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Study Protocol and Statistical Analysis Plan STUDY00008815 Approval: 4/1/2019 Protocol Title: PSCI 17-056 A Phase II Study of Pevonedistat (MLN4924, TAK924) and Azacitidine as Maintenance Therapy after Allogeneic Stem Cell Transplantation for Non-Remission Acute Myelogenous Leukemia Principal Investigator: Shin Mineishi, M.D. Professor and Director, Blood and Marrow Transplant Program 500 University Drive, CH46 Hershey, PA 17111 717-531-8678 (Office) 717-531-4969 (Fax) Email:[email protected] Site PIs Additional sites may be added in the future. Co-Investigators: David Claxton, M.D. Hong Zheng, M.D. Ph.D. Seema Naik, M.D. Muhammad Khawaja, M.D. Jason Liao, Ph.D. Co-Investigator/MD Coordinator Kevin Rakszawski, MD Fellow, Hematology & Oncology Email:[email protected] Version Date: Version 1.8.5, 07-26-2018 Clinicaltrials.gov Registration #: 03709576 Page 1 of 75 (V.1.8.5, 07/26/2018) STUDY00008815 Approval: 4/1/2019 Contents LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS......................................................................................................6 1.0 Objectives .......................................................................................................................................................10 1.1. Primary Objective.................................................................................................................................................10 1.2. Secondary Objectives ...........................................................................................................................................10 1.3. Primary Endpoint..................................................................................................................................................10 1.4. Secondary Endpoints ............................................................................................................................................10 2.0 Background ....................................................................................................................................................10 2.1. Background...........................................................................................................................................................10 2.1.1. High-risk AML particularly Non-remission AML..............................................................................10 2.1.2. Intensification of conditioning – experience with CloBu4 conditioning trials for Non-remission AML 11 2.1.3. Relapsed AML after allogeneic HSCT, another population with Poor Prognosis ..............................12 2.1.4. Maintenance therapy after allogeneic stem cell transplantation.........................................................12 2.1.5. Use of Azacitidine post-transplant........................................................................................................................13 2.2. Scientific Background of Pevonedistat.................................................................................................................13 2.3. Preclinical Experience with Pevonedistat.............................................................................................................14 2.4. Clinical Experience with Pevonedistat .................................................................................................................16 2.4.1. Pharmacokinetics ................................................................................................................................17 2.4.2. Pharmacodynamics .............................................................................................................................18 2.4.3. Phase 1 Monotherapy Studies .............................................................................................................18 2.4.4. Phase 1 Combination Studies ..............................................................................................................19 2.5. Potential risks of Pevonedistat..............................................................................................................................21 2.5.1. Potential Risks from Phase 1 Studies ..................................................................................................21 2.5.2. Potential Risks Confounded by Underlying Disease or Malignancy ...................................................22 2.5.3. Potential Risks Primarily Based on Findings from Animal Studies....................................................22 2.5.4. Additional Safety Considerations........................................................................................................23 Experience with Pevonedistat in AML induction and post-transplant treatment .............................................................25 2.6. Azacitidine and Pevonedistat as combination therapy for AML ..........................................................................25 2.7. Proposed Study...............................................................................................................................................26 3.0 Inclusion and Exclusion Criteria ....................................................................................................................26 3.1. Inclusion Criteria for Study Registration..............................................................................................................26 3.2. Exclusion Criteria for Study Registration.............................................................................................................27 3.3. Additional Eligibility Criteria for Initiating Study Treatment ..............................................................................29 3.4. Inclusion of Women and Minorities: ....................................................................................................................29 3.5. Vulnerable Populations........................................................................................................................................29 3.6. Registration and Early Withdrawal/Discontinuation of the Study.......................................................................29 3.6.1. REGISTRATION PROCEDURES .....................................................................................................29 3.6.2. Discontinuation of the Study/Withdrawal...........................................................................................30 3.6.3. Follow-up for withdrawn subjects.......................................................................................................30 4.0 Recruitment Methods...........................................................................................................................................30 4.1. Identification of subjects.......................................................................................................................................30 4.2. Recruitment process .............................................................................................................................................30 4.3. Recruitment materials...........................................................................................................................................30 Page 2 of 75 (V.1.8.5, 07/26/2018) STUDY00008815 Approval: 4/1/2019 4.4. Eligibility/screening of subjects............................................................................................................................30 5.0 Consent Process and Documentation ...................................................................................................................30 5.1. Consent Process....................................................................................................................................................30 5.1.1. Obtaining Informed Consent ..............................................................................................................31 5.1.2 Waiver or alteration of the informed consent requirement ................................................................31 5.2. Consent Documentation........................................................................................................................................31 5.2.1. Written Documentation of Consent.....................................................................................................31 5.2.2. Waiver of Documentation of Consent (Implied consent, Verbal consent, etc.) ...................................31 5.2.3. Consent – Other Considerations ...........................................................................................................................31 6.0. HIPAA Research Authorization and/or Waiver or Alteration of Authorization ...........................................31 6.1. Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures of PHI......................31 6.2. Waiver or Alteration of Authorization for the Uses and Disclosures of PHI........................................................32 7.0. Study Design and Procedures .........................................................................................................................32 7.1. Study Treatment ...................................................................................................................................................32 7.2. Study Drug Administration...................................................................................................................................34
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