Clovis Oncology, Inc. Clinical Protocol Oral rucaparib (CO-338) CO-338-017 Amendment 6 17 July 2019 A Phase 2, Open-Label Study of Rucaparib in Patients with Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Protocol Number: CO-338-017 Investigational Product: Oral rucaparib (CO-338) Eudra CT Number: IND Number: Development Phase: Phase 2 Indication Studied: Relapsed, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer Sponsor Name and Address: Clovis Oncology, Inc. 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 International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines ICH E6(R2). Essential study documents will be archived in accordance with applicable regulations. Amendment 6 Date: 17 July 2019 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 that is indicated as privileged or confidential. 1 Confidential DocuSign Envelope ID: 29E87828-DC1E-46E2-90E0-1CB6C17AB849 Clovis Oncology, Inc. Clinical Protocol Oral rucaparib (CO-338) CO-338-017 Amendment 6 17 July 2019 Protocol Approval Signature Page Protocol: CO-338-017 Title: A Phase 2, Open-Label Study of Rucaparib in Patients with Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Date: 17 July 2019 Amendment: 6 2 Confidential Clovis Oncology, Inc. Clinical Protocol Oral rucaparib (CO-338) CO-338-017 Amendment 6 17 July 2019 Protocol Acceptance Form Protocol: CO-338-017 Title: A Phase 2, Open-Label Study of Rucaparib in Patients with Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Date: 17 July 2019 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) 3 Confidential Clovis Oncology, Inc. Clinical Protocol Oral rucaparib (CO-338) CO-338-017 Amendment 6 17 July 2019 Table of Contents Description Page 1 SYNOPSIS ............................................................................................................................ 11 2 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................. 21 3 INTRODUCTION................................................................................................................ 24 3.1 Ovarian Cancer ............................................................................................................... 24 3.1.1 General Overview ................................................................................................... 24 3.1.2 Treatment of Ovarian Cancer .................................................................................. 24 3.1.3 Role of BRCA and HRD in Ovarian Cancer .......................................................... 25 3.2 PARP Inhibitors .............................................................................................................. 26 3.3 Rucaparib ........................................................................................................................ 28 3.3.1 Nonclinical Experience ........................................................................................... 28 3.3.1.1 Rucaparib Absorption, Distribution, Metabolism, and Excretion ............... 28 3.3.1.2 Multiple-Dose Toxicity Studies .................................................................. 30 3.3.1.3 Additional Observations .............................................................................. 31 3.3.2 Clinical Experience ................................................................................................. 32 3.3.2.1 Rucaparib Monotherapy .............................................................................. 32 3.3.2.1.1 Safety ............................................................................................. 33 3.3.2.1.2 Efficacy .......................................................................................... 34 3.3.2.1.3 Pharmacokinetics ........................................................................... 36 3.3.2.2 Studies A4991002 and A4991005, and A4991014 ..................................... 37 3.4 Rationale for Study ......................................................................................................... 37 4 STUDY OBJECTIVES ........................................................................................................ 39 4.1 Objectives and Endpoints ............................................................................................... 39 5 STUDY DESIGN .................................................................................................................. 41 5.1 Overall Study Design and Plan ....................................................................................... 41 5.1.1 Screening Phase ...................................................................................................... 41 5.1.2 Treatment Phase ...................................................................................................... 42 5.1.3 Post-Treatment Phase.............................................................................................. 43 5.2 Study Schema ................................................................................................................. 44 5.3 End of Study ................................................................................................................... 45 6 STUDY POPULATION ...................................................................................................... 46 4 Confidential Clovis Oncology, Inc. Clinical Protocol Oral rucaparib (CO-338) CO-338-017 Amendment 6 17 July 2019 6.1 Number of Patients and Sites .......................................................................................... 46 6.2 Inclusion Criteria ............................................................................................................ 46 6.3 Exclusion Criteria ........................................................................................................... 48 6.4 Patients or Partners of Patients of Reproductive Potential ............................................. 49 6.5 Waivers of Inclusion/Exclusion Criteria ......................................................................... 49 7 DESCRIPTION OF STUDY TREATMENTS AND DOSE MODIFICATIONS ......... 50 7.1 Description of Investigational Product ........................................................................... 50 7.2 Method of Assigning Patients to Treatment Groups ...................................................... 50 7.3 Preparation and Administration of Protocol-Specified Treatment ................................. 50 7.3.1 Dietary Restrictions ................................................................................................ 51 7.4 Starting Dose and Dose Modifications of Protocol-Specified Treatment ...................... 51 7.4.1 Starting Dose ........................................................................................................... 51 7.4.2 Dose Modification Criteria ..................................................................................... 51 7.4.3 Criteria for Re-Treatment ....................................................................................... 53 7.4.4 Treatment Beyond Progression ............................................................................... 53 7.5 Accountability of Protocol-Specified Treatment ............................................................ 53 7.6 Blinding/Masking of Treatment ...................................................................................... 53 7.7 Treatment Compliance .................................................................................................... 54 8 PRIOR AND CONCOMITANT THERAPIES................................................................. 55 8.1 Anticancer or Experimental Therapy .............................................................................. 55 8.2 Hematopoietic Growth Factors and Blood Products ...................................................... 55 8.3 CYP450 Isoenzyme Inhibitors, Inducers, and Substrates ............................................... 55 8.4 Bisphosphonates ............................................................................................................. 55 8.5 Anticoagulants ................................................................................................................ 56 8.6 Other Concomitant Medications ..................................................................................... 56 8.7 General Restrictions