(rJ GILEAU CLINICAL STUDY PROTOCOL Study Title: A Phase 2, Open-Label Study Evaluating the Efficacy, Safety, Tolerability, and Phaimacodynamics of GS-9973 in Subjects with Relapsed or Refracto1y Hematologic Malignancies Sponsor: Gilead Sciences, Inc. 333 Lakeside Drive Foster City, CA 94404 IND No.: 116416 Clinical Trials.gov NCT0l 799889 Identifier: EudraCT No. 2013-001845-15 Indication: Chronic Lymphocytic Leukemia and non-Hodgkin Lymphomas Protocol ID: GS-US-339-0102 Gilead Sciences Medical Name: IPIPD Monitor: Telephone: IPIPD E-mail: PPU Protocol Version/Date: Original: 19 November 2012 Amendment 1: 11 Januaiy 2013 Amendment 2: 04 June 2013 Amendment 3: 04 November 2013 Amendment 4: 20 December 2013 Amendment 5: 06 June 2014 Amendment 6: 03 August 2015 Amendment 7: 13 November 2015 Amendment 8: 31 Mai·ch 2017 CONFIDENTIALITY STATEMENT The info1mation contained in this document, paiiiculai·ly unpublished data, is the prope1iy or under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, potential investigator, or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 infonnation is only to be used by you in connection with authorized clinical studies of the investigational dmg described in the protocol. You will not disclose any of the info1mation to others without written authorization from Gilead Sciences, Inc., except to the extent necessaiy to obtain infonned consent from those persons to whom the dmg may be administered. GS-9973 Protocol GS-US-339-0102 Final Gilead Sciences, Inc. Amendment 8 TABLE OF CONTENTS TABLE OF CONTENTS ..............................................................................................................................................2 LIST OF IN-TEXT TABLES........................................................................................................................................6 LIST OF IN-TEXT FIGURES ......................................................................................................................................6 PROTOCOL SYNOPSIS ..............................................................................................................................................7 GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................17 1. INTRODUCTION ..............................................................................................................................................21 1.1. Background ............................................................................................................................................21 1.2. Chronic Lymphocytic Leukemia............................................................................................................21 1.3. Non-Hodgkin Lymphoma ......................................................................................................................22 1.4. Spleen Tyrosine Kinase..........................................................................................................................24 1.4.1. Spleen Tyrosine Kinase in Hematologic Malignancies........................................................24 1.4.2. Clinical Experience in Hematologic Malignancies treated with SYK Inhibitors ..............................................................................................................................25 1.4.3. Mechanism of action of SYK Target Inhibition...................................................................26 1.5. GS-9973 .................................................................................................................................................27 1.5.1. Nonclinical Pharmacology ...................................................................................................27 1.5.2. Nonclinical Drug Metabolism and Pharmacokinetics ..........................................................29 1.5.3. Nonclinical Toxicology........................................................................................................30 1.5.4. Clinical Trials of GS-9973 ...................................................................................................31 1.5.5. GS-9973 Target Drug Concentrations..................................................................................33 1.5.6. Use of Concomitant Medications with GS-9973..................................................................34 1.6. Rationale for the Current Study and Design...........................................................................................35 1.6.1. Rationale for the Dose Selection ..........................................................................................35 1.6.2. Rationale for Dose Exploration in GS-9973 Sensitive Malignancies...................................36 1.7. Rationale for Amendment 5 ...................................................................................................................36 1.7.1. Initial Clinical Experience with GS-9973 in Subjects with CLL .........................................36 1.7.2. Rationale for addition of three CLL cohorts ........................................................................38 2. OBJECTIVES AND ENDPOINTS ....................................................................................................................40 2.1. Objectives...............................................................................................................................................40 2.2. Endpoints ...............................................................................................................................................40 3. STUDY DESIGN................................................................................................................................................42 3.1. Overview................................................................................................................................................42 3.1.1. CLL, FL, DLBCL, MCL......................................................................................................43 3.1.2. CLL Dose Ranging Cohort...................................................................................................43 3.1.3. LPL, SLL, MZL ...................................................................................................................44 3.2. Treatment Regimen................................................................................................................................45 4. SUBJECT POPULATION..................................................................................................................................46 4.1. Number of Subjects and Subject Selection ............................................................................................46 4.2. Eligibility Criteria ..................................................................................................................................46 4.2.1. Inclusion Criteria..................................................................................................................46 4.2.2. Exclusion Criteria.................................................................................................................49 5. INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................51 5.1. Enrollment..............................................................................................................................................51 5.2. Description and Handling of GS-9973 and GS-9973 SDD....................................................................51 CONFIDENTIAL Page 2 31 March 2017 GS-9973 Protocol GS-US-339-0102 Final Gilead Sciences, Inc. Amendment 8 5.2.1. Formulation ..........................................................................................................................51 5.2.2. Source...................................................................................................................................51 5.2.3. Packaging and Labeling .......................................................................................................52 5.2.4. Storage and Handling ...........................................................................................................52 5.2.5. Study Drug Accountability...................................................................................................52 5.3. Treatment Plan .......................................................................................................................................52 5.3.1. Premedication.......................................................................................................................52 5.3.2. Administration Instructions..................................................................................................53 5.3.3. Dosing Schedule...................................................................................................................53 5.3.4. Dose Schedule Interruptions and Vomited Doses ................................................................53 5.3.5. Transition of GS-9973 MM formulation to GS-9973 SDD formulation..............................53 5.3.6. Management of Dose Limiting Toxicities............................................................................54 5.3.7. Management of Low Grade Chronic Toxicities