routine care. (c) Aged 18 years or older of either gender. (d) Unequivocal diagnosis of HCC (as defined above) (e) HCC that is not amenable to surgical resection or immediate liver transplantation, or that which cannot be optimally treated with local ablative techniques such as radio-frequency ablation, consistent with the practice of the clinical trial centre. (f) Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as 10 mm with spiral CT scan or MRI. (g) ECOG performance status 0 1. (Appendix 1) (h) Child-Pugh A B (up to 7 points). (Appendix 2) (i) Adequate haematological, renal and hepatic function as follows*: Leukocytes 2,500/μL Platelets 80,000/μL Haemoglobin > 9.5 g/dl Total bilirubin < mg/dl INR ALP 5 x institutional upper limit of normal AST and ALT 5 x institutional upper limit of nor mal Albumin 2.5 g/dl Creatinine mg/dl *The above blood results can be used to confirm eligibility if they were performed within 28 days prior to signing of informed consent document by patient. (j) Life expectancy of at least 3 months without any active treatment. (k) Suitable for protocol treatment as determined by clinical assessment undertaken by the Investigator. (l) Female patients must be either postmenopausal or, if premenopausal, must have a negative pregnancy test and agree to use two forms of contraception if sexually active during their study participation. (m) Male patients must be surgically sterile, or if sexually active and having a pre-menopausal female partner then must be using an acceptable form of contraception. Page 34 of 106

36 7.3 Exclusion Criteria (a) Subjects who have had > 2 administrations of hepatic artery directed therapy. (b) Subjects who have had hepatic artery directed therapy done < 4 weeks prior to study entry. (c) Subjects who have had systemic chemotherapy for HCC except for prior adjuvant or neoadjuvant therapy given more than 6 months from enrolment. (d) Patient who have had prior treatment with Sorafenib or VEGF inhibitors. (e) Prior hepatic radiation therapy for HCC or other malignancy. (f) Currently receiving any other investigational agents for the treatment of their cancer. (g) Has intractable clinical ascites (in spite of optimal diuretic treatment) or any other clinical signs of liver failure, on physical examination. (h) Complete main portal vein thrombosis. (i) Any metastatic disease. In this context local-regional lymph nodes measuring < 2 cm in greatest diameter or lung nodules measuring < 1 cm are not contraindications at the discretion of site PI. (j) Any other concurrent malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for at least five years. (k) Presence of clinical signs of CNS metastases due to their poor prognosis and because progressive neurologic dysfunction would confound the evaluation of neurologic and other adverse events. (l) Uncontrolled inter-current illness including, but not limited to, ongoing or active infection (except viral hepatitis), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. (m) Any of the following contraindications to angiography and selective visceral catheterization: Bleeding diathesis, not correctable by the standard forms of therapy. Severe peripheral vascular disease that would preclude arterial catheterization. Portal hypertension with hepato-fugal flow as documented on baseline spiral CT scan. (n) History of allergic reactions attributed to compounds of similar chemical or biologic composition to SIR-Spheres or Sorafenib. (o) Inability or unwillingness to understand or sign a written informed consent Page 35 of 106

37 document. (p) Female subjects who are pregnant or currently breastfeeding. (q) For female subjects, unless postmenopausal or surgically sterile, unwillingness to practice effective contraception, as defined by the Investigator, during the study. The rhythm method is not to be used as the sole method of contraception. (r) For male subjects, unwillingness to practice effective contraception (as defined by the Investigator) while taking part in this study, because the effect of the SIR-Spheres treatment on sperm or upon the development of an unborn child are unknown. (s) Current enrolment in any other investigational therapeutic drug or device study. Page 36 of 106

38 8. STUDY ENTRY AND RANDOMISATION 8.1 Patient Screening 35 Figure 1: Overview of study timeline All patients referred for possible participation in this study must be screened (see Section 9 Screening/Baseline Investigations) by the Investigator to confirm the patient s eligibility to be randomised (see Section 7 Study Design and Patient Eligibility). A patient is considered to be a Screen failure if the patient signs the study ICF, but is ineligible or withdraws before being randomized into the study. All data for Screen failure patients will be recorded on patient s medical records and on ecrf. All documentation supporting the inclusion and exclusion criteria and screening investigation results are to be retained by the Investigator and made available for study monitoring from time to time. All patients deemed ineligible to receive protocol treatment will have their initials recorded on the Patient Screening Log. The Patient Screening Log will include the reason(s) for the patient s exclusion from receiving protocol treatment and will be retained and maintained by the investigational site. The Study Principal Investigator should be contacted in the event of any query or uncertainty relating to a patient s eligibility to receive protocol treatment: Pierce KH Chow FRCSE PhD Department of General Surgery Singapore General Hospital, Outram Road Singapore Tel: Fax: pierce.chow.k.h@sgh.com.sg pierce.chow@duke-nus.edu.sg Page 37 of 106

39 8.2 Patient Informed Consent No patient may undergo screening to assess their eligibility to be randomised into the study or commence protocol treatment prior to signing the informed consent document. However, screening assessment performed within 28 days prior to signing of informed consent can be used to confirm eligibility. Screened patients who are eligible will be randomised into the study. 8.3 Patient Stratification Prior to randomisation, patients will be stratified by: Branch Portal Vein Thrombosis Institution 8.4 Study Entry and Patient Randomisation Study entry is defined as the date of patient randomization into the study. Once patients have been screened and deemed eligible to participate in the study, treatment will be allocated randomly using the method of stratified block randomisation. A patient will be considered to have been randomised into the study once a subject identification number has been assigned to the patient. Randomisation will be performed by a centralised Study Randomisation Centre. At randomisation, the Study Randomisation Centre will assign a unique 7 alpha-numeric Subject Identification Number (SIN) to each patient (the first three alphabets represent the investigational site and the first digit represent the Branch PVT status while the last three digits represent the patient at that investigational site). The patient s Subject Identification Number will be used on all of that patient s Case Report Forms (CRFs). Example: S G H A web-based randomization structure or randomisation envelope will be provided by Singapore Clinical Research Institute (SCRI). When a subject meets inclusion/exclusion criteria and gives written informed consent, investigator will randomise subject via web randomisation or randomisation envelope to receive a subject number. The randomisation method for each site will be determined by SCRI. In case of site failure to achieve web randomisation investigators should contact SCRI for assistance, who will attempt to randomize the patient on behalf of the investigator. If for any reason web randomization is not possible the investigators or the authorised site personnel will use the backup envelope for randomisation. Please make sure the informed consent has been obtained, and all eligibility criteria, as detailed in the study protocol, are fulfilled before proceeding to the backup envelope randomisation. Complete all the necessary information (Subject Initials, Date of Birth and Eligibility) on the backup randomisation form and fax to SCRI at within 24 hours after randomisation. Page 38 of 106

40 9. SCREENING / BASELINE ASSESSMENTS 9.1 Clinical Assessment All patients must be assessed clinically by the Investigator to determine the patient s eligibility to be randomised into the study. Clinical assessments as stated below can be performed less than 28 days prior to signing of informed consent document. (See section 8.1 Figure 1: Overview of Study Timeline): Demographics Medical and surgical history, Physical Examinations Height (only at Screening/baseline), Weight, Blood Pressure (Systolic & Diastolic) and Body Temperature. Concurrent illness and concomitant medication (at the time of signature of the informed consent document) Performance Status - ECOG 9.2 Haematological and Biochemical Investigations All patients are required to undergo the following haematological and biochemical investigations before being randomised into the study. These investigations can be performed less than 28 days prior to signing of informed consent document. (See section 8.1 Figure 1: Overview of Study Timeline): Haematological Renal Liver Tumour marker Pregnancy test Leukocytes, Platelets, Haemoglobin, INR Creatinine Liver Function Tests (AST/ALT, ALP, Total Bilirubin, Albumin) *Hepatitis Status Hep Bsag, Anti-HCV IgG, Hep B core Antibody IgG (optional) Serum Alpha Feto-Protein (AFP) Serum or urine pregnancy test in female patients of reproductive potential (as appropriate) *Notes i) If either the Hepatitis B Surface Antigen Test or anti-hcv IgG Test is positive, the other test will be optional. The Hepatitis B Core Antibody IgG Test is optional. ii) If there is documented proof that the subject s hepatitis status is positive for Hep B or Hep C then it is not required to repeat the hepatitis serology test at baseline. In this case laboratory results from outside the 28 day window period prior to signing of the informed consent document can be used. 9.3 Radiological and Nuclear Medicine Investigations All patients are required to undergo the following investigation in order to determine their eligibility to be randomised into the study CT Scan of the Chest, Abdomen, Pelvis A thoracic CT scan to determine the presence or absence of lung metastases. Page 39 of 106

41 A multi-phase (at least three-phase) contrast-enhanced spiral CT scan of the abdomen/pelvis to determine the extent of liver disease and to determine the presence and extent of intra-peritoneal extra-hepatic metastases. Each of these CT series can be performed less than 28 days prior to signing of informed consent document. (See section 8.1 Figure 1: Overview of Study Timeline). Appendix 13 provides the recommended CT image acquisition guidelines. Note: MRI is acceptable in lieu of CT, e.g. for patients with contrast allergy that prevents optimal CT imaging. 9.4 Baseline Assessment of Patient Suitability for Selective Internal Radiation Therapy (ONLY for patients randomised to SIRT-arm) Patients randomised to SIRT-arm must be assessed in order to determine their eligibility to receive protocol SIRT therapy. This assessment must be performed after randomisation but prior to commencement of study treatment. (See section 8.1 Figure 1: Overview of Study Timeline) Visceral and Hepatic Angiogram Patients randomised to SIRT -arm must undergo diagnostic visceral and hepatic angiogram to determine the vascular anatomy of the liver and to perform a nuclear medicine liver-to-lung shunt study. The hepatic angiogram will provide a road map of the arterial supply of the liver in order to plan the optimal delivery of the SIR-Spheres. The hepatic angiogram should be performed together with the lung shunt study and the results of these two assessments must be available prior to implanting the SIR-Spheres. The diagnostic visceral and hepatic angiogram must be performed in order to: Fully identify and define all relevant visceral and hepatic arterial vasculature: o Aortogram o Superior mesenteric artery (SMA) o Coeliac axis (CA) o Left gastric artery (LGA) o Common hepatic artery (CHA) o Gastroduodenal artery (GDA) o Proper hepatic artery (PHA) o Right gastric artery (RGA) o Left hepatic artery (LHA) o Right hepatic artery (RHA) o Middle hepatic artery(ies) (MHA) o Supraduodenal artery, retroduodenal artery, inferior phrenic arteries o Cystic artery o Replaced, accessory and aberrant arteries. Confirm the ability to selectively catheterise the hepatic arterial vasculature. Page 40 of 106

42 Assess the flow characteristics in the hepatic arteries. Determine the hepatic arterial supply to the tumour(s) i.e. right, left, middle hepatic arteries; replaced, accessory hepatic arteries; extra-hepatic arteries; other aberrant arteries. Determine the influence of hepatic arterial anatomy relative to the tumour(s) distribution on the ability to treat the entire diseased portion of the liver as a whole liver treatment at one setting. Confirm the absence of uncorrectable blood shunting from the liver to the gastrointestinal tract or other abdominal organs, e.g. pancreas. If the hepatic angiogram indicates an uncorrectable risk of flow to any of the gastrointestinal organs, then SIRT treatment must not be administered. Perform a technetium-99m macro-aggregated albumin (Tc-99m MAA) lung shunt study to assess the presence and degree of lung shunting from the liver Tc-99m MAA Lung Shunt Study In approximately 10% 15% of patients with primary HCC there will be sufficient arterio-venous shunts present in the liver to allow SIR-Spheres injected into the liver to pass through the liver and lodge in the lungs. As excessive liver-to-lung shunting may result in radiation damage to the lungs, a nuclear medicine break-through scan must be performed in all patients to quantify the extent of liver-to-lung shunting. See Appendix 6 for details of the technique for performing the Tc-99m MAA lung shunt study. The percentage of Tc-99m MAA that has escaped through the liver and lodged in the lungs may be expressed as a percentage lung shunt. Normally this should be less than 20%. The total lung radiation dose delivered by SIR-Spheres must be 20Gy in order to ensure that the patient does not develop radiation induced lung disease. Table 9.4 shows the approximate lung radiation dose delivered for different combinations of 1) implanted activity of SIR-Spheres and 2) percentage liver-to-lung shunting. The table assumes that the mass of both lungs plus blood is 1000g. Table 9.4 Lung Radiation Dose Calculation (Gy delivered to the lungs) Implanted activity of SIR-Spheres microspheres (GBq) Percentage liver-to-lung shunting 10 % % % Page 41 of 106

43 9.4.3 Exclusion Criteria specific to patients randomised to SIRT-arm There is no data on the safety of SIR-Spheres in pregnant women or children. SIR-Spheres are contraindicated in patients who have (SIR-Spheres Package Insert, Appendix 4): (a) i. If the Body Surface Area (BSA) method is used for dose calculation and the percentage lung shunting exceeds 20% of the hepatic artery blood flow, as determined by TC-99m MAA scan. In the event that the lung shunt study indicates that pulmonary shunt exceeds 20%, the partition model (ii below) may be used to adjust the prescribed activity so that radiation absorbed dose to the lungs does not exceed 20 Gy. Instructions for calculating absorbed dose to the lungs and liver using the partition model are presented in Appendix 7. ii. Partition model (pre-assessment dosimetry) calculations based on Tc-99m MAA and CT scans show that any of the following radiation dose limits are exceeded: - radiation absorbed dose to the lungs > 20Gy - radiation absorbed dose to cirrhotic liver > 50Gy - radiation absorbed dose to non-cirrhotic liver > 70Gy (b) Pre-assessment angiogram and Tc-99m MAA scan that demonstrates significant and uncorrectable activity in the stomach, pancreas or bowel. (c) Disseminated or extra-hepatic disease excluding local regional lymph nodes that may be reactive. (d) Hepatic arterial anatomy not suitable for implantation of SIR-Spheres, as assessed by hepatic angiogram. (e) Subjects who require more than one session of SIR-Spheres administration, as assessed by study interventional radiologist. Page 42 of 106

44 10. TREATMENT PLAN Patients should begin protocol treatment as soon as possible after randomisation (but not more than 35 days after signing of informed consent document). All patients will be followed until death or, for patients undergoing surgical resection, liver transplantation, or ablative therapy (e.g. radio-frequency ablation) after study entry, for a period of five years after surgical resection, liver transplantation, or ablative therapy, or until death if recurrent disease has been recorded by that time Treatment Arm A: Sorafenib Sorafenib therapy will commence as soon as possible after randomisation: Sorafenib 400mg orally, twice daily. Consumer medicine information for sorafenib is provided in Appendix 10. Continued until: evidence of treatment failure (lack of efficacy resulting in disease progression); or unacceptable toxicity occurs Precautions Every attempt should be made to continue sorafenib therapy for a minimum of three months, at which time a clinical decision will be made to continue or not continue protocol therapy, based on the results of clinical assessment, serial CT scans and biochemical tests. 10. Duration of Treatment Sorafenib therapy should be administered indefinitely and only modified or discontinued for one of the following reasons: Objective evidence of tumour progression at any site as determined by CT/MRI scan. Patient request. Patient cure or complete response. Patient responds to treatment and becomes eligible for surgical resection, liver transplantation, or ablative therapy. Unacceptable toxicity as determined by objective evidence, clinical judgement or patient request (See section 10. Cessation of Sorafenib Therapy). All sorafenib therapy will be recorded on the CRF. 10. Sorafenib Dose and Schedule Modifications The following five tables (Table 10.1 A, Table 10.1 B, Table 10.1 C, Table 10.1 D and Table 10.1 E) describe the relevant dose and schedule modifications for sorafenib. The justification for the dose or schedule modification should be recorded in the patient record and on the CRF. Page 43 of 106

45 Doses will be delayed or reduced for clinically significant hematologic and other toxicities that are related to protocol therapy. If a patient experiences several toxicities and there are conflicting recommendations, the recommended dose adjustment that reduces the dose to the lowest level will be used. All dose modifications will follow predefined dose levels: i. ii. iii. 400mg administered orally (po) twice daily (bid) every day 200mg administered orally (po) twice daily (bid) every day 200mg administered orally (po) twice daily (bid) every 2 days If further dose reduction is required, the patient should be discontinued from the study. Also, at the discretion of the investigator, the dose may be re-escalated to 400 mg po bid after the resolution of the adverse event. Table 10.1 A: Haematologic Criteria for Dose Delay and Dose Modification of Sorafenib Grade Dose Delay Dose Modification Grade 0-2 Treat on time No change Grade 3 Treat on time Decrease one dose level b a Grade 4 Delay until Grade 2 Decrease one dose level b a If no recovery after 3 consecutive weeks delay, treatment will be discontinued unless patient is deriving clinical benefit b If more than 2 dose reductions are required, treatment will be discontinued Table 10.1 B: Non-Haematologic Criteria for Dose Delay and Dose Modification of Sorafenib (except skin toxicity)a Grade Dose Delay Dose Modification Grade 0-2 Treat on time No change b Grade 3 Delay until Grade 2 Decrease one dose level c Grade 4 Off protocol therapy Off protocol therapy a Also excludes nausea/vomiting that has not been premedicated, and diarrhoea b If no recovery after 3 consecutive weeks delay, treatment will be discontinued unless patient is deriving clinical benefit c If more than 2 dose reductions are required, treatment will be discontinued Table 10.1 C: Management of Treatment-emergent Hypertension Grade of Event Grade 1 Grade 2 asymptomatic and diastolic BP < 110 mmhg Management/Next Dose Consider increased BP monitoring Begin anti-hypertensive therapy and continue sorafenib Grade 2 symptomatic/persistent OR diastolic BP 110 mmhg OR Grade 3 1. Sorafenib should be held a until symptoms resolve and diastolic BP 110 mmhg; also treat patient with anti-hypertensives and when sorafenib is restarted, decrease one dose level a 2. If diastolic BP not controlled ( 110 mmhg) on therapy, decrease another dose level b Discontinue protocol therapy Grade 4 a May be able to resume full dose later b Patients requiring > 2 dose reductions should go off protocol therapy Page 44 of 106

46 10..1 Dose Modification of Sorafenib for Skin Toxicity Patients experiencing hand-foot syndrome should have their signs and symptoms graded according to the grading system in Table 10.1 D: Grading of Hand-Foot Syndrome. Other skin toxicities will be graded according to CTCAE Version 4.02 unless as specified in the protocol. (Appendix 11) Table 10.1 D: Grading of Hand-Foot Syndrome Grade 1 Grade 2 Grade 3 Numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort, which does not disrupt normal activities. Painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient s activities. Moist desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. According to the grade and incidence of skin toxicity (including rash and hand-foot syndrome) for a given patient, the following dose modification schedule will be followed (see Table 10.1 E: Skin Toxicity Criteria for Dose Delay and Dose Modification of Sorafenib). Table 10.1 E: Skin Toxicity Criteria for Dose Delay and Dose Modification of Sorafenib Toxicity Grade Grade 1 Grade 2 1st appearance 2nd appearance 3rd appearance 4th appearance Grade 3 1st appearance 2nd appearance 3rd appearance During a Course of Therapy Maintain dose level Dose at Reintroduction Maintain dose level Interrupt until resolved Maintain dose level to grade 0-1 Interrupt until resolved 200 mg BD every day to grade 0-1 Interrupt until resolved 200 mg BD every 2 days to grade 0-1 Discontinue treatment permanently Interrupt until resolved 200 mg BD every day to grade 0-1 Interrupt until resolved 200 mg BD every 2 days to grade 0-1 Discontinue treatment permanently For patients who require a dose reduction for grade 3 rash or hand-foot skin reaction, the dose of study drug may be increased to the starting dose after 28 days of therapy has been administered at the reduced dose without the appearance of rash or hand-foot skin reaction grade 1. Patients who develop rash/desquamation or hand-foot skin reaction during treatment with sorafenib should have the involved area photographed if possible. Patients with discomfort due to hand-foot syndrome may be treated with topical emollients, low potency topical steroids, or urea-containing cream. Page 45 of 106

47 10. Cessation of Sorafenib Therapy Sorafenib therapy will be ceased if any of the following events occur: Life threatening grade 4 toxicity. Repetition of non-life threatening grade 4 toxicity despite adequate dose reduction. Anaphylactic reaction. Cardiac event grade 2. If sorafenib therapy has to be delayed due to adverse events for more than 3 consecutive weeks Patient Non Compliance - If patient has missed dose for more than 10% of the total dosage duration (not applicable for dose missed for Adverse Events and Serious Adverse Events) Treatment Arm B: SIR-Spheres SIR-Spheres will be administered at the patient-specific prescribed activity as soon as possible after randomisation and passed the Baseline Assessment of Patient Suitability for Selective Internal Radiation Therapy. The prescribed activity of SIR-Spheres will be calculated using the body surface area (BSA) method, which is presented in table form in Appendix 9 or the Partition Model (Appendices 7 and 8). However, where possible, the Partition Model Methodology is preferred. To use the BSA method the following information needs to be known about the patient: 1. Body surface area (in square meters) 2. Percent tumour involvement 3. Percent lung shunting Calculation of Body Surface Area The patient s body surface area should be calculated from standard height/weight charts Calculation of Percent Tumour Involvement The tumour volume will be determined from the screening (i.e. baseline) CT scan of the liver. The tumour volume will be determined independently by MeVis Distant Services, Bremen, Germany on a 1 working day turn-around basis. DICOM data files will be uploaded to MeVis Labs via secure web-link by the Radiologist Investigator. MeVis Labs will then provide an Adobe pdf file of the tumour volume and normal liver volume to the Radiologist Investigator. This document must be stored in the patient file and is to be used as the basis for calculating the patient s prescribed activity of SIR-Spheres to implant into the hepatic tumour feeding vessel(s). The percent tumour involvement must be calculated either: 1. For the whole liver (in the case of a whole liver treatment for bi-lobar disease), or Page 46 of 106

48 2. For that lobe of the liver which is to be treated (in the case of a uni-lobar treatment for uni-lobar disease). The lobe(s) of the liver that is(are) to be treated is(are) determined by the location of disease and the intended treatment plan, as summarised in Table Table 10.2 Location of Disease and Treatment Plan Location of disease Intended treatment plan Explanation of intended treatment plan Comment Right lobe only ( Uni-lobar disease ) Single right lobe treatment only Patient has HCC confined to the right lobe of the liver. Therefore, the prescribed activity of SIR-Spheres is calculated for the right lobe only and is injected selectively into the right hepatic arterial circulation(1) Left lobe does not receive treatment Left lobe only ( Uni-lobar disease ) Single left lobe treatment only Patient has HCC confined to the left lobe of the liver. Therefore, the prescribed activity of SIR-Spheres is calculated for the left lobe only and is injected selectively into the left hepatic arterial circulation(1) Right lobe does not receive treatment Right lobe and left lobe ( Bi-lobar disease ) Whole liver treatment Patient has HCC in both lobes of the liver. The prescribed activity of SIR-Spheres is calculated for the whole liver. The prescribed activity of SIR-Spheres is injected into the proper hepatic artery, or selectively into the right and left hepatic arterial circulation. Both lobes are treated (1) super-selective treatment is possible; the contra-lateral lobe may be targeted in case of atypical blood supply; extra-hepatic (parasitic) supply of HCC nodules should be embolised (coiled) before SIRT Calculating Whole Liver Percent Tumor Involvement If a whole liver treatment is planned, then the tumour and normal liver tissue volumes must be calculated from the baseline CT scan using a volumetric software algorithm. The percent tumour involvement is then calculated as the total tumour volume divided by the total liver volume (including tumour), multiplied by 100. Calculating Percent Tumor Involvement for Each Lobe Separately(1) If a uni-lobar treatment is planned, then the tumour and normal liver tissue volumes must be calculated separately for the right and left lobes. The right and left lobe volumes are calculated from the baseline CT scan using a volumetric software algorithm, using the typical anatomic delineator (middle hepatic vein or gall bladder fossa) to separate the right and left lobes. The percent tumor involvement in the right lobe is then calculated as the tumour volume in the right lobe divided by the total right lobe volume (including right lobe tumour), multiplied by 100. Likewise, the percent tumour involvement in the left lobe is calculated as the tumour volume in the left lobe divided by the total left lobe volume (including left lobe tumour), multiplied by 100. Page 47 of 106

49 In the case of watershed lesions (occupying the caudate lobe) or branching vessels (e.g. lateral and medial branches), the vessels feeding the tumour bed from the intended position of the delivery catheter may be used to determine the tumour volume. This will require mapping the diagnostic hepatic angiogram to the CT image to obtain the adjusted tumour volume. For SIR-Spheres prescribed activity calculation examples, please see Appendix Calculation of Percent Lung Shunting In about 15% of patients with HCC there will be abnormal intra-tumoural arteriovenous connections which will allow more than 10% of the SIR-Spheres injected into the hepatic circulation to pass through the liver and lodge in the lungs. As excessive liver-to-lung shunting may cause radiation damage to the lungs, a nuclear medicine breakthrough scan must be performed in all patients during the pre-treatment evaluation. The percentage of Tc-99m labelled macro-aggregated albumin (Tc-99m MAA) that has escaped through the liver and lodged in the lungs can then be expressed as a percent lung shunt. Regions of interest are defined over the total lungs and total liver (including tumours), and the percent lung shunting calculated as the ratio of total lung geometric mean counts to the sum of total lung plus total liver counts: L = 100 [NlungA NlungP]1/2 / ([NlungA NlungP]1/2 + [NliverA NliverP]1/2) where: NlungA and NlungP are the anterior and posterior total lung region counts NliverA and NliverP are the anterior and posterior total liver region counts Once the body surface area, percent tumour involvement, and percent lung shunt are known, the prescribed activity of SIR-Spheres may be calculated using the BSA tables presented in Appendix 9(1). Notes: (1) The BSA tables in Appendix 9 provide the correct prescribed activity of SIR-Spheres for as whole liver treatment. In the case that uni-lobar lobe treatment is planned, the prescribed activity of SIR-Spheres provided by the BSA tables must be multiplied by the respective percentage of total liver volume that lobe to be treated represents Administration of SIR-Spheres SIRT may be administered with overnight stay. Patients in this multi-center trial will receive SIR-Spheres therapy at designated regional centers in the Asia-Pacific, the main center being at the Singapore General Hospital. The technique for delivering SIR-Spheres microspheres is provided in the SIR-Spheres Training Manual and in Appendix 5. Patients will receive the calculated dose of SIR-Spheres microspheres as described in Section 10.2, however when encountering partly necrotic or cystic tumours, the treating physician may recalculate the dose based on the tumour load and dose patient according to the re-calculated dose. Page 48 of 106

50 The pre-determined end-points for the administration of SIR-Spheres into the hepatic arterial circulation are: 1) Administration of the prescribed activity of SIR-Spheres as calculated from using the BSA method above, or 2) Infusion of SIR-Spheres to the point of sluggish antegrade hepatic arterial flow, at which point further infusion of SIR-Spheres could result in non-targeted embolisation. The stopping point for the infusion of SIR-Spheres is at the discretion of the treating Interventional Radiologist. Due to the relative increased risk of non-targeted delivery when a base catheter and proper hepatic arterial infusion is used to administer SIR-Spheres, the treating Interventional Radiologist is encouraged to administer SIR-Spheres using a microcatheter and super-selective technique. In instances where multiple vascular origins arising from the proper hepatic arteries are recognised, optimisation of flow and super-selective administration of SIR-Spheres may include the following techniques: 1) Individual super-selection with separate infusion of SIR-Spheres into each involved segment. 2) Optimisation of segments through selected branch vessel embolisation at the time of diagnostic hepatic angiogram, allowing for cross-perfusional filling. (Note: this technique cannot be performed if embolisation may result in complete exclusion of an entire vascular territory secondary to the crossing of the falciform ligament, e.g. left hepatic artery cannot be embolised to optimise therapy from right hepatic artery, however middle hepatic artery may be embolised if anticipated right/left two point administration). 3) Free float technique: selection and partial embolisation with resultant free manipulation of a 'hot' microcatheter into a secondary vascular territory without removal of the catheter from the hepatic arterial bed. At the discretion of the treating Interventional Radiologist, selective embolisation of the cystic artery may be performed Measurement of Residual SIR-Spheres Activity Post-Treatment Once the pre-determined end-point for the administration of SIR-Spheres into the hepatic arterial circulation has been reached, the microcatheter will be removed from the patient and the amount of activity remaining in the SIR-Spheres v-vial should be assayed. Additionally delivery tubing and microcatheter can be assayed, in order to determine the amount of activity that was actually administered to the patient. In particular, if stasis is encountered before completion of SIR-Spheres delivery, it is recommended that the team measures the residual Y-90 activity within the microcatheter and delivery tubing. Page 49 of 106

51 However, this is at the discretion of the team.this is done by subtracting the residual SIR-Spheres activity from the pre-treatment SIR-Spheres activity, to arrive at an administered activity. The method for measuring the residual activity of SIR-Spheres is at the discretion of the treating site. Most centres measure residual SIR-Spheres activity using equidistant measurements with o o o o a G-M probe taken at four positions around the v-vial at 0, 90, 180, 270 prior to, and immediately after treatment. Some centres place the v-vial, delivery tubing and microcatheter back into the dose calibrator which was used to assay the amount of SIR-Spheres activity during dose preparation. Either method is acceptable in this study protocol Non-Protocol Chemotherapy Once protocol therapy has been discontinued, the patient should receive the best available care as determined by the treating Investigator. Patients are not permitted to receive second line therapy until they have documented progression of disease. If this includes any active cancer treatment then details of this treatment must be recorded on the follow-up form CRF. The treating Investigator may continue to administer the same therapy regimen as was administered during protocol treatment and there are no restrictions on further treatment Supportive (Non-Protocol) Treatment Supportive treatment should be given when required, according to the patient s condition. Such supporting treatment may include, but is not limited to, anti-emetics, pain relief etc. All supportive treatment should be recorded on the CRF, including any supportive treatment provided for the implantation of SIR-Spheres. Prophylactic anti-emetic therapy (e.g. Ondansetron, Granisetron) may be administered at the discretion of the treating Investigator or as per usual institutional policy. Prophylactic proton pump inhibitor therapy (e.g. Omeprazole or Pantoprazole) commencing 1 week prior to treatment with SIRT and continuing for 4 weeks post treatment is recommended, unless otherwise contra-indicated. Prophylaxis of post-embolisation syndrome using a tapering dose of oral corticosteroids (e.g. Methyl-prednisolone or Dexamethasone) commencing on the first day post-sirt is recommended, unless otherwise contra-indicated. Oral analgesia (e.g. Ketorolac) may be required for 1 week following SIRT treatment to relieve pain from radiation injury and the embolic effect of SIR-Spheres, and liver capsular pain from tumour edema Concomitant Medications All medications taken by patients, including medications that are unrelated to their cancer management should be recorded in the CRF. These include long-term as well as short-term or acute medications ongoing at the time of signature of the informed consent document or started any time after signature of the informed consent document until 30 Page 50 of 106

52 days post study conclusion (or until commencement of the next alternative therapy, whichever is earlier). Routine medications should be listed in the appropriate section and need only be recorded on the CRF at the commencement of protocol therapy, unless they are changed. Additional routine medications should be recorded on the CRF when they commence. Commencement and cessation dates for concomitant medications are required. Page 51 of 106

53 11. SERIAL STUDY ASESSMENTS 11.1 Study Assessments All patients will receive their study assessments according to the following study calendar. Additional non-study assessments may be performed as clinically indicated at the discretion of the treating Investigator. 1 Study Calendar Screening/ Baseline (Eligibility) + Randomisat ion Schedule Informed Consent Demographics Medical and Surgical History Concurrent Illness Concomitant Medications Clinical Assessment & Physical Exam Height (only at Screening assessment performed within 28 days prior to signing of informed consent can be used to confirm eligibility *During Protocol Therapy Sorafenib Arm ONLY During Protocol Therapy SIRT Arm & Sorafenib Arm Study Conclusion *Post Study Conclusio n Follow-Up 4th week (visit 1), 2nd week 8th week (toxicity (Visit 2), assessment) 12th week (Visit 3) 12 weekly thereafter As appropriate 12 weekly k g g g g g a a a a a a a a a a a a Screening/Baseline) Weight Blood Pressure (Systolic & Diastolic) Body Temperature Performance Status ECOG Haematology Leukocytes Platelets Haemoglobin INR Hepatitis Serology Hep Bsag Anti-HCV IgG Hep B Core l Page 52 of 106

54 Antibody IgG (optional) Renal Creatinine Liver Function AST/ALT ALP Total Bilirubin Albumin Pregnancy Test (as appropriate) Tumor Marker Serum AFP a a a a a a a a f On week 12 f f EQ-5D QoL d d Every 12 weeks f Every 12 weeks d CT Chest / Abdomen/ Pelvis or MRI h, i On week 12 c Every 12 weeks c On week 12 i Every 12 weeks i i m m m SIRT-arm ONLY Hepatic Angiogram e b d d e SIRT-arm ONLY Tc-99m MAA Lung Shunt Study e Response Assessment e Sorafenib Arm ONLY Toxicity assessment Dose delay / modification m AE/SAE for the Sorafenib arm will be recorded from the time of signing the ICF until 30 days after the last dose of Sorafenib (or until commencement of the next alternative therapy, whichever is earlier) AE/SAE for the SIRT arm will be recorded from the time of signing the ICF until 30 days post SIRT regardless of causality and for a further 5 months thereafter if judged by the investigator to be causally related to SIRT or Sir-Spheres (or until commencement of the next alternative therapy, whichever is earlier). AE/SAE If the AE/SAE is a Sorafenib or SIRT related toxicity follow-up will continue until resolution. j Survival 1.1 Notes to Study Plan a) Tests and assessments must be performed within 28 days prior to signing of informed consent, at every scheduled visit and study conclusion. Blood tests do not need to be repeated for Study Conclusion Visit if they have been performed within the last 28 days. b) Women of reproductive potential must have a negative urine or serum pregnancy test before commencing protocol treatment. This test should be repeated if pregnancy is suspected during the study. c) Every 12 weeks from the date of randomization until first disease progression. If a Page 53 of 106

55 complete response is detected, then perform a further CT scan 4 weeks later. d) EQ-5D Quality of life questionnaires to be filled out at baseline, while on study, i.e. Week 4, Week 8, Week 12 and every 12 weeks thereafter, at Study Conclusion and 12 weekly during Post Study Conclusion Follow up. EQ-5D Quality of Life questionnaire does not need to be repeated for Study Conclusion if it has been performed within the last 28 days. e) Hepatic angiogram and Tc-99m MAA lung shunt study to be performed after randomization and prior to treatment commencement ONLY for SIRT Arm group. f) Serum AFP to be performed during screening/baseline and every 12 weeks from date of randomization thereafter. Serum AFP does not need to be repeated for Study Conclusion Visit if it has been performed within the last 28 days. g) Concomitant medication to be recorded from screening/baseline up to 30 days post study conclusion (or until commencement of the next alternative therapy, whichever is earlier). h) The same radiological assessment method must be used throughout the study. i) Assessment for tumour response rate to be done every 12 weeks plus at first disease progression. Radiological assessment for tumour response rate to be done every 12 weeks from date of randomization until first evidence of disease progression. j) Patients post study conclusion will be followed up for survival until death every 12 weekly. k) Patients will be considered to have reached study conclusion based on the following: Patient s request for withdrawal, lost to follow-up, death, disease progression,, complete regression, unacceptable toxicity, patient responds to treatment and becomes eligible for surgical resection, liver transplantation or ablative therapy, patient fails MAA/Lung Shunt & Hepatic Angiogram and unable to receive SIR-Spheres therapy. l) If either the Hepatitis B Surface Antigen Test or anti-hcv IgG Test is positive, the other test will be optional. The Hepatitis B Core Antibody IgG Test is optional. m) Sorafenib patients will be contacted at week two to assess treatment related toxicity and interrupt/modify the dose as necessary (according to dose delay and modification guidelines in the protocol). * Denotes visits that may be done either in person or remotely by telephone. 1.2 Window Period The acceptable tolerances in the time points listed in table 1 above are: Week 2 toxicity assessment (Sorafenib arm ONLY) may be +/- 1 week 4 weekly assessments may be +/- 1 week 12 weekly assessments may be +/- 1 week Page 54 of 106

56 1 Study Flow Chart 1 Visit Schedule Following randomization into the study the subject s visit schedule will be calculated using the date of randomization as the reference date. 1.1 During Protocol Therapy Patients for both Sorafenib and SIRT arm will be followed up 4 weekly for the first 3 months and 12 weekly thereafter. Patients in the Sorafenib arm will be contacted at week 2 to assess treatment related toxicity and interrupt/modify the dose as necessary (according to the dose delay and modification guidelines in the protocol). The objective of this visit is to identify adverse events earlier and therefore prevent them becoming more acute. Page 55 of 106

57 Post Study Conclusion Patients post study conclusion will be followed up for survival until death every 12 weekly. Lost to follow up Patients will be considered as Lost to follow up if they are not contactable by phone or or any other means for a period of 6 months from the date of last active visit. 1.4 Patient withdrawal from the study A patient may voluntarily discontinue participation in this study at any time (i.e. consent withdrawal). The investigator may also, at his/her discretion and in the best interest of the patient, discontinue the patient from study treatment while ensuring follow up for survival. In addition, if the study is discontinued or could not be continue due to ethical or other concerns, no further study procedures (including administration of the study treatment) will occur. Information relative to the withdrawal will be documented on both the medical records and ecrf. The investigator will document whether the decision to withdraw from the study was made by the patient or the investigator and the reason responsible for withdrawal both on medical records and ecrf. Page 56 of 106

58 12. RESPONSE ASSESSMENT The following criteria will be used to assess response to treatment and for the evaluation of study end points Overall Survival Overall survival (OS) is defined as the time from the date of randomisation to the date of death due to any cause. All patients will be followed until death Tumour Response Tumour response will be calculated using RECIST (Response Evaluation Criteria In Solid Tumours) criteria (Therasse 2009) RECIST Guidelines Response and progression will be evaluated in this study using the new response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) [European Journal of Cancer (45): , 2009] ( Changes in only the largest diameter (unidimensional measurement) of the tumour lesions are used in the RECIST criteria. For tumour lymph nodes, the short axis must be measured. Note: Lesions are either measurable or non-measurable using the criteria provided below. The term evaluable in reference to measurability will not be used because it does not provide additional meaning or accuracy Measurable disease Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm with conventional techniques (CT, MRI, x-ray) or as > 10 mm with spiral CT scan. All tumour measurements must be recorded in millimeters Non-measurable disease All other lesions (or sites of disease), including small lesions (longest diameter <20 mm with conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all non-measurable Target lesions All measurable lesions up to a maximum of two lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions will Page 57 of 106

59 be calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference by which to characterize the objective tumour response. Lymph nodes with tumour burden will be considered as target lesions if the short axis is > 15 mm. (The short axis is measurement perpendicular to longest measurement of the node assed in plane of measurement) Non-target lesions All other lesions (or sites of disease) should be identified as non-target lesions and should also be recorded at baseline. Non-target lesions include measurable lesions that exceed the maximum numbers per organ or total of all involved organs as well as non-measurable lesions. Repeat measurements of these lesions are not required, but the presence, absence or unequivocal progression of each should be noted throughout the tumour re-assessments. Lymph nodes will be considered as non-target lesions if the short axis is > 10 mm and < 15 mm and considered as normal if the short axis is < 10 mm Guidelines for Evaluation of Measurable Disease All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment. Note: Tumour lesions that are situated in an area previously treated with local therapy ( such as surgery, radiation therapy, hepatic artery therapy, chemo-embolization radiofrequency ablation) can be considered as target lesion if measurable and viable. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during the tumour re-assessments. Imaging-based evaluation is preferred to evaluation by clinical examination when both methods have been used to assess the antitumor effect of a treatment. Clinical lesions. Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. CT and MRI. Spiral CT should be performed using a 3 mm contiguous reconstruction algorithm. This applies to tumors of the chest, abdomen, and pelvis. Head and neck tumors and those of extremities usually require specific protocols. Tumour markers. Tumour markers alone cannot be used to assess response. If markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Specific additional criteria for standardized usage of prostate-specific antigen (PSA) and CA-125 response in support of clinical trials are being developed. Cytology, Histology. These techniques can be used to differentiate between partial responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumour types, such as germ cell tumours, where known residual benign tumours can remain). The cytological confirmation of the neoplastic origin of any effusion that appears or Page 58 of 106

60 worsens during treatment when the measurable tumour has met criteria for response or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease Response Criteria Complete Response (CR): Disappearance of all target lesions associated with the disappearance of all non-target lesions and normalisation of the tumour marker. CR is confirmed if determined by two observations not less than 4 weeks apart. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter of the target lesions, taking as a reference the baseline sum longest diameter, or a CR associated with an abnormal tumour marker and/or persistence of non-target lesions. Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter of the target lesions, taking as a reference the smallest sum longest diameter recorded since treatment started or the appearance of new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for a partial response nor sufficient increase to qualify for progressive disease, taking as a reference the smallest sum longest diameter since the start of treatment. Notes: (1) Elevated serum AFP alone is not sufficient evidence of progression and requires imaging examinations to assess disease progression. (2) As patients may experience downsizing of their HCC and become candidates for surgical resection either during or after protocol treatment, it is possible that undiagnosed disease may be found at the time of attempted resection. For the purpose of defining progressive disease, any disease that is found solely as a result of the patient undergoing surgical resection will not be considered as progressive disease Best Overall Response Best overall response (BOR) is the best tumour response designation over the study as a whole, recorded between the date of randomization and the last tumour assessment for an individual subject in the study Tumour Response Rate Tumour response rate is defined as the number of subjects whose BOR is PR or CR, divided by the total number of subjects in the analysis population Disease Control Rate Disease control rate is defined as the number of subjects whose BOR is PR, CR or SD, divided by the total number of subjects in the analysis population Time to Disease Progression Time to disease progression is defined as the time between randomization and the date of tumour progression at any site in the body. For those who remain alive or died or stop periodic tumour assessments due to any reasons before tumour progression, TDP will be Page 59 of 106

61 censored on the date of last evaluable tumour assessment Progression-Free Survival Progression-Free Survival Overall Progression-free survival overall (PFSO) is defined as the time interval between randomization and the date of tumour progression at any site in the body or death, whichever is earlier. For those who remain alive and have not progressed, PFSO will be censored on the date of last evaluable tumor assessment Progression-Free Survival in the Liver Progression-free survival in the liver (PFSL) is defined as the time interval between randomization and the date of tumour progression in the liver or death, whichever is earlier Health-related Quality of Life Health-related quality of life (HRQoL) is measured by using the EQ-5D questionnaire. The EQ-5D (see Appendix 12) will be collected at baseline, while on study i.e. Week 4, Week 8, Week 12 and every 12 weeks thereafter, at Study Conclusion and 12 weekly during post Study Conclusion Follow-up. If the patient is unable to visit the clinic in person the EQ5D questionnaire may be administered over the telephone instead. EQ-5D questionnaire does not need to be repeated for Study Conclusion if it has been performed within the last 28 days Toxicity and Safety Toxicity will be assessed using the National Cancer Institute Common Terminology Criteria (NCI-CTC) version 4.02 (see Appendix 11). Definitions and requirements for reporting adverse events (AEs) and serious adverse events (SAEs) are detailed in Section Post-study HCC Treatment All subjects after the study conclusion will be asked for whether they have received any HCC related treatment (liver transplantation, liver resection, RFA, TACE, SIRT, Sorafenib, other clinical trials, other treatment). Page 60 of 106

62 13. STATISTICAL CONSIDERATIONS AND METHODOLOGY Study Design and Sample Size: This Phase III study will be conducted as an international, multi-centre, randomised controlled clinical trial by the Asia Pacific Hepatocellular Carcinoma Trials Group that will assess the safety and efficacy of SIRT compared to sorafenib for the first-line treatment of patients with primary HCC in whom surgical resection is not feasible. The total trial size will be 360 patients (180 per group). From the data provided by Kang et all 2008 and Sangro et all 2010, we assume a median survival time of 9.35 months for patients treated with Sorafenib and 14 months for patients treated with SIR-Sphere, in patients with locally advanced HCC. This represents the minimum clinically meaningful difference to be detected. Group-sequential methods are used to determine the sample size and study duration. Two interim analyses and a final data analysis are planned to occur at equally spaced intervals after one-third, two-thirds and all of the planned number of deaths (events) have been reported. The planned sample size is determined assuming the use of a 2-sided log rank test with type I error of 0.05, statistical power of 90%, and an O Brien-Fleming boundary, as specified using the Lan-DeMets type I error spending function. A dropout rate of up to 20% is also factored into the computations. The study duration is anticipated to be 5 years; with 3 years of accrual and 2 years of follow-up. The planned interim efficacy analyses are to occur after 87 and 174 deaths have been reported, with the nominal critical points for these interim analyses (and p-values) being (p<0.0001) and (p=0.006). The final analysis will be performed after 260 reported deaths with a nominal critical point of 93 (p=0.0231). An independent Data and Safety Monitoring Committee (DSMC) will be established to review and make recommendations based on the interim results of the study. Calculations were done with EAST Version 5 (East-5, Cytel Software Corporation, Cambridge, MA, USA). Stratification and Randomisation: Stratified block randomization will be carried out, with stratification by: 1. Institution 2. Absence/presence of branch portal vein thrombosis A randomization list will be prepared by the Study Statistician from the Singapore Clinical Research Institute (SCRI), and from which eligible patients will be assigned to Sir-Sphere or Sorafenib. The allocation ratio will be 1:1 between the two groups. Block randomization with size to be determined by the SCRI statistician will be used so as to help ensure a balanced number of patients in the two groups. There will be no blinding for the study. Implementation of the randomization will be carried out by using the SCRI web-based randomization program. Back up randomization envelopes will be provided to each site in case of internet failure. Page 61 of 106

63 13.1 Statistical Analysis Primary and secondary objectives will be analysed with patients being included in the treatment group to which they were randomised (i.e. the intention-to-treat principle). For the primary objective, survival curves will be constructed using the Kaplan-Meier method with a log rank test used to test the null hypothesis of no difference in overall survival between the two groups. The hazard ratio (HR) and its corresponding 95% confidence interval (CI) will be computed with the Cox proportional hazards model used to adjust the HRs for the trial stratification factors. For the secondary objectives of time to disease progression, progression-free survival overall and progression-free survival in the liver, HR and its corresponding 95% CI and Kaplan-Meier plot will again be computed in a similar manner as for the primary endpoint. For the purpose of evaluating the tumour response rate and disease control rate, Chi-square test or Fisher exact test will be applied to compare the statistical significance of the two groups as appropriate. The rate of down-staging to surgical resection, radio-frequency ablation or transplantation will be analyzed in a similar manner as for tumour response rate. HRQoL data will be analyzed using a mixed model approach and follow the guidelines of the EQ-5D questionnaire. Appropriate graphical representation will be used to describe changes in these scores over time. All laboratory samples must be determined within an accredited facility. All CT scans will be independently assessed in a blinded fashion prior to any statistical outcomes being determined. Page 62 of 106

64 14. DEVIATIONS/AMENDMENTS OF THE STUDY PROTOCOL 14.1 Deviations from the Study Protocol The Investigator will record any deviation from the study protocol and provide an explanation for such a deviation. Deviations shall be reviewed to determine if the study protocol requires amendment or if the study requires termination. Reasons for withdrawal and/or discontinuation of any patient from the study will be recorded. If the discontinuation is related to toxicity or lack of effectiveness, the patient will still be followed in the study, wherever possible. Where relevant, the Ethics Committee and/or regulatory authority will be notified of any deviations Amendments to the Study Protocol All amendments to the study protocol will be approved by the Steering Committee and modifications will be recorded with a justification for the amendments Early Stopping Due to Toxicity Notwithstanding the potential benefit of treatment, if excess toxicity is observed, then this may provide grounds for treatment modification, dose reduction or stopping the study earlier than planned. Based on the charts given in Mehta and Cain, and based on a 95% confidence boundary using a non-informative prior (or based on a one-sided 95% binomial confidence interval), consideration to adjust the dose of study treatment will be made if any of the following number of events are evident. Total number of patients entered in each arm Maximum number of grade 3/4 toxicities (within first 4 weeks) 15/20 27/40 39/60 Thus, if for example, after 40 patients have been accrued into each arm, if 27 or more grade 3/4 events are observed, then consideration will be given to adjusting the dose of study treatment based on safety considerations. These toxicities will be reviewed by an Independent Data Safety Monitoring Committee (DSMC). Page 63 of 106

65 15. REGULATORY & REPORTING REQUIREMENTS 15.1 Definitions Adverse Event An adverse event (AE) is defined by ISO :2003 as any untoward medical occurrence experienced by a patient and which does not necessarily have a causal relationship with any component of the study treatment. An adverse event can be any sign, abnormal laboratory value, symptom or diagnosis/disease that is unfavourable or unintended, that is new, or if pre-existing, worsens in a patient, and that may or may not be related to the study treatment. 15. Serious Adverse Event A serious adverse event (SAE) is defined by ISO :2003 as an adverse event that: a) led to a death, or b) led to a serious deterioration in the health of the patient that 1) resulted in a life-threatening illness or injury, 2) resulted in a permanent impairment of a body structure or a body function, 3) required in-patient hospitalisation or prolongation of existing hospitalisation, 4) resulted in medical or surgical intervention to prevent permanent impairment to body structure or a body function, or c) led to foetal distress, foetal death or a congenital abnormality or birth defect. 15. Unexpected Adverse Drug Reaction An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g. investigator s brochure for an unapproved investigational product or package insert/summary of product characteristics for an approved product) Study Safety Recording Sorafenib All adverse events for subjects in the Sorafenib arm will be recorded from the time of signing of the Informed Consent Form until 30 days after the last dose of Sorafenib (or until commencement of the next alternative therapy, whichever is earlier). If the adverse event is a Sorafenib related toxicity, follow-up will continue until resolution SIR-Spheres All adverse events for subjects in the SIRT arm will be recorded from the time of signing the Informed Consent Form until 30 days post SIRT regardless of causality, and for a further 5 months thereafter if judged by the investigator to be causally related (definitely, probably or possibly) to SIRT or Sir-spheres (or until commencement of next alternative therapy, whichever is earlier). If the adverse event is a SIRT related toxicity, follow-up will continue until resolution. Page 64 of 106

66 General All adverse events and serious adverse events will be recorded on adverse event form and serious adverse event form respectively of subject case report form and on medical records. Grade of Adverse Events should be judged by Site Investigator as per latest CTCAE guidelines and recorded on medical records and ecrf. Treatment of any AEs or SAEs is at the sole discretion of the investigator and according to current good medical practice. Any medication administered for the treatment of an AE or SAE should be recorded in the patient s medical records and on ecrf. If an SAE is unresolved when a patient permanently discontinues the study, the patient must be followed until the SAE resolves or the clinical course is stabilised Exceptions Disease progression, which is part of the natural course of the disease under study, is one of the Secondary Endpoints of the study. Death due to progressive disease is to be recorded on the Death Form but not as an SAE. Death due to any other event (not related to the disease) should be captured and reported as an SAE Safety Reporting In order to adhere to all applicable laws and regulations for reporting serious adverse events (SAE), the Investigator must formally notify ALL SAEs within 24 hours of becoming aware of it to the following: a) Institutional IRB/Ethics Committee (where applicable) b) Regulatory Authorities (where applicable) c) Protocol Chair Pierce KH Chow FRCSE PhD Dept of General Surgery Singapore General Hospital Fax: Duke-NUS Graduate Medical School Singapore Fax: d) AHCC Trial Group Singapore Clinical Research Institute Pte Ltd Fax: SAEs of all SIRT arm patient(s) should be reported to the following: e) Device Manufacturer Clinical Department Sirtex Technology Pty. Ltd. address: qa@sirtex.com Page 65 of 106

67 15.4 Pregnancy During the Study Protocol therapy must be discontinued immediately in the event of pregnancy in a female patient enrolled in this study. The investigational site must report the pregnancy to the Protocol Chair, Sirtex Technology Pty. Ltd. and to Singapore Clinical Research Institute Pte Ltd within 24 hours of becoming aware of the pregnancy. Reporting of pregnancy also applies to pregnancies following the administration of the investigational product to the father. The outcome of the pregnancy should be followed to term. Page 66 of 106

68 16. ETHICAL CONSIDERATIONS This study will be performed in accordance with ISO which includes a requirement to operate in accordance with the World Medical Association Declaration of Helsinki (see Appendix 14). The Investigator must comply with all instructions, regulations and agreements in this study protocol, using applicable ICH-GCP guidelines. The Investigator must additionally ensure that the study is conducted in accordance with all applicable local regulations. All participating institutions must obtain approval from their institution s Human Research Ethics Committee Informed Consent Written informed consent is required prior to randomisation. The consent form is filed in the patient record. Patients will be given a full explanation, in lay terms, of the aims of the study and the potential benefits as well as the possible side effects and risks involved. It will be explained that they may refuse to take part in, or withdraw from the study without prejudice to their future care and treatment. Written informed consent will be obtained from all patients prior to study entry. Consent to participate in this study will be obtained from the patient both verbally and in writing. In the case where the patient is not fluent in English an interpreter will be present during the consenting process. Patients will be issued with a copy of the information provided and their consent to participate in the study. All Informed Consent Documents used in this study must be approved by the relevant Human Research Ethics Committee and Regulatory Authority of the country (if applicable) Confidentiality All patient data collected as a part of this study will be treated according to ISO :2003 Part 6.5 Confidentiality concerning the protection of patient information at all times. All data generated from this study will remain confidential and no published report will contain any reference to patient identifiable data Changes to Final Study Protocol All study amendments must be submitted to the relevant Human Research Ethics Committee. Study modifications that impact patient safety, the scope of the study, or affect the scientific quality of the study must be approved by the Ethics Committee. In the event of a study protocol modification, the Informed Consent Document may require similar modifications. Page 67 of 106

69 17. PUBLICATION POLICY The results of this study will be published. All publications will be overseen by the Steering Committee which has been established to support the Principal Investigator of this study in all aspects regarding the scientific conduct of the study and the publication of results. Any publication will be reviewed prior to submission by Sirtex Technology Pty Ltd, but as this is an Investigator Initiated Study, the Steering Committee will make the final decisions on all matters pertaining to publications. Publication of subgroup data and single center data shall not be performed until the complete study has been published. Publication of single centre data is the responsibility of each individual participating centre. The information regarding the study protocol will be made available on a publically searchable database of clinical trials at: Page 68 of 106

70 18. ADMINISTRATIVE PROCEDURES 18.1 Site Initiation Visit The Investigator must not enrol any patients prior to completion of a site initiation visit conducted by the Principal Investigator or his/her designee. The site initiation visit will include a detailed review of the study protocol and procedures with study-associated site personnel Investigator File The Investigator will be provided with an Investigator File. This file should be used for filing all study-related documents. The Investigator will be responsible for keeping the Investigator File updated and for ensuring that all required documents are filed during and after the study. The Investigator File will be inspected during monitoring visits and will remain with the Investigator for 15 years after study closure Monitoring of the Study During the course of the study, the Principal Investigator s clinical research associate (CRA) or designee will visit the site at regular intervals by prior arrangement. The monitoring visits must be conducted according to the applicable ISO and ICH-GCP guidelines to ensure adherence to the study protocol, quality of data, compliance with regulatory requirements, and continued adequacy of the site and its facilities. During these visits, CRFs and other data related to the study will be reviewed and any discrepancies or omissions will be resolved. The CRA will be given access to relevant source documents (including medical records) to enable source data verification Quality Assurance During and/or after completion of the study, quality assurance officers named by the study Principal Investigator or regulatory authorities may wish to perform on-site audits. The Investigator and site personnel will be expected to cooperate with any audit and to provide assistance and documentation (including source data) as requested. The Investigator and site personnel will immediately inform the study Principal Investigator of any audit to be performed by a regulatory authority Study Funding This investigator-initiated study is supported by National Medical Research Council (NMRC), Singapore and Sirtex Technology Pty. Ltd Study Completion The Ethics Committee must be notified of completion or termination of this study in a timely manner. The site Investigator must provide a final clinical summary report to the Ethics Committee and maintain in the Investigator File an accurate and complete record of all submissions made to the Ethics Committee. Page 69 of 106

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73 Asia-Pacific with Hepatocellular Carcinoma: Subgroup analysis of effect or macroscopic vascular invasion, extra-hepatic spread and ECOG performance status on Outcome. In: 59th Annual Meeting of the American Association for the Study of Liver Diseases; 2008 Oct 31 - Nov 4; San Francisco; Kang Y, Guan Z, Chen Z, Tsao,C, Qin S, Kim J.S, Burrock K, Zou J, Voliotis D, Cheng A. Sorafenib Is Effective In Patients From The Asia Pacific Region With Hepatocellular Carcinoma (Hcc): Subgroup Analysis Of Macroscopic Vascular Invasion (Mvi), Extrahepatic Spread (Ehs), And Ecog Performance Status. Annals of Oncology Abstract 2008; 19: Supplement 8: 177) Kemeny N, Daly J, Oderman P et al. Hepatic artery pump infusion: toxicity and results in patients with metastatic colorectal carcinoma. J Clin Oncol. 1984; 2(6): Kennedy A, Coldwell D, Nutting C et al. Resin 90Y-microsphere brachytherapy for unresectable colorectal liver metastases: Modern USA experience. Int J Radiation Oncology Biol Phys. 2006; 65: Kennedy A, Nutting C, Coldwell D, et al. Pathologic response and microdosimetry of 90Y microspheres in man: review of four explanted whole livers. Int J Radiation Oncology Biol Phys 2004; 60: Kjellstrom J, Kjellen E, Johnsson A. In vitro radiosensitization by oxaliplatin and 5-fluorouracil in a human colon cancer cell line. Acta Oncol. 2005; 44: Lau W, Leung W, Ho S et al. Treatment of inoperable hepatocellular carcinoma with intrahepatic arterial yttrium-90 microspheres: a phase I and II study. Brit J Cancer 1994; 70: Lau YW, Ho S, Leung WT et al. Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intraarterial infusion of 90Yttrium microspheres. Int J Radiation Oncology Biol Phys 1998; 40: Leung T, Lau W, Ho S et al. Radiation pneumonitis after selective internal radiation treatment with intra-arterial tumour-microspheres for inoperable hepatic tumours. Int J Radiation Oncology Biol Phys 1995; 33; Lewandowski RJ, Kulik LM, Riaz A, et al. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization. Am J Transplant 2009;9: Liu D, Salem R, Bui J et al. Angiographic considerations in patients undergoing liver-directed therapy. J Vasc Inter Radiol. 2005; 16: Llovet JM, Ricci S, Mazzaferro V et al. Sorafenib in advanced hepatocellular carcinoma. New Engl J Med 2008; 90: Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359: Page 72 of 106

74 Llovet JM, Fuster J, Bruix J. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl 2004;10:S Louvet C, de Gramont A. Colorectal Cancer: Integrating Oxaliplatin. Current Treatment options in Oncology 2003; 4: Machover D. A comprehensive review of 5-fluorouracil and leucovorin in patients with metastatic colorectal carcinoma. Cancer 1997; 80: Machover D, Diaz-Rubio E, de Gramont et al. Two consecutive phase II studies of oxaliplatin for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines. Ann Oncol, 1996; 7: McGlynn KA, Tsao L, Hsing AW, Devesa SS, Fraumeni JF, Jr. International trends and patterns of primary liver cancer. Int J Cancer 2001;94: Meta-analysis group in cancer. Reappraisal of hepatic arterial infusion in the treatment of non-resectable liver metastases from colorectal cancer. J. Natl. Cancer Inst. 1996; 88: Meade V, Burton M, Gray B et al. Distribution of different sized microspheres in experimental hepatic tumours. Eur J Clin Oncol. 1987; 23: Metha C and Cain K. Charts for the Early Stopping of Pilot Studies. Am J Clin Oncol, 1984; 6: Nowak AK, Chow PK, Findlay M. Systemic therapy for advanced hepatocellular carcinoma: a review. Eur J Cancer 2004;40: Pawarode A, Tangkijvanich P, Voravud N. Outcomes of primary hepatocellular carcinoma treatment: an 8-year experience with 368 patients in Thailand. J Gastroenterol Hepatol 2000;15: Poon D, Anderson BO, Chen LT, et al. Management of hepatocellular carcinoma in Asia: consensus statement from the Asian Oncology Summit Lancet Oncol 2009;10: Poon MA, O Connell MJ, Moertel C et al. Biochemical modulation of Fluorouracil;evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 1989; 7: ). Raymond E, Buquet-Fagot C, Djelloul S et al. Antitumour activity of oxaliplatin in combination with 5-fluorouracil and the thymidylate synthase inhibitor AG337 in human colon, breast and ovarian cancers. Anticancer Drugs 1997; 8: Ryan D. Rectal cancer: integrating oxaliplatin into chemoradiation studies. Oncology (Huntingt). 2000; 14: Page 73 of 106

75 Salem R, Lewandowski R, Mulcahy M et al. Radioembolization for hepatocellular carcinoma using yttrium-90 microspheres: A comprehensive report of long-term outcomes. Gastroenterology, 2010; 138: Sangro B.; Carpanese L; Cianni R; Golfieri R; Gasparini D; Ezzidin S; Hoffmann R; Fiore F on behalf of ENRY, European Network on Radioembolization with 90Y resin microspheres European multicenter evaluation of survival for patients with HCC treated by radioembolization [RE] with 90Y-labelled resin microspheres. In: Presentation at the proceedings of The Association of Clinical Oncology Gastrointestinal Cancer January 22nd-25th; Orlando, Florida, USA; 2010 Sangro B, Cianni R, Ezziddin S, et al. Predictors of survival following radioembolization using 90Y-labeled resin microspheres in unresectable hepatocellular carcinoma (HCC): Results from a European multi-center evaluation. In: 60th Annual Meeting of the American Association for the Study of Liver Diseases October 30th November 3rd,; Boston, USA; 2009 Sangro B, Bilbao JI, Boan J et al. Radioembolization using 90Y- resin microspheres for patients with advanced hepatocellular carcinoma. Int J Radiation Oncology Biol Phys 2006; 66, Scheele J, Stangl R, Altendorf-Hofmann A. Hepatic metastases from colorectal carcinoma: Impact of surgical resection on the natural history. Br J Surg 1990; 77: Sharma R, van Hazel G, Blanshard K et al. Internal Radiation Treatment of Liver Metastases From Colorectal Cancer With Concomitant Systemic Radiosensitizing Chemotherapy, WCGI. Barcelona, Silverberg E. Cancer Statistics CA Cancer J Clin. 1977; 27(1): Stangl R, Altendorf-Hofmann A, Charnley RM et al. Factors influencing the natural history of colorectal liver metastases. Lancet, 1994; 343: Stubbs R, O'Brien I, Correia M. Selective Internal Radiation Therapy with 90Y Microspheres for colorectal liver metastases: single-centre experience with 100 patients. ANZ J Surg. 2006; 76: Stubbs R, Wickremesekera S. Selective internal radiation therapy (SIRT): a new modality for treating patients with colorectal liver metastases. HPB 2004; 6: Therasse P, Arbuck S, Eisenhauer E et al. New guidelines to evaluate the response to treatment in solid tumours. Journal of the National Cancer Institute, 2000; 92: Turitto G, Panelli G, Frattolillo A et al. Phase II study of neoadjuvant concurrent chemoradiotherapy with oxaliplatin-containing regimen in locally advanced rectal cancer. Front Biosci. 2006; 11: Van Hazel G, Blackwell A, Anderson J, et al. Randomised phase 2 trial of SIR-Spheres plus Fluorouracil/Leucovorin chemotherapy versus Fluorouracil/Leucovorin Page 74 of 106

76 chemotherapy alone in advanced colorectal cancer. J Surg Oncol. 2004; 88: Van Hazel G, Blanshard K, Steward W, et al. Selective Internal Radiation Therapy (SIRT) Plus Systemic Chemotherapy with Oxaliplatin, 5-Fluorouracil and Leucovorin: A Phase I Dose Escalation Study. ASCO GI Symposium, Van Hazel G, Pavlakis N, Goldstein D, et al. Selective Internal Radiation Therapy (SIRT) plus systemic chemotherapy with Irinotecan. A phase I dose escalation study. ASCO GI Symposium Van Hazel G, Pavlakis N, Goldstein D, et al. SIR-Spheres plus systemic chemotherapy with irinotecan-based treatment arms. Interim report on a phase I dose escalation study. Clinical Oncology Society of Australia. Canberra; Vietti J, Eggerding F, Valeriote E. Combined effect of radiation and 5FU on survival of transplanted leukemia cells. J Nat Cancer Inst. 1971, 47: Walsh L, Poston G. The potential to increase curative liver resection rates in metastatic colorectal cancer. Eur J Surg Oncol 2002; 28(8): Welch J, Donaldson G. The clinical correlation of an autopsy study of recurrent colorectal cancer. Annals of Surgery. 1979; 189: WHO handbook for reporting results in cancer treatment. Geneva (Switzerland): World Health Organisation Offset Publication No.48; Wong C, Savin M, Sherpa K, et al. Regional Tumour Microsphere Treatment of Surgically Unresectable and chemotherapy-refractory Metastatic Liver Carcinoma. Cancer Biotherapy & Radiopharmaceuticals. 2006; 21: Woynarowski J et al. Mechanisms of action of Oxaliplatin: oxaliplatin-induced lesions in cellular DNA; San Antonio (TX): Institute for Drug Development Report; 1997 Jan. Research Report. Page 75 of 106

77 APPENDIX 1 ECOG Performance Status (Definitions) ECOG Performance Status Patient Description 0 Fully active, able to carry on all pre-disease performance without restriction. 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 Dead. APPENDIX 2 Child-Pugh-Turcotte Prognostic Criteria 1 Point 2 Points 3 Points > < 2.8 <2 2 3 >3 Ascites None Minimal Moderate Encephalopathy None Grade 1-2 Grade 3 4 <4 4 6 >6 < 2.3 > 2.3 Albumin (g/dl) Bilirubin (mg/dl) PT (sec prolonged) OR INR Child s A: Child s B: Child s C: 5 6 Points 7 9 Points Points Page 76 of 106

78 APPENDIX 3 HCC Staging Classifications BCLC Staging Classification Adapted from A. Forner, J. M. Llovet, J. Bruix, Lancet 2012; 379: Staging Performanc e Status (ECOG) Stage 0: very early stage# 0 Stage A: early stage# 0 Stage B: intermediate stage 0 Stage C: advanced stage 1-2* Stage D: terminal stage# 3-4** Tumour Status Single <2cm Single or 3 nodules <3 cm Large multinodular Portal invasion Extrahepatic spread * Any Liver Functional Status Child-Pugh A Child-Pugh A-B Child-Pugh A-B Child-Pugh A-B Child-Pugh C** # Patients classified as stage 0, A and D at baseline are not eligible for the AHCC06 Trial. Stage A and B: All criteria should be fulfilled. Stage C: At least one criteria*: ECOG 1-2 or Portal invasion or extrahepatic metastasis Stage D: At least one criteria**: ECOG 3-4 or Child-Pugh C. Okuda Classification of HCC A. V. C. Franca, J. E. Junior, B. L. G. Lima, A. L. C. Martinelli, F. J. Carrilho, Brazilian Journal of Medical and Biological Research (2004); 37: Tumour Size Ascites Serum Albumin Bilirubin Negative <50% of liver Absent >3 g/dl <3 mg/dl Positive >50% of liver Present <3 g/dl >3 mg/dl Okuda I: No positive factor Okuda II: 1 or 2 positive factors Okuda III: 3 or 4 positive factors Page 77 of 106

79 TNM Staging AJCC/UICC 7th Edition Page 78 of 106

80 APPENDIX 4 SIR-Sphere Package Insert Page 79 of 106

81 Page 80 of 106

82 APPENDIX 5 Technique for Administration of SIR-Spheres SIR-Spheres are administered by injection through a trans-femoral catheter into the hepatic artery. As there are frequent arterial anomalies in the blood supply to the liver, the radiologist must be familiar with those anomalies. Only radiologists that have received formal training and have been approved by Sirtex may participate in this study and administer SIRT. All areas of tumour within the liver are to be targeted with SIR-Spheres and this usually involves treating both lobes of the liver. However, it is essential that the SIR-Spheres are not delivered to other organs such as the duodenum, stomach, pancreas etc. If the metastases are limited to only one lobe, the radiologist can insert the catheter selectively into the lobar artery supplying only that lobe that contains the metastases. The SIR-Spheres will then be delivered only to the lobe containing the metastases with sparing of the other normal lobe. This is an excellent way of delivering high doses of radiation to the tumour without any chance of damaging the normal liver. It is most important to inject the SIR-Spheres slowly into the hepatic artery. If they are injected too quickly they may reflux back down the hepatic artery and lodge in the pancreas, stomach and other organs. The following principles dictate where the catheter is placed when delivering SIRT: Treat only those parts of the liver that contain tumour. If possible then try and not treat some normal liver parenchyma from SIRT. Even a small amount of normal liver that remains untreated provides extra protection against the possibility of radiation hepatitis. Review with extreme vigilance the pre-treatment angiogram to look for anatomical abnormalities. Never allow SIR-Spheres to enter any vessel supplying the gut. Always inject SIR-Spheres slowly with repeated fluoroscopy to check the position of the catheter and to look for slowing of blood flow and possible reflux of SIR-Spheres. Dealing with Anatomical Anomalies Note: Inadvertent injection of SIR-Spheres into small arteries passing from major arteries vessels in the hilum of the liver to the stomach and duodenum is by far the commonest cause of serious adverse events. These small aberrant vessels are NOT described in the standard anatomy texts and the cause of these SAEs is because the radiologists do not recognise these small vessels and allow SIR-Spheres to flow to the gut. Radiologists are referred to the review article of Liu et al, 2005 (below) attached to this protocol for an additional comprehensive description of how to administer SIRT. If there is a dual blood supply to the liver, then the radiologist will have to catheterise each artery separately to inject the SIR-Spheres if there is tumour in both lobes. If there is only Page 81 of 106

83 tumour in one lobe, then the radiologist only needs to inject the SIR-Spheres into that side of the liver. For instance, if all the metastases were in the right lobe of the liver and there was an accessory right hepatic artery arising from the superior mesenteric artery, then injecting all the SIR-Spheres into this accessory right hepatic artery would deliver all the radiation to metastases in the right lobe where it is wanted. If there are separate right and left arteries and there are metastases in both right and left lobes, then it is necessary to inject some of the SIR-Spheres separately into both arteries in order to deliver radiation to the metastases in both lobes. The following anomalies in vascular supply must be noted: 1 In 20% of patients there will be an accessory right hepatic artery arising from the superior mesenteric artery (see diagram b below). This accessory right hepatic artery will supply most of the right lobe of liver and is easily demonstrated on an angiogram. If present, it must be accessed to deliver SIR-Spheres to the right lobe of the liver as well as the main hepatic artery, otherwise the radiation will not be delivered to metastases in the right lobe of the liver. 2 In 17% of patients an accessory left hepatic artery will arise from the left gastric artery (see diagram c below). This accessory left artery is usually difficult to demonstrate on an angiogram, and is often not recognised at the time of angiography. It is usually possible to get a co-axial catheter into this artery if it is necessary to deliver SIR-Spheres to the left lobe of the liver. If there is no tumour in the left lobe then it can be ignored. 3 In a minority of patients the gastro-duodenal artery arises from the main hepatic artery distal to the origin of the left hepatic artery. It is imperative that the SIR-Spheres not be delivered into the gastro-duodenal artery, as this will result in the SIR-Spheres lodging in the duodenum and pancreas with severe side effects. In this situation the gastro-duodenal artery should be embolised to occlude it before administering the SIR-Spheres into the hepatic artery. Page 82 of 106

84 MAJOR VARIATIONS IN ARTERIAL BLOOD SUPPLY TO THE LIVER a (50%) In the normal setting the gastro-duodenal (GD) artery comes off the common hepatic artery proximal to the bifurcation into the right hepatic (RH) and left hepatic (LH) arteries. The left gastric (LG) and splenic (SPL) arteries come off the celiac axis separately. b: (20%) When the right hepatic artery is replaced the whole blood supply to the right lobe comes off the superior mesenteric artery (SMA). In the case of an accessory right hepatic artery, the vasculature off the celiac axis is normal but there is an additional right hepatic artery off the superior mesenteric artery. c: (17%)When the left hepatic (LH) artery is replaced, the whole blood supply to the left lobe comes off the left gastric (LG) artery. In the case of an accessory left hepatic artery the vasculature of the common hepatic artery is normal but there is an additional left hepatic artery off the left gastric artery. d: (3%) In this situation the entire common hepatic artery arises from the superior mesenteric artery e: (9%) A trifurcation occurs when the bifurcation of the left hepatic and right hepatic arteries occurs at the same spot as the take off of the gastro-duodenal (GD) artery. Page 83 of 106

85 APPENDIX 6 Purpose: Agent: Dose: Equipment: Administration: Imaging: Analysis: Interpretation: Nuclear Medicine Tc-99m MAA Lung Shunt Study To assess arterial perfusion of the liver and the fraction of radiopharmaceutical tracer that will pass through the liver and lodge in the lungs. Technetium-99 labelled MAA (Macro-aggregated Albumin) 185MBq Any large FOV gamma camera with SPECT capability The patient needs to have a trans-femoral catheter placed in the hepatic artery. The Technetium 99 labelled MAA is injected through the catheter into the hepatic artery by a qualified physician. Depending on the hepatic arterial anatomy, the radiotracer may be injected via the main hepatic artery or apportioned as separate injections to different arteries supplying the liver or liver tumours. The patient is positioned supine under the gamma camera and the images recorded. Planar images: 4 frames; 300 / frame. at least 128 x 128 matrix Word mode. Image anterior and posterior abdomen Image anterior and posterior thorax SPECT imaging of the liver or SPECT/CT (if available): to provide quantitative data for partition model dose calculation Draw ROI around whole of liver and whole of lung fields. Calculate Geometric mean for liver region and lung region. Calculate Lung/liver ratio If lung/liver ratio is >20% and the Partition Model cannot be used to adjust the prescribed activity so that radiation absorbed dose to the lungs does not exceed 20 Gy, the patient is not eligible for SIR-Spheres therapy. Page 84 of 106

86 APPENDIX 7 SIR-Spheres Radiation Absorbed Dose/Activity Calculation Procedure The step-by-step procedures required for calculation of the various dosimetric parameters using the partition model are as follows (see section above for details on the derivation of the various partition model formulas): 1. Perform a contrast-enhanced CT scan of the liver no more than one month before scheduled date of treatment with SIR-Spheres. 2. From the CT scan of the abdomen, obtain volume estimates of the entire liver, V total (right and left hepatic lobes, including tumour) and tumour, Vtumour, and normal liver, Vliver = Vtotal Vtumour. Calculate masses from volumes: Mtotal, Mtumour or Mliver = Vtotal, Vtumour or Vliver in cc 1.03 g/cc 3. Following hepatic arterial infusion of 4 mci 99mTc MAA, estimate percent lung shunting (L) from a nuclear medicine break-through scan, consisting of planar imaging of the liver and lung fields (in the same image) in anterior (A) and posterior (P) projections ( matrix, k counts). Regions of interest (ROIs) are drawn around the total liver (including tumour) and both lungs on the A image, and mirrored onto the P image. Percent lung shunting, L, is calculated as 100 times the ratio of geometric mean total counts in the lung ROIs ([NlungA NlungP]1/2) to that of liver plus lungs ([NliverA NliverP]1/2 + [NlungA NlungP]1/2). 4. Immediately following the break-through scan, perform 99mTc MAA SPECT imaging of the liver ( matrix, 120 views over 360º, 20 sec/view, with attenuation correction), to estimate the SIR-Spheres microspheres tumour-to-normal activity ratio (activity per unit mass of the organ or tissue, R). The value R represents the ratio of concentrations of SIR-Spheres microspheres in the tumour and normal liver compartments after delivery into the hepatic artery, corrected for any SIR-Spheres microspheres that are shunted to the lungs calculated from the nuclear medicine break-through scan. For up to five (5) of the largest tumours visible in the SPECT volume, in the transaxial SPECT slice demonstrating the largest tumour size, regions of interest (ROI) are drawn around the tumour and adjacent normal liver. For each tumour-normal liver pair, R is calculated as the ratio of the ROI average counts per pixel (Ctumour / Cliver), and an average of the one to five R values calculated (Ravg). The counts per pixel in a SPECT image corrected for attenuation (ignoring the partial volume effect) is directly proportional to activity per unit mass, and thus can be used as a surrogate. 5. Determine the total activity to be administered to the patient, considering that the maximum tolerated radiation absorbed dose in normal liver (Dliver) would be 70 Gy (50 Gy in the case of cirrhosis): AtotalLiver = Dliver ([Ravg Mtumour] + Mliver) / [ (1 [L/100]) ] 6. Determine the total activity to be administered to the patient, considering that the maximum tolerated dose in the lungs (Dlung) would be 20 Gy (assuming Mlung = 1000 g): Page 85 of 106

87 Atotal Lung = (20 Gy 1000 g / 49670) (100 / L) If Atotal Lung is less than Atotal Liver, then the total activity to be administered, Atotal, will be reduced from Atotal Liver to Atotal Lung, in order not to exceed 20 Gy in the lungs. In that case, the estimated dose in normal liver is calculated as: Dliver = Atotal Lung [ (1 [L/100]) ] / ([Ravg Mtumour] + Mliver) 7. The expected dose (in Gy) in the tumour mass may be estimated from the total activity to be administered: Dtumour = Atumour / Mtumour where Atumour = Atotal (1 [L/100]) / (1 + [Mliver / (Ravg Mtumour)]) Page 86 of 106

88 APPENDIX 8 Example SIR-Spheres Radiation Absorbed Dose/Activity Calculation Suppose a patient has a single (to make it simple) tumour mass in the liver. The total mass of the liver is calculated from contrast enhanced CT scan to be 2100g and of the tumour mass 300g (obtained from estimated volumes using the formula: mass = volume in cc 1.03 g/cc). The normal liver mass would then be = 2100g 300g = 1800g. After drawing ROIs around normal liver and the tumour mass from the transaxial SPECT image that best demonstrates the tumour mass (slice with the largest diameter of tumour mass), suppose the average counts per pixel in the tumour ROI is 3500, and for the liver it is 500. The tumour-to-normal activity ratio R would be = 3500 / 500 = 7 Also, suppose that lung shunting is 5%. 20 Gy 1000 (100/5) Total activity from Eq. 6 = = 8.1 GBq Gy [(7 300) ] Total activity from Eq. 8 = = = 5.8 GBq (1 [5/100]) The total activity based on lung dose is greater than that based on normal liver, so 5.8 GBq of activity would deliver an estimated 80 Gy to normal liver. However, since the maximum allowable activity to be administered at any one treatment is capped at 3.0 GBq, this is the final amount of activity that would be administered. The estimated dose delivered to the lungs from 3.0 GBq using Eq. 6 would be: Lung dose = = = 7.5 Gy 1000g (100/5) The total activity in the tumour can be calculated from Eq. 10: 3.0 GBq (1 [5/100]) 2.85 Activity in tumour = = = GBq (1 + [1800g / (7 300g)]) 6 The estimated dose delivered to the tumour from Eq. 11 would be: GBq Dose to tumour = = 254 Gy 300g Page 87 of 106

89 APPENDIX 9 SIR-Spheres Administered Activity Calculation Tables The following document provides patient dosing information and is for the Interventional Radiologist and Authorised User performing the SIRT procedure. Note: These tables replace all previous formulae that have been used in previous trials. Note that the dose to be administered is the maximum total dose for treatment of the whole liver. If treatment is restricted to one lobe of the liver then the dose should be decreased to account for the size of the lobe as a fraction of the total liver size. The exception to this rule is that if the SIR-Spheres are to be delivered by super-selective catheterisation ONLY to the tumour and not to the normal liver parenchyma, then there is no upper limit of dose that can be delivered, provided the radiation dose to the lungs is kept to a tolerable level. To determine the amount of activity of SIR-Spheres to be implanted the Interventional Radiologist will need to know the following information about the patient to be treated: 1. Lung break-through (%) 2. Body Surface Area (BSA) 3. Tumour Involvement (%) The appropriate chart, as determined by the lung breakthrough, can then be cross-indexed in order to calculate the activity of SIR-Spheres (GBq) to be implanted. The 3 charts that follow are all based on different lung breakthrough percentages. These are: Chart 1: 0 10% lung breakthrough Chart 2: 11 15% lung breakthrough Chart 3: 16 20% lung breakthrough If lung/liver ratio is >20% and the Partition Model cannot be used to adjust the prescribed activity so that radiation absorbed dose to the lungs does not exceed 20 Gy, the patient is not eligible for SIR-Spheres therapy. Page 88 of 106

90 Administered Dose Calculator (GBq) 0-10% Lung Break-Through Percentage Tumour Involvement BSA Page 89 of

91 Administered Dose Calculator (GBq) 11-15% Lung Break-Through Percentage Tumour Involvement BSA Page 90 of

92 Administered Dose Calculator (GBq) 16-20% Lung Break-Through Percentage Tumour Involvement BSA Page 91 of

93 APPENDIX 10 Consumer Medicine Information For Sorafenib Please note, this is a sample Consumer Medicine Information leaflet for use in Australia and New Zealand. Please refer to local package inserts for country-specific information. Page 92 of 106

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