AMC AIDS ASSOCIATED MALIGNANCY CLINICAL TRIALS CONSORTIUM AMC PROTOCOL #042 A Phase II Trial of Imatinib Mesylate (GLEEVEC) in Patients with HIV Related Kaposi's Sarcoma A Multi-Center Trial of the AIDS Malignancy Consortium Sponsored by: The National Cancer Institute Division of Cancer Treatment and Diagnosis Pharmaceutical Support Provided by: Novartis IND# 69,364 Protocol Chair: Henry B. Koon, M.D. Protocol Co-Chair: Ariela Noy, M.D. AMC # 042 (Version 7.0) 07/24/2007 NCI Version Date 07/24/07 i AMC PROTOCOL SIGNATURE PAGE I, , Principal Investigator at site , agree to conduct and follow this protocol: AMC Protocol #042 - A Phase II Trial of Imatinib Mesylate (GLEEVEC) in Patients with HIV Related Kaposi’s Sarcoma (Version 7.0, 07/24/2007), as written according to AMC, NCI and FDA guidelines. I understand that no deviations from the above protocol may be made without written permission from the Protocol Chair (s). _________________________________ _____________________ Signature Date (mm/dd/yyyy) AMC # 042 (Version 7.0) 07/24/2007 NCI Version Date 07/24/07 ii TABLE OF CONTENTS 1.0 Background/Rationale................................................................................................ 1 1.1 GLEEVEC® ...............................................................................................................................................1 1.2 BIOLOGIC/CORRELATIVE STUDIES..........................................................................................................11 1.3 STUDY DESIGN .......................................................................................................................................15 2.0 STUDY OBJECTIVES............................................................................................. 16 2.1 PRIMARY OBJECTIVES.............................................................................................................................16 2.2 SECONDARY OBJECTIVES........................................................................................................................16 3.0 PATIENT SELECTION .......................................................................................... 16 3.1 INCLUSION CRITERIA ..............................................................................................................................16 3.2 EXCLUSION CRITERIA .............................................................................................................................17 3.3 ENROLLMENT PROCEDURES....................................................................................................................18 4.0 CLINICAL AND LABORATORY EVALUATIONS........................................... 19 4.1 ELIGIBILITY/SCREENING .........................................................................................................................19 4.2 EVALUATIONS DURING TREATMENT ......................................................................................................21 4.3 EVALUATIONS AT THE TIME OF TREATMENT DISCONTINUATION ..........................................................22 4.4 FINAL EVALUATIONS/OFF DRUG, OFF STUDY ........................................................................................23 5.0 STUDY TREATMENT ............................................................................................ 24 5.1 DRUG REGIMENS, ADMINISTRATION AND DURATION ............................................................................24 5.2 DRUG ORDERS, TRANSFERS, RETURNS, AND ACCOUNTABILITY ............................................................24 5.3 DOSING ...................................................................................................................................................25 5.4 DOSE MODIFICATIONS FOR NON-HEMATOLOGICAL TOXICITY...............................................................25 5.5 DOSE MODIFICATIONS FOR HEMATOLOGICAL TOXICITY........................................................................27 5.6 CONCOMITANT THERAPY........................................................................................................................28 5.7 PERMITTED MEDICATIONS ......................................................................................................................29 5.8 PROHIBITED MEDICATIONS.....................................................................................................................30 5.9 PROHIBITED FOODS.................................................................................................................................30 5.10 TREATMENT COMPLIANCE......................................................................................................................30 6.0 REPORTING OF ADVERSE EVENTS................................................................. 31 6.1 CLASSIFICATION OF ADVERSE EVENTS BY SEVERITY & RELATIONSHIP TO STUDY DRUG ADMINISTRATION ...................................................................................................................................31 6.2 ADVERSE EVENT REPORTING TO NOVARTIS...........................................................................................32 6.3 ADVERSE EVENTS WITH COMMERCIAL AGENTS ....................................................................................33 7.0 CRITERIA FOR TREATMENT DISCONTINUATION..................................... 35 8.0 POST-TREATMENT EVALUATION AND EVALUATION AT EARLY DISCONTINUATION OF THERAPY................................................................... 36 9.0 EVALUATION OF RESPONSE............................................................................. 37 9.1 DEFINITION OF RESPONSE.......................................................................................................................37 10.0 RECORDS TO BE KEPT........................................................................................ 40 11.0 ROLE OF DATA MANAGEMENT ....................................................................... 41 11.1 CRF INSTRUCTIONS ................................................................................................................................41 11.2 DATA QUALITY.......................................................................................................................................41 AMC # 042 (Version 7.0) 07/24/2007 NCI Version Date 07/24/07 iii 12.0 STATISTICAL CONSIDERATIONS .................................................................... 42 12.1 SAMPLE SIZE ESTIMATION ......................................................................................................................42 12.2 STATISTICAL ANALYSIS PLAN ................................................................................................................42 12.3 AMC POLICY FOR MONITORING OF PHASE I AND PHASE II TRIALS........................................................43 13.0 ETHICAL AND REGULATORY CONSIDERATIONS ..................................... 44 13.1 INFORMED CONSENT...............................................................................................................................44 13.2 CHANGES TO THE PROTOCOL .................................................................................................................44 13.3 WOMEN AND MINORITIES ......................................................................................................................44 14.0 REFERENCES.......................................................................................................... 45 APPENDIX I: Schedule of Events............................................................................................ 47 APPENDIX II: Definition of AIDS Indicator Conditions....................................................... 48 APPENDIX III: Criteria for Acceptable AIDS Defining Events .......................................... 49 Appendix IV: Karnofsky Performance Scale........................................................................... 50 APPENDIX V: Recommended Staging Classification for Kaposi's Sarcoma ...................... 51 APPENDIX VI: Model Informed Consent.............................................................................. 52 APPENDIX VII: ACSR Informed Consent ............................................................................. 62 APPENDIX VIII: AIDS And Cancer Specimen Resource (ACSR) - Specimen Preparation & Shipping Instructions ........................................................................................... 65 APPENDIX IX: Punch Biopsy................................................................................................... 69 APPENDIX X: Punch Biopsy .................................................................................................... 72 APPENDIX XI: Cytokine Profiles Analysis............................................................................ 76 APPENDIX XII: Pharmacokinetic Analysis............................................................................ 79 APPENDIX XIII: HHV-8 Viral Load And Gene Expression................................................. 82 APPENDIX XIV: New York Heart Association Criteria ....................................................... 85 APPENDIX XV: Drugs Metabolized By CYP450 Isoenzymes 2D6 And 3A4....................... 86 APPENDIX XVI: Data Safety And Monitoring Plan.............................................................. 91 APPENDIX XVII: Novartis SAE Coversheet ........................................................................