Clovis Oncology, Inc. Clinical Protocol Oral rucaparib (CO-338) CO-338-014 7 July 2016 CONFIDENTIAL A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Rucaparib as Switch Maintenance Following Platinum-Based Chemotherapy in Patients with Platinum-Sensitive, High-Grade Serous or Endometrioid Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer Protocol Number: CO-338-014 Investigational Product: Rucaparib (CO-338) Eudra CT Number: IND Number: Development Phase: Phase 3 Indications Studied: Platinum-sensitive, high-grade serous and endometrioid epithelial ovarian, primary peritoneal, and fallopian tube cancer Sponsor Name and Address: Clovis Oncology, Inc. 5500 Flatiron Parkway Suite 100 Boulder, CO 80301 USA Phone Number: 303-625-5000 Facsimile Number: 303-245-0360 Responsible Medical Officer: Compliance Statement: This study will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, clinical research guidelines established by the Code of Federal Regulations (Title 21, CFR Parts 50, 56, and 312), and ICH GCP Guidelines. Essential study documents will be archived in accordance with applicable regulations. CONFIDENTIALITY STATEMENT The information in this document contains commercial information and trade secrets that are privileged or confidential and may not be disclosed unless such disclosure is required by applicable laws and regulations. In any event, persons to whom the information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally to all future information supplied to you which is indicated as privileged or confidential. 1 Clovis Oncology, Inc. Clinical Protocol Oral rucaparib (CO-338) CO-338-014 Coordinating Investigators for the Study Coordinating Investigator for North America: Coordinating Investigator for Europe, Middle East, and Asia Pacific: 2 Clovis Oncology, Inc. Clinical Protocol Oral rucaparib (CO-338) CO-338-014 Protocol Acceptance Form Protocol: CO-338-014 Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Rucaparib as Switch Maintenance Following Platinum-Based Chemotherapy in Patients with Platinum-Sensitive, High-Grade Serous or Endometrioid Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer Date: I have carefully read this protocol and agree that it contains all of the necessary information required to conduct this study. I agree to conduct this study as described and according to the Declaration of Helsinki, ICH Guidelines for GCP, and all applicable regulatory requirements. Investigator’s Signature Date Name (printed) 4 Clovis Oncology, Inc. Clinical Protocol Oral rucaparib (CO-338) CO-338-014 Table of Contents Description Page 1 SYNOPSIS ............................................................................................................................ 12 2 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................. 23 3 INTRODUCTION................................................................................................................ 27 3.1 Ovarian Cancer ............................................................................................................ 27 3.1.1 General Overview ................................................................................................... 27 3.1.2 Treatment of Ovarian Cancer ................................................................................. 27 3.1.3 Homologous Recombination Deficiency ................................................................ 28 3.1.4 Role of HRD in Ovarian Cancer ............................................................................. 29 3.2 PARP Inhibitors ........................................................................................................... 30 3.3 Rucaparib ..................................................................................................................... 31 3.3.1 Nonclinical Experience ........................................................................................... 31 3.3.1.1 Rucaparib Absorption, Distribution, Metabolism, and Excretion ............... 31 3.3.1.2 Multiple-Dose Toxicity Studies .................................................................. 32 3.3.1.3 Additional Observations .............................................................................. 34 3.3.2 Clinical Experience ................................................................................................. 34 3.3.2.1 Rucaparib Monotherapy .............................................................................. 35 3.3.2.1.1 Study CO-338-010 ......................................................................... 35 3.3.2.1.2 Study CO-338-017 ......................................................................... 37 3.3.2.1.3 Study A4991002, A4991005, and A4991014 ................................ 38 3.3.2.1.4 Safety: Events of Special Interest .................................................. 38 3.4 Rationale for Study ...................................................................................................... 39 4 STUDY OBJECTIVES ........................................................................................................ 40 4.1 Objectives and Endpoints ............................................................................................ 40 5 STUDY DESIGN .................................................................................................................. 42 5.1 Overall Study Design and Plan .................................................................................... 42 5.1.1 Screening Phase ...................................................................................................... 42 5.1.2 Randomization ........................................................................................................ 43 5.1.3 Double-Blind Treatment Phase ............................................................................... 43 5.1.4 Treatment Discontinuation ..................................................................................... 44 5.1.5 Follow-Up Phase..................................................................................................... 44 5 Clovis Oncology, Inc. Clinical Protocol Oral rucaparib (CO-338) CO-338-014 5.2 Study Schema .............................................................................................................. 45 5.3 End of Study ................................................................................................................ 46 5.4 Discussion of Study Design ......................................................................................... 46 6 STUDY POPULATION ...................................................................................................... 47 6.1 Number of Patients and Sites ....................................................................................... 47 6.2 Inclusion Criteria ......................................................................................................... 47 6.3 Exclusion Criteria ........................................................................................................ 49 6.4 Patients or Partners of Patients of Reproductive Potential .......................................... 50 6.5 Waivers of Inclusion/Exclusion Criteria ..................................................................... 51 7 DESCRIPTION OF STUDY TREATMENTS AND DOSE MODIFICATIONS ......... 52 7.1 Description of Investigational Product ........................................................................ 52 7.2 Method of Assigning Patients to Treatment Groups ................................................... 52 7.3 Preparation and Administration of Protocol-Specified Treatment .............................. 52 7.3.1 Dietary Restrictions ................................................................................................ 53 7.4 Starting Dose and Dose Modifications of Protocol-Specified Treatment ................... 53 7.4.1 Starting Dose........................................................................................................... 53 7.4.2 Dose Modification Criteria ..................................................................................... 53 7.4.3 Criteria for Re-Treatment ....................................................................................... 55 7.5 Accountability of Protocol-Specified Treatment ......................................................... 55 7.6 Blinding/Masking of Treatment .................................................................................. 55 7.7 Treatment Compliance ................................................................................................ 56 8 PRIOR AND CONCOMITANT THERAPIES................................................................. 57 8.1 Anticancer or Experimental Therapy .......................................................................... 57 8.2 Hematopoietic Growth Factors and Blood Products ................................................... 57 8.3 CYP450 Isoenzyme Inhibitors, Inducers, and Substrates ............................................ 57 8.4 Bisphosphonates .......................................................................................................... 57 8.5 Anticoagulants ............................................................................................................