Study Protocol

GILEAU CLINICAL STUDY PROTOCOL Study Title: A Phase 1 Study to Evaluate the Safety, Tolerability, Phaim acokinetics, and Phaim acodynamics of GS-5829 as a Monotherapy in Subjects with Advanced Solid Tumors and Lymphomas and in Combination with Exemestane or Fulvestrant in Subjects with Estrogen Receptor Positive Breast Cancer Sponsor: Gilead Sciences, Inc. 333 Lakeside Drive Foster City, CA 94404 IND Number: 124032 EudraCT Number: 2016-001912-39 Clinical Trials.gov Identifier: NCT02392611 Indication: Solid tumors and lymphomas Protocol ID: GS-US-350-1599 Clinical Program Name: IPIPD Manager: Telephone: IPIPD Email: IPIPD Gilead Medical Monitor: Name: IPIPD Telephone: IPIPD Fax: IPIPD Mobile: IPIPD Email: IPIPD Protocol Version/Date: Original: 10 December 2014 Amendment 1: 26 Januaiy 2015 Amendment 2: 06 April 2015 Amendment 3: 04 November 2015 Amendment 4: 21 Mai·ch 2016 Amendment 5: 24May2016 Amendment 6: 20 June 2016 CONFIDENTIALITY STATEMENT The info1m ation contained in this document, paiiiculai·ly unpublished data, is the prope1iy or under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, potential investigator, or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 Boai·d or Independent Ethics Committee. The infonnation is only to be used by you in connection with authorized clinical studies of the investigational diug 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 info1m ed consent from those persons to whom the di11g may be adininistered. GS-5829 Protocol GS–US-350-1599 Final Gilead Sciences, Inc. Amendment 6 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....................................................................20 1. INTRODUCTION ..............................................................................................................................................23 1.1. Background ............................................................................................................................................23 1.2. GS-5829 .................................................................................................................................................24 1.2.1. General Information .............................................................................................................24 1.2.2. Preclinical Pharmacology and Toxicology...........................................................................25 1.2.3. Clinical Trials of GS-5829 ...................................................................................................26 1.2.4. Information on Exemestane..................................................................................................26 1.2.5. Information on Fulvestrant...................................................................................................27 1.3. Rationale for Development of GS-5829 in Advanced Solid Tumors and Lymphomas (Group 1)................................................................................................................................................27 1.3.1. Rationale for Development of GS-5829 in Combination with Exemestane or Fulvestrant for the Treatment of Estrogen Receptor Positive Breast Cancer (Group 2)..................................................................................................................28 1.3.2. Rationale to Evaluate GS-5829 in Specific Aggressive Non-Hodgkin’s Lymphoma: DLBCL and PTCL (Group 3)..........................................................................30 1.3.3. Rationale for the Dose Selection ..........................................................................................30 1.4. Compliance ............................................................................................................................................31 1.5. Risk/Benefit Assessment for the Study..................................................................................................31 2. OBJECTIVES.....................................................................................................................................................33 3. STUDY DESIGN................................................................................................................................................34 3.1. Endpoints ...............................................................................................................................................34 3.2. Study Design ..........................................................................................................................................34 3.3. Study Treatments ...................................................................................................................................38 3.4. Criteria for Discontinuation of Study Drug............................................................................................38 3.5. Criteria for Removal from Study............................................................................................................39 4. SUBJECT POPULATION..................................................................................................................................40 4.1. Number of Subjects and Subject Selection ............................................................................................40 4.2. Inclusion Criteria....................................................................................................................................40 4.3. Exclusion Criteria...................................................................................................................................41 5. INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................44 5.1. Enrollment..............................................................................................................................................44 5.2. Description and Handling of GS-5829, Exemestane and Fulvestrant ....................................................44 5.2.1. Formulation ..........................................................................................................................44 5.2.2. Packaging and Labeling .......................................................................................................44 5.2.3. Storage and Handling ...........................................................................................................45 5.3. Dosage and Administration of GS-5829, Exemestane and Fulvestrant..................................................45 5.4. Prior and Concomitant Medications.......................................................................................................46 5.5. Accountability for GS-5829...................................................................................................................46 5.5.1. GS-5829 Return or Disposal ................................................................................................47 CONFIDENTIAL Page 2 20 June 2016 GS-5829 Protocol GS-US-350-1599 Final Gilead Sciences, Inc. Amendment6 6. STUDY PROCEDURES .. .................................................................................................................................. 48 6.1. Study Procedw·e Descriptions ................................................................................................................ 48 6 .1.1. Info1med Consent ................................................................................................................. 48 6.1.2. Medical & Medication Histoiy .... ......................................................................................... 48 6.1.3. Physical Examination .. ......................................................................................................... 49 6.1.4. Vital Signs .. .......................................................................................................................... 49 6.1.5. Electrocardiogra1n Assess1nent ... ......................................................................................... 49 6.1.6. Echocardiograrn ................................................................................................................... 49 6.1.7. ECOG Perfonnance Status .. ................................................................................................. 49 6.1.8. Prior and Concomitant Medications ..... ................................................................................ 50 6.1.9. Adverse Events ... .................................................................................................................. 50 6.1.10. CT or MRI .. .........................................................................................................................

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