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Clinical Study Protocol CLINICAL STUDY PROTOCOL Study Title: A Phase 1b/2 Study of Entospletinib (GS-9973) Monotherapy and in Combination with Chemotherapy in Patients with Acute Myeloid Leukemia (AML) Sponsor: Gilead Sciences, Inc. 333 Lakeside Drive Foster City, CA 94404 IND Number: 116416 EudraCT Number: 2016-003353-16 Clinical Trials.gov Identifier: NCT02343939 Indication: Acute Myeloid Leukemia Protocol ID: GS-US-339-1559 Gilead Medical Monitor: Name: PPD Telephone: PPD E-mail: PPD Protocol Version/Date: Original: 05 December 2014 Amendment 1: 21 January 2015 Amendment 2: 12 May 2015 Amendment 3: 24 November 2015 Amendment 4: 05 August 2016 Amendment 5: 14 February 2017 Amendment 6: 04 August 2017 Amendment 7: 15 February 2018 CONFIDENTIALITY STATEMENT The information contained in this document, particularly unpublished data, is the property or under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, potential investigator, or consultant, for review by you, your staff, and an applicable Institutional Review Board or Independent Ethics Committee. The information is only to be used by you in connection with authorized clinical studies of the investigational drug described in the protocol. You will not disclose any of the information to others without written authorization from Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those persons to whom the drug may be administered. Entospletinib Protocol GS-US-339-1559 Final Gilead Sciences, Inc. Amendment 7 TABLE OF CONTENTS TABLE OF CONTENTS ..............................................................................................................................................2 LIST OF IN-TEXT TABLES........................................................................................................................................5 LIST OF IN-TEXT FIGURES ......................................................................................................................................5 PROTOCOL SYNOPSIS ..............................................................................................................................................6 GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................16 1. INTRODUCTION ..............................................................................................................................................21 1.1. Acute Myeloid Leukemia.......................................................................................................................21 1.1.1. SYK Biology in Stem Cells and AML .................................................................................21 1.2. Entospletinib ..........................................................................................................................................23 1.2.1. Nonclinical Pharmacology ...................................................................................................23 1.2.2. Nonclinical Drug Metabolism and Pharmacokinetics ..........................................................25 1.2.3. Nonclinical Toxicology........................................................................................................26 1.2.4. Clinical Trials of Entospletinib ............................................................................................27 1.2.5. Entospletinib Target Drug Concentrations...........................................................................29 1.2.6. Use of Concomitant Medications with Entospletinib...........................................................30 1.3. Rationale for the Current Study and Design...........................................................................................30 1.3.1. Rationale for the Entospletinib Dose Selection....................................................................31 1.4. Cytarabine arabinoside...........................................................................................................................32 1.5. Daunorubicin..........................................................................................................................................32 1.6. Azacitidine .............................................................................................................................................32 1.7. Decitabine ..............................................................................................................................................33 1.8. Entospletinib ..........................................................................................................................................34 1.8.1. Formulation ..........................................................................................................................34 1.8.2. Source...................................................................................................................................34 1.8.3. Packaging and Labeling .......................................................................................................34 1.8.4. Storage and Handling ...........................................................................................................34 1.8.5. Study Drug Accountability...................................................................................................35 1.9. Compliance ............................................................................................................................................35 1.10. Risk/Benefit Assessment for the Study..................................................................................................35 1.10.1. Potential Risks Based on Nonclinical Safety Data with Entospletinib.................................35 1.10.2. Potential Risks Based on Clinical Safety Data with Entospletinib.......................................36 1.10.3. Potential Benefits with Entospletinib ...................................................................................37 2. OBJECTIVES AND ENDPOINTS ....................................................................................................................38 2.1. Objectives...............................................................................................................................................38 2.2. Endpoints ...............................................................................................................................................38 3. STUDY DESIGN................................................................................................................................................41 3.1. Overview................................................................................................................................................41 3.1.1. Group A Phase 1b (Dose Escalation): Entospletinib + cytarabine + daunorubicin (7+3)...............................................................................................................42 3.1.2. Group A Phase 2 (Dose Expansion): Entospletinib + cytarabine + daunorubicin (7+3)...............................................................................................................44 3.1.3. Group B Phase 1b (Dose Escalation): Entospletinib + decitabine.......................................46 3.1.4. Group B Phase 2 (Dose Expansion): Entospletinib + Hypomethylating agent.....................................................................................................................................48 3.1.5. Group C Phase 1b (Dose Escalation): Entospletinib Monotherapy......................................51 3.1.6. Group C Phase 2 (Dose Expansion): Entospletinib Monotherapy .......................................52 3.2. Dose Limiting Toxicities........................................................................................................................52 CONFIDENTIAL Page 2 15 February 2018 Entospletinib Protocol GS-US-339-1559 Final Gilead Sciences, Inc. Amendment 7 3.2.1. Guidelines for Phase 1b Dose Escalation and Phase 2 Group B Dose Expansion.............................................................................................................................54 3.3. Dosing Delays/Dose Modifications Attributed to Entospletinib (Beyond Cycle 1)...............................54 3.3.1. Management of Low Grade Chronic Toxicities ...................................................................59 3.3.2. Specific Considerations for Managing Hyperbilirubinemia.................................................60 3.4. Duration of Treatment............................................................................................................................60 4. SUBJECT POPULATION..................................................................................................................................63 4.1. Number of Subjects and Subject Selection ............................................................................................63 4.2. Inclusion Criteria....................................................................................................................................63 4.3. Exclusion Criteria...................................................................................................................................65 5. TREATMENT PLAN .........................................................................................................................................67 5.1. Treatment Plan .......................................................................................................................................67
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