Clinical trial NCT01968213
Conditions: Ovarian Cancer Fallopian Tube Cancer Peritoneal Cancer
Keywords: ARIEL3 ARIEL 3 platinum sensitive PARP Inhibitor rucaparib homologous recombination homologous recombination deficiency CO-338 PF 01367338 AG 14699 platinum sensitive ovarian cancer platinum sensitive fallopian tube cancer platinum sensitive primary peritoneal cancer platinum sensitive peritoneal cancer gynecological cancer Clovis Clovis Oncology
Sponsor: pharmaand GmbH
Start date: 2014-04-07; Completion date: 2022-07-07
Enrollment: 564 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Patients enrolled into this study will be stratified into 3 groups based on gene mutations identified in their tumor tissue. The purpose of this study is to evaluate patient response to maintenance treatment with rucaparib versus placebo. Response to treatment will be analyzed based on homologous recombination (HR) status of tumor samples.

Detailed description:
Rucaparib is an orally available, small molecule inhibitor of poly-adenosine diphosphate \[ADP\] ribose polymerase (PARP) being developed for treatment of ovarian cancer associated with homologous recombination (HR) DNA repair deficiency (HRD). Clinical data have shown that ovarian cancer patients with and without evidence of a gBRCA mutation benefit from treatment with a PARP and that maintenance treatment with a PARP inhibitor following a response to platinum-based treatment increases PFS in patients with ovarian cancer. While patients with a BRCA mutation derived the most benefit, patients without evidence of a BRCA mutation also derived significant benefit.

Patients enrolled into this study will be stratified into 3 groups based on tumor HRD status. The purpose of this study is to identify which of these groups of patients will most likely benefit from treatment with rucaparib. It is anticipated that rucaparib will provide therapeutic benefit and increase PFS in patients with HRD associated with a BRCA gene mutation or other HR gene alteration.

Arms: arm 1: Oral tablets administered twice daily with 8 oz (240 mL) of water on an empty stomach or with food; 28-day cycles of treatment. Doses should be taken as close to 12 hours apart as possible, preferably at the same times every day. Tablets should be swallowed whole. arm 2: Oral tablets administered twice daily with 8 oz (240 mL) of water on an empty stomach or with food; 28-day cycles of treatment. Doses should be taken as close to 12 hours apart as possible, preferably at the same times every day. Tablets should be swallowed whole.
Interventions: intervention 1: Rucaparib intervention 2: Placebo
Intervention descriptions: intervention 1: Oral tablets administered twice daily with 8 oz (240 mL) of water on an empty stomach or with food; 28-day cycles of treatment. Doses should be taken as close to 12 hours apart as possible, preferably at the same times every day. Tablets should be swallowed whole. intervention 2: Oral tablets administered twice daily with 8 oz (240 mL) of water on an empty stomach or with food; 28-day cycles of treatment. Doses should be taken as close to 12 hours apart as possible, preferably at the same times every day. Tablets should be swallowed whole.

Protocol documents:
Prot_002.pdf: 
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. 
 
 
 
 
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. 
Protocol Date: 
 
 
 
 
 
 
 
 
 
Amendment 5 Date: 
06 July 2020 
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. 


Clovis Oncology, Inc. 
 
Clinical Protocol CO-338-014 
Oral rucaparib (CO-338) 
06 July 2020  
Amendment 5 
2 
 
Coordinating Investigators for the Study 
Coordinating Investigator for North America: 
 
 
 
  
Coordinating Investigator for Europe, Middle East, and Asia Pacific: 
 
 
 
 
 
 
 
 
 
 


CloYil ODcoloaY, Inc. 
Oral rucapml, (co-338) 
Protocol ApproVII Signature Page 
Cliaical l'lotocol C0-33S,,Ol4 
06July2020 
Protocol: 
Title: 
C0-338-014 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 3 
Study of Rw:apanb as Switch Maintenance Following Platinum-Based 
Chemotherapy in Patients with Platinum-Sensitive. High-Glade Serous or 
Endometrioid Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube 
Cancer 
· 
Date: 
06July2020 
Amendment: 
s 


Clovis Oncology, Inc. 
 
Clinical Protocol CO-338-014 
Oral rucaparib (CO-338) 
06 July 2020  
Amendment 5 
4 
 
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: 
06 July 2020 
Amendment: 
5 
 
 
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 
dd Month yyyy 
 
 
 
  
Name (printed) 
  
 
 
 


Clovis Oncology, Inc. 
 
Clinical Protocol CO-338-014 
Oral rucaparib (CO-338) 
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Amendment 5 
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TABLE OF CONTENTS 
Description 
Page 
Table of Contents ......................................................................................................................... 5 
List of Tables .............................................................................................................................. 10 
List of Figures ............................................................................................................................. 10 
1 SYNOPSIS ............................................................................................................................ 11 
2 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................. 22 
3 INTRODUCTION................................................................................................................ 26 
3.1 
Ovarian Cancer ............................................................................................................ 26 
3.1.1 
General Overview ................................................................................................... 26 
3.1.2 
Treatment of Ovarian Cancer ................................................................................. 26 
3.1.3 
Homologous Recombination Deficiency ................................................................ 27 
3.1.4 
Role of HRD in Ovarian Cancer ............................................................................. 28 
3.2 
PARP Inhibitors ........................................................................................................... 29 
3.3 
Rucaparib ..................................................................................................................... 30 
3.3.1 
Nonclinical Experience ........................................................................................... 30 
3.3.1.1 
Rucaparib Absorption, Distribution, Metabolism, and Excretion ............... 30 
3.3.1.2 
Multiple-Dose Toxicity Studies .................................................................. 32 
3.3.1.3 
Additional Observations .............................................................................. 33 
3.3.2 
Clinical Experience ................................................................................................. 34 
3.3.2.1 
Rucaparib Monotherapy .............................................................................. 34 
3.3.2.1.1 
Study CO-338-010 ......................................................................... 34 
3.3.2.1.2 
Study CO-338-017 ......................................................................... 36 
3.3.2.1.3 
Study A4991002, A4991005, and A4991014 ................................ 37 
3.3.2.1.4 
Safety: Events of Special Interest .................................................. 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 
Randomization ........................................................................................................ 43 


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Clinical Protocol CO-338-014 
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5.1.3 
Double-Blind Treatment Phase ............................................................................... 43 
5.1.4 
Treatment Discontinuation ..................................................................................... 44 
5.1.5 
Follow-Up Phase .................................................................................................... 44 
5.2 
Study Schema .............................................................................................................. 44 
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 .............................. 53 
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 ..................................................................................... 54 
7.4.3 
Criteria for Re-Treatment ....................................................................................... 55 
7.5 
Accountability of Protocol-Specified Treatment ......................................................... 56 
7.6 
Blinding/Masking of Treatment .................................................................................. 56 
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 ............................................................................................................. 58 
8.6 
Other Concomitant Medications .................................................................................. 58 
8.7 
General Restrictions .................................................................................................... 58 
9 STUDY PROCEDURES ..................................................................................................... 59 


Clovis Oncology, Inc. 
 
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Oral rucaparib (CO-338) 
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9.1 
Schedule of Assessments ............................................................................................. 59 
9.2 
Screening Phase ........................................................................................................... 62 
9.3 
Treatment Phase .......................................................................................................... 63 
9.3.1 
Day 1 of Cycles 1 and 2 .......................................................................................... 63 
9.3.2 
Day 15 of Cycles 1 and 2 ........................................................................................ 64 
9.3.3 
Cycles 3 and Beyond .............................................................................................. 64 
9.4 
Post-Treatment Phase .................................................................................................. 65 
9.4.1 
Treatment Discontinuation ..................................................................................... 65 
9.4.2 
28-day Follow-up .................................................................................................... 66 
9.4.3 
Long-term Follow-up .............................................................................................. 66 
9.5 
Methods of Data Collection ......................................................................................... 67 
9.5.1 
Pharmacokinetic Evaluations and AAG Measurement .......................................... 67 
9.5.2 
Biomarker Analysis – FFPE Tumor Tissue ............................................................ 67 
9.5.3 
Biomarker Analysis – Blood................................................................................... 67 
9.5.4 
Safety Evaluations .................................................................................................. 67 
9.5.4.1 
Adverse Event Assessment ......................................................................... 67 
9.5.4.2 
Prior and concomitant medications ............................................................. 67 
9.5.4.3 
Clinical Laboratory Investigations .............................................................. 68 
9.5.4.4 
Vital Signs ................................................................................................... 68 
9.5.4.5 
12-Lead Electrocardiograms ....................................................................... 68 
9.5.4.6 
Body Weight and Height ............................................................................. 68 
9.5.4.7 
Physical Examinations ................................................................................ 68 
9.5.4.8 
ECOG Performance Status .......................................................................... 68 
9.5.5 
Efficacy Evaluations ............................................................................................... 69 
9.5.5.1 
Disease Assessments ................................................................................... 69 
9.5.5.2 
Tumor Markers ............................................................................................ 69 
9.5.6 
Patient-Reported Outcomes .................................................................................... 69 
9.5.7 
Appropriateness of Measurements .......................................................................... 70 
10 ADVERSE EVENT MANAGEMENT .............................................................................. 71 
10.1 
Definition of an Adverse Event ................................................................................... 71 
10.2 
Definition of a Serious Adverse Event ........................................................................ 71 
10.3 
Definition of an Adverse Event of Special Interest ..................................................... 71 
10.4 
Exceptions to Serious Adverse Event Reporting ......................................................... 72 


Clovis Oncology, Inc. 
 
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Oral rucaparib (CO-338) 
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10.5 
Clinical Laboratory Assessments and Other Abnormal Assessments as Adverse 
Events and Serious Adverse Events ............................................................................ 72 
10.6 
Pregnancy or Drug Exposure during Pregnancy ......................................................... 73 
10.7 
Recording of Adverse Events, Serious Adverse Events, and Adverse Events of 
Special Interest ............................................................................................................ 73 
10.7.1 Intensity of Adverse Events .................................................................................... 74 
10.7.2 Causal Relationship of Adverse Events to Study Drug .......................................... 74 
10.7.3 Outcome .................................................................................................................. 75 
10.7.4 Follow-up of Adverse Events, Serious Adverse Events, and Adverse 
Events of Special Interest ....................................................................................... 75 
10.8 
Regulatory Aspects of Adverse Event Reporting ........................................................ 75 
10.9 
Independent Data Monitoring Committee ................................................................... 76 
11 STATISTICAL METHODS ............................................................................................... 77 
11.1 
Analysis Populations ................................................................................................... 77 
11.2 
Statistical Methods ...................................................................................................... 77 
11.2.1 General Considerations ........................................................................................... 77 
11.2.2 Patient Disposition .................................................................................................. 78 
11.2.3 Baseline Characteristics .......................................................................................... 78 
11.2.4 Efficacy Analyses ................................................................................................... 78 
11.2.4.1 Primary Efficacy Analysis .......................................................................... 78 
11.2.4.2 Secondary Efficacy Analyses ...................................................................... 79 
11.2.5 Safety Analyses....................................................................................................... 79 
11.2.5.1 Adverse Events ............................................................................................ 80 
11.2.5.2 Clinical Laboratory Evaluations ................................................................. 80 
11.2.5.3 Vital Sign Measurements ............................................................................ 81 
11.2.6 Population PK Analysis .......................................................................................... 81 
11.2.7 Exploratory Analyses .............................................................................................. 81 
11.2.7.1 Change from Baseline in CA-125 ............................................................... 82 
11.2.7.2 Progression Free Survival 2 (PFS2) ............................................................ 82 
11.2.7.3 Overall Response Rate ................................................................................ 82 
11.2.7.4 Duration of Response .................................................................................. 82 
11.2.7.5 Patient Reported Outcome EQ-5D .............................................................. 82 
11.2.7.6 Relationship between Rucaparib Exposure and Efficacy and Safety ......... 83 


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11.3 
Interim Analysis .......................................................................................................... 83 
11.4 
Sample Size Considerations ........................................................................................ 83 
12 PATIENT DISPOSITION................................................................................................... 85 
12.1 
Removal of patients from therapy or assessment ........................................................ 85 
12.2 
Procedures for discontinuation .................................................................................... 85 
13 STUDY ADMINISTRATION............................................................................................. 86 
13.1 
Regulatory and Ethical Considerations ....................................................................... 86 
13.2 
Regulatory Authority Approvals ................................................................................. 86 
13.2.1 Institutional Review Board or Independent Ethics Committee Approval .............. 87 
13.3 
Patient Information and Informed Consent ................................................................. 87 
13.3.1 General Aspects of Informed Consent .................................................................... 87 
13.3.2 Informed Consent Process ...................................................................................... 88 
13.3.3 Additional Informed Consent Documentation ........................................................ 88 
13.4 
Patient Confidentiality ................................................................................................. 88 
13.5 
Study Monitoring ......................................................................................................... 88 
13.6 
Case Report Form ........................................................................................................ 89 
13.7 
Study Termination and Site Closure ............................................................................ 90 
13.8 
Study Protocol Amendments ....................................................................................... 91 
13.9 
Retention of Study Documents .................................................................................... 91 
13.10 Quality Control and Assurance.................................................................................... 92 
13.10.1 Protocol Deviations................................................................................................. 92 
13.10.2 Study Site Training ................................................................................................. 92 
13.10.3 Quality Assurance Audits and Inspections ............................................................. 92 
13.10.4 Direct Access to Source Data/Documents for Audits and Inspections ................... 92 
13.11 Clinical Study Report .................................................................................................. 93 
13.12 Study Publication and Disclosure Policy..................................................................... 93 
13.13 Investigator Oversight ................................................................................................. 93 
14 REFERENCES ..................................................................................................................... 94 
15 APPENDICES ...................................................................................................................... 99 
15.1 
Appendix A................................................................................................................ 100 
15.2 
Appendix B ................................................................................................................ 101 
15.3 
Appendix C ................................................................................................................ 105 
15.4 
Appendix D................................................................................................................ 106 


Clovis Oncology, Inc. 
 
Clinical Protocol CO-338-014 
Oral rucaparib (CO-338) 
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15.5 
Appendix E ................................................................................................................ 108 
15.6 
Appendix F ................................................................................................................ 113 
 
LIST OF TABLES 
Description 
Page 
Table 1. 
Primary, Secondary, and Exploratory Objectives and Endpoints ........................ 39 
Table 2. 
Dose Reduction Steps .......................................................................................... 55 
Table 3. 
Schedule of Assessments After Implementation of Amendment 5 ..................... 60 
Table 4. 
Estimated Sample Sizes and Power Calculations ................................................ 84 
 
LIST OF FIGURES 
Description 
Page 
Figure 1 
Best Response in Target Lesions – Phase 2 Portion of Study 
CO-338-010 ......................................................................................................... 36 
Figure 2 
Study Schema....................................................................................................... 45 
 


Clovis Oncology, Inc. 
 
Clinical Protocol CO-338-014 
Oral rucaparib (CO-338) 
06 July 2020  
Amendment 5 
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1 
SYNOPSIS 
Protocol Number 
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 
Study Phase 
Phase 3 
Introduction  
 
Rucaparib is an orally available, small molecule inhibitor of poly (adenosine 
diphosphate [ADP]-ribose) polymerase (PARP)-1, PARP-2, and PARP-3 and is 
being developed for treatment of ovarian cancer associated with homologous 
recombination deoxyribonucleic acid (DNA) repair deficiency. The safety and 
efficacy of rucaparib has been evaluated in several Phase 1, Phase 2, and Phase 3 
studies. Rucaparib (Rubraca®) is approved in the United States (US) as 
monotherapy treatment for adult patients with deleterious breast cancer gene 
(BRCA) mutation (germline and/or somatic)-associated epithelial ovarian (EOC), 
fallopian tube (FTC), or primary peritoneal (PPC) cancer who have been treated 
with 2 or more prior chemotherapies, and for the maintenance treatment of adult 
patients with recurrent EOC, FTC, or PPC who have a complete or partial 
response to platinum-based chemotherapy.1 Rucaparib is also approved in the 
European Union (EU) as monotherapy treatment of adult patients with platinum-
sensitive, relapsed or progressive, BRCA mutated (germline and/or somatic), 
high-grade EOC, FTC, or PPC who have been treated with 2 or more prior lines 
of platinum-based chemotherapy, and who are unable to tolerate further platinum-
based chemotherapy, and for maintenance treatment of adult patients with 
platinum-sensitive recurrent EOC, FTC, or PPC who are in response (complete or 
partial) to platinum-based chemotherapy.2 
Normal cells repair single-strand breaks (SSBs) in DNA primarily through base 
excision repair (BER). While there are several variations of BER, all pathways 
rely on PARP enzymes, of which PARP-1 is the best characterized. SSBs that are 
not repaired result in stalled replication forks and the development of double-
strand breaks (DSBs), which are in turn primarily repaired by homologous 
recombination DNA repair, a complex process involving multiple proteins, 
including those encoded by breast cancer gene 1 and 2 (BRCA1 and BRCA2), as 
well as many others. 
Homologous recombination pathway defects, either as an initiating event or late 
event in the carcinogenetic process, may be responsible for the genetic instability 
observed in many cancers. An analysis of the Cancer Genome Atlas (TCGA), 
which examined molecular changes in high-grade serous ovarian cancer 
(HGSOC), estimated that approximately 50% of patients with HGSOC have 
homologous recombination deficiency (HRD).3 Drivers of HRD include: 
1. Germline mutations in the BRCA1 and BRCA2 genes (gBRCA). These are 
the strongest known hereditary factors for EOC, accounting for up to 15% of 
all EOC.4, 5 These patients carry heterozygous deleterious mutations in their 
germline DNA and develop tumors when the remaining wild-type functional 
allele is inactivated (i.e. “second hit”). 
2. Somatic BRCA1/2 mutations (sBRCA) (6 – 8% of HGSOC patients)3, 6 
3. Mutation in a homologous recombination gene other than BRCA1/2 
(approximately 16% of HGSOC patients).3 Nonclinical studies by several 


Clovis Oncology, Inc. 
 
Clinical Protocol CO-338-014 
Oral rucaparib (CO-338) 
06 July 2020  
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groups have identified RAD proteins (eg, RAD51, RAD51C, RAD52, 
RAD54L),7-10 Fanconi Anemia proteins (eg, FANCA, FANCC, FANCD2),11-
13 and many others (eg, ATM, ATR, CHEK1, CHEK2)14-17 as being involved 
in homologous recombination. 
4. Functional silencing of homologous recombination genes, such as through 
BRCA1 promoter methylation (approximately 10% of HGSOC patients)3 or 
other mechanisms 
Inhibition of DNA damage repair in cancer cells, which are intrinsically 
genetically unstable, represents an attractive opportunity for the development of 
new therapies. Given the overlap in various DNA repair pathways, inhibition of a 
single pathway is unlikely to have a significant effect, whereas inhibition of 
multiple DNA repair pathways may lead to cell death, a concept known as 
synthetic lethality. Normal cells, with only one DNA repair pathway affected by 
inhibition of PARP, still have an intact DNA repair pathway that can compensate, 
whereas cancer cells with pre-existing HRD that are treated with a PARP 
inhibitor develop critically DNA repair deficiency and enter apoptosis. This 
concept of synthetic lethality has been demonstrated in landmark in vitro and 
in vivo studies18, 19 as well as in several clinical trials that evaluated a single agent 
PARP inhibitor for the treatment of relapsed ovarian cancer and metastatic breast 
cancer with or without an associated germline BRCA mutation.20-26 In vitro 
studies have also shown that cells deficient in or depleted of homologous 
recombination proteins other than BRCA1/2 have been associated with PARP 
inhibitor sensitivity.27-30 It is possible that the 24% overall response rate (ORR) 
observed in olaparib-treated ovarian cancer patients without evidence of a 
gBRCA1/2 mutation23 was due to HRD driven by a sBRCA1/2 mutation or by an 
alteration in another key homologous recombination gene. 
Clinical activity in HGSOC has also been observed with switch maintenance 
PARP inhibitor therapy following response to platinum-based chemotherapy. 
Patients with platinum-sensitive relapsed ovarian cancer who achieved a response 
to another regimen of platinum-based chemotherapy followed by olaparib as 
switch maintenance treatment experienced a statistically significant improvement 
in median progression-free survival (PFS) (8.3 months) compared to patients who 
received placebo as maintenance therapy (4.8 months); hazard ratio (HR) of 0.35 
(95% confidence interval [CI], 0.25 – 0.49).31 Patients with a BRCA mutation 
derived the most benefit (median PFS 11.2 vs 4.3 months; HR=0.18; 
95% CI 0.11-0.31; P<0.00001).32 It should be noted that the outcomes of sBRCA 
+ gBRCA mutant patients were the same as gBRCA mutant patients alone, 
suggesting that, for stratification and analysis purposes in the present study, it is 
appropriate to not differentiate between germline and somatic mutations. Patients 
without a BRCA mutation also experienced significant benefit from treatment 
with olaparib (HR=0.53; 95% CI 0.33-0.84; P=0.007), suggesting that patients 
with DNA repair defects in genes other than BRCA are likely contributing to the 
overall PFS result.32  
The purpose of this study is to evaluate PFS of patients with platinum-sensitive, 
relapsed high-grade EOC, FTC, or PPC who receive rucaparib or placebo as 
switch maintenance therapy following a response to platinum-based 
chemotherapy. Prior to final analysis, patients will be placed into molecularly 
defined subgroups of HRD based on the Final Clinical Trial Assay (FCTA). It is 
anticipated that rucaparib will provide therapeutic benefit and increase PFS in 
patients with HRD.  


Clovis Oncology, Inc. 
 
Clinical Protocol CO-338-014 
Oral rucaparib (CO-338) 
06 July 2020  
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Study Overview  
This is a randomized, international, double-blind, placebo-controlled Phase 3 
study evaluating rucaparib maintenance therapy in advanced ovarian cancer. The 
primary endpoint is PFS by Response Evaluation Criteria in Solid Tumors 
(RECIST) version (v)1.133 as assessed by the investigator. Risk/benefit will be 
assessed regularly by an Independent Data Monitoring Committee (IDMC) that 
will have access to unblinded datasets. 
This study will enroll patients with platinum-sensitive, high-grade serous or 
endometrioid epithelial ovarian, primary peritoneal, or FTC who achieved either a 
complete response (CR) by RECIST v1.1 or a partial response (PR), defined as 
either a RECIST v1.1 PR or a cancer antigen 125 (CA-125) response by 
Gynecologic Cancer Intergroup (GCIG) criteria,34 to their last platinum-based 
regimen. All responses will require CA-125 that is within the  
upper limit of normal (ULN). During the screening phase, each patient will have 
archival tumor tissue analyzed for mutations in homologous recombination 
pathway genes. Genes of interest will be sequenced using Foundation Medicine’s 
next generation sequencing (NGS) test, which examines a panel of cancer-related 
genes, including BRCA1/2 and other homologous recombination pathway genes. 
Patients will be stratified into one of three HRD subgroups (BRCA1/2 mutation in 
tumor tissue [tBRCA], HRD due to mutation in a homologous recombination 
gene other than BRCA1/2 [nonBRCA HRD (nbHRD)], or biomarker negative) 
for randomization based on the results obtained with Foundation Medicine’s 
Initial Clinical Trial Assay (ICTA) (Appendix A). Enrollment of patients known a 
priori to harbor a gBRCA mutation classified as deleterious (pathogenic), 
suspected deleterious, or equivalent, on the most recent assessment, will be 
limited to 150. Enrollment of patients with a BRCA gene mutation detected in 
tumor tissue (tBRCA), including those known to harbor a gBRCA mutation, will 
be limited to 200. Once this cap is reached, newly screened patients identified as 
having a BRCA mutation in tumor tissue will be offered treatment in another 
study. 
The complete results of the Foundation Medicine NGS test, which examines 
exons of 287 genes as well as introns of 19 genes, will be provided to all patients 
who opt to receive this information and provide appropriate consent. Tumor tissue 
results for the BRCA genes will be provided to patients who consent to receive 
this information upon availability. Results for the remainder of the gene panel will 
be provided to consenting patients upon study treatment discontinuation. Results 
are to be disclosed to consenting patients by the study physician as part of an 
overall clinical discussion. In the event a mutation associated with hereditary 
cancer or other syndrome is detected in tumor tissue, the patient will be referred 
by the investigator for genetic counseling and potential germline testing per 
institutional guidelines. If the patient chooses to have germline BRCA testing, this 
result will be entered into the clinical trial database.  
Mutations detected in tumor tissue may be somatic or germline; however, the 
NGS test will not distinguish between the two. A blood sample will therefore be 
collected for all patients and stored. Prior to final efficacy analysis, genomic DNA 
may be subjected to exploratory analysis in order to determine whether any 
mutation identified is of germline or somatic origin. 
Tumor DNA will also be assessed by the NGS test to detect the presence of 
genomic scars.35-38 Analysis of specific genomic scarring patterns may identify 
tumors with HRD regardless of the underlying mechanism(s). The extent of 
genomic scarring and its utility in predicting clinical outcome with rucaparib will 


Clovis Oncology, Inc. 
 
Clinical Protocol CO-338-014 
Oral rucaparib (CO-338) 
06 July 2020  
Amendment 5 
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be assessed in a Phase 2 study (CO-338-017) that will be initiated in parallel with 
this Phase 3 study, but will be completed earlier. The insights from study 
CO-338-017 will be applied prospectively to the analysis of this Phase 3 study. 
The FCTA analysis plan (gene mutation and/or genomic scarring) and 
classification of HRD subgroups will be finalized and locked down prior to the 
completion of the Phase 3 study and applied prospectively to the primary efficacy 
analysis. The sponsor will remain blinded to all tumor tissue and germline test 
results until the primary efficacy analysis is conducted. 
Number of 
Patients 
Approximately 540 patients will be enrolled. A minimum of 180 and a maximum 
of 200 patients with a deleterious tBRCA mutation will be enrolled. Enrollment of 
patients with a known deleterious gBRCA mutation documented in their medical 
record will not exceed 150. There is no minimum number of patients required for 
each of the nbHRD and biomarker negative subgroups; however, no more than 
360 total patients will be randomized for stratification into these subgroups 
combined. 
Number of Sites 
This is a multicenter, multinational study. Patients will be enrolled from 
approximately 90 – 100 study sites. 
Study Duration 
Q4 2013 – Q2 2022 (estimated last patient, last visit [LPLV]) 
Study Objectives 
The primary objective of this study is: 
• 
To evaluate PFS by RECIST, as assessed by the investigator, in 
molecularly-defined HRD subgroups 
The secondary objectives of this study are: 
• 
To evaluate patient-reported outcome (PRO) of disease-related symptoms 
utilizing the disease-related symptoms – physical (DRS–P) subscale of 
the National Comprehensive Cancer Network-Functional Assessment of 
Cancer Therapy (NCCN-FACT) FACT-Ovarian Symptom Index 18 
(FOSI-18)  
• 
To evaluate PRO utilizing the complete FOSI-18 
• 
To evaluate survival benefit 
• 
To evaluate PFS by RECIST, as assessed by independent radiology 
review (IRR), in molecularly-defined HRD subgroups  
• 
To evaluate safety 
• 
To determine the population pharmacokinetics (PK) of rucaparib 
The exploratory objectives of this study are: 
• 
To evaluate the relationship between CA-125 levels and disease 
progression as assessed by investigator (invPFS) 
• 
To evaluate PFS2 (PFS on the subsequent line of treatment) 
• 
To evaluate ORR 
• 
To evaluate duration of response (DOR) 
• 
To evaluate PRO utilizing the Euro-Quality of Life 5D (EQ-5D) 
• 
To explore the relationship between rucaparib exposure, efficacy, and 
safety 
Study Population 
  
 
Inclusion Criteria 
All patients enrolling into the study must meet all of the following inclusion 
criteria: 
1. Have signed an Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC)-approved informed consent form prior to any study-specific 


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evaluation 
2. Be ≥18 years of age at the time the informed consent form is signed 
3. Have a histologically confirmed diagnosis of high-grade (Grade 2 or 3) serous 
or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal 
cancer 
− For mixed histology, >50% of the primary tumor must be confirmed to be 
high-grade serous or endometrioid 
− Grade 2 tumors classified under a 3-tier system should be re-reviewed by 
local pathology and confirmed as high-grade under the 2-tier system  
4. Received prior platinum-based therapy and have platinum-sensitive disease 
(i.e. documented radiologic disease progression >6 months following the last 
dose of the penultimate platinum administered) 
− Received ≥2 prior platinum-based treatment regimens, including platinum-
based regimen that must have been administered immediately prior to 
maintenance therapy in this trial. In addition, up to 1 non-platinum 
chemotherapy regimen is permitted. Prior hormonal therapy is permitted; 
this treatment will not be counted as a non-platinum regimen.  
− There is no upper limit on the number of prior platinum-based regimens 
that may have been received, but the patient must have been sensitive to 
the penultimate platinum-based regimen administered. 
− If both neoadjuvant and adjuvant treatment were administered pre/post any 
debulking surgery, this will be considered 1 treatment regimen 
− Prior maintenance therapy following a prior treatment regimen is 
permitted, with the exception of the regimen received immediately prior to 
maintenance in this study. No anticancer therapy is permitted to be 
administered as maintenance treatment in the interval period between 
completion of the most recent platinum-based therapy and initiation of 
study drug in this trial. 
5. 
Achieved best response of either CR or PR to the most recent platinum-based 
regimen administered and is randomized to study treatment within 8 weeks 
of the last dose of platinum received.  
− The most recent platinum-based regimen must have been a chemotherapy 
doublet. The choice of the platinum and the 2nd chemotherapy agent is per 
investigator’s discretion. 
− A minimum of 4 cycles of platinum chemotherapy must have been 
administered. There is no cap on the maximum number of cycles; however, 
additional cycles of treatment administered following completion of 
therapy for the specific purpose of enabling patient eligibility and 
randomization within 8 weeks of the last platinum dose is not permitted. 
− A CR is defined as a complete radiologic response per RECIST v1.1, i.e. 
absence of any detectable disease and CA-125 <ULN.* 
− A PR is defined as either a partial response per RECIST v1.1 (if disease 
was measurable prior to chemotherapy) or a serologic response per GCIG 
CA-125 response criteria (if disease was not measurable according to 
RECIST v1.1).* 
o CA-125 must also be <ULN for all responses classified as a PR 


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− R0 surgery (no visible tumor) or R1 surgery (residual disease <1 cm) as a 
component of the most recent treatment regimen is not permitted. The 
response assessment must be determined solely in relation to the 
chemotherapy regimen administered. The presence of measurable disease 
or CA-125 > 2 x ULN immediately prior to the chemotherapy regimen is 
required. 
− Responses must have been maintained through the completion of 
chemotherapy and during the interval period between completion of 
chemotherapy and entry in the study. 
− 
All disease assessments performed prior to and during this chemotherapy 
regimen must be adequately documented in the patient’s medical record 
6. 
Have sufficient archival formalin-fixed paraffin-embedded (FFPE) tumor 
tissue (1 x 4 µm section for hematoxylin and eosin [H&E] stain and 
approximately 8 to 12 x 10 µm sections, or equivalent) available for planned 
analyses. 
− 
The most recently collected tumor tissue should be provided, if available 
− 
Submission of a tumor block is preferred; if sections are provided, these 
must all be from the same tumor sample. 
− 
Sample must be received at the central laboratory at least 3 weeks prior 
to start of treatment in order to enable stratification for randomization 
7. 
Have CA-125 measurement that is < ULN 
8. 
Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 
to 1 
9. 
Have adequate organ function confirmed by the following laboratory values 
obtained within 14 days of the first dose of study drug: 
− 
Bone Marrow Function 
o 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
o 
Platelets > 100 × 109/L  
o 
Hemoglobin ≥ 9 g/dL 
− 
Hepatic Function 
o Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) ≤ 3 × ULN; if liver metastases, then ≤ 5 × ULN 
o Bilirubin ≤ 1.5 × ULN (< 2 x ULN if hyperbilirubinemia is due to 
Gilbert’s syndrome) 
− 
Renal Function  
o Serum creatinine ≤ 1.5 × ULN or estimated glomerular filtration rate 
(GFR) ≥ 45 mL/min using the Cockcroft Gault formula 
* Note: It is acceptable for sites to utilize local and contemporaneous clinical 
imaging reports to record lesion measurement history and define a burden of 
disease according to RECIST; it is not a requirement to re-read radiological 
scans to collect this data. 


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Exclusion Criteria 
Patients will be excluded from participation if any of the following criteria apply: 
1. History of a prior malignancy except: 
− Curatively treated non-melanoma skin cancer 
− Breast cancer treated curatively > 3 years ago, or other solid tumor treated 
curatively > 5 years ago, without evidence of recurrence 
− Synchronous endometrioid endometrial cancer (Stage 1A G1/G2) 
2. Prior treatment with any PARP inhibitor, including oral or intravenous 
rucaparib. Patients who previously received iniparib are eligible. 
3. Required drainage of ascites during the final 2 cycles of their last platinum-
based regimen and/or during the period between the last dose of chemotherapy 
of that regimen and randomization to maintenance treatment in this study 
4. Symptomatic and/or untreated central nervous system (CNS) metastases. 
Patients with asymptomatic previously treated CNS metastases are eligible 
provided they have been clinically stable for at least 4 weeks. 
5. Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that 
would, in the opinion of the investigator, interfere with absorption of study 
drug 
6. Known human immunodeficiency virus (HIV) or acquired immunodeficiency 
syndrome (AIDS)-related illness, or history of chronic hepatitis B or C 
7. Pregnant or breast feeding. Women of child-bearing potential must have a 
negative serum pregnancy test ≤ 3 days prior to first dose of study drug. 
8. Received treatment with chemotherapy, radiation, antibody therapy or other 
immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or 
experimental drugs ≤14 days prior to first dose of study drug and/or ongoing 
adverse effects from such treatment > NCI-CTCAE Grade 1, with the 
exception of Grade 2 non-hematologic toxicity such as alopecia, peripheral 
neuropathy and related effects of prior chemotherapy that are unlikely to be 
exacerbated by treatment with study drug 
− Ongoing hormonal treatment for previously treated breast cancer is 
permitted 
− Refer also to inclusion criteria #4 for guidelines pertaining to prior 
maintenance therapy 
9. Received administration of strong CYP1A2 or CYP3A4 inhibitors ≤ 7 days 
prior to first dose of study drug or have on-going requirements for these 
medications (Appendix F) 
10. 
Non-study related minor surgical procedure ≤5 days, or major surgical 
procedure ≤21 days, prior to first dose of study drug; in all cases, the patient 
must be sufficiently recovered and stable before treatment administration 
11. Presence of any other condition that may increase the risk associated with 
study participation or may interfere with the interpretation of study results, 
and, in the opinion of the investigator, would make the patient inappropriate 
for entry into the study 
Pregnancy is an exclusion criterion and women of child-bearing potential must 
not be considering getting pregnant during the study. 
Female patients of reproductive potential must practice a highly effective method 


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of contraception (failure rate < 1% per year) with their male partners during 
treatment and for 6 months following the last study drug dose. 
No waivers of these inclusion or exclusion criteria will be granted by the 
investigator and the sponsor or its designee for any patient enrolled into the study. 
Study Treatment  Eligible patients will be randomized 2:1 to receive rucaparib (600 mg twice a day 
[BID]) or placebo. Randomization will occur by a central randomization 
procedure using an Interactive Voice Response System/Interactive Web Response 
System (IVRS/IWRS). The following will be included as randomization 
stratification factors at study entry to ensure treatment groups are balanced:  
• 
HRD classification (tBRCA, nbHRD, or biomarker negative) by the ICTA 
(Appendix A). 
• 
Interval between completion of the penultimate platinum-based regimen and 
disease progression (6 to 12 or >12 months) by radiologic assessment 
• 
Best response to the most recent platinum-based regimen (CR [defined as 
complete radiologic response by RECIST or PR [defined as partial response 
by RECIST and/or a GCIG CA-125 response]). All responses require that 
CA-125 be <ULN. 
Randomization to study treatment must occur within 8 weeks following a 
patient’s last dose of platinum-based chemotherapy. Study drug will be taken 
orally twice daily (12 hours apart) with at least 8 oz (240 mL) of water. Study 
drug may be taken with an empty stomach or with food. 
Patients will take study drug twice daily for continuous 28-day cycles until 
disease progression by RECIST as assessed by the investigator, or other reason 
for discontinuation. Treatment interruptions and/or dose reductions are permitted 
in the event of unacceptable toxicity. 
Withdrawal 
Criteria 
A patient must be discontinued from treatment with study drug if any of the 
following apply: 
• Consent withdrawal at the patient’s own request or at the request of their 
legally authorized representative 
• Progression of patient’s underlying disease by RECIST as assessed by the 
investigator 
• Any event, adverse or otherwise, that, in the opinion of the investigator, would 
pose an unacceptable safety risk to the patient 
• An intercurrent illness that, in the opinion of the investigator, would affect 
assessments of the clinical status to a significant degree and requires 
discontinuation of therapy 
• A positive pregnancy test at any time during the study 
Disease 
Assessments for 
Efficacy 
Efficacy measures will include clinical examination, CA-125 measurement, and 
appropriate imaging (CT scans of the chest, abdomen, and pelvis with appropriate 
slice thickness per RECIST); other studies (magnetic resonance imaging [MRI], 
X ray, positron emission tomography [PET], and ultrasound) may be performed if 
required. Disease assessment will be performed at screening, at the end of every 
12 calendar weeks after start of treatment on Day 1 of Cycle 1, at discontinuation 
of treatment, and as clinically indicated 
Disease progression will be determined by RECIST (Appendix B). Patients with a 
CR at study entry will only be considered to have disease progression if a new 


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lesion is identified. Patients who meet GCIG CA-125 criteria (Appendix C) for 
disease progression should have a radiologic assessment by RECIST. If the 
radiologic assessment does not confirm disease progression, patients should 
continue on treatment and be assessed by RECIST per the protocol schedule.  
Patients who discontinued treatment for reason other than disease progression or 
death should continue to have tumor scans performed at 12-week intervals (up to 
1 week prior is permitted) until disease progression, as assessed by the 
investigator. Patients who have been on study at least 18 months may 
decrease the frequency of disease assessments to every 16 (±2) weeks. 
Investigator should consult with sponsor’s medical monitor before 
decreasing frequency.   
Safety 
Assessments 
Safety assessments may include adverse events (AEs), hematology, serum 
chemistry, vital signs, body weight, concomitant medications/procedures, ECOG 
performance status (Appendix D), and study drug modifications. As of 
implementation of Protocol Amendment 5, AEs will be monitored but only 
serious adverse events (SAEs)/adverse events of special interest (AESIs) will be 
recorded in the eCRF. Ongoing SAEs and AESIs will be followed until 
resolution, stabilization, or lost to follow-up. 
Statistical 
Procedures  
Sample Size Justification 
The total enrollment planned is 540 patients. A minimum of 180 and a maximum 
of 200 patients with a deleterious tBRCA mutation will be enrolled. Enrollment 
of patients with a known deleterious gBRCA mutation documented in their 
medical record will not exceed 150. There is no minimum number of patients 
required for each of the nbHRD and biomarker negative subgroups; however, no 
more than 360 total patients will be randomized for stratification into these 
subgroups combined. Prior to final efficacy analysis, HRD classification will be 
determined by the FCTA that will evaluate homologous recombination gene 
mutations and/or extent of genomic scarring in tumor tissue. 
The table below provides estimated sample sizes and power calculations. 
Group 
Hazard 
Ratio 
Cumulative 
N  
Minimum 
Number of 
Events 
(70%) 
Median 
PFS 
Placebo vs 
Rucaparib 
(months) 
Power 
One-
sided 
Alpha 
tBRCA  
0.50 
180 
126 
6 vs 12 
90% 
0.025 
All HRD 
(tBRCA + 
nbHRD) 
0.60 
300 
210 
6 vs 10 
90% 
0.025 
ITT 
Population 
(tBRCA + 
nbHRD + 
Biomarker 
Negative) 
0.70 
540 
378 
6 vs 8.5 
90% 
0.025 
Analysis Populations 
Safety: The safety population will consist of all patients who received at least one 
dose of protocol-specified treatment. 
Intent-to-treat (ITT): The ITT population will consist of all randomized patients.  


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Response evaluable: The response evaluable population will consist of all patients 
who have measurable or evaluable disease at study entry, received at least one 
dose of study drug, and who had at least one post-baseline disease assessment. 
General Statistical Considerations 
Quantitative variables will be summarized using descriptive statistics. For 
variables registered on a continuous scale, the following will be presented: N, 
mean, standard deviation, median, minimum and maximum. Categorical variables 
will be presented using frequencies and percentages. The Kaplan-Meier 
methodology will be used to summarize time-to-event variables. The stratified 
hazard ratio from the Cox proportional hazards model will be used to estimate the 
HR between the randomized treatment groups. The primary and key secondary 
endpoints will be tested among the tBRCA subgroup, all HRD subgroup, and all 
randomized patients, using an ordered step-down multiple comparisons 
procedure.  
Investigator-determined PFS (invPFS) in the tBRCA subgroup will be tested first 
at a one-sided 0.025 significance level. If invPFS in the tBRCA subgroup is 
statistically significant, then invPFS will be tested in the all HRD subgroup 
followed by invPFS in all randomized patients. Continuing in an ordered step-
down manner, the PRO of disease symptoms utilizing the DRS-P subscale of the 
FOSI-18 will be tested at the one-sided 0.025 significance level in the tBRCA, all 
HRD, and all randomized patients subgroups and then for the remaining key 
secondary endpoints of PRO utilizing the FOSI-18 total score and OS. Once 
statistical significance is not achieved for one test the statistical significance will 
not be declared for all subsequent analyses in the ordered step-down procedure. 
PFS by IRR will be evaluated as a stand-alone secondary endpoint. 
Primary Efficacy Analysis 
The primary efficacy analysis for the study is investigator-determined PFS 
(invPFS) by RECIST. Investigator-determined PFS is defined as the time 
from randomization to disease progression, according to RECIST v1.1 
criteria as assessed by the investigator, or death due to any cause, 
whichever occurs first. The stratification factors included in the primary 
analysis of invPFS will be HRD classification (tBRCA, nbHRD or biomarker 
negative), interval between completion of penultimate platinum regimen and 
disease progression (6 to 12 months or >12 months) by radiologic assessment, 
and best response to the most recent platinum-based regimen (either CR [defined 
as complete radiologic response by RECIST] or PR [defined as partial response 
by RECIST and/or a GCIG CA-125 response]). All responses require that 
CA-125 be <ULN. 
Tumor HRD status by the FCTA will be determined after randomization, but 
before the final efficacy analysis, so that the primary endpoint (PFS in 
molecularly defined subgroups) can be assessed prospectively. 
Secondary Efficacy Analyses 
Secondary efficacy endpoints include: 
• 
PRO of disease-related symptoms as measured by the DRS-P 
subscale score of the FOSI-18 
• 
PRO as measured by the total score of the FOSI-18 
• 
Overall survival (OS) 


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• 
PFS by RECIST v1.1 as assessed by IRR 
The time to an event in PRO of worsening of disease symptoms will be defined as 
the time from randomization to a 4-point reduction in the FOSI-18 DRS−P 
subscale score. Similarly, an event in worsening of PRO utilizing the FOSI-18 
total score will be defined as the time from randomization to an 8-point reduction 
in the total score. 
OS, time to death from any cause, is defined as the number of days from the date 
of randomization to the date of death (due to any cause). Patients without a 
known date of death will be censored on the date the patient was last known to be 
alive. 
PFS for secondary efficacy analysis is defined as the time from randomization to 
disease progression, according to RECIST v1.1 criteria as assessed by IRR, or 
death due to any cause, whichever occurs first.  
Safety Analysis 
Data from all patients who receive at least one dose of study drug will be included 
in the safety analyses. AEs, clinical laboratory information, vital signs, ECOG 
performance status, body weight, and concomitant medications/procedures will be 
tabulated and summarized. 
AEs will be summarized overall, with separate summaries for SAEs, AEs leading 
to treatment discontinuation or death, and CTCAE Grade 3 or higher AEs. 
Independent Data Monitoring Committee (IDMC) 
No formal efficacy interim analyses for early stopping are planned.  
An IDMC will meet regularly to review the efficacy and safety data from this 
study. The IDMC will: 
• 
Review efficacy and safety of rucaparib compared to placebo to ensure 
the study is beneficial to patients;  
• Ensure the study is conducted in a high quality manner; and 
• 
Monitor the size of the tBRCA subgroup and known gBRCA subgroup 
 
The IDMC will hold meetings and continue to review data until the protocol-
specified primary endpoint collection is complete (i.e., 70% of the patients in the 
tBRCA subgroup have an event of PFS) and the IDMC recommend the sponsor to 
unblind the treatment assignments for assessment of primary efficacy. The 
treatment assignment was unblinded in June 2017 for the primary efficacy 
analysis and thus no further IDMC meetings are planned. 


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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AAG 
alpha-1 acid glycoprotein 
ADP 
adenosine diphosphate 
AE 
adverse event 
AESI 
adverse event of special interest 
AIDS 
acquired immunodeficiency syndrome 
ALCOA+ 
attributable, legible, contemporaneous, original, and accurate 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration curve 
AUCR 
ratio of the area under the curve 
BCRP 
breast cancer resistance protein 
BER 
base excision repair 
BID 
twice a day 
BRCA 
breast cancer gene 
BRCA1 
breast cancer gene 1 
BRCA2 
breast cancer gene 2 
BUN 
blood urea nitrogen 
CA-125 
cancer antigen 125 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum concentration 
CNS 
central nervous system 
CR 
complete response  
CRO 
contract research organization  
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events (version 4.03) 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DLT 
dose-limiting toxicity  
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DSB 
double-strand break 
DRS−P 
disease-related symptoms−physical 


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ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
EOC 
epithelial ovarian cancer 
EQ-5D 
Euro-Quality of Life 5D 
EU 
European Union 
FCTA 
Final Clinical Trial Assay 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FOSI-18 
FACT-Ovarian Symptom Index 18 
FSH 
follicle-stimulating hormone 
FTC 
fallopian tube cancer 
GALT 
gut-associated lymphoid tissue 
gBRCA 
germline BRCA 
gBRCAmut 
deleterious germline BRCA mutation 
BRCAwt 
wild-type BRCA 
GCIG 
Gynecologic Cancer InterGroup 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GFR 
glomerular filtration rate 
h 
Hour 
Hct 
Hematocrit 
HDL 
high-density lipoprotein 
H&E 
hematoxylin and eosin 
hERG 
human ether-a-go-go-related gene 
Hgb 
hemoglobin  
HGSOC 
high grade serous ovarian cancer 
HIPAA 
Health Information Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HNSTD 
highest non-severely toxic dose 
HR 
hazard ratio 
HRD 
homologous recombination deficiency 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
ICTA 
Initial Clinical Trial Assay 


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ICxx 
concentration where maximum response is inhibited by XX% 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
invPFS 
disease progression according to RECIST v1.1 as assessed by the investigator, or 
death from any cause 
IRB 
Institutional Review Board  
IRR 
independent radiology review 
irrPFS 
disease progression according to RECIST v1.1 as assessed by independent 
radiology review, or death from any cause 
ITT 
Intent-to-treat 
IV 
intravenous  
IVRS/IWRS 
Interactive Voice Response System/Interactive Web Response System 
LDL 
low-density lipoprotein 
LOH 
loss of heterozygosity 
LPLV 
last patient, last visit 
MATE 
multidrug and toxin extrusion transporter 
MCV 
mean corpuscular volume 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MDS 
Myelodysplastic Syndrome 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
Min 
minute 
MRI 
magnetic resonance imaging 
mut 
mutant 
nbHRD 
non-BRCA homologous recombination deficiency 
NCCN-FACT 
National Comprehensive Cancer Network-Functional Assessment of Cancer 
NCI 
National Cancer Institute 
NGS 
next generation sequencing 
NOAEL 
no-observed-adverse-effect level 
OCT 
organic cation transporter 
ORR 
overall response rate 
OS 
overall survival 
PARP 
poly (adenosine diphosphate [ADP]-ribose) polymerase 
PD 
progressive disease 
PET 
positron emission tomography 
PLD 
PEGylated liposomal doxorubicin 
PFS 
progression-free survival 
PFS2 
second event of progression-free survival 


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06 July 2020  
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P-gp 
P-glycoprotein 
PID 
poly (adenosine diphosphate [ADP]-ribose) polymerase inhibiting dose 
PIS 
patient information sheet 
PK 
pharmacokinetic(s) 
PPC 
primary peritoneal cancer 
PR 
partial response 
PRO 
patient-reported outcome 
PS 
performance status 
QD 
once a day 
QoL 
quality of life 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAS 
statistical analysis software 
sBRCA 
somatic breast cancer gene 1 or 2 mutation 
SD 
stable disease 
SNP 
single-nucleotide polymorphism 
SOC 
system organ class 
SOP 
Standard operating procedure 
SSB 
single-strand break 
SUSAR 
suspected unexpected serious adverse reaction 
tBRCA 
tumor tissue alteration in BRCA1 or BRCA2, includes gBRCA and sBRCA 
TCGA 
The Cancer Genome Atlas 
TEAE 
treatment-emergent adverse events 
Tmax 
time to maximum concentration 
UGT 
uridinediphosphate-glucuronosyletransferase 
ULN 
upper limit of normal 
unk 
unknown 
UV 
ultraviolet 
US 
United States 
v 
version  
VEGF 
Vascular endothelial growth factor 
WBC 
white blood cell 
WOCBP 
women of child-bearing potential 
WT 
wild type 


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3 
INTRODUCTION 
3.1 
Ovarian Cancer 
3.1.1 General Overview 
Ovarian cancer is the second most common gynecologic malignancy worldwide and the leading 
cause of death attributed to gynecological cancer.39, 40 After initial therapy, most women will 
have a progression-free interval of approximately 1.5 to 2 years, depending on the extent of post-
operative residual disease and response to chemotherapy.41 Relapse still occurs, however, in the 
majority of cases, and only 10−30% of women experience long-term survival.41 Advanced stage 
disease is associated with a 5-year survival rate of only 30−40%.39  
Approximately 90% of ovarian tumors are surface epithelial in origin, and the papillary serous 
histology subtype accounts for approximately 75%, of which the large majority (70%) is 
high-grade.41 The site of origin of epithelial ovarian cancer (EOC) remains unclear. Some studies 
suggest that serous EOC and primary peritoneal cancer (PPC) arise from the fallopian tube 
epithelium;42, 43 however, other studies suggest an origin within stem cells of the ovarian surface 
epithelium.41, 44 EOC, PPC and fallopian tube cancer (FTC) behave very similarly, and are 
therefore treated in the same way. 
The median age at presentation of EOC is 60 years. Many women present with advanced disease 
and therefore have a poor prognosis. 
3.1.2  Treatment of Ovarian Cancer 
The standard approach to treatment of advanced ovarian cancer is cytoreductive surgery (either 
at time of diagnosis or interval debulking following 2 – 3 cycles of neoadjuvant chemotherapy), 
with the goal of minimizing residual tumor to no visible residual disease, a major prognostic 
indicator for improved survival. Six to eight cycles of platinum- and taxane-based chemotherapy 
is the global standard of care. If initial cytoreduction is not performed, interval debulking surgery 
is considered. This surgery may be carried out after three or four cycles of primary 
chemotherapy, followed by three further cycles of chemotherapy. Platinum analogues, such as 
carboplatin and cisplatin, are the most active agents, mediating their effects through the 
formation of inter- and intra-strand cross-links with deoxyribonucleic acid (DNA).45, 46  
The choice of treatment for relapsed disease is based on the treatment-free interval relative to last 
therapy administered and chemotherapy agents used. As many patients experience multiple 
relapses, prognosis and response to therapy decreases as the interval between last chemotherapy 
exposure and disease relapse shortens. The treatment-free, or specifically the platinum-free 
interval, provides further prognostic information for patients, as therapeutic options lessen and 
survival shortens as a patient’s tumor becomes less responsive to platinum-based therapy.  
Platinum-based regimens dominate ovarian cancer therapy and define treatment groups.46 In 
general, patients whose disease progresses during treatment with a platinum-based regimen are 
considered to have platinum-refractory disease; patients whose disease relapses within 6 months 
after the last platinum agent was administered are considered to have platinum-resistant disease; 


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and patients whose disease relapses more than 6 months after the last platinum-based therapy 
was administered are considered to have platinum-sensitive disease. These classifications are 
clinical, and not based on a mechanistic definition of platinum sensitivity or resistance. 
PARP inhibitor monotherapy has elicited objective responses in patients with platinum-sensitive 
disease as well as in patients with platinum-resistant disease, although response rates are higher 
in the former population.23-25 This indicates that using platinum-sensitivity alone as a selection 
marker for PARP inhibitor therapy is not a very effective tool, although it is a reasonable place to 
begin predictive biomarker development.  
Maintenance therapy following a response to standard treatment provides an opportunity to 
extend the disease-free period. Maintenance strategies evaluated to date for ovarian cancer have 
focused on the prolonged use of single-agent chemotherapy, antiangiogenesis agents, hormonal 
therapy, vaccines, and intraperitoneal chemotherapy. The OCEANS study evaluated carboplatin 
and gemcitabine with or without bevacizumab as part of the initial treatment and then as 
maintenance in women with platinum-sensitive ovarian, primary peritoneal, or FTC who were in 
their first relapse following primary chemotherapy. The addition of bevacizumab resulted in a 
statistically significant improvement in progression-free survival (PFS) (median 12.4 vs 8.4 
months; HR=0.484 [95% CI, 0.388 to 0.605; log-rank P<0.00001]).47 The PFS benefit of 
bevacizumab administered together with chemotherapy followed by single agent bevacizumab 
maintenance treatment compared to chemotherapy alone and placebo maintenance was further 
established in two front-line Phase 3 studies, GOG-218 (HR=0.717 [95% CI, 0.625 to 0.824; log-
rank P<0.001])48 and ICON-7 (HR=0.81 [95% CI, 0.70 to 0.94; log-rank P<0.04]).49 Based on 
these trials, the European Medicines Agency (EMA) approved bevacizumab, in combination 
with carboplatin and paclitaxel, for front-line treatment of advanced (International Federation of 
Gynecology and Obstetrics [FIGO] stages III B, III C and IV) epithelial ovarian, fallopian-tube, 
or primary peritoneal cancer, and, in combination with carboplatin and gemcitabine, for 
treatment of first recurrence of platinum-sensitive epithelial ovarian, fallopian-tube or primary 
peritoneal cancer in women who have not received prior therapy with bevacizumab or other 
vascular-endothelial-growth-factor (VEGF) inhibitors or VEGF-receptor-targeted agents. 
3.1.3 Homologous Recombination Deficiency 
DNA is constantly damaged by both endogenous and exogenous (environmental) assaults. A 
common type of DNA damage is the formation of DNA single-strand breaks (SSBs). During 
normal cell cycling, DNA is replicated and replication forks are eventually stalled by persistent 
SSBs. If stalled replication forks are not rapidly repaired, they can often degenerate and form 
DNA double-strand breaks (DSBs), which are highly likely to be lethal to the cell.  
Normal cells repair SSBs in DNA primarily through base excision repair (BER). While there are 
several variations of BER, all pathways rely on PARP enzymes, of which PARP1 is the best 
characterized. SSBs that are not repaired result in stalled replication forks and the development 
of DSBs, which are in turn primarily repaired by homologous recombination DNA repair, a 
complex process involving multiple proteins, including those encoded by breast cancer gene 1 
and 2 (BRCA1 and BRCA2), among others. 


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If either the BER or homologous recombination pathway is rendered non-functional, the 
remaining functional pathway can compensate to ensure ongoing DNA repair and cell cycling. 
For example, when the BRCA-associated homologous recombination pathway is lost or 
dysfunctional, repair shifts towards the BER repair pathway that is dependent on PARP 
enzymes. In contrast, in the setting in which both repair pathways (BER and homologous 
recombination) are rendered non-functional, the cell dies. This concept, where a defect in either 
of two pathways can be withstood by a cell, but defects in both are lethal, is referred to as 
synthetic lethality. This type of lethality can arise from a variety of different interactions. In the 
case of DNA damage repair, dual non-functionality can be achieved by enzymatic inhibition of 
PARP in the context of a genetic mutation in the BRCA1 or BRCA2 genes. 
Synthetic lethality has been demonstrated in landmark in vitro and in vivo studies as well as in 
several clinical trials that evaluated a single agent PARP inhibitor for the treatment of relapsed 
ovarian cancer and metastatic breast cancer. Bryant and colleagues showed that cell lines and a 
tumor xenograft deficient in homologous recombination (via a defect in a BRCA or other 
homologous recombination gene) were highly sensitive to PARP inhibition.18 This study also 
showed that synthetic lethality could be achieved regardless of whether the mutation was in 
BRCA1 or BRCA2. In a parallel set of experiments, Farmer and colleagues illustrated that 
chemical inhibition of PARP1 was more potent in homozygous BRCA-deficient cell lines than in 
heterozygous mutant or wild-type cell lines.19 These findings were also supported by a 
BRCA2-deficient murine model. Taken together, these studies provided support for the treatment 
of patients with a BRCA-deficient tumor with a PARP inhibitor. 
3.1.4 Role of HRD in Ovarian Cancer 
Homologous recombination pathway defects, either as an initiating event or late event in the 
carcinogenetic process, may be responsible for the genetic instability observed in many cancers. 
An analysis of the Cancer Genome Atlas (TCGA), which examined molecular changes 
associated with high-grade serous ovarian cancer (HGSOC), estimated that approximately 50% 
of patient with HGSOC have homologous recombination deficiency (HRD).3 Drivers of HRD in 
ovarian cancer include: 
1. Germline mutations in the BRCA1 and BRCA2 genes (gBRCA). These are the strongest 
known hereditary factors for EOC, accounting for up to 15% of all EOC.4, 5 These 
patients carry heterozygous deleterious mutations in their germline DNA and develop 
tumors when the remaining wild-type functional allele is inactivated (i.e. “second hit”). 
2. Somatic BRCA1/2 mutations (sBRCA) (approximately 6 – 8% of HGSOC patients)3, 6  
3. Mutation in a homologous recombination gene other than BRCA1/2 (approximately 16% 
of HGSOC patients).3 Nonclinical studies by several groups have identified RAD 
proteins (eg, RAD51, RAD51C, RAD52, RAD54L),7-10 Fanconi Anemia proteins (eg, 
FANCA, FANCC, FANCD2),11-13 and many others (eg, ATM, ATR, CHEK1, CHEK2)14-
17 as being involved in homologous recombination. 
4. Functional silencing of homologous recombination genes, such as through BRCA1 
promoter methylation (approximately 10% of HGSOC patients)3 or other mechanisms 


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Mutations in the BRCA genes in the tumor can be detected through next-generation sequencing 
(NGS). A possible approach to identify non-BRCA patients with HRD is to detect genomic scars 
within the tumor, which arise from the use of error-prone DNA repair pathways when HRR is 
compromised. Through a series of experiments and data analyses, the sponsor has determined 
that a potential method for identifying patients who may be sensitive to rucaparib is to assess 
genomic scarring by quantifying the extent of loss of heterozygosity across the tumor genome 
(tumor genomic loss of heterozygosity [LOH]). One of the main advantages of detecting tumor 
genomic LOH is that it can identify HRD tumors regardless of the underlying mechanisms, 
which include both known (i.e. BRCA mutations) and unknown genomic mechanisms.35, 38  
3.2 
PARP Inhibitors 
Please refer to the current Investigator’s Brochure for comprehensive information on 
rucaparib. 
PARP inhibitors have been evaluated in the clinic for the past decade. Olaparib (AZD-2281), the 
most advanced investigational PARP inhibitor, has demonstrated compelling Phase 2 clinical 
activity, both in treatment and maintenance settings, in relapsed, HGSOC patients (both germline 
BRCA mutant and wild-type) and in metastatic breast cancer patients with a gBRCA mutation. 
The concept of synthetic lethality was exploited in two proof-of-concept clinical studies with 
olaparib in patients with BRCA-associated tumor types. These studies evaluated the efficacy and 
safety of continuous oral dosing with olaparib in women with either relapsed ovarian cancer or 
advanced breast cancer and a gBRCA mutation.21, 22 In these patients, who had received a 
median of three prior chemotherapy regimens, encouraging overall response rates of 33% and 
41%, were observed, in gBRCA ovarian and gBRCA breast cancer, respectively. In a third study, 
olaparib treatment was associated with a greater overall response rate (ORR) in patients with 
gBRCA-associated ovarian cancer compared with the patients in the non-gBRCA associated 
cohort (41% vs 24%, respectively).23 In a fourth study that evaluated olaparib versus PEGylated 
liposomal doxorubicin (PLD) in patients with a gBRCA mutation and relapsed ovarian cancer, 
the efficacy of olaparib was consistent with that observed in previous studies.24  
Activity in HGSOC has also been observed with PARP inhibitor switch maintenance therapy 
following response to platinum-based chemotherapy.31, 32 Patients with platinum-sensitive 
relapsed ovarian cancer who achieved a response to another regimen of platinum-based 
chemotherapy followed by olaparib as switch maintenance treatment experienced a statistically 
significant improvement in median PFS (8.3 months) compared to patients who received placebo 
as maintenance therapy (4.8 months); hazard ratio of 0.35 (95% CI, 0.25 – 0.49).31 Patients with 
a BRCA mutation derived the most benefit (median PFS 11.2 vs 4.3 months; HR=0.18; 95% CI 
0.11-0.31; P<0.00001).32 It should be noted that the outcomes of sBRCA + gBRCA mutant 
patients were the same as gBRCA mutant patients alone, suggesting that, for stratification and 
analysis purposes in the present study, it is appropriate to not differentiate between germline and 
somatic mutations. Patients without a BRCA mutation also experienced significant benefit from 
treatment with olaparib (HR=0.53; 95% CI 0.33-0.84; P=0.007).32  
Niraparib (MK-4827) has exhibited clinical activity in a Phase 1 study in both BRCA-mutated 
ovarian cancer (8 RECIST PRs) and sporadic ovarian cancer (5 RECIST PRs and/or GCIG 


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CA-125 responses).25 In a Phase 1 evaluation of BMN 673, 11 of 17 BRCA-mutated ovarian 
cancer patients treated at doses ≥100 µg/day exhibited a RECIST and/or CA-125 response.26  
Taken together, these data support the potential role for the PARP inhibitor rucaparib in the 
treatment of patients with BRCA-associated ovarian cancer. Furthermore, the 24% ORR and HR 
of 0.53 in the non-BRCA cohorts described above23, 32 suggests that the clinical utility of PARP 
inhibitors can be extended to a larger patient group. Patients with HRD due to defects in 
homologous recombination genes other than BRCA, i.e. nbHRD, may be part of this larger 
group. 
3.3 
Rucaparib 
Rucaparib (formerly known as AG-014447 and PF-01367338) refers to the free base. The 
camphorsulfonic acid salt form (also referred to as camsylate salt) CO-338 (formerly known as 
PF-01367338-BW) will be used in this clinical trial. 
Rucaparib (Rubraca®) is a small molecule inhibitor of PARP-1, PARP-2, and PARP-3 approved 
in the United States (US) as monotherapy treatment for adult patients with deleterious BRCA 
mutation (germline and/or somatic)-associated EOC, FTC, or PPC cancer who have been treated 
with 2 or more prior chemotherapies, and for the maintenance treatment of adult patients with 
recurrent EOC, FTC, or PPC who have a complete or partial response to platinum-based 
chemotherapy.1 Rucaparib is also approved in the European Union (EU) as monotherapy 
treatment of adult patients with platinum-sensitive, relapsed or progressive, BRCA mutated 
(germline and/or somatic), high-grade EOC, FTC, or PPC who have been treated with 2 or more 
prior lines of platinum-based chemotherapy, and who are unable to tolerate further platinum-
based chemotherapy, and for maintenance treatment of adult patients with platinum-sensitive 
recurrent EOC, FTC, or PPC who are in response (complete or partial) to platinum-based 
chemotherapy.2 
Nonclinical evaluation has demonstrated exquisite sensitivity of BRCA1 and BRCA2 
homozygous mutant cell lines to rucaparib and provides a rationale for the clinical assessment of 
rucaparib as monotherapy in patients with hereditary deficiencies of BRCA1 and/or BRCA2. 
Rucaparib has also shown antitumor activity as a single agent in the MDA-MB-436 (BRCA1 
mutant) xenograft mouse model. The activity of rucaparib in these nonclinical experiments was 
similar to that of olaparib. 
Comprehensive nonclinical and clinical information for rucaparib is available in the current 
Investigator’s Brochure. 
3.3.1 Nonclinical Experience 
3.3.1.1 
Rucaparib Absorption, Distribution, Metabolism, and Excretion 
The pharmacokinetics (PK) and toxicokinetics of rucaparib (as camsylate salt) following oral 
administration, the intended route of administration in humans, was evaluated in the mouse, rat, 
and dog. The time at which the peak plasma concentrations were observed (Tmax) occurred at 1–
3 hours post dose in the mouse and dog, with the rat generally exhibiting a later Tmax (4–8 hours). 


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The oral bioavailability was 17%, 36%, and 62%, respectively, in the mouse (50 mg/kg), rat 
(100 mg/kg), and dog (20 mg/kg). In the rat and dog, there were no marked gender-related 
differences and no accumulation after repeat oral administration. A less than dose-proportional 
increase in exposure was observed in the rat and dog when rucaparib was administered as a 
suspension in 0.5% methylcellulose; however, a greater than dose-proportional increase in 
exposure was observed in the 1-month dog toxicity study when rucaparib was administered in 
capsules.  
In vitro plasma protein binding studies in mouse, rat, and dog plasma showed moderate binding 
and ranged from 49.5% to 73%. Plasma protein binding in humans ranged from 55% to 75%.  
Recombinant cytochrome P450 (CYP) studies indicated that CYP2D6, and to a lesser extent, 
CYP1A2 and CYP3A4, have the ability to metabolize rucaparib.  
In vitro studies indicated that rucaparib reversibly inhibited (in order of decreasing potency) 
CYP1A2, CYP2C19, CYP2C9, CYP3A, CYP2C8, and CYP2D6. Rucaparib demonstrated 
concentration-dependent induction of CYP1A2 and down-regulation of CYP3A4 and CYP2B6 at 
clinically relevant concentrations in a hepatocyte incubation study. No time-dependent CYP 
inhibition was observed. Rucaparib also moderately inhibited uridinediphosphate-
glucuronosyletransferase (UGT)1A1. Based on in vitro CYP interaction data, the drug-drug 
interaction (DDI) potential of rucaparib as a CYP inhibitor and/or inducer was assessed by 
calculating the ratio of AUC (AUCR) of CYP substrate drugs in the presence and absence of 
rucaparib at target clinical exposures (600 mg twice a day [BID]) using the mechanistic static 
modeling.50, 51 AUCR allows a conservative estimation of the magnitude of DDIs. Based on this 
analysis, the DDI potential for rucaparib was estimated to be moderate (AUCR 2 to 5) for 
CYP3A (AUCR=5.0), CYP1A2 (AUCR=2.9), CYP2C8 (AUCR=2.6), and CYP2D6 
(AUCR=2.3); but appeared to be strong (AUCR > 5) for CYP2C19 (AUCR=11) and CYP2C9 
(AUCR=5.2). Clinical implication of CYP3A downregulation was unknown and thus not 
considered in the modeling; however, downregulation could further increase AUCR for CYP3A 
and result in elevated exposures of drugs that are CYP3A substrates.  
Rucaparib is a substrate for both P-glycoprotein (P-gp) and breast cancer resistance protein 
(BCRP). In vitro data indicate rucaparib is a potent inhibitor of multidrug and toxin extrusion 
transporter (MATE)-1 and MATE2-K (efflux transporters on renal tubule cells), and moderate 
inhibitor of organic cation transporter (OCT)1, BCRP, and P-gp.  
Quantitative whole body autoradiography studies in Long Evans rats showed [14C] rucaparib 
radioequivalents were rapidly and widely distributed to tissues following IV administration, 
consistent with a large volume of distribution. At 2 minutes after dosing, highest concentrations 
were found in kidney, lung, thyroid gland, heart, stomach mucosa, liver adrenal glands, spleen, 
and blood. Little radioactivity was present in brain; levels were undetectable at 15 minutes after 
dosing. Activity was undetectable in most tissues by 96 hours after dosing, however levels in the 
choroid/retina declined more slowly, and persistent radioactivity was also found in hair follicles 
through 192 hours, indicating that drug equivalents have high affinity and long half-life in 
pigmented tissues. High levels of radioactivity were observed in ureters, bladder, and bile ducts, 
indicating both renal and biliary routes eliminated drug equivalents.  


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3.3.1.2 
Multiple-Dose Toxicity Studies 
Rucaparib was evaluated in both rat and dog in oral and IV infusion toxicity studies. Only the 
multiple-dose toxicity studies utilizing the oral formulation are summarized below. Details of all 
other toxicity studies are provided in the Investigator’s Brochure. 
Target organs identified in studies where rucaparib was administered orally include the 
hematopoietic system and gastrointestinal tract. No cardiovascular findings were noted in any of 
the oral toxicity studies. 
Multiple-Dose Oral Toxicity in Rats 
Administration of rucaparib camsylate salt via oral gavage was generally well-tolerated in the rat 
up to 1000 mg/kg/day for 7 days and up to 150 mg/kg/day for 28 days. Decreases in body weight 
gain and food consumption were noted in both studies. In the 7-day study, target organs 
identified microscopically were bone marrow, spleen, and thymus. Minimal to mild bone 
marrow hypocellularity was noted in all dose groups. The no-observed-adverse-effect-level 
(NOAEL) was established at 500 mg/kg/day. 
In the 28-day study, there were 3 rucaparib-related deaths at 500 mg/kg/day immediately after 
blood collection on Day 28 (n=1) or Day 29 (first day of recovery phase (n=2). These deaths 
likely resulted from the marked anemia identified hematologically. Other rucaparib-related 
clinical signs at 500 mg/kg/day included thinning haircoat and pale eyes. Identified target organs 
included bone marrow, spleen, lymphoid tissue (thymus, gut-associated-lymphoid tissue 
[GALT], and lymph nodes), and cecum (at 500 mg/kg/day only). Following cessation of 
rucaparib dosing, most findings reversed. In this study, the severe toxic dose in 10% of the 
animals (STD10) was 500 mg/kg/day and the NOAEL was 50 mg/kg/day. 
Rucaparib camsylate in capsules was also given orally to rats at doses of 10, 40, and 
100 mg/kg/day for 91 consecutive days with a 28-day recovery period. Decreased body weight 
and body weight gain were observed for animals given ≥40 mg/kg/day. At the end of the 
recovery phase, mean body weight was still lower for males given 100 mg/kg/day and females 
given ≥40 mg/kg/day. Hematological findings included decreases in red blood cell mass 
parameters in animals given ≥40 mg/kg/day (which correlated with decreased bone marrow 
hypocellularity), and decreases in reticulocytes, white blood cells (WBC) and absolute 
lymphocytes at ≥40 mg/kg/day. The latter changes correlated with the microscopic findings of 
decreased lymphocytes in the mandibular lymph nodes and gut-associated lymphoid tissue. All 
effects were reversible. Microscopically, bone marrow hypocellularity at 100 mg/kg/day and 
minimally decreased lymphocytes in lymphoid tissues at ≥40 mg/kg/day were noted and were 
completely reversed at the end of the recovery period. The NOAEL was established to be 
100 mg/kg/day. 
Multiple-Dose Oral Toxicity in Dogs 
Oral gavage administration of the camsylate salt form of rucaparib to dogs for 7 days resulted in 
gastrointestinal clinical signs at the 80 mg/kg/day high-dose group. Hematopoietic effects of 
decreased reticulocytes were noted in mid- to high-dose groups and leukopenia was exhibited in 
all treatment groups. Lymphoid atrophy occurred in both sexes and in all treatment groups. 


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Decreased bone marrow cellularity was seen in both sexes (males at all doses; females at 
80 mg/kg/day). A 7-day repeat-dose toxicity study using oral capsules in dogs was repeated in 
order to characterize the toxicity of a new lot of rucaparib camsylate. Similar to the results of the 
prior 7-day study in dog, gastrointestinal clinical findings were noted at 80 mg/kg/day. Vomiting 
was observed throughout the dosing phase for males as well as liquid and/or mucoid feces in 
both genders. Decreased food consumption was observed at 80 mg/kg/day that correlated with 
the body weight loss that was considered adverse. Decreases in erythroid, platelet, and leukocyte 
parameters were observed primarily at 80 mg/kg/day and occasionally at 20 or 5 mg/kg/day. 
These data indicated that the drug targeted multiple bone marrow lineages in a dose-related 
pattern. 
Rucaparib camsylate salt in capsules was administered orally to dogs for 30 consecutive days 
with a 29-day recovery. Gastrointestinal clinical signs were noted at ≥5 mg/kg/day, with 
decrease in food consumption at 75 mg/kg/day. Adverse hematological changes (decrease in 
erythroid, myeloid, and megokaryocytic lineages) occurred at ≥20 mg/kg/day. Effects were fully 
reversible. The NOAEL in this study was 5 mg/kg/day. 
Rucaparib camsylate in capsules was also given orally to dogs at doses of 3, 15/10, 
40/30/20 mg/kg/day for 91 consecutive days with a 29-day recovery period. Body weight losses 
and inappetance observed at the high dose in both sexes during the first quarter of the dosing 
phase were considered adverse and resulted in dose reductions (40 to 30 to 20 mg/kg/day for 
toxicity and 15 to 10 mg/kg day in order to maintain multiples of exposures for optimal testing of 
dose response) for the remainder of the study. Clinical pathology findings were indicative of 
bone marrow toxicity; these changes were non-progressive over time suggesting potential 
adaptation to these initial effects. Hematological findings at 40/30/20 mg/kg/day correlated with 
erythroid atrophy of the bone marrow detected microscopically. By Day 29 of recovery, most 
effects reversed. The highest non-severely toxic dose (HNSTD) for this study was 20 mg/kg/day 
for male dogs. No HNSTD was established for female dogs. The NOAEL was 10 and 
20 mg/kg/day for male and female dogs, respectively. 
3.3.1.3 
Additional Observations 
In vitro genetic toxicology assays demonstrated oral rucaparib to be clastogenic. Bacterial 
mutagenicity data for rucaparib were clearly negative in four microbial tester strains, both with 
and without metabolic activation, and equivocal in a fifth tester strain.  
In an in vitro assay for human ether-a-go-go-related gene (hERG) activity, the IC50 and IC20 for 
the inhibitory effects of rucaparib (50% inhibitory concentration and 20% inhibitory 
concentration) on hERG potassium currents were 24 µM (7761 ng/mL) and 7 µM (2264 ng/mL), 
respectively. These values are 9-fold and 2.6-fold higher, respectively, than the mean unbound 
steady state plasma concentration (858 ng/mL) observed to date in humans at a dose of 600 mg 
BID rucaparib administered orally. 
Effects on appearance and behavior, motor activity, body temperature, and a number of 
neurofunctional tests and reflexes were evaluated in rats. A dose of 50 mg/kg of rucaparib 
administered via IV infusion (mean maximum concentration [Cmax]=13629 ng/mL) resulted in a 
significant reduction in motor activity compared with vehicle-treated animals; however, there 


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were no effects on neurofunctional or reflex testing at this dose. The plasma concentration 
measured at this dose is 4.7-fold above the mean steady state plasma concentration (2880 ng/mL) 
observed to date in humans at a dose of 600 mg BID rucaparib administered orally. 
Administration of rucaparib to Long-Evans rats orally at doses up to 750 mg/kg/dose, followed 
by a single exposure to solar-simulated ultraviolet radiation approximately 4 hours after the final 
dose elicited no skin or ocular reactions indicative of phototoxicity. The no-observed-effect-level 
(NOEL) for phototoxicity was >750 mg/kg/day. 
3.3.2 Clinical Experience 
The early clinical program assessed safety and efficacy of rucaparib in patients with 
malignancies commonly treated with chemotherapeutic agents. Initially, the IV formulation of 
rucaparib was administered in combination with a variety of chemotherapies; later, the oral 
formulation of rucaparib was administered in combination with chemotherapy and as a 
monotherapy. The oral formulation as monotherapy is the focus of current development efforts. 
Information regarding clinical studies with rucaparib is available in the Investigator’s Brochure. 
3.3.2.1 
Rucaparib Monotherapy 
3.3.2.1.1 Study CO-338-010 
Clovis-sponsored study CO-338-010 is a 2-part, open-label, safety, PK, and preliminary efficacy 
study of oral rucaparib administered daily for continuous 21-day cycles. Part 1 is a Phase 1 
portion in patients with any solid tumor, including lymphoma, who have progressed on standard 
treatment. The primary objective of Part 1 is to determine the optimal monotherapy dose for 
orally administered rucaparib. Part 2 is a Phase 2 portion in patients with platinum-sensitive 
relapsed ovarian cancer with evidence of a gBRCA mutation who have received at least 2, but no 
more than 4, prior regimens. The primary objective of Part 2 is to assess the overall objective 
response rate by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 
Study CO-338-010 was initiated in Q4 2011. As of 27 June 2014, 56 patients (median age 50 yrs 
[range 21−71]; 51 female; 27 breast cancer, 20 ovarian/peritoneal cancer, 9 other tumor) were 
treated at dose levels of 40, 80, 160, 300, and 500 mg once daily (QD), and 240, 360, 480, 600, 
and 840 mg BID rucaparib administered continuously in the Phase 1 portion of the study. A total 
of 50 patients discontinued rucaparib; n=46 due to disease progression; n=2 due to an adverse 
event (AE) (unrelated to rucaparib); n=1 due to consent withdrawal; and n=1 due to an eligibility 
criteria violation. One of 6 patients treated with 360 mg BID rucaparib experienced a dose-
limiting toxicity (DLT) of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 
nausea despite maximal intervention in Cycle 1 of treatment. No DLTs were observed during 
Cycle 1 in the 480 (n=9), 600 (n=5), and 840 mg BID (n=3) cohorts; however, similar to other 
PARP inhibitors, non-DLT myelosuppression was observed beyond Cycle 1. The dose of 
600 mg BID rucaparib was selected as the recommended dose for Phase 2 and Phase 3 studies 
based on the overall safety & tolerability, PK, and clinical activity profile. As of June 27, 2014, 
15 patients (median age=58 [range=45-84]; 9 ECOG PS=0) with platinum-sensitive, relapsed 


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ovarian cancer associated with a deleterious BRCA1/2 mutation have been enrolled in the 
Phase 2 portion of the study. One patient has discontinued rucaparib due to disease progression. 
Treatment-related AEs (all grades) reported in ≥15% of patients treated with 600 mg BID 
rucaparib include gastrointestinal and related symptoms (nausea, vomiting, dysgeusia, diarrhea, 
abdominal pain, and decreased appetite), anemia, fatigue/asthenia, and headache. Elevations of 
alanine aminotransferase (ALT) and/or AST have been reported. The ALT/AST elevations occur 
early (within first 2-4 weeks of treatment), were generally mild to moderate (Gr 1-2), not 
accompanied by any changes in bilirubin levels, and often transient and resolved to within 
normal ranges, or stabilize. No patient met the laboratory criteria for Hy’s Law.52 As has been 
observed with rucaparib and other PARP inhibitors, myelosuppression may be delayed and 
observed after a period of continuous dosing. All treatment-related AEs were successfully 
managed with concomitant medication, supportive care, treatment interruption and/or dose 
reduction. No patient discontinued rucaparib treatment due to a treatment-related AE. A total of 
five patients have died on study or within 30 days of last dose of rucaparib; all deaths were due 
to disease progression and were assessed as not related to rucaparib. 
Extensive centrally-reviewed electrocardiogram (ECG) monitoring was conducted in the Phase I 
portion of Study CO-338-010. ECG results (as triplicate reads) are available for all 56 treated 
patients. No patient had a QTcF measurement ≥500 msec at any time during study participation. 
Only one patient had a QTcF measurement ≥480 msec. This measurement occurred in a patient 
receiving 480 mg BID rucaparib and concomitant administration of citalopram, a medication 
with known potential to cause QT prolongation. This patient has continued to receive 
monotherapy rucaparib at a dose of 480 mg BID with no further QTcF measurement ≥480 msec. 
No patient experienced a ≥60 msec increase in QTcF over baseline. The data suggest no 
relationship between QTcF increase and dose or exposure. In addition, there were no AEs 
suggestive of cardiac arrhythmia (eg, presyncope, syncope, sudden death) in any patient. ECG 
and AE data as of the cutoff date in patients receiving monotherapy rucaparib at doses up to 
840 mg BID suggest there is a minimal risk of QTc prolongation. 
In the Phase 1 portion, 2 patients (1 breast cancer, 1 ovarian cancer, both gBRCAmut) achieved a 
RECIST CR and 7 patients (2 ovarian cancer, 4 breast cancer, 1 pancreatic cancer; all 
gBRCAmut) achieved a RECIST PR (n=2 at 300 mg QD; n=2 at 360 mg BID; n=3 at 480 mg 
BID; and n=2 at 600 mg BID). In addition, 3 patients with ovarian cancer achieved a cancer 
antigen 125 (CA-125) response as defined by Gynecologic Cancer InterGroup (GCIG) criteria. 
The disease control rate (CR, PR, or SD>12 wks at doses ≥360 mg BID in evaluable ovarian 
cancer patients is 92% (11/12). Responses have been durable across tumor types. 
Preliminary efficacy data are available for 16 patients in the Phase 2 portion of Study 
CO-338-010. Currently, 12 of 16 (75%) patients have achieved a RECIST PR. Response to 
treatment occurs rapidly; the majority of these patients achieved a PR by the first disease 
assessment (week 6). All responses are ongoing, with several patients in Cycle 5 of treatment or 
beyond. The vast majority of patients had some level of target lesion measurement reduction as 
shown in Figure 1. 


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Figure 1 
Best Response in Target Lesions – Phase 2 Portion of Study CO-338-010 
 
After once daily oral administration of rucaparib for 15 days, steady state Cmax and AUC0-24 
generally increased dose proportionally. Tmax and t1/2 were independent of dose. Steady state 
exposure increased by an average of 89%, consistent with accumulation expected for a 
compound exhibiting a t1/2 of approximately 17 hours administered once daily. Following BID 
oral administration of rucaparib for 15 days, steady state Cmax and AUC0-24 generally increased 
dose proportionally. Moreover, BID dosing delivered a lower Cmax with a low peak to trough 
plasma concentration variation. The target trough level of 2 µM was achieved in 100% of 
patients (n=14) at ≥240 mg BID with low inter-patient variability (<4-fold) within each dose 
group. Steady state trough levels also exhibited low intra-patient variability (24% coefficient of 
variation). No sporadically high exposures were observed. The effect of food on rucaparib PK 
was evaluated at 40 mg (n=3) and 300 mg (n=6) doses administered once daily. There was no 
food effect; patients may take rucaparib on an empty stomach or with food.  
Updates of study information may be found in the Investigator’s Brochure. 
3.3.2.1.2 Study CO-338-017 
Study CO-338-017 (ARIEL2) is a Phase 2 study of rucaparib as monotherapy treatment for 
relapsed, platinum-sensitive high-grade ovarian, fallopian tube or primary peritoneal cancer. The 
purpose of this study is to define a tumor-based molecular signature of HRD in ovarian cancer 
that correlates with response to rucaparib and enables selection of appropriate ovarian cancer 


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patients for treatment with rucaparib. The trial is enrolling patients with and without a BRCA1/2 
mutation in order to enable identification of this response signature, which will then be 
prospectively applied to the primary analysis of study CO -338-014 (ARIEL3). Tumor HRD 
status is assessed using next generation sequencing, with an algorithm for HRD status based on 
the presence of a BRCA mutation (germline or somatic) and/or degree of tumor genomic LOH, a 
phenotypic consequence of HRD.  
All patients enrolled into Clinical Study CO-338-017 (ARIEL2) must have received at least 1 
prior platinum-based treatment regimen, received a platinum-based regimen as their last course 
of treatment and have platinum-sensitive disease, defined as disease progression >6 months after 
the last dose of platinum. In addition, all patients must have disease that can be biopsied and is 
measurable by RECIST v1.1. Rucaparib 600 mg BID is administered continuously until disease 
progression. 
Clinical Study CO-338-017 (ARIEL2) was initiated in October 2013. As of 27 June 2014, 72 of 
180 planned patients have been enrolled. The median age is 65.5 years (range 44 – 83) and the 
majority of patients (n= 54, 75%) had Eastern Cooperative Oncology Group (ECOG) 
performance status of 0.  
The most frequent (reported in ≥15% of patients treatment-related AEs (all grades) as of 27 June 
2014 are gastrointestinal-related toxicities (nausea, constipation, vomiting, diarrhea, and 
abdominal pain), fatigue, elevations in ALT/AST, decreased appetite, and dysgeusia. 
Transaminase elevations occur early in treatment and are generally transient and resolve or 
stabilize. All patients who experienced AEs related to rucaparib, including those with Grade 3 
transaminase elevation, were successfully managed by treatment interruption and/or a dose 
reduction. No patient has discontinued rucaparib due to a treatment-related AE. No patients have 
died on study or within 30 days of last dose of rucaparib. 
Response data are preliminary, yet indicate that rucaparib has activity in BRCAwt patients with 
high level of LOH as well as in BRCAmut patients. 
Updates of study information may be found in the Investigator’s Brochure. 
3.3.2.1.3 Study A4991002, A4991005, and A4991014 
Further details of these studies are provided in the Investigator’s Brochure. 
3.3.2.1.4 Safety: Events of Special Interest 
The current list of adverse events of special interest (AESIs) is located in the rucaparib IB.  
3.4 
Rationale for Study 
In vitro studies have shown that cells deficient in BRCA1/2 as well as cells deficient in or 
depleted of homologous recombination proteins other than BRCA1/2 have been associated with 
PARP inhibitor sensitivity in vitro.18, 19, 27-30 Clinical data have shown that ovarian cancer 
patients with and without evidence of a gBRCA mutation benefit from treatment with a PARP 
inhibitor20-24 and that maintenance treatment with a PARP inhibitor following a response to 


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platinum-based treatment increases PFS in patients with ovarian cancer.31, 32 While patients with 
a BRCA mutation derived the most benefit, patients without evidence of a BRCA mutation also 
derived significant benefit.23, 32 The purpose of this study is to evaluate PFS of patients with 
platinum-sensitive, high-grade serous or endometrioid epithelial ovarian, fallopian tube, or 
primary peritoneal cancer who receive rucaparib or placebo as switch maintenance therapy 
following a response to platinum-based chemotherapy in order to identify the patients most 
likely to benefit from treatment with rucaparib. It is anticipated that rucaparib will provide 
therapeutic benefit and increase PFS in patients with HRD associated with a BRCA gene 
mutation or other HR gene alteration. 
Patients will be stratified into one of 3 HRD subgroups (tBRCA, nbHRD, and biomarker 
negative) (Appendix A) by Foundation Medicine’s ICTA, which will determine HRD status 
through analysis of homologous recombination gene mutations in tumor tissue. Tumor DNA will 
also be assessed to detect the presence of genomic scars.35-38 Analysis of specific genomic 
scarring patterns may identify tumors with HRD regardless of the underlying mechanism(s). 
Homologous recombination gene mutation analysis and genomic scarring will also be assessed in 
a Phase 2 study (CO-338-017) that will be initiated in parallel with this Phase 3 study. The 
insights from study CO-338-017 will be applied prospectively to the analysis of this Phase 3 
trial. The Final Clinical Trial Assay (FCTA) analysis plan (gene mutation and/or genomic 
scarring) and classification of HRD subgroups will be finalized and locked down prior to the 
completion of the Phase 3 study and applied prospectively to the analysis of this Phase 3 study. 


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4 
STUDY OBJECTIVES 
4.1 
Objectives and Endpoints 
This is a double-blind efficacy study of oral rucaparib in patients with platinum-sensitive, 
relapsed high-grade serous or endometrioid epithelial ovarian, fallopian tube, or primary 
peritoneal cancer who receive rucaparib or placebo as switch maintenance therapy following a 
response to platinum-based chemotherapy. 
Primary, secondary, and exploratory objectives and endpoints are shown in Table 1. 
Table 1. 
Primary, Secondary, and Exploratory Objectives and Endpoints 
Primary Objectives 
Primary Endpoints 
1. To evaluate PFS by RECIST, as assessed by 
the investigator, in molecularly-defined 
HRD subgroups 
1. 
Disease progression according to 
RECIST v1.1, as assessed by the investigator, 
or death from any cause (invPFS), in 
molecularly defined subgroups 
Secondary Objectives 
Secondary Endpoints 
1. To evaluate patient-reported outcome (PRO) 
of disease related symptoms utilizing the 
disease-related symptoms – physical 
(DRS−P) subscale of the National 
Comprehensive Cancer Network-Functional 
Assessment of Cancer Therapy 
(NCCN-FACT) FACT-Ovarian Symptom 
Index 18 (FOSI-18) 
1. 
Time to a 4-point decrease in the DSR−P 
subscale of the FOSI-18 
2. To evaluate PRO utilizing the complete 
FOSI-18 
2. Time to an 8-point decrease in the total score of 
the FOSI-18 
3. To evaluate survival benefit 
3. Overall survival (OS) 
4. To evaluate PFS by RECIST, as assessed by 
independent radiology review (IRR), in 
molecularly-defined HRD subgroups 
4. Disease progression according to RECIST v1.1, 
as assessed by IRR, or death from any cause 
(irrPFS), in molecularly defined subgroups 
5. To evaluate safety  
5. Incidence of AEs, clinical laboratory 
abnormalities, and dose modifications 
6. To determine the population PK of rucaparib 6. Individual model parameter estimates of 
rucaparib and covariates identification 
Exploratory Objectives 
Exploratory Endpoints 
1. To evaluate the relationship between CA-
125 levels and invPFS 
1. Association between the change from baseline 
in CA-125 measurements and invPFS 
2. To evaluate PFS2 (PFS on the subsequent 
line of treatment) 
2. Time to the next event of disease progression or 
death, as assessed by the investigator 
3. To evaluate ORR 
3. ORR per RECIST v1.1, as assessed by both 
investigator and IRR, in patients with 
measureable disease at study entry 


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Table 1. 
Primary, Secondary, and Exploratory Objectives and Endpoints 
4. To evaluate duration of response (DOR) 
4. DOR per RECIST v1.1, as assessed by both 
investigator and IRR 
5. To evaluate PRO utilizing the Euro-Quality 
of Life 5D (EQ-5D) 
5. PRO as measured by the total score on the 
EQ-5D 
6. To explore the relationship between 
rucaparib exposure, efficacy, and safety 
6. Rucaparib PK, invPFS, irrPFS, CA-125, AEs, 
clinical laboratory abnormalities, and dose 
modifications 


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5 
STUDY DESIGN 
5.1 
Overall Study Design and Plan 
This is a double-blind efficacy study of oral rucaparib in patients with platinum-sensitive, 
high-grade serous or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer 
who receive rucaparib or placebo as switch maintenance therapy following a response to 
platinum-based chemotherapy. 
5.1.1 Screening Phase 
All patients will undergo screening assessments within 120 days prior to randomization.  
The study will enroll patients with platinum-sensitive (defined as disease with confirmed 
radiologic relapse > 6 months after the last dose of the penultimate platinum regimen received), 
high-grade serous or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer 
who achieved a response to platinum-based chemotherapy administered for relapsed disease. 
Patients must have received ≥ 2 prior platinum-based treatment regimens, inclusive of the 
regimen that must have been administered immediately prior to maintenance therapy in this trial. 
There is no limit on the number of prior platinum-regimens that may have been received, but the 
patient must have been sensitive to the penultimate platinum regimen received. In addition, up to 
1 prior non-platinum chemotherapy regimen is permitted. Prior hormonal therapy is permitted; 
this treatment will not be counted as a non-platinum regimen. Prior maintenance therapy may 
have been administered with any prior treatment, with the exception of the platinum regimen 
received immediately prior to maintenance in this study. For the last chemotherapy course prior 
to study entry, patients must have received a platinum-based doublet chemotherapy regimen 
(minimum 4 cycles) and have achieved a CR (defined as complete radiologic response by 
RECIST [Appendix B] or PR (defined as partial response by RECIST [Appendix B] and/or a 
GCIG CA-125 response [Appendix C]. All responses require that CA-125 be < ULN. The 
response must be maintained through the completion of chemotherapy and during the interval 
period between completion of chemotherapy and entry in the study.  
Screening assessments will include demographics and medical history, prior treatments for 
serous or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer (and other 
malignancies, if applicable), prior and current medications and procedures, 12 lead 
electrocardiogram (ECG), ECOG performance status, central laboratory hematology, serum 
chemistry, and CA-125 measurement, serum pregnancy (for women of child-bearing potential 
only), urinalysis, physical examination, height, weight, and vital signs measurements, AEs, and 
radiologic assessment by CT or MRI. PRO will be collected using the FOSI-18 and EQ-5D 
instruments. 
Germline BRCA mutation results should be obtained for all patients who are known to have been 
tested prior to enrollment in order to determine whether any mutation was reported and if so, 
whether the mutation was classified as deleterious/pathogenic or other. Enrollment of patients 
with a gBRCA mutation classified as deleterious (i.e. pathogenic), suspected deleterious, or the 
equivalent, on the most recent assessment by a testing laboratory will be limited to 150. Patients 
with a BRCA mutation detected in tumor tissue (tBRCA) will be limited to 200. Once this cap is 


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reached, newly screened patients identified as having a BRCA mutation in tumor tissue will be 
offered treatment in another study. 
The complete results of the Foundation Medicine NGS test, which examines exons of 287 genes 
as well as introns of 19 genes, will be provided to all patients who opt to receive this information 
and provide appropriate consent. Results for the BRCA genes will be provided to patients who 
consent to receive this information upon availability. Results for the remainder of the gene panel 
will be provided to consenting patients upon treatment discontinuation. All results are to be 
disclosed to consenting patients by the study physician as part of an overall clinical discussion. 
In the event a mutation associated with hereditary cancer or other syndrome is detected in tumor 
tissue, the patient will be referred by the investigator for genetic counseling and potential 
germline testing per institutional guidelines. If the patient chooses to have germline BRCA 
testing, this result will be entered into the clinical trial database. The sponsor will remain blinded 
to all NGS test results (including all tBRCA results), as well as existing BRCA data, until the 
primary efficacy analysis is conducted. 
Mutations detected in tumor tissue may be somatic or germline; however, the NGS test will not 
distinguish between the two. A blood sample will therefore be collected for all patients and 
stored. Prior to final efficacy analysis, genomic DNA may be subjected to exploratory analysis in 
order to determine whether any mutation identified is of germline or somatic origin. This data 
will be generated in a research setting and will not be provided to the investigator or patient. 
However, if an actionable mutation, as defined by the American College of Medical Genetics 
and Genomics, is revealed that was not classified as deleterious on the tumor-based NGS test 
report, these blood-based incidental findings will be made available to the investigator, provided 
the results are generated from a Clinical Laboratory Improvement Amendment-certified 
laboratory.53 
Enrollment will require Clovis (or designee) review of eligibility, including, but not limited to: 
• The number of prior therapies and the details for the penultimate and most recent 
platinum-based regimens, including dates administered; 
• documentation supporting platinum sensitivity; 
• documentation supporting a RECIST or GCIG CA-125 response to most recent 
platinum-based treatment; 
• confirmation if patient has had local gBRCA testing;  
• confirmation that sufficient tumor tissue was submitted for HRD stratification for 
randomization and storage for potential bridging to a validated companion 
diagnostic test and analysis results were successfully transmitted to IXRS 


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5.1.2 Randomization 
Randomization to study treatment must occur within 8 weeks following a patient’s last dose of 
platinum-based chemotherapy, and is described in more detail in Section 7.2. Study treatment 
must be initiated within 3 days of randomization. 
5.1.3 Double-Blind Treatment Phase 
For patients remaining on treatment as of implementation of Protocol Amendment 5, a more 
limited number of assessments will be performed during the treatment period as compared to 
previously; however, an appropriate level of safety monitoring will remain in place. A revised 
Schedule of Assessments, which replaces all prior schedules of assessments and should be 
followed for all patients who remain on treatment or in long-term follow-up, is provided in 
Section 9.1. 
During the double-blind treatment phase (continuous 28-day treatment cycles), patients will be 
monitored for safety and efficacy. Assessments will include AEs; serum pregnancy for women of 
child-bearing potential; complete blood count (monthly assessment advised); subsequent 
medications, therapies and procedures; and study drug administration and accountability. In 
addition, clinical chemistry, urinalysis, and vital signs may be performed per local standard of 
care practices.  
Patients will be assessed for disease status per RECIST v1.1 every 12 calendar weeks (up to 
1 week prior is permitted) following initiation of study treatment on Day 1 of Cycle 1. Patients 
experiencing disease progression by RECIST v1.1, as assessed by the investigator, will be 
discontinued from treatment and enter follow-up. Disease progression will only be determined 
by RECIST v1.1. Patients with a CR at study entry will only be considered to have disease 
progression if a new lesion is identified. Patients who meet GCIG CA-125 criteria for disease 
progression should have a radiologic assessment and be assessed by RECIST v1.1. If the 
radiologic assessment does not confirm disease progression, patients should continue on 
treatment and be assessed by RECIST v1.1 per the protocol schedule of assessments. Patients 
who have been on study at least 18 months may decrease the frequency of disease assessments to 
every 16 (±2) weeks. Investigator should consult with sponsor’s medical monitor before 
decreasing frequency.  
Sites were previously notified that as of 06 December 2019, CT scans (and other imaging, as 
appropriate) performed during the treatment period and at treatment discontinuation will no 
longer be collected for IRR. 
Patients were continuously monitored for safety. An Independent Data Monitoring Committee 
(IDMC) with multidisciplinary representation evaluated safety in compliance with a prospective 
charter.  
The IDMC was discontinued when the primary study endpoint of progression-free survival was 
reached.  


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5.1.4 Treatment Discontinuation 
Upon treatment discontinuation, regardless of reason, patients will have a Treatment 
Discontinuation visit. Assessments at this visit will include AEs, serum pregnancy for women of 
child-bearing potential, disease status assessment, and study drug accountability; in addition, 
complete blood count, clinical chemistry, urinalysis, and vital signs may be performed per local 
standard of care practices. An optional tumor biopsy will be collected from patients who 
experience disease progression and provide appropriate consent prior to the start of any 
subsequent anticancer treatment. If disease progression is caused by appearance of a new 
lesion(s), the lesion(s) should be prioritized for the optional biopsy. All patients discontinued 
from treatment will be followed for 28 days following the last dose of study drug for the 
collection of AEs. 
5.1.5 Follow-Up Phase 
After the Treatment Discontinuation visit, all patients will be followed for AEs up to 28 days 
after last dose of study drug. All serious adverse events (SAEs) and AESIs are to be followed to 
resolution, stabilization, or lost to follow-up (refer to Section 10.7) even if the duration extends 
beyond the 28-day follow-up period. Patients will also be followed for survival, subsequent 
treatments, and monitoring for secondary malignancy approximately every 12 weeks (± 14 days) 
until death, loss to follow-up, withdrawal of consent, or study closure.  
Patients who discontinued treatment for reason other than disease progression or death should 
continue to have tumor scans performed at 12 week intervals from Cycle 1 Day 1 (a window of 
up to 7 days prior is permitted) until disease progression by RECIST v1.1, as assessed by the 
investigator, or death. Patients who have been on study at least 18 months may decrease the 
frequency of disease assessments to every 16 (±2) weeks. Investigator should consult with 
sponsor’s medical monitor before decreasing frequency.  
5.2 
Study Schema 
An overview of the study design is provided in Figure 2. 


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Figure 2 
Study Schema 
 
NOTE: With the implementation of Protocol Amendment 4, the collection of PRO data was no longer 
required. Other assessments have been revised with the implementation of Protocol Amendment 5. Please 
refer to the schedule of assessments (Table 3). 


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5.3 
End of Study 
The trial is monitored on an ongoing basis by an IDMC for the number of PFS events required 
for the primary endpoint and for safety signals. An unblinding of treatment assignment might be 
performed when the study is still ongoing if the IDMC recommends it. However, the study is not 
anticipated to close until all patients are off treatment and sufficient OS follow up has occurred, 
which could include patients being transferred to another study for OS follow up. Upon formal 
closure of the study, individual patients who are continuing to benefit from treatment with 
rucaparib at the time of study closure, and who do not meet any of the criteria for withdrawal, 
will have the option of receiving rucaparib via another access mechanism.  
The sponsor may discontinue the study early for any reason as noted in Section 13.7. 
5.4 
Discussion of Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled study. 
Sponsor personnel (with the exception of individuals responsible for clinical supply chain), 
investigator and clinical site staff, and patient will all be blinded to study treatment to avoid bias 
in the interpretation of the efficacy and safety results. To avoid bias between treatment groups, 
patients will be randomized to treatment with active drug or placebo with stratification according 
to HRD classification, interval between completion of penultimate platinum-based regimen and 
disease progression by radiologic assessment, and best response to platinum regimen received 
immediately before initiation of maintenance therapy.  
PFS by RECIST will be assessed by the investigator for the primary endpoint (invPFS) and by a 
blinded independent radiologist for the secondary endpoint (irrPFS). 
Ongoing benefit/risk will be assessed regularly by an IDMC that will have access to unblinded 
datasets. The IDMC will hold meetings and continue to review data until the protocol specified 
primary endpoint collection is complete (i.e., 70% of the patients in the tBRCA subgroup have an 
event of PFS) and the IDMC recommend the sponsor to unblind the treatment assignments for 
assessment of primary efficacy. The treatment assignment was unblinded in June 2017 for the 
primary efficacy analysis and thus no further IDMC meetings are planned. Unless a patient is 
unblinded for safety reasons or following approval by Clovis Oncology, all study investigators 
will remain blinded to patient treatment assignment until final study analysis. 


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6 
STUDY POPULATION 
6.1 
Number of Patients and Sites 
Approximately 540 patients with platinum-sensitive, relapsed, high-grade serous or endometrioid 
epithelial ovarian, fallopian tube, or primary peritoneal cancer will be enrolled at approximately 
90 – 100 study sites. A minimum of 180 and a maximum of 200 patients with a deleterious 
tBRCA mutation will be enrolled. Enrollment of patients with a known deleterious gBRCA 
mutation documented in their medical record will not exceed 150. There is no minimum number 
of patients required for each of the nbHRD and biomarker negative subgroups; however, no 
more than 360 total patients will be randomized for stratification into these subgroups combined. 
6.2 
Inclusion Criteria 
All patients enrolling into the study must meet all of the following inclusion criteria: 
1. Have signed an Institutional Review Board/Independent Ethics Committee-approved 
informed consent form prior to any study-specific evaluation 
2. Be ≥18 years of age at the time the informed consent form is signed 
3. Have a histologically confirmed diagnosis of high-grade (Grade 2 or 3) serous or 
endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer  
− For mixed histology, >50% of the primary tumor must be confirmed to be high-grade 
serous or endometrioid 
− Grade 2 tumors classified under a 3-tier system should be re-reviewed by local pathology 
and confirmed as high-grade under the 2-tier system  
4. Received prior platinum-based therapy and have platinum-sensitive disease (i.e. documented 
radiologic disease progression >6 months following the last dose of the penultimate platinum 
administered) 
− Received ≥2 prior platinum-based treatment regimens, including platinum-based regimen 
that must have been administered immediately prior to maintenance therapy in this trial. 
In addition, up to 1 non-platinum chemotherapy regimen is permitted. Prior hormonal 
therapy is permitted; this treatment will not be counted as a non-platinum regimen. 
− There is no upper limit on the number of prior platinum-based regimens that may have 
been received, but the patient must have been sensitive to the penultimate platinum-based 
regimen administered. 
− If both neoadjuvant and adjuvant treatment were administered pre/post any debulking 
surgery, this will be considered 1 treatment regimen 
− Prior maintenance therapy following a prior treatment regimen is permitted, with the 
exception of the regimen received immediately prior to maintenance in this study. No 
anticancer therapy is permitted to be administered as maintenance treatment in the 
interval period between completion of the most recent platinum-based therapy and 
initiation of study drug in this trial. 


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5. Achieved best response of either CR or PR to the most recent platinum-based regimen 
administered and is randomized to study treatment within 8 weeks of the last dose of 
platinum received 
− The most recent platinum-based regimen must have been a chemotherapy doublet. The 
choice of the platinum and the 2nd chemotherapy agent is per investigator’ discretion. 
− A minimum of 4 cycles of platinum chemotherapy must have been administered. There is 
no cap on the maximum number of cycles; however, additional cycles of treatment 
administered following completion of therapy for the specific purpose of enabling patient 
eligibility and randomization within 8 weeks of the last platinum dose is not permitted. 
− A CR is defined as a complete radiologic response per RECIST v1.1, i.e. absence of any 
detectable disease and CA-125 <ULN* 
− A PR is defined as either a partial response per RECIST v1.1 (if disease was measurable 
prior to chemotherapy) or a serologic response per GCIG CA-125 response criteria (if 
disease was not measurable according to RECIST v1.1)* 
− CA-125 must also be <ULN for all responses classified as a PR 
− R0 surgery (no visible tumor) or R1 surgery (residual disease <1 cm) as a component of 
the most recent treatment regimen is not permitted. The response assessment must be 
determined solely in relation to the chemotherapy regimen administered. The presence of 
measurable disease or CA-125 >2 x ULN immediately prior to the chemotherapy regimen 
is required. 
− Responses must have been maintained through the completion of chemotherapy and 
during the interval period between completion of chemotherapy and entry in the study 
− All disease assessments performed prior to and during this chemotherapy regimen must 
be adequately documented in the patient’s medical record 
6. Have sufficient archival formalin-fixed paraffin-embedded (FFPE) tumor tissue (1 x 4 µm 
section for hematoxylin and eosin [H&E] stain and approximately 8 – 12 x 10 µm sections, 
or equivalent) available for planned analyses. 
− The most recently collected tumor tissue sample should be provided, if available  
− Submission of a tumor block is preferred; if sections are provided, these must all be from 
the same tumor sample 
− Sample must be received at the central laboratory at least 3 weeks prior to planned 
start of treatment in order to enable stratification for randomization 
7. Have CA-125 measurement that is < ULN 
8. Have ECOG performance status of 0 to 1 
9. Have adequate organ function confirmed by the following laboratory values obtained within 
14 days of the first dose of study drug: 
− Bone Marrow Function 
o 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 


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o 
Platelets > 100 × 109/L  
o 
Hemoglobin ≥ 9 g/dL 
− Hepatic Function 
o 
Aspartate aminotransferase (AST) and ALT ≤ 3 × ULN; if liver metastases, then 
≤ 5 × ULN 
o 
Bilirubin ≤ 1.5 × ULN (< 2 x ULN if hyperbilirubinemia is due to Gilbert’s 
syndrome) 
− Renal Function  
o 
Serum creatinine ≤ 1.5 × ULN or estimated glomerular filtration rate (GFR) 
≥ 45 mL/min using the Cockcroft Gault formula 
* Note: It is acceptable for sites to utilize local and contemporaneous clinical imaging reports 
to record lesion measurement history and define a burden of disease according to RECIST; it 
is not a requirement to re-read radiological scans to collect this data. 
6.3 
Exclusion Criteria 
Patients will be excluded from participation if any of the following criteria apply: 
1. History of a prior malignancy except: 
− Curatively treated non-melanoma skin cancer 
− Breast cancer treated curatively >3 years ago, or other solid tumor treated curatively >5 
years ago, without evidence of recurrence 
− Synchronous endometrioid endometrial cancer (Stage 1A G1/G2) 
2. Prior treatment with any PARP inhibitor, including oral or intravenous rucaparib. Patients 
who previously received iniparib are eligible. 
3. Required drainage of ascites during the final 2 cycles of their last platinum-based regimen 
and/or during the period between the last dose of chemotherapy of that regimen and 
randomization to maintenance treatment in this study 
4. Symptomatic and/or untreated central nervous system (CNS) metastases. Patients with 
asymptomatic previously treated CNS metastases are eligible provided they have been 
clinically stable for at least 4 weeks. 
5. Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that would, in the 
opinion of the investigator, interfere with absorption of study drug 
6. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS)-related illness, or history of chronic hepatitis B or C 
7. Pregnant or breast feeding. Women of child-bearing potential must have a negative serum 
pregnancy test ≤ 3 days prior to first dose of study drug 
8. Received treatment with chemotherapy, radiation, antibody therapy or other immunotherapy, 
gene therapy, vaccine therapy, angiogenesis inhibitors, or experimental drugs ≤ 14 days prior 


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to first dose of study drug and/or ongoing adverse effects from such treatment > 
NCI-CTCAE Grade 1, with the exception of Grade 2 non-hematologic toxicity such as 
alopecia, peripheral neuropathy, and related effects of prior chemotherapy that are unlikely to 
be exacerbated by treatment with study drug 
− Ongoing hormonal treatment for previously treated breast cancer is permitted 
− Refer also to inclusion criteria #4 for guidelines pertaining to prior maintenance therapy 
9. Received administration of strong CYP1A2 or CYP3A4 inhibitors ≤7 days prior to first dose 
of study drug or have on-going requirements for these medications (Appendix F) 
10. Non-study related minor surgical procedure ≤5 days, or major surgical procedure ≤21 days, 
prior to first dose of study drug; in all cases, the patient must be sufficiently recovered and 
stable before treatment administration 
11. Presence of any other condition that may increase the risk associated with study participation 
or may interfere with the interpretation of study results, and, in the opinion of the 
investigator, would make the patient inappropriate for entry into the study 
6.4 
Patients or Partners of Patients of Reproductive Potential 
Pregnancy is an exclusion criterion and women of child-bearing potential must not be 
considering getting pregnant during the study. Female patients are considered to be of 
child-bearing potential unless 1 of the following applies: 
• Postmenopausal, defined as no menses for at least 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level consistently in the 
postmenopausal range (30 mIU/mL or higher) may be used to confirm a postmenopausal 
state in women not using hormonal contraception or hormonal replacement therapy; 
however, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient to confirm a postmenopausal state: or  
• Considered to be permanently sterile. Permanent sterilization includes hysterectomy, 
bilateral salpingectomy, and/or bilateral oophorectomy.  
Female patients of child-bearing potential must have a negative serum pregnancy test result 
≤ 3 days prior to administration of the first dose of study drug. In addition, a serum pregnancy 
test must be performed within ≤ 3 days prior to Day 1 of every subsequent cycle during the 
treatment phase and at the Treatment Discontinuation visit. All pregnancy testing will be 
performed by the local laboratory. 
Female patients of reproductive potential must practice highly effective methods of 
contraception (failure rate < 1% per year) with their male partners during treatment and for 
6 months following the last dose of study drug. Highly effective contraception includes: 
• Ongoing use of progesterone-only injectable or implantable contraceptives (eg, Depo 
Provera, Implanon, Nexplanon); 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS); 


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• Bilateral tubal occlusion;  
• Male sterilization, with appropriate post-vasectomy documentation of absence of sperm 
in ejaculate; or 
• Sexual abstinence as defined as complete or true abstinence, acceptable only when it is 
the usual and preferred lifestyle of the patient; periodic abstinence (eg, calendar, 
symptothermal, post-ovulation methods) is not acceptable. 
Patients will be instructed to notify the investigator if pregnancy is discovered either during or 
within 6 months of completing treatment with study drug.  
6.5 
Waivers of Inclusion/Exclusion Criteria 
No waivers of these inclusion or exclusion criteria will be granted by the investigator and the 
sponsor or its designee for any patient enrolling into the study. 


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7 
DESCRIPTION OF STUDY TREATMENTS AND DOSE MODIFICATIONS 
7.1 
Description of Investigational Product 
Rucaparib camsylate (also known as CO-338; previously known as PF-01367338-BW) is an oral 
formulation with a molecular weight of 555.67 Daltons. Rucaparib tablets for oral administration 
and matched placebo tablets will be supplied to the study sites by the sponsor. A brief 
description of the investigational product is provided below.  
Drug Name: 
CO-338 
rINN: 
rucaparib  
Formulation: 
Tablet; film coated; 120 mg (salmon, oval), 200 mg (blue, round, 
debossed with C2), 250 mg (white, rounded diamond shape, debossed 
with C25), 300 mg (yellow, oval, debossed with C3) 
How Supplied: 
120, 200, 250, and 300 mg (as free base) strength tablets in high-density 
polyethylene bottles or equivalent with child-resistant caps. Patients may 
receive one or more strengths. 
Storage Conditions: 
15–30 °C/ 59-86 ºF 
 
Placebo tablets will be identical in appearance to the rucaparib tablets, matched for each strength. 
Study drug containers containing rucaparib or placebo tablets will be labeled according to 
national regulations for investigational products together with the batch expiry date. 
Exceptionally, where accepted, the expiry date for the 120 mg strength tablets will not appear on 
the labels, but will be controlled by the use of an Interactive Voice Response System/Interactive 
Web Response System (IVRS/IWRS). 
7.2 
Method of Assigning Patients to Treatment Groups 
Following confirmation of eligibility in the screening phase, patients will be randomized 2:1 to 
receive rucaparib or placebo. Randomization will occur by a central randomization procedure 
using IVRS/IWRS. The following will be included as randomization stratification factors at 
study entry to ensure treatment groups are balanced:  
• HRD classification (tBRCA, nbHRD, or biomarker negative) by the ICTA 
(Appendix A) 
• Interval between completion of the penultimate platinum-based regimen and 
disease progression (6 to 12 or >12 months) by radiologic assessment 
• Best response (CR [defined as complete radiologic response by RECIST] or PR 
[defined as partial response by RECIST and/or a GCIG CA-125 response] to 
platinum regimen received immediately prior to initiation of maintenance therapy. 
All responses require that CA-125 be <ULN. 
Randomization to study treatment must occur within 8 weeks following a patient’s last dose of 
platinum-based chemotherapy. Study treatment must be initiated within 3 days of randomization. 


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7.3 
Preparation and Administration of Protocol-Specified Treatment 
The investigator or designee will be responsible for distributing study drug to all patients. Study 
drug will be assigned by the IVRS/IWRS according to the patient’s randomization assignment. 
The system must be accessed at each dispensation in order to retrieve the bottle number 
appropriate to the patient’s treatment. Study sites should follow local guidelines for the handling 
of oral cytotoxic drugs. 
All patients will ingest study drug twice a day. Patients may take study drug on an empty 
stomach or with food (with a regular meal or within 30 minutes after a regular meal). Each dose 
should be taken with at least 8 oz (240 mL) of room temperature water. Tablets should be 
swallowed whole.  
Patients should take study drug doses as close to 12 hours apart as possible, preferably at the 
same times every day. If a patient misses a dose (i.e. does not take it within 4 hours of the 
scheduled time), she should skip the missed dose and resume taking study drug with their next 
scheduled dose. Missed or vomited doses should not be made up. 
A sufficient number of tablets will be provided to the patient to last until the next scheduled visit. 
Patients will be instructed to bring their study drug tablets and all containers (empty, partially 
used, and/or unopened) to the next scheduled visit for reconciliation by site personnel. A 
compliance check and tablet count will be performed by study personnel during clinic visits and 
the dose dispensation will be entered in the eCRF. 
• 
Once available supplies of 120 mg tablets/matching placebo are exhausted or the expiry 
date is reached, patients receiving this dose strength will be transitioned to 200 mg, 
250 mg or 300 mg tablets/matching placebo, or combination of dose strengths. If/when 
patients are transitioned from 120 mg to 200 mg, 250 mg, or 300 mg strength tablets, the 
investigator has the discretion to select the dose most appropriate for the patient, 
rounding up or down as necessary. 
• 
The dose that a patient will receive upon transition from 120 mg to 200 mg, 250 mg or 
300 mg tablets/matching placebo will be agreed upon between the investigator and 
sponsor (or designee) in advance of any dosing change. 
7.3.1 Dietary Restrictions 
All patients participating in the study should be instructed not to consume any grapefruit 
products or any of the CYP1A2 or CYP3A4 inhibitors noted in Appendix F for 7 days prior to 
their first scheduled dose of oral rucaparib or placebo. 
7.4 
Starting Dose and Dose Modifications of Protocol-Specified Treatment 
7.4.1 Starting Dose 
The starting dose in this study will be 600 mg rucaparib or matched placebo, BID. 


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7.4.2 Dose Modification Criteria  
Treatment with study drug should be held if any of the following are observed and a dose 
reduction should be considered or implemented: 
• Grade 3 or 4 hematologic toxicity  
Grade 3 or 4 non-hematologic toxicity (except for nausea, vomiting, or diarrhea 
adequately controlled with systemic antiemetic/antidiarrheal medication administered in 
standard doses according to the study center routines). Grade 3 or Grade 4 ALT/AST 
elevations should be managed as described below.  
• In addition, and at the discretion of the investigator, the dose of study drug may be held 
and/or reduced for Grade 2 toxicity not adequately controlled by concomitant 
medications and/or supportive care. 
MANAGEMENT OF STUDY DRUG TREATMENT-EMERGENT ALT/AST 
ELEVATIONS 
• Grade 4 ALT/AST elevations: hold study drug until values have returned to Grade 2 or 
better, then resume study drug with a dose reduction. Monitor liver function tests weekly 
for 3 weeks after study drug has been restarted. 
• Grade 3 ALT/AST elevations, in the absence of other signs of liver dysfunction, should 
be managed as follows:  
– Monitor liver function tests weekly until resolution to ≤ Grade 2. 
– Continuation of study drug with elevation of ALT/AST up to Grade 3 is permitted 
provided bilirubin is < ULN and alkaline phosphatase is < 3 x ULN.  
– If patient has Grade 3 ALT/AST and continues on study drug, and levels do not 
decline within 2 weeks or they continue to rise, treatment interruption and 
resolution to ≤ Grade 2 will be required before study drug can be resumed, either 
at the current dose or at a reduced dose. 
Treatment with study drug should be held until the toxicity resolves to ≤ CTCAE Grade 2. Twice 
daily dosing may then be resumed at either the same dose or a lower dose, per investigator 
discretion. If treatment is resumed at the same dose, and the patient experiences the same 
toxicity, the dose should be reduced following resolution of the event to ≤ CTCAE Grade 2. If a 
patient continues to experience toxicity despite dose reduction to 240 mg/300 mg BID rucaparib 
or placebo, or if dosing with study drug is interrupted for > 14 consecutive days due to toxicity, 
treatment discontinuation or further dose reduction should be discussed and agreed between the 
investigator and the sponsor. 
MANAGEMENT OF NEW OR WORSENING PULMONARY SYMPTOMS 
If new or worsening unexplained pulmonary symptoms suggestive of pneumonitis (including, 
but not limited to, dyspnea) occur, or a deterioration of pulmonary function is observed, and/or 
radiologic abnormality is detected in the lungs, and this occurs in the absence of any clear 
diagnosis, a diagnostic workup (including high-resolution CT scan) in consultation with a 


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pulmonologist should be performed in order to rule out pneumonitis. During this time, treatment 
with study drug may be interrupted or continued per investigator discretion. If study drug is 
given in combination with another agent, the contribution of the other agent should also be 
assessed independently. 
Following investigation, if pneumonitis is not confirmed, treatment with study drug may be 
resumed/continued as deemed appropriate by the investigator and in accordance with the study 
protocol directions for management of AEs. All confirmed events of pneumonitis should be 
treated as appropriate per medical judgement and institutional guidelines. If the event resolves 
and retreatment with study drug is being considered, please consult the study Medical Monitor. 
Retreatment with study drug may be resumed at the current or a reduced dose, if appropriate.  
Refer to Section 10.3 and Section 10.8 of the protocol for additional information regarding 
classification and reporting of pneumonitis (and related events) as an AESI. 
Dose reduction steps are presented in Table 2. 
Dose re-escalation upon resolution of toxicity to ≤ CTCAE Grade 1 is permitted at the discretion 
of the investigator. 
Table 2. 
Dose Reduction Steps 
Tablets 
120 mg 
200/250/300 mg 
Starting Dose 
600 mg BID  
Dose Level -1 
480 mg BID 
500 mg BID  
Dose Level -2 
360 mg BID 
400 mg BID  
Dose Level -3* 
240 mg BID 
300 mg BID 
*Additional dose reduction steps should be discussed with the medical monitor. 
7.4.3 
Criteria for Re-Treatment 
A new cycle of treatment may begin if: 
• ANC ≥1.0 x 109/L 
• Platelet count ≥75 x 109/L 
• Non-hematologic toxicities have returned to baseline or ≤ CTCAE Grade 1 
severity (or, at the investigator’s discretion, ≤ CTCAE Grade 2 severity if not 
considered a safety risk for the patient). Grade 3 or Grade 4 ALT/AST elevations 
should be managed as described above. 


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7.5 
Accountability of Protocol-Specified Treatment 
Study personnel will maintain accurate records of study drug receipt, dispensation, use, return, 
destruction, and reconciliation. An IVRS/IWRS will be used to manage study drug inventory at 
all sites. In order to function properly, and to ensure patients receive the correct study drug 
according to the treatment assigned at randomization, the system will require real-time entry of 
study drug receipt, dispensation, or destruction, etc. by study personnel at the study center. 
The site is responsible for the return or destruction of study drug as required. Authorization to 
destroy study drug at the site that has not been dispensed to a patient (eg, expired study drug), 
must be requested from the sponsor prior to destruction. Any study drug accidentally or 
deliberately destroyed must be accounted for. All study drug containers must be accounted for 
prior to their destruction at the study center, according to institutional procedures for disposal of 
cytotoxic drugs. Unused study drug containers should be destroyed on-site if possible. 
Destruction of damaged or expired study drug at the site requires prior approval by the sponsor. 
If destruction on site is not possible, supply should be returned to the drug depot.  
During the course of the study and at completion of the study, the number of study drug 
containers received, dispensed, returned, and destroyed must be reconciled.  
7.6 
Blinding/Masking of Treatment 
Active and matching placebo tablets of the same dose strength will be identical in appearance 
and supplied in identical containers. The medication labeling will ensure that no staff member or 
patient will be able to identify whether the tablets are placebo or contain active medication. 
Patients will take the equivalent number of active or placebo tablets according to the treatment 
assignment and scheduled dose. 
In the event of a medical emergency, an individual patient’s treatment assignment may be 
unblinded using IVRS/IWRS. The module to unblind treatment assignment is accessible only to 
specific authorized study personnel. AEs per se are not a reason to break the treatment code. 
Unblinding should only occur for medical emergencies that require explicit knowledge of the 
treatment administered in order to determine the next course of action. The IVRS/IWRS vendor 
operates a 24-hour/365-day helpline as a back-up in the rare event the electronic system is 
unavailable when unblinding is required. 
The study will not be unblinded for overall safety evaluation. 
7.7 
Treatment Compliance 
Study site personnel will review dosing information with the patient (or legally authorized 
representative) on scheduled clinic visit days, providing instructions regarding dose, dose 
frequency and the number of tablets to be taken for each dose as well as requirements to return 
all containers at next clinic visits for accountability purposes. A compliance check and tablet 
count will be performed by study personnel during clinic visits and the dose dispensation will be 
entered in the eCRF. 


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8 
PRIOR AND CONCOMITANT THERAPIES 
Patients who have received prior treatment with a PARP inhibitor including IV or oral rucaparib, 
are not eligible to participate in this study. Patients having received prior treatment with iniparib 
are eligible. 
During the study, supportive care (eg, antiemetics; analgesics for pain control) may be used at 
the investigator’s discretion and in accordance with institutional procedures. 
All procedures performed (eg, thoracentesis, etc.) and medications used during the study must be 
documented on the eCRF.  
8.1 
Anticancer or Experimental Therapy 
No anticancer therapy is permitted to have been administered as maintenance treatment in the 
interval period between completion of the most recent platinum-based chemotherapy and 
initiation of maintenance treatment in this study. 
No other anticancer therapies (including chemotherapy, radiation, hormonal treatment, antibody 
or other immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or other 
experimental drugs) of any kind will be permitted while the patient is participating in the study, 
with the exception of ongoing hormonal treatment for previously treated breast cancer.  
8.2 
Hematopoietic Growth Factors and Blood Products 
Erythropoietin, darbepoetin alfa, and/or hematopoietic colony-stimulating factors for treatment 
of cytopenias should be administered according to institutional guidelines. Transfusion 
thresholds for blood product support will be in accordance with institutional guidelines. 
8.3 
CYP450 Isoenzyme Inhibitors, Inducers, and Substrates 
Based on the results from the in vivo CYP-interaction clinical study CO-338-044, rucaparib is a 
moderate inhibitor of CYP1A2, a weak inhibitor of CYP2C9, CYP2C19, and CYP3A, and 
shows no clinically significant effect on P-gp. Caution should be used in patients taking 
concomitant medicines that are substrates of CYP1A2, CYP2C9, CYP2C19, and/or CYP3A with 
narrow therapeutic windows; dose adjustments may be considered, if clinically indicated 
(Appendix F). Please refer to current IB for further information. 
Although in vitro rucaparib metabolism mediated by CYP3A4 was slow, a significant 
contribution of CYP3A4 in vivo cannot be excluded. Caution should be used for concomitant use 
of strong CYP3A4 inhibitors or inducers. 
8.4 
Bisphosphonates 
Bisphosphonates are permitted. 


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8.5 
Anticoagulants 
Rucaparib is a weak inhibitor of CYP2C9 in vivo. Caution should be exercised in patients 
receiving study drug and concomitant warfarin (Coumadin). Patients taking warfarin should have 
international normalized ratio (INR) monitored regularly per standard institutional practice.  
8.6 
Other Concomitant Medications 
Therapies considered necessary for the patient’s well-being may be given at the discretion of the 
investigator and should be documented on the eCRF. Other concomitant medications, except for 
analgesics, chronic treatments for concomitant medical conditions, or agents required for 
life-threatening medical problems, should be avoided. Herbal and complementary therapies 
should not be encouraged because of unknown side effects and potential DDIs, but any taken by 
the patient should be documented appropriately on the eCRF. 
Rucaparib marginally increased digoxin area under the plasma concentration-time curve (AUC) 
by 20%. Caution should be exercised for patients receiving rucaparib and requiring concomitant 
medication with digoxin. Patients taking digoxin should have their digoxin levels monitored after 
starting rucaparib and then regularly per standard clinical practice. 
In vitro, rucaparib is a potent inhibitor of MATE1 and MATE2-K, a moderate inhibitor of OCT1, 
and a weak inhibitor of OCT2. As inhibition of these transporters could increase metformin renal 
elimination and decrease liver uptake of metformin, caution is advised when metformin is co-
administered with rucaparib. In addition, rucaparib is an inhibitor of the BCRP with IC50 value 
suggesting potential BCRP inhibition and increased exposures of medicinal products that are 
BCRP substrate (eg, rosuvastatin).  
8.7 
General Restrictions 
Photosensitivity has been observed in patients treated with rucaparib. Patients should avoid 
spending time in direct sunlight because they burn more easily during treatment with rucaparib. 
When outdoors, patients should use typical precautions such as applying sunscreen (sun 
protection factor 50 or greater) and/or covering exposed skin with clothing and wearing a hat and 
sunglasses. 


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9 
STUDY PROCEDURES 
9.1 
Schedule of Assessments 
Table 3 summarizes the procedures and assessments to be performed for all patients 
remaining on treatment or in follow up as of implementation of Protocol Amendment 5. 
The revised evaluations should commence immediately after the patient has provided 
appropriate informed consent, maintaining previous treatment cycle and day sequence. 
The revised Schedule of Assessments replaces all prior schedules of assessment. 
All procedures and assessments are to be completed within ±3 days of the scheduled time point 
unless otherwise stated.  
The purpose of the revised schedule of assessment is to allow patients who continue to benefit 
from treatment with rucaparib to continue on treatment and follow-up but to reduce the number 
of assessments required at study visits (including at the end of treatment and follow-up 
assessments), while maintaining an appropriate level of safety monitoring.


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Table 3. 
Schedule of Assessments After Implementation of Amendment 5 
Procedurea 
Blinded Treatment Phase 
(±3 days) 
Cycle X Day 1 
Post-Treatment Phase 
Treatment 
Discontinuation 
28-day 
Follow-up 
Long-term 
Follow-up 
Adverse Eventsb 
The investigator should monitor and educate patients on possible 
AEs observed with rucaparib 
X 
 
Complete Blood Count 
Monthly assessments advised 
 
 
Clinical Chemistry, Urinalysis, Vital Signs 
Local standard of care practices per investigator 
 
 
Serum Pregnancy Test (WOCBP only)c 
X 
X 
 
 
Disease Assessment (Tumor Scans/CA-125)d 
Xe 
X 
Xf 
Xf 
Study Drug Dispensation/Administration/Accountability 
X 
X 
 
 
Tumor Tissue Biopsy (optional)g 
X 
 
Subsequent Treatments, Secondary Malignancy 
Monitoring, and Overall Survivalh 
 
X 
X 
Abbreviations: AE = Adverse event; AESI = adverse event of special interest; CA-125 = cancer antigen 125; CR = complete response; CT = computed 
tomography; GCIG = Gynecologic Cancer InterGroup;MRI = magnetic resonance imaging; PET = positron emission tomography; RECIST = Response 
Evaluation Criteria in Solid Tumors; SAE = serious adverse event; WOCBP = women of child-bearing potential. 
a 
The study visit window in the double-blind treatment phase is ± 3 days, unless noted otherwise for a particular assessment. Study visits should take into 
account the subject’s investigational product supply. Study drug should be dispensed as applicable. 
b 
AEs will be monitored but only SAEs/AESIs are recorded through 28 days after last dose of rucaparib. Only treatment-related SAEs and all AESIs, 
regardless of causality, need to be reported after the 28-day window. Ongoing SAEs and AESIs will be followed until resolution, stabilization, or lost to 
follow-up.  
c 
Women of child-bearing potential must have a negative serum pregnancy test result ≤ 3 days prior to the first dose of study drug. A serum pregnancy test 
must also be performed ≤ 3 days prior to Day 1 of every cycle during the treatment phase and at the treatment discontinuation visit. All tests will be 
performed by a local laboratory. 
d 
Disease assessments to consist of clinical examination and appropriate imaging techniques (preferably CT scans of the chest, abdomen and pelvis, with 
appropriate slice thickness per RECIST); other assessment techniques (MRI, X-ray, PET, and ultrasound) may be performed if required. The same 
methods used to detect lesions at baseline are to be used to follow the same lesions throughout the clinical study. CT/MRI scans of the chest, abdomen, 
and pelvis performed to determine the extent of disease at baseline should also be performed at each time of disease assessment, even if the scans were 
negative at baseline. 
e 
Tumor scans to be performed every 12 calendar weeks (a 7-day window prior is permitted) after start of treatment on Day 1 of Cycle 1. Disease 
progression will only be determined by RECIST v1.1. Patients with a CR at study entry will only be considered to have disease progression if a new 


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lesion is identified. Patients who meet GCIG CA-125 criteria for disease progression should have a radiologic assessment and be assessed by RECIST 
v1.1. If the radiologic assessment does not confirm disease progression, patients should continue on treatment and continue to be assessed by RECIST 
v1.1 per the protocol schedule of assessments. Patients who have been on study at least 18 months may decrease the frequency of disease assessments to 
every 16 (±2) weeks. Investigator should consult with sponsor’s medical monitor before decreasing frequency. 
f 
To be performed every 12 calendar weeks (up to 7 days prior is permitted) through to investigator-assessed radiologic disease progression by RECIST 
v1.1 for any patient who discontinued from study treatment for reason other than disease progression or death. Patients who have been on study at least 
18 months may decrease the frequency of disease assessments to every 16 (±2) weeks. Investigator should consult with sponsor’s medical monitor before 
decreasing frequency. 
g 
An optional tumor biopsy may be collected from patients from time of radiographic disease progression until the start of the subsequent anticancer 
treatment. Additional consent is required. Refer to the Pathology Charter for detailed sample handling instructions. If disease progression is caused by 
appearance of a new lesion(s), the lesion(s) should be prioritized for the optional biopsy.  
h 
All patients discontinued from treatment, regardless of reason, should be followed for subsequent treatments, secondary malignancy, and survival 
approximately every 12 weeks (± 14 days) from Cycle 1 Day 1 until death, loss to follow-up, withdrawal of consent from study, or closure of the study. 
Follow-up can be performed via the telephone. Diagnosis of any secondary malignancy requires appropriate documentation (i.e., laboratory and/or 
pathology reports) and should be reported as specified in Section 10.  


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9.2 
Screening Phase 
Following written informed consent, and unless otherwise specified, the following assessments 
will be performed prior to randomization. Assessments performed within the specified windows, 
but prior to patient signing informed consent, are acceptable only if confirmed to have been 
standard of care. 
Up to 120 days prior to randomization: 
• Medical history, including demographic information (birth date, race, gender, etc.) and 
smoking status, and oncology history, including date of diagnosis for ovarian, primary 
peritoneal, or FTC (and other malignancy, if applicable), prior treatments received, dates of 
administration, best response achieved, date of progression and how assessed, radiology 
reports, and gBRCA mutation status (if known) 
• FFPE archival tumor tissue sample. Sufficient archival FFPE tumor tissue (enough for 
1 x 4 µm section for H&E and approximately 8 to 12 x 10 µm sections, or equivalent) for 
planned analyses should be provided. Refer to the Pathology Charter for detailed sample 
handling instructions.  
o 
The most recently collected tumor tissue sample should be provided, if available.  
o 
Submission of a tumor block preferred; if sections are provided, these must all be 
from the same tumor sample. 
o 
Tumor content ≥30% is strongly preferred for successful genomic scarring/LOH 
analysis 
o 
Sample must be submitted to the central laboratory at least 3 weeks prior to 
planned start of treatment in order to enable stratification for randomization 
• AE monitoring (only if related to screening procedure) 
Up to 28 days prior to randomization: 
• PRO collected using the FOSI-18 and EQ-5D instruments 
• Physical examination by body system, including height and weight 
• Vital signs (blood pressure, pulse, and temperature) 
• 12-lead ECG 
• Prior and concomitant medications and any surgical procedures  
• Disease assessment/tumor scans: tumor assessments should consist of clinical examination 
and appropriate imaging techniques (including CT scans of the chest, abdomen, and pelvis 
with appropriate slice thickness per RECIST; other studies (magnetic resonance imaging 
[MRI], X-ray, positron emission tomography [PET], and ultrasound) may be performed if 
required. The same methods used to detect lesions at baseline are to be used to follow lesions 
throughout the clinical study. If a patient has known brain metastases, this disease should be 
evaluated at each required assessment. CT/MRI scans of the chest, abdomen, and pelvis 


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performed to determine the extent of disease at baseline should also be performed at each 
time of disease assessment, even if the scans were negative at baseline.  
• ECOG performance status (Appendix D) 
• AE monitoring (only if related to screening procedure) 
Up to 14 days prior to randomization: 
• Hematology (RBC and parameters [Hgb, Hct, MCH, MCV, and MCHC] and reticulocyte 
count, white blood cell [WBC] and differential [with ANC], and platelet count 
• Serum chemistry (total protein, albumin, creatinine, or estimated GFR using the Cockcroft 
Gault formula, blood urea nitrogen [BUN] or urea, total bilirubin, alkaline phosphatase 
(ALP), ALT, AST, glucose, sodium, potassium, chloride, CO2, calcium, and phosphorus) and 
lipid panel (total cholesterol, low density lipoprotein [LDL], high density lipoprotein [HDL], 
and triglycerides). Note: fasting is not required. 
• Urinalysis performed on freshly voided clean sample (dipstick for protein, glucose, blood, 
pH, and ketones) ≤14 days prior to the first dose of study drug. If dipstick findings are 
abnormal based on investigator judgment, then a microscopic evaluation will be performed to 
assess the abnormal findings 
• CA-125 measurement 
• AE monitoring (only if related to screening procedure) 
Up to 3 days prior to first dose of study drug: 
• Serum pregnancy test for women of child-bearing potential 
• AE monitoring (only if related to screening procedure) 
9.3 
Treatment Phase 
9.3.1 Day 1 of Cycles 1 and 2 
The following procedures/assessments will be completed before study drug is administered: 
• PRO using the FOSI-18 and EQ-5D instruments 
• Physical examination 
• Weight 
• Vital Signs 
• Concomitant medications and procedures 
• ECOG performance status (Appendix D) 
• Hematology  
• Serum chemistry (fasting is not required) 


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• Serum pregnancy for women of child-bearing potential (Cycle 2 only) 
• CA-125 measurement (Cycle 1 only) 
• Blood sample for storage (Cycle 1 only; if sample is not collected on Day 1 of Cycle 1, it 
should be collected as soon as possible thereafter) 
• Study drug dispensation 
• AE monitoring 
• Plasma PK sample (prior to first dose taken that day) (Cycle 2 only; see Section 9.5.1) 
• Serum sample for alpha-1 acid glycoprotein (AAG) sample (Cycle 2 only) 
Study drug will be dispensed to the patient in sufficient quantity to last until the next treatment 
cycle. Patients will ingest study drug twice daily at about the same times every day, as close to 
12 hours apart as possible. Each dose of study drug should be taken with at least 8 oz (240 mL) 
of room temperature water. Patients may take study drug on an empty stomach or with food 
(with a regular meal or within 30 minutes after a regular meal). Patients will record dosing 
information in their electronic dosing diary. 
Patients will be instructed to refrain from taking their first dose of study drug at home on the day 
of their clinic visits because certain assessments must be performed prior to dosing. 
9.3.2 Day 15 of Cycles 1 and 2 
The following procedures will be completed: 
• Concomitant medications and procedures 
• Hematology 
• Serum chemistry (fasting is not required) 
• AE monitoring 
• Plasma PK sample (in morning or afternoon following the first dose of study drug taken this 
day; see Section 9.5.1) 
• Serum sample for AAG analysis (note: sample can be collected at the same time as 
hematology and serum chemistry and/or with the PK sample)  
Patients will ingest study drug twice daily at about the same times every day, at close to 12 hours 
apart as possible. Each dose of study drug should be taken with at least 8 oz (240 mL) of room 
temperature water. Patients may take study drug on an empty stomach or with food (with a 
regular meal or within 30 minutes after a regular meal). Patients will record dosing information 
in their electronic dosing diary. 
9.3.3 Cycles 3 and Beyond 
The revised Schedule of Assessments shown in Table 3 replaces all prior schedules of 
assessments as of implementation of Protocol Amendment 5. 


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Disease assessment/tumor scans will be performed every 12 calendar weeks (within 7 days prior 
is permitted) after start of treatment on Day 1 of Cycle 1. Patients who have been on study at 
least 18 months may decrease the frequency of disease assessments to every 16 (±2) weeks. 
Investigator should consult with sponsor’s medical monitor before decreasing frequency. 
The following procedures are advised: 
• Hematology (complete blood count); monthly assessments advised 
• Clinical chemistry, urinalysis, and vital signs according to local standard of care per 
investigator 
• Serum pregnancy for women of child-bearing potential 
• CA-125 measurement (Day 1 of Cycles 4, 7, 10, etc.) 
• AE monitoring 
• Study drug accountability 
Study drug will be dispensed to the patient in sufficient quantity to last until the next clinic visit. 
A single dose of study drug will be administered during the current clinic visit with at least 8 oz 
(240 mL) of room temperature water. Patients may take study drug on an empty stomach or with 
food (with a regular meal or within 30 minutes after a regular meal).  
Patients will continue dosing with study drug at home on an empty stomach or with food (with a 
regular meal or within 30 minutes after a regular meal), taking doses twice daily at about the 
same times every day. Study drug should be taken with at least 8 oz (240 mL) of room 
temperature water. 
9.4 
Post-Treatment Phase 
9.4.1 Treatment Discontinuation 
The revised Schedule of Assessments shown in Table 3 replaces all prior schedules of 
assessments as of implementation of Protocol Amendment 5. 
Upon treatment discontinuation, regardless of the reason, patients will have a Treatment 
Discontinuation visit. The following procedures will be performed: 
• Tumor scans (using the same methodology as was used at screening) if reason for treatment 
discontinuation was other than disease progression based on radiologic assessment 
• CA-125 measurement 
• Study drug accountability 
 
The following procedures are advised: 
• ECOG performance status (Appendix D) 


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• Hematology (complete blood count) 
• Clinical chemistry, urinalysis, and vital signs according to local standard of care per 
investigator 
• Serum chemistry (fasting is not required) 
• Serum pregnancy test for women of child-bearing potential 
• AE monitoring 
• Optional tumor tissue biopsy collection at time of disease progression/treatment 
discontinuation until the start of the subsequent anticancer treatment (requires additional 
consent). If disease progression is caused by appearance of a new lesion(s), the lesion(s) 
should be prioritized for the optional biopsy. Tumor tissue will be processed locally as FFPE 
tissue. Refer to the Pathology Charter for detailed sample handling instructions.  
9.4.2 28-day Follow-up 
The following procedures will be performed for all patients at 28 (±3) days after the last dose of 
study drug: 
• Disease assessment for patients who discontinued treatment for reason other than disease 
progression or death. Tumor scans should continue to be performed at 12-week intervals (up 
to 7 days prior permitted) until radiologic disease progression by RECIST v1.1, as assessed 
by the investigator. Patients who have been on study at least 18 months may decrease the 
frequency of disease assessments to every 16 (±2) weeks. Investigator should consult with 
sponsor’s medical monitor before decreasing frequency.  
• AE monitoring (only SAEs/AESIs are recorded through 28 days after last dose of rucaparib. 
Ongoing SAEs and AESIs will be followed until resolution, stabilization, or lost to follow-
up). 
• Subsequent treatments, secondary malignancy monitoring, and overall survival (OS) 
9.4.3 Long-term Follow-up 
• Disease assessment for patients who discontinued treatment for reason other than disease 
progression or death. Tumor scans should continue to be performed at 12-week intervals (up 
to 7 days prior permitted) until radiologic disease progression by RECIST v1.1, as assessed 
by the investigator. Patients who have been on study at least 18 months may decrease the 
frequency of disease assessments to every 16 (±2) weeks. Investigator should consult with 
sponsor’s medical monitor before decreasing frequency.  
• Subsequent treatments, secondary malignancy monitoring, and OS information will be 
collected for all patients approximately every 12 weeks (± 14 days) until death, loss to 
follow-up, withdrawal of consent from study, or closure of the study. Follow-up can be 
performed via the telephone. Diagnosis of any secondary malignancy requires appropriate 
documentation (i.e., laboratory and/or pathology reports) and should be reported as indicated 
in Section 10.8. 


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• SAEs related to study drug and all AESIs, irrespective of causality, are to be reported as 
specified in Section 10.8. 
9.5 
Methods of Data Collection 
Hematology, clinical chemistry, urinalysis, serum CA-125, and serum pregnancy in women of 
child-bearing potential will be performed locally.  
9.5.1 Pharmacokinetic Evaluations and AAG Measurement 
As of implementation of Protocol Amendment 5, samples will no longer be collected for PK 
and AAG analyses. 
9.5.2 Biomarker Analysis – FFPE Tumor Tissue 
Archival tumor tissue must be located during the screening process and submitted to the central 
laboratory directly as soon as possible for determination of HRD status. Archival tumor tissue 
is required for HRD stratification for randomization and for storage for potential bridging to a 
validated companion diagnostic test.  
9.5.3 Biomarker Analysis – Blood 
As of implementation of Protocol Amendment 5, blood samples will no longer be collected for 
biomarker analyses. 
9.5.4 Safety Evaluations 
9.5.4.1 
Adverse Event Assessment 
The investigator is responsible for assessing the safety of the patients and for compliance with 
the protocol to ensure study integrity. Patients will be monitored for AEs during study 
participation, beginning after the first dose of study drug and until 28 days after the last dose of 
study drug. Any ongoing SAEs and AESIs will be recorded and followed until resolution, 
stabilization, or loss to follow-up. Only treatment-related SAEs and all AESIs, regardless of 
causality, need to be reported after the 28-day window. SAEs will be graded according to the 
NCI-CTCAE grading system (v4.03) and recorded on the eCRF. 
Complete details for monitoring AEs, including the definition of drug-related AEs, are provided 
in Section 10. 
9.5.4.2 
Prior and concomitant medications 
Prior concomitant medications will be recorded during screening and concomitant medications 
will be collected from study entry until the Treatment Discontinuation visit. 


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9.5.4.3 
Clinical Laboratory Investigations 
Certified local laboratories will perform study-related clinical laboratory tests according to 
institutional procedures, and the results will be reviewed by the investigator. The panels of 
laboratory tests to be performed are shown below: 
Hematology: As of implementation of Protocol Amendment 5, monthly hematology assessment, 
consisting of a complete blood count, is advised.  
Clinical Chemistry: As of implementation of Protocol Amendment 5, clinical chemistry 
assessments may be performed according to local standard of care per investigator. 
Urinalysis: As of implementation of Protocol Amendment 5, urinalysis may be performed 
according to local standard of care per investigator. 
Laboratory reports should be reviewed by the investigator or delegated physician who will assess 
clinical significance. 
Serum Pregnancy: For women of child-bearing potential only. Serum pregnancy testing is to be 
performed ≤ 3 days prior to first dose of study drug, ≤ 3 days prior to the start of every cycle 
during the treatment phase, and at the Treatment Discontinuation visit. 
9.5.4.4 
Vital Signs 
As of implementation of Protocol Amendment 5, vital signs may be performed according to local 
standard of care per investigator.  
9.5.4.5 
12-Lead Electrocardiograms 
As of implementation of Protocol Amendment 5, ECGs will no longer be a required procedure 
for this protocol. 
9.5.4.6 
Body Weight and Height 
As of implementation of Protocol Amendment 5, body height and weight assessments will no 
longer be a required procedure for this protocol.  
9.5.4.7 
Physical Examinations 
As of implementation of Protocol Amendment 5, physical examinations will no longer be a 
required procedure for this protocol.  
9.5.4.8 
ECOG Performance Status 
As of implementation of Protocol Amendment 5, ECOG performance status assessments will no 
longer be a required procedure for this protocol. 


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9.5.5 Efficacy Evaluations 
9.5.5.1 
Disease Assessments 
Tumor assessment measurements will be performed at screening, at the end of every 12 weeks of 
treatment (up to 1 week prior permitted) relative to Cycle 1 Day 1, at discontinuation of 
treatment, and as clinically indicated. Patients who have been on study at least 18 months may 
decrease the frequency of disease assessments to every 16 (±2) weeks. Investigator should 
consult with sponsor’s medical monitor before decreasing frequency.  
Disease assessment will comprise clinical examination and appropriate imaging techniques (CT 
scans of the chest, abdomen, and pelvis with appropriate slice thickness per RECIST); other 
studies (MRI, X-ray, PET, and ultrasound) may be performed if required. If a patient has known 
brain metastases, this disease should be evaluated at each required assessment. The same 
methods used to detect lesions at baseline are to be used to follow the same lesions throughout 
the clinical study. CT/MRI scans of the chest, abdomen, and pelvis performed to determine the 
extent of disease at baseline should also be performed at each time of disease assessment, even if 
the scans were negative at baseline. Investigators should perform scans of other anatomical sites 
that, in their judgment, are appropriate to assess based on each patient’s tumor status. Imaging 
guidelines provided in the Bioclinica Site Manual should be followed for the collection of 
images and the radiological assessment of disease.  
Tumor response will be interpreted using RECIST v1.1 (Appendix B). Disease progression will 
only be determined by RECIST v1.1. Patients with a CR at study entry will only be considered to 
have disease progression if a new lesion is identified. Patients who meet GCIG CA-125 criteria 
for disease progression should have a radiologic assessment and be assessed by RECIST. If the 
radiologic assessment does not confirm disease progression, patients should continue on 
treatment and continue to be assessed by RECIST v1.1 per the protocol schedule of assessments. 
Patients who discontinued treatment for reason other than disease progression or death should 
continue to have tumor scans performed at 12-week intervals (up to 7 days prior permitted) until 
radiologic disease progression by RECIST v1.1, as assessed by the investigator. Patients who 
have been on study at least 18 months may decrease the frequency of disease assessments to 
every 16 (±2) weeks. Investigator should consult with sponsor’s medical monitor before 
decreasing frequency. 
9.5.5.2 
Tumor Markers 
CA-125 measurement will be performed at screening, on Day 1 of Cycle 1, at the start of every 
3rd cycle thereafter (i.e., Day 1 of Cycle 4, Cycle 7, Cycle 10, etc.), at discontinuation of 
treatment, and as clinically indicated. 
9.5.6 Patient-Reported Outcomes 
With the implementation of Protocol Amendment 4, the collection of patient-reported outcomes 
was no longer required.   


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9.5.7 Appropriateness of Measurements 
The assessments planned in the protocol are widely used and recognized as reliable, accurate and 
relevant. 


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10 ADVERSE EVENT MANAGEMENT 
10.1 
Definition of an Adverse Event 
An AE is any untoward medical occurrence, including the exacerbation of a pre-existing 
condition, in a patient administered a pharmaceutical product. The pharmaceutical product does 
not necessarily have a causal relationship with the AE. Anticipated fluctuations of pre-existing 
conditions, including the disease under study, that do not represent a clinically significant 
exacerbation or worsening are not considered AEs. 
For the purposes of this study, disease progression of the patient’s tumor with new or worsening 
symptoms must be documented as an AE. However, disease progression documented solely by 
radiographic evidence with no new or worsening symptoms will not require reporting as an AE.  
It is the responsibility of the investigator to document all AEs that occur during the study. AEs 
should be elicited by asking the patient a nonleading question (eg, “Have you experienced any 
new or changed symptoms since we last asked/since your last visit?”). The existence of an AE 
may be concluded from a spontaneous report of the patient; from the physical examination; or 
from special tests such as the ECG, laboratory assessments, or other study-specified procedure 
(source of AE). AEs will be reported on the AE eCRF. Symptoms reported spontaneously by the 
patient during the physical examination will also be documented on the AE eCRF. 
10.2 
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that occurs at any dose that: 
• Results in death. 
• Is immediately life-threatening (i.e. the patient is at risk of death at the time of the event; it 
does not refer to an event that hypothetically might have caused death if it were more 
severe). 
• Requires in-patient hospitalization or prolongation of existing hospitalization. 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• Results in a congenital anomaly or birth defect. 
• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, or the 
development of drug dependency or drug abuse. 
10.3 
Definition of an Adverse Event of Special Interest 
An AESI (serious or nonserious) is one of scientific and medical concern specific to the 
sponsor’s product or program, for which ongoing monitoring and rapid communication by the 


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investigator to the sponsor can be appropriate. Such an event might warrant further investigation 
in order to characterize and understand it. Depending on the nature of the event, rapid 
communication by the trial sponsor to other parties (eg, health authorities or ethics committees) 
might also be warranted. 
Details on the sponsor’s currently agreed list of AESIs for rucaparib can be found in the current 
rucaparib IB. These AESIs are to be reported to the sponsor expeditiously (see Section 10.8 for 
reporting instructions).  
Report any AE of pneumonitis, or any of the following AEs, irrespective of causality assessment 
and severity, as an AESI within 24 hours using the study Serious Adverse Event Form and the 
applicable procedures as outlined in Section 10.8:  
• pneumonitis 
• interstitial lung disease 
• pulmonary fibrosis 
• acute interstitial pneumonitis 
• alveolitis necrotizing 
• alveolitis 
• hypersensitivity pneumonitis 
• organizing pneumonia 
 
10.4 
Exceptions to Serious Adverse Event Reporting 
The following are not considered SAEs and therefore are not required to be reported to the 
sponsor: 
• Pre-planned or elective hospitalization, including social and/or convenience situations (eg, 
respite care). 
• Hospital visits of less than 24 hours duration (eg, patient presents to the emergency room, but 
is not admitted to a ward).  
• Overdose of either study drug or concomitant medication, unless associated with an SAE. If 
the event does not meet SAE criteria, it should still be captured as a non-serious AE on the 
appropriate eCRF. 
• Events of disease progression of the patient’s underlying cancer as well as events clearly 
related to disease progression (i.e., signs and symptoms) should not be reported as a SAE 
unless the outcome is fatal and occurs during the safety reporting period. If the event has a 
fatal outcome during the safety reporting period, then the event of Progression of Disease 
must be recorded as an AE/SAE with CTC Grade 5 (fatal outcome) indicated. 
• Diagnosis of progression of disease or hospitalization due to signs and symptoms of disease 
progression alone should not be reported as a SAE. 
10.5 
Clinical Laboratory Assessments and Other Abnormal Assessments as 
Adverse Events and Serious Adverse Events 
It is the responsibility of the investigator to assess the clinical significance of all abnormal 
laboratory values as defined by the list of reference ranges from the local laboratory. In some 


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cases, significant change in laboratory values within the normal range may require similar 
assessment. 
An abnormal value that is not already associated with an AE is to be recorded as an AE only if 
one of the following criteria is met: 
• It resulted in treatment modification (reduction of dose, interruption of dosing, or permanent 
discontinuation of study drug) 
• It required intervention/management 
• It is suggestive of organ toxicity 
• The investigator considers it to be clinically significant 
10.6 
Pregnancy or Drug Exposure during Pregnancy 
If a patient becomes pregnant during the course of the study, study drug dosing should be held 
immediately. 
Pregnancy is not considered to be an AE or SAE; however, all pregnancies occurring during 
study participation or within 6 months of last dosing must be reported to the sponsor using the 
Clinical Pregnancy Report form within the same timelines as for as SAE. 
All pregnancies should be followed through to outcome whenever possible. Once the outcome of 
a pregnancy is known, the Clinical Pregnancy Outcome Report form should be completed and 
submitted to the sponsor. 
AEs, SAEs, or AESIs that occur during pregnancy will be assessed and processed according to 
the AE or SAE/AESI processes using the appropriate AE or SAE/AESI forms.  
10.7 
Recording of Adverse Events, Serious Adverse Events, and Adverse Events 
of Special Interest 
As of the implementation of Amendment 5, only SAEs/AESIs will be fully documented on the 
appropriate eCRF. For each SAE/AESI, the investigator must provide duration (start and end 
dates or ongoing), intensity, relationship to study drug, and indicate whether specific action or 
therapy was required. 
Any SAE/AESI that occurs after the first dose of study drug until 28 days after last dose of study 
drug administration will be collected, documented and reported to the sponsor by the investigator 
according to the specific definitions and instructions detailed within this protocol, whether 
dosing has occurred or not. In addition, any AE/SAE that occurs after informed consent is 
obtained and is deemed related to a screening procedure for the study should also be reported on 
the AE eCRF and, if applicable, the SAE report form. Events that occur after signing of informed 
consent but prior to initiation of study drug, unless due to a protocol-mandated procedure, should 
be recorded on the Medical History eCRF. In order to avoid vague, ambiguous, or colloquial 
expressions, the AE should be recorded in standard medical terminology rather than the patient’s 
own words. Whenever possible, the investigator should combine signs and symptoms that 


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constitute a single disease entity or syndrome into a final diagnosis. For example, fever, cough, 
and shortness of breath may be reported as pneumonia, if that is a reasonable diagnosis. 
All SAEs/AESIs that occur during the study or within 28 days after receiving the last dose of 
study drug, regardless of relationship to study drug, must be reported to the sponsor/designated 
safety contact immediately (i.e., within 24 hours of the investigator’s knowledge of the event). 
This should be done by faxing or emailing the completed SAE/AESI report to the 
sponsor/designee contact provided on the SAE/AESI report form. After the 28-day window after 
treatment discontinuation, only SAEs assessed as related to study drug and all AESIs, 
irrespective of causality, should be reported. If a patient is determined to be a screen failure, no 
further AEs/SAEs are required to be reported once that determination has been made, with the 
exception of AEs/SAEs deemed related to a protocol-specified procedure. Information on the 
follow-up of AEs, SAEs, and AESIs is provided in Section 10.7.4.  
10.7.1 Intensity of Adverse Events 
Severity refers to the intensity of an AE. The severity of each AE will be categorized using the 
NCI-CTCAE, v4.03.54 
For any term that is not specifically listed in the CTCAE, intensity should be assigned a grade of 
1-5 using the following CTCAE guidelines:  
• Mild (Grade 1): mild or asymptomatic symptoms; clinical or diagnostic observations only; 
intervention not indicated 
• Moderate (Grade 2): limiting age-appropriate instrumental activities of daily living; minimal, 
local or noninvasive intervention indicated 
• Severe (Grade 3): limiting self-care activities of daily living; hospitalization indicated 
• Life threatening (Grade 4): life-threatening consequences; urgent intervention indicated 
• Fatal (Grade 5): results in death 
10.7.2 Causal Relationship of Adverse Events to Study Drug  
Medical judgment should be used to determine the cause of the AE considering all relevant 
factors such as, but not limited to, the disease under study, concurrent disease, concomitant 
medication, relevant history, pattern of the AE, temporal relationship to the study medication, 
dechallenge or rechallenge with the study drug.  
Not Related 
To Study Drug 
An AE that is clearly due to extraneous causes (eg, concurrent disease, concomitant 
medication, disease under study, etc.) 
An AE that does not follow a reasonable temporal sequence from administration of 
the study drug. 
An AE that does not follow a known pattern of response to study drug. 
An AE that does not reappear or worsen when study drug is restarted. 
An AE for which an alternative explanation is likely, but not clearly identifiable. 


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Related to 
Study Drug 
An AE that is difficult to assign to alternative causes. 
An AE that follows a strong or reasonable temporal sequence from administration of 
study drug. 
An AE that could not be reasonably explained by the patient’s clinical state, 
concurrent disease, or other concomitant therapy administered to the patient. 
An AE that follows a known response pattern to study drug. 
An AE that is confirmed with a positive rechallenge or supporting laboratory data. 
10.7.3 Outcome  
The investigator will record the outcome for each AE according to the following criteria: 
• Recovered/Resolved 
• Recovered/Resolved with sequelae 
• Improved 
• Ongoing 
• Death 
• Unknown/Lost to follow-up 
10.7.4 Follow-up of Adverse Events, Serious Adverse Events, and Adverse Events of 
Special Interest  
All AEs (including SAEs and AESIs) occurring during the study are to be followed up in 
accordance with good medical practice until resolved; judged no longer clinically significant; or, 
if a chronic condition, until fully characterized until 28 days after the last dose of study 
treatment. Any SAE/AESI must be followed until the event has resolved, the condition has 
stabilized, or the patient is lost to follow up. If the patient is lost to follow-up with an ongoing 
SAE/AESI, this should be captured accordingly on a follow-up SAE/AESI report. 
10.8 
Regulatory Aspects of Adverse Event Reporting 
All SAEs and AESIs, irrespective of relationship to study treatment, as well as all pregnancies, 
must be reported to the sponsor’s SAE designee within 24 hours of knowledge of the event, 
occurring during the study through 28 days after receiving the last dose of study treatment, 
according to the procedures below. After the 28-day specified window, SAEs considered to be 
treatment related and all AESIs, regardless of treatment relationship, should be reported if 
occurring. Pregnancies that occur within 6 months of the last dose of study drug should be 
reported. It is important that the investigator provide an assessment of relationship of the 
SAE/AESI to study treatment at the time of the initial report. The SAE/AESI Report form must 
be used for reporting SAEs/AESIs. The contact information for reporting of SAEs/AESIs can be 
found on the SAE/AESI Reporting Form and Pregnancy Report Forms. 
Clovis Oncology, Inc. (Clovis Oncology), or its designee is responsible for submitting reports of 
AEs associated with the use of the drug that are both serious and unexpected to the Food and 
Drug Administration (FDA), according to 21 Code of Federal Regulations (CFR) 312.32; to the 


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European regulatory authorities according to the European Commission Clinical Trials Directive 
(2001/20/EC); and to other regulatory authorities, according to national law and/or local 
regulations. All investigators participating in ongoing clinical studies with the study medication 
will receive copies of these reports for prompt submission to their IRB or IEC. In accordance 
with the European Commission Clinical Trials Directive (2001/20/EC), Clovis Oncology or its 
designee will notify the relevant ethics committees in concerned member states of applicable 
suspected unexpected serious adverse reactions (SUSARs) as individual notifications or through 
periodic line listings. 
Clovis Oncology or its designee will submit all safety updates and periodic reports to the 
regulatory authorities as required by applicable regulatory requirements. 
10.9 
Independent Data Monitoring Committee 
No formal efficacy interim analyses are planned. 
An IDMC will be established to review safety and efficacy data in compliance with a prospective 
charter and will be involved until the primary endpoint has been met and the study unblinded. 
The IDMC will be comprised of medical oncologists with experience in treating women with 
ovarian cancer and a statistician, all of whom are not otherwise involved in the study as 
investigators. The IDMC responsibilities, authorities, and procedures will be documented in the 
IDMC charter, which will be endorsed and signed by the IDMC prior to the first data review 
meeting.  
The IDMC will: 
• Review safety and efficacy of rucaparib compared with placebo to ensure the study is 
beneficial to patients 
• Ensure the study is conducted in a high quality manner 
• Monitor the size of the tBRCA subgroup and the known gBRCA group 
Following data review, the IDMC will recommend continuation, revision, or termination of the 
study and/or continuing or halting enrollment into a particular subgroup. The IDMC will meet at 
least semi-annually after sufficient data has been collected. The IDMC chairperson may convene 
formal IDMC meeting if there are safety concerns. The sponsor can also request an IDMC 
review of safety data. 


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11 STATISTICAL METHODS 
11.1 
Analysis Populations 
The following analysis populations are defined for the study: 
Safety Table Population – The safety population will consist of all patients who received at 
least one dose of protocol-specified treatment. 
Intent-to-treat (ITT) Population − The ITT population will consist of all randomized patients. 
11.2 
Statistical Methods 
11.2.1 General Considerations 
Variables registered on a continuous scale will be presented using the following descriptive 
statistics: N, mean, standard deviation, median, minimum and maximum. Continuous variables 
may also be presented using frequencies and percentages among appropriate categorizations. 
Categorical variables will be presented using frequencies and percentages. The Kaplan-Meier 
methodology will be used to summarize time-to-event variables. The number of patients with 
events and the number of censored patients will also be presented. The stratified logrank test will 
be used to compare the time-to-event distributions between the randomized treatment groups. In 
addition, the Cox proportional hazards model will be used to estimate the HR between the 
randomized treatment groups. 
The primary and key secondary endpoints will be tested among the tBRCA and all HRD 
subgroups, and all randomized patients, using an ordered step-down multiple comparisons 
procedure. Investigator determined PFS (invPFS) in the tBRCA subgroup will be tested first at a 
one-sided 0.025 significance level. If invPFS in the tBRCA subgroup is statistically significant, 
then invPFS will be tested in the all HRD subgroup followed by invPFS in all randomized 
patients. Continuing in an ordered step-down manner, the PRO of disease symptoms utilizing the 
FOSI-18 DRS-P subscale will be tested at the one-sided 0.025 significance level in the tBRCA, 
all HRD, and all randomized patients subgroups and then for the remaining key secondary 
endpoints of PRO utilizing the FOSI-18 total score and OS. Once statistical significance is not 
achieved for one test the statistical significance will not be declared for all subsequent analyses 
in the ordered step-down procedure.  
PFS by IRR will be evaluated as a stand-alone secondary endpoint. 
All data will be used to their maximum possible extent but without any imputations for missing 
data. 
All statistical analyses will be conducted with the SAS® System, v9.1 or higher.  
Unless otherwise specified, baseline is defined as the last measurement on or prior to the first 
day of study drug administration. 


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11.2.2 Patient Disposition  
Patient disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency counts, and the corresponding 
percentages. 
11.2.3 Baseline Characteristics  
All demographic and baseline characteristics will be summarized for the safety population. 
The following variables will be summarized with frequency tabulations: 
• Time since diagnosis (months): > 12-24, > 24 
• Baseline laboratory parameters: graded based on CTCAE 
• HRD status for stratification at randomization: tBRCA, nbHRD, biomarker 
negative 
• Interval between completion of penultimate platinum regimen and disease 
progression (6 to 12 months of >12 months) by radiologic assessment 
• Best response to most recent platinum-based regimen (CR [defined as complete 
radiologic response by RECIST v1.1 with normalization of CA-125] or PR 
[defined as partial radiologic response by RECIST v1.1 and/or a GCIG CA-125 
response]). All responses require that CA-125 be <ULN. 
Descriptive statistics may also be used to summarize the continuous variables.  
11.2.4 Efficacy Analyses  
All efficacy evaluations will be conducted using the ITT population. 
11.2.4.1 
Primary Efficacy Analysis 
The primary efficacy endpoint for the study is invPFS by RECIST v1.1. Investigator-determined 
PFS is defined as the time from randomization to disease progression, according to RECIST v1.1 
criteria (Appendix B), as assessed by the investigator, or death due to any cause, in molecularly 
defined subgroups. The stratification factors included in the primary analysis of invPFS will be 
as follows: 
• HRD classification (tBRCA or nbHRD or biomarker negative) 
• Interval between completion of penultimate platinum regimen and disease 
progression (6 to 12 months or >12 months) by radiologic assessment 
• Best response to the most recent platinum-based regimen (CR [defined as 
complete radiologic response by RECIST v1.1 with normalization of CA-125] or 
PR [defined as partial response by RECIST v1.1 and/or a GCIG CA-125 
response]). All responses required that CA-125 be <ULN. 


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Tumor HRD status by the FCTA will be determined after randomization, but before the final 
efficacy analysis, so that the primary endpoint (PFS in molecularly-defined HRD subgroups) can 
be assessed prospectively. 
11.2.4.2 
Secondary Efficacy Analyses 
Secondary efficacy endpoints are: 
• Time to a 4-point decrease in the FOSI-18 DSR−P subscale 
• Time to an 8-point decrease in the FOSI-18 total score 
• OS 
• PFS by RECIST v1.1 as assessed by IRR (irrPFS) 
PRO of disease-related symptoms as measured by the FOSI-18 DRS−P subscale 
The time to an event in PRO of worsening of disease symptoms will be defined as the time from 
randomization to a 4-point reduction in the FOSI-18 DRS-P subscale. Patients without a 4-point 
reduction will be censored on the date of their last PRO evaluation.  
PRO as measured by the total score of the FOSI-18 
An event in worsening of PRO utilizing the complete FOSI-18 instrument will be defined as the 
time from randomization to an 8-point reduction in the total score. Patients without an 8-point 
reduction will be censored on the date of their last PRO evaluation. 
Overall survival 
Overall survival (OS) is defined as the number of days from the date of randomization to the date 
of death (due to any cause). Patients without a known date of death will be censored on the date 
the patient was last known to be alive. 
An interim OS was determined at the time of the primary endpoint unblinding (Section 11.3). 
The final OS analysis will be performed at the time of the study close. See Section 11.3 for 
further details. 
irrPFS 
PFS for secondary efficacy analysis is defined as the time from randomization to disease 
progression, according to RECIST v1.1 criteria as assessed by IRR, or death due to any cause, 
whichever occurs first. 
11.2.5 Safety Analyses  
Safety endpoints are incidence of AEs, clinical laboratory abnormalities, and dose modifications. 


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Data from all patients who receive at least one dose of study drug will be included in the safety 
analyses. AEs, clinical laboratory information, vital signs, ECG results, ECOG performance 
status, body weight, and concomitant medications/procedures will be tabulated and summarized. 
11.2.5.1 
Adverse Events 
AEs will be classified using the Medical Dictionary for Drug Regulatory Activities (MedDRA) 
classification system. The severity of the toxicities will be graded according to the NCI-CTCAE 
whenever possible. Only treatment-emergent adverse events (TEAEs) will be collected: TEAEs 
are defined as AEs with onset date on or after the date of first dose of study medication until the 
date of the last study medication dose plus 28 days.  
The number and percentage of patients who experienced TEAEs for each system organ class 
(SOC) and preferred term will be presented. Multiple instances of the TEAE in each SOC and 
multiple occurrences of the same preferred term are counted only once per patient. The number 
and percentage of patients with at least one TEAE will also be summarized.  
Separate tables will be presented as follows: 
• All TEAEs 
• TEAEs by CTCAE grade 
• Grade 3 or greater TEAEs 
• Serious TEAEs 
• TEAEs with an outcome of death 
• TEAEs leading to discontinuation of study medication 
• TEAEs resulting in interruption/delay of study medication 
• TEAEs resulting in dose reduction of study medication 
If a patient experiences multiple occurrences of the same AE with different toxicity grades, the 
patient will be counted once for the maximum (most severe) toxicity grade. AEs with a missing 
toxicity grade will be presented in the summary table with a toxicity grade of “Missing.” For 
each toxicity grade, the number and percentage of patients with at least one TEAE of the given 
grade will be summarized.  
11.2.5.2 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations include the continuous variables for hematology, serum 
chemistry, and urinalysis. The laboratory values will be presented in SI units. The on-treatment 
period will be defined as the time from the first dose of study drug to 28 days after the last dose 
of study drug. Laboratory values collected during the on-treatment period will be included in the 
summary tables. The laboratory values collected after the on-treatment period will only be 
presented in the data listings.  


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The summary of laboratory data will include shift tables based on CTCAE for shifts in grade 
from baseline to maximum, minimum and last value during the on-treatment period.  
Supporting laboratory data including normal ranges and abnormal laboratory flags will be 
provided using by-patient listings. Separate listings will be produced for clinically significant 
laboratory abnormalities (i.e. those that meet Grade 3 or 4 criteria according to CTCAE). 
11.2.5.3 
Vital Sign Measurements 
The on-treatment period will be defined as the time from the first dose of study drug to 28 days 
after the last dose of study drug. Vital sign measurements collected during the on-treatment 
period will be included in the summary tables. The vital sign measurements collected after the 
on-treatment period will only be presented in the data listings.  
The summary of vital sign data will include descriptive statistics (N, mean, SD, minimum, 
median, third quartile and maximum) of the maximum, minimum and last value during the on-
treatment period. Summaries using descriptive statistics (N, mean, SD, minimum, median and 
maximum) of the change from baseline to the maximum, minimum, and last value during the 
on-treatment period will also be given.  
11.2.6 Population PK Analysis 
The PK endpoint is individual model parameter estimates of rucaparib and covariates 
identification. 
A specific population PK data analysis plan will be developed that will outline the detailed 
approach to data handling, model development and diagnostics, individual model parameter 
estimation, exploration of covariate effects, and final model evaluation techniques. 
11.2.7 Exploratory Analyses 
The endpoints for the exploratory analyses are: 
• Change from baseline in CA-125 measurements by the central laboratory 
• PFS2 (PFS on the subsequent line of treatment) defined as the time from randomization 
to the second event of disease progression or death, as assessed by the investigator 
• ORR per RECIST v1.1, as assessed by both the investigator and IRR, in patients with 
measureable disease at study entry 
• DOR per RECIST v1.1, as assessed by both the investigator and IRR  
• PRO as measured by the EQ-5D total score 
• Rucaparib PK, invPFS, irrPFS, CA-125, AEs, clinical laboratory abnormalities, and dose 
modifications 


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11.2.7.1 
Change from Baseline in CA-125 
Analyses of changes and/or percent changes from baseline will be analyzed for each scheduled 
post-baseline visit and for the final visit for the CA-125 measurements from the central 
laboratory. Patients that do not have both a baseline measurement and at least one post-baseline 
measurement will not be included. 
At a given visit, the change and/or percent change from baseline will be compared between the 
randomized treatment groups using an ANCOVA using the treatment as a categorical factor and 
baseline measurement for the parameter as a continuous covariate. 
The association between the change from baseline in CA-125 measurements and invPFS will be 
evaluated using a Cox proportional hazards model. A measure of CA-125 kinetics such as the 
rate of change from baseline in CA-125 may also be associated with invPFS using a Cox model. 
11.2.7.2 
Progression Free Survival 2 (PFS2) 
The second event of PFS, PFS2, is defined as the time from randomization to the second event of 
disease progression as assessed by the investigator, or death due to any cause. The first event of 
disease progression will be captured as the primary endpoint in this study and thus the second 
event will be the next event of disease progression as assessed by the investigator. This second 
event of PFS may be a documented event per RECIST guidelines or may be an event of 
symptomatic progression.  
11.2.7.3 
Overall Response Rate 
ORR is defined as a best response of CR or PR using the RECIST v1.1 criteria (Appendix B), as 
assessed by both investigator and IRR, in patients with measurable disease at study entry. ORR 
will be summarized with frequencies and percentages in the safety population. 
11.2.7.4 
Duration of Response 
The DOR is measured from the time measurement criteria are met for CR/PR per RECIST v1.1 
criteria (Appendix B), as assessed by both the investigator and IRR, until the first date that 
recurrent or progressive disease (PD) is objectively documented. The DOR will be summarized 
with descriptive statistics. Only patients with a response will be included in the summary. 
11.2.7.5 
Patient Reported Outcome EQ-5D 
Analyses of changes and/or percent changes from baseline will be analyzed for each scheduled 
post-baseline visit and for the final visit for the EQ-5D instrument. Patients that do not have both 
a baseline measurement and at least one post-baseline measurement will not be included. 
At a given visit, the change and/or percent change from baseline will be compared between the 
randomized treatment groups using an ANCOVA using the treatment as a categorical factor and 
baseline measurement for the parameter as a continuous covariate. 


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11.2.7.6 
Relationship between Rucaparib Exposure and Efficacy and Safety 
The primary endpoint of invPFS will be presented for subgroups of patients defined by levels of 
rucaparib exposure. These analyses are exploratory in nature so the definition of relevant 
subgroups may be data-driven.  
11.3 
Interim Analysis 
No formal interim efficacy analyses will be performed. 
All endpoints were summarized at the time the primary endpoint (invPFS) was unblinded in 
April 2017; however, the following efficacy endpoints are still being collected and will be 
summarized at the time of the study closing:  
• 
Secondary Endpoint of Final OS 
• 
Post-progression exploratory endpoints (PFS2, time to first subsequent anticancer 
treatment, time to second subsequent anticancer treatment, and chemotherapy-free interval)  
The OS data were heavily censored at the time of the primary endpoint analysis. In order to 
adjust for multiple analyses of OS at a later stage, a stopping rule will be applied. The Haybittle-
Peto55, 56 stopping rule will be applied, where an OS result with a p-value < 0.001 can be used to 
claim superiority of rucaparib compared to placebo. This means that a p-value < 0.05 can be 
utilized at the final analysis, which is projected to occur once 70% of the death events have been 
collected. 
11.4 
Sample Size Considerations 
The total enrollment planned is 540 patients. A minimum of 180 and a maximum of 200 patients 
with a deleterious tBRCA mutation will be enrolled. Enrollment of patients with a known 
deleterious gBRCA mutation documented in their medical record will not exceed 150. There is 
no minimum number of patients required for each of the nbHRD and biomarker negative 
subgroups; however, no more than 360 total patients will be randomized for stratification into 
these subgroups combined. Prior to final efficacy analysis, HRD classification will be 
determined by the FCTA, which will evaluate homologous recombination gene mutations and/or 
extent of genomic scarring in tumor tissue. 
Table 4 below provides estimated sample sizes and power calculations. 


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Table 4. 
Estimated Sample Sizes and Power Calculations 
Group 
Hazard 
Ratio 
Cumulative 
N  
Minimum 
Number of 
Events 
(70%) 
Median PFS 
Placebo vs 
Rucaparib 
(months) 
Power 
One-
sided 
Alpha 
BRCA HRD  
0.50 
180 
126 
6 vs 12 
90% 
0.025 
All HRD 
(BRCA + 
nbHRD) 
0.60 
300 
210 
6 vs 10 
90% 
0.025 
ITT Population 
(BRCA + 
nbHRD + 
Biomarker 
Negative) 
0.70 
540 
378 
6 vs 8.5 
90% 
0.025 
 
The study will end after 70% of the patients in the tBRCA subgroup have an observed event of 
investigator-determined disease progression or death. If the minimum number of tBRCA patients 
are enrolled, then the study will end following the 126th event of investigator-determined disease 
progression or death. Similarly, if the maximum number of tBRCA patients are enrolled, then the 
study will end following the 140th event of investigator-determined disease progression or death. 
The IDMC will inform the sponsor when the required number of PFS events have been observed 
in order to ensure the sponsor remains blinded to which patients are in the tBRCA subgroup. If 
the nbHRD and/or biomarker negative subgroups have observed events of invPFS in fewer than 
60% of the patients, the IDMC may recommend that the study continue for up to 6 more months 
if it is likely that the nbHRD and biomarker negative subgroups will observe enough additional 
events of PFS to reach 60%.  
Following the collection of the required number of PFS events, the outstanding queries for all 
visits and events prior to the data cutoff date will be resolved and the database will be locked 
before the blind break and subsequent primary analysis.  


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12 
PATIENT DISPOSITION 
12.1 
Removal of patients from therapy or assessment 
A patient must be discontinued from treatment with study drug if any of the following apply: 
• Consent withdrawal at the patient’s own request or at the request of their legally 
authorized representative 
• Progression of patient’s underlying disease by RECIST v1.1 as assessed by the 
investigator 
• Any event, adverse or otherwise, that, in the opinion of the investigator, would pose an 
unacceptable safety risk to the patient 
• An intercurrent illness that, in the opinion of the investigator, would affect assessments of 
the clinical status to a significant degree and requires discontinuation of therapy 
• A positive pregnancy test at any time during the study. 
The sponsor may discontinue the trial early for any of the reasons noted in Section 13.7. 
12.2 
Procedures for discontinuation 
The sponsor (or designee) should be notified of all study terminations as soon as possible. The 
date and reason for cessation of study drug must be documented in the eCRF and source 
documents. To the extent possible, end-of-study procedures should be performed on all patients 
who receive study drug. The Treatment Discontinuation visit should occur 28 (±3) days 
following the last dose of study drug. Patients will be followed for 28 days after the last dose of 
study drug for safety; those with ongoing SAEs/AESIs will be followed until either resolution or 
stabilization has been determined. 


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13 STUDY ADMINISTRATION 
13.1 
Regulatory and Ethical Considerations 
The study will be conducted in accordance with the protocol and applicable standard operating 
procedures (SOPs); and in compliance with applicable guidelines and regulations.  
The investigator will assure that no amendments to the protocol will take place without prior 
agreement from the sponsor and documented approval from the IRB/IEC, and local health 
authority (where applicable), except where necessary to eliminate an immediate hazard(s) to the 
study participants. 
Significant noncompliance with the protocol, SOPs, Good Clinical Practice (GCP), and/or 
applicable regulatory requirement(s) by an investigator/institution, or by member(s) of the 
sponsor staff or its representatives will lead to prompt action by the sponsor to secure 
compliance. If monitoring and/or auditing identifies serious noncompliance on the part of an 
investigator/institution, the sponsor will take steps to secure compliance or terminate the 
investigator's/institution’s participation in the study. When an investigator's/institution’s 
participation is terminated because of significant noncompliance, the sponsor will promptly 
notify the regulatory authority(ies) and other appropriate parties (eg, IRB/IEC). 
All potential serious breaches of GCP must be reported to the sponsor or designee within 
24 hours. A serious breach is a breach of the conditions and principles of GCP in connection 
with the study or the protocol, which is likely to affect, to a significant degree, the safety or 
physical or mental integrity of the participants of the study or the scientific value of the study. 
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. 
This study will not use the services of study site personnel where sanctions have been invoked or 
where there has been scientific misconduct (eg, debarment). 
13.2 
Regulatory Authority Approvals 
The sponsor or designee will submit the study protocol plus all relevant study documents to 
concerned regulatory agencies for approval prior to the study start. No patient will begin 
study-specific screening until appropriate regulatory approval of the study protocol has been 
received. 
Each investigator must complete a Form FDA 1572 (or equivalent, when participating in a US 
Investigational New Drug Application [IND] study). In addition, local statement of investigator 
documents must be provided where required. Each investigator must submit to the sponsor (or 
designee) financial disclosure information for studies under a US IND or if required by national 
law and/or local regulations. 
The study will be registered on regionally-relevant registries, including www.clinicaltrials.gov, 
EU Clinical Trials Register, and other applicable trial registry systems as appropriate. Data 
generated from this study must be handled in accordance with any laws, rules, and regulations 


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related to the privacy of personal data or medical information applicable in the jurisdiction where 
the data is processed, including without limitation, the US Health Information Portability and 
Accountability Act of 1996 (HIPAA), and its implementing regulations, and the European Union 
General Data Protection Regulation 2016/679 (GDPR). 
13.2.1 Institutional Review Board or Independent Ethics Committee Approval 
The protocol, all protocol amendments, and any material to be provided to the patient (such as 
the ICF, Patient Information Sheets (PIS), advertisements, drug dosing diaries, or descriptions of 
the study used to obtain informed consent) must be reviewed and approved by an IRB/IEC 
before study start, according to national law and/or local regulations. There must be proof of 
submission of the Investigator’s Brochure (IB) to the IRB/IEC. The sponsor will supply relevant 
information to the investigator to use for submission of the study protocol and additional study 
documents to the IRB/IEC. Verification of the IEC’s/IRB’s unconditional approval of the study 
protocol and the written ICF will be transmitted to Clovis Oncology by the investigator or by 
other means as determined between the investigator and the sponsor. 
No patient will begin study specific screening until appropriate IEC/IRB approval of the study 
protocol and ICF/PIS have been received and the investigator has obtained the patient’s legally 
effective ICF.  
The investigator will submit appropriate reports on the progress of the study to the IEC/IRB at 
least annually in accordance with applicable national law and/or local regulations and in 
agreement with the policy established by the IEC/IRB.  
The IEC/IRB must be informed by the investigator of all SAEs or SUSARs occurring during the 
study that are likely to affect the safety of the patients or the conduct of the study, according to 
IRB/IEC policies. 
13.3 
Patient Information and Informed Consent 
13.3.1 General Aspects of Informed Consent 
All information about the clinical study, including the patient information sheet and the ICF, is 
prepared and used for the protection of the human rights of the patient according to ICH GCP 
guidelines, the Declaration of Helsinki, and local requirements. 
The ICF, prepared by the investigator with the assistance of the sponsor, must comply with all 
applicable regulations, be approved along with the study protocol by the IRB/IEC, and be 
acceptable to the sponsor. 
It is the responsibility of the investigator to obtain legally effective informed consent from each 
patient participating in this study after adequate explanation of the aims, methods, objectives, 
and potential hazards of the study, answering all questions from the patient regarding the study, 
and prior to undertaking any study-related procedures. 


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13.3.2 Informed Consent Process 
The patient must be provided with the patient information, if applicable, and the most current 
IRB/IEC approved ICF. The investigator or their designee shall discuss with each patient the 
nature of the study, its requirements, and that participation is voluntary and may be terminated at 
any time by the investigator or participant. To participate in the study, informed consent must be 
obtained from each prospective patient prior to any protocol specific activities.  
The ICF must be in language fully comprehensible to the prospective patient or legally 
authorized representative. Patients or legally authorized representatives (where acceptable 
according to national law and/or local regulations) must be given sufficient time and opportunity 
to inquire about the details of the study and to discuss and decide on their participation in the 
study with the investigator. The patient or legally authorized representative and the person 
conducting the informed consent discussion for the study will personally sign and date the ICF in 
addition to any other required signatures (if applicable). A copy of the signed ICF will be 
provided to the patient or legally authorized representative and the original will be filed in the 
investigator’s file. The process of obtaining informed consent will be documented in the patient’s 
source documents. The date when a patient’s informed consent was obtained will be captured in 
the patient’s source documents and eCRF. The patient or legally authorized representative will 
need to re-consent if the ICF is updated during the study, such as after an amendment to the 
protocol, if mandated by the IRB/IEC. 
13.3.3 Additional Informed Consent Documentation 
Patients providing an optional tumor tissue biopsy sample at the time of radiographic disease 
progression/treatment discontinuation must consent to this procedure. A separate consent form 
may be used for tissue testing. 
13.4 
Patient Confidentiality  
The investigator must assure that patients’ anonymity is strictly maintained and that their 
identities are protected from unauthorized parties. Only patient initials and an identification 
code (i.e., no names or, in some regions, initials or date of birth) according to country 
regulations will be recorded on any form submitted to the sponsor and the IEC/IRB. The 
investigator must have a list where the identity of all treated patients can be found, but not 
intended for use by the sponsor. 
13.5 
Study Monitoring 
The sponsor, or contract research organization (CRO) or contract monitor acting on the sponsor’s 
behalf, will contact or visit the investigator at the study center prior to the entry of the first 
patient (unless the sponsor or the CRO has worked with the center recently in the same or 
comparable indication, the site location and facilities have not changed significantly since after 
the last visit by the sponsor or CRO, and the potential investigator/site are currently in good 
standing with respect to regulatory compliance, in which case this initial visit may be waived) 
and at predetermined appropriate intervals during the study until after the last patient is 
completed. The monitor will also perform a study closure visit. 


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In accordance with ICH GCP and local regulations, the clinical monitor will periodically review, 
via direct access, all eCRFs, study documents, medical records (office, clinic, or hospital) for 
patients in this study (anonymity is to be preserved), research facilities, and clinical laboratory 
facilities associated with the study at mutually convenient times until completion of the study. If 
these requirements are in conflict with local regulatory restrictions or institutional requirements, 
the investigator must inform the sponsor of these restrictions before initiation of the study. 
The investigator must ensure provision of sufficient time, reasonable space, and adequate 
qualified personnel for the monitoring visits. The visits are for the purpose of the monitor to 
verify adherence to the study protocol and the completeness, consistency, and accuracy of data 
recorded on the eCRF and other documents; however, the investigator retains ultimate 
responsibility for the quality and integrity of data generated by the site. Aspects of the study that 
are essential for human patient protection and safety and the reliability of study data shall be 
confirmed. The investigator will make all source data (ie, the various study records, laboratory 
test reports, other patient records, drug accountability forms, and other pertinent data) and eCRFs 
for the entire study period available to the monitor. Monitoring is done by comparing the 
relevant site records of the patients with the entries on the eCRF (ie, source data verification).  
By agreeing to participate in the study, the investigator agrees to cooperate with the monitor to 
ensure that any issues detected in the course of the monitoring visits are resolved. Contact 
information for the study monitor is located in the investigator file.  
13.6 
Case Report Form  
The data will be collected using an electronic data capture (EDC) system by remote data entry on 
eCRFs. Sites will receive training on the EDC system. All users will be supplied with unique 
login credentials. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported.  
All source documents should be completed in a neat, legible manner according to the principles of 
Attributable, Legible, Contemporaneous, Original or Certified Copy, Accurate, and ‘Plus’ (+) 
Complete, Consistent, Enduring, and Available (ALCOA+), to ensure accurate interpretation of data. 
Data recorded in the eCRF should be consistent with the data recorded on the source documents.  
Prior to study start, the investigator will prepare a list showing the all individuals delegated 
responsibility on this study. This “study site personnel and delegation list” must be kept current 
throughout the study. 
Full information regarding electronic data capture and completing eCRFs is included in the 
investigator files. All questions or comments related to electronic capture should be directed to 
the assigned monitor. 
Data collection will be decreased at the time of implementation of Protocol Amendment 5, as all 
endpoints except those associated with long-term follow up have been met and reported. As of 


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the implementation of Protocol Amendment 5, the assessments required to be entered into the 
study eCRFs/eCRF modules for patients are as follows:  
• Log Forms 
− Adverse Events (SAE/AESIs only) 
− Subsequent Anticancer Therapy (SAT) 
• TA_Scan 
• EOT 
• 28-Day Post 
• Long-Term Follow-Up 
• Death 
• PI_Sign 
Updated eCRF Completion Guidelines will be provided to the sites for further detail regarding 
what should be entered for patients that are ongoing on treatment or in long-term follow-up at the 
time Protocol Amendment 5 is implemented. 
13.7 
Study Termination and Site Closure 
The sponsor, the investigator/institution, or IRB/IEC reserve the right to terminate the study at 
any time. Should this be necessary, the sponsor and investigator will arrange discontinuation 
procedures. In terminating the study, the sponsor and the investigator will assure that adequate 
consideration is given to the protection of the patients’ interests. 
The sponsor reserves the right to terminate the study at any time for medical or administrative 
reasons. When feasible, a 30-day written notification will be given. 
The entire study will be stopped if any of the following applies: 
• The protocol-specified treatment is considered too toxic to continue the study; 
• Evidence has emerged that, in the opinion of the sponsor or the investigator(s), makes the 
continuation of the study unnecessary or unethical; 
• The stated objectives of the study are achieved; or 
• The sponsor discontinues the development of oral rucaparib 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in source documents and on the eCRF. All 
reasons for discontinuation of treatment must be documented. 
If the study is terminated prematurely the sponsor will promptly inform the 
investigators/institutions, and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension. The investigators will promptly inform their 


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IRB/IEC, providing the reason(s) for the termination or suspension by the sponsor or by the 
investigator/institution, as specified by the applicable regulatory requirement(s). 
13.8 
Study Protocol Amendments 
Protocol amendments must be made only with the prior approval of Clovis Oncology. 
Agreement from the investigator must be obtained for all protocol modifications and changes to 
the informed consent document. The IEC/IRB must be informed of all amendments and give 
approval prior to their implementation. The sponsor will submit any study protocol amendments 
to the applicable regulatory authorities for approval and keep the investigator(s) updated as 
detailed in the ICH GCP guidelines. Management of protocol deviations is described in 
Section 13.10.1. 
13.9 
Retention of Study Documents 
The study site will maintain a study file, which will contain all documents defined in the ICH 
E6(R2) Guideline for Good Clinical Practice. The investigator will have control of all essential 
documents generated by the site. Source documents must be maintained and ALCOA+ 
documentation practice used. Any changes to source data will be traceable, will not obscure the 
original entry, and will be explained if necessary (via an audit trail). The investigator must 
implement procedures to ensure the integrity of any data generated.  
The sponsor and investigator will maintain a record of the location(s) of their respective essential 
documents including source documents. The storage systems used during the study and for 
archiving (irrespective of media used) must provide for documentation identification, version, 
history, search, and retrieval. The investigator agrees to keep records and those documents that 
include (but are not limited to) the identification of all participating patients, medical records, 
study specific source documents, all original signed and dated ICFs, copies of all eCRFs, query 
responses, and detailed records of drug disposition to enable inspections or audits from 
regulatory authorities, the IRB/IEC, and the sponsor or its designees. The investigator shall retain 
records and documents, including signed ICFs, pertaining to the conduct of the study for a period 
of 25 years after study completion or, if no application is to be filed or if the application is not 
approved for such indication, until at least 5 years after the investigation is discontinued. 
However, these documents will be retained for a longer period if required by the applicable 
regulatory requirement(s), institutional policies, or if needed by Clovis Oncology. In addition, 
the investigator must make provision for the patients’ medical records to be kept for the same 
period of time. 
No data should be destroyed without the agreement of Clovis Oncology. Copies of original 
documents will fulfill the ICH E6(R2) requirements for certified copies. Should the investigator 
wish to assign the study records to another party or move them to another location, Clovis 
Oncology must be notified in writing of the new responsible person and/or the new location. 
Clovis Oncology will inform the investigator, in writing, when the trial-related records are no 
longer needed. 
All clinical study information will be recorded, handled, and stored in a way that allows accurate 
reporting, interpretation, and verification, irrespective of the media used. 


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Patients’ medical records and other original data will be archived in accordance with the 
archiving regulations or facilities of the investigational site; but at a minimum, for the period 
defined by the applicable regulatory requirements. 
13.10 
Quality Control and Assurance 
The sponsor will implement and maintain quality control and quality assurance procedures with 
written SOPs to ensure that the study is conducted, and data are generated, documented, and 
reported in compliance with the protocol, GCP, and applicable regulatory requirements.  
13.10.1 Protocol Deviations 
The investigator may not deviate from the protocol unless necessary to eliminate immediate 
hazards to the patient. A deviation may result in the patient having to be withdrawn from the 
study and rendering that patient’s data nonevaluable. Any deviation must be documented in the 
source documents and reported to the sponsor and to the IRB/IEC according to institutional and 
sponsor requirements.  
13.10.2 Study Site Training 
Each investigator and the site personnel for this study will be trained by the sponsor and/or a 
designee (ie, a CRO) on GCP and on the design, conduct, procedures, and administrative aspects 
of this study. This training may include, but is not limited to, on-site training, Investigator 
Meeting(s), and/or tele/videoconferencing. Training may be ongoing as refresher, to address 
specific items, or to introduce changes in the study. When site staff join after study training has 
been conducted, the investigator is responsible for ensuring that the new staff member is trained.  
13.10.3 Quality Assurance Audits and Inspections 
An audit of a clinical center may be conducted by a quality assurance auditor appointed by the 
sponsor. The purpose of an audit, which is independent of and separate from routine monitoring 
or quality control functions, is to evaluate study conduct and compliance with the protocol, 
SOPs, ICH GCPs, and the applicable regulatory requirements. The investigator will be informed 
if an audit is to take place and advised as to the scope of the audit. IRB/IEC representatives may 
also conduct an audit of the study at any time. 
Representatives of the FDA, EMA, or other regulatory agencies may conduct an inspection of 
the study at any time. If informed of such an inspection, the investigator will notify the sponsor 
immediately. 
13.10.4 Direct Access to Source Data/Documents for Audits and Inspections 
The investigator will ensure that the auditors or inspectors have access to the clinical supplies, 
study site facilities, and laboratory, and that all data (including original source documentation) 
and all paper and electronic study files and audit trails are available, if requested. It is important 
that the investigator(s) and their staff cooperate with the quality assurance auditor or regulatory 
authority inspector during the audit or inspection. 


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13.11 
Clinical Study Report 
A clinical study report (CSR) will be prepared under the responsibility and supervision of Clovis 
Oncology and signed by the sponsor’s chief medical officer, head of biostatistics, and head of 
regulatory affairs; thereby indicating their agreement with the analyses, results, and conclusions 
of the clinical study report. The CSR will be provided to the clinical investigator(s) and 
regulatory agency(ies) as required by the applicable regulatory requirements. 
13.12 
Study Publication and Disclosure Policy 
All information for the study provided by the sponsor or designee to the investigator, including, 
but not limited to, the IB, this protocol, eCRFs, the protocol-specified treatment, and any other 
study information, will remain the sole and exclusive property of the sponsor during the conduct 
of the study and thereafter. This information is not to be disclosed to any third party (except 
employees or agents directly involved in the conduct of the study or as required by law) without 
prior written consent from the sponsor. The investigator further agrees to take all reasonable 
precautions to prevent the disclosure by any employee or agent of the study center to any third 
party or otherwise into the public domain. 
All data generated from this study will be maintained by the sponsor. All data generated from 
this study, and all information furnished by the sponsor, the investigators, and other participating 
study groups shall be held in strict confidence. Independent analysis and/or publication of study 
data by the investigator(s) or any member of their staff are not permitted without the prior 
written consent of the sponsor. Any collaborative publications will be authored in accordance 
with the applicable guidelines (eg, International Committee of Medical Journal Editors 
[ICMJE]).57 Written permission to the investigator will be contingent on the review of the 
statistical analysis and manuscript/abstract by the sponsor and participating cooperative groups, 
and will provide for nondisclosure of the confidential or proprietary information. In all cases, the 
parties agree to provide all manuscripts or abstracts to all other parties 60 days prior to 
submission. This timeframe will enable all parties to protect proprietary information and to 
provide comments based on information that may not yet be available to other parties.  
13.13 
Investigator Oversight 
The investigator has full responsibility for supervising any individual or party to whom they 
delegate study-related duties and functions conducted at the study site, including satellite 
locations. The responsibility for supervision includes the services of any party or individual 
retained by the investigator for this purpose, regardless of location. All staff-delegated study 
responsibilities must be documented on an approved study site personnel and delegation log for 
the study and this log filed with the essential documents. In addition, the investigator must 
ensure that delegated staff are qualified by documented education, training, experience and 
licensure (as applicable). The investigator will implement procedures to ensure integrity of the 
study related duties, functions performed, and any data generated.  


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27. McCabe N, Turner NC, Lord CJ, Kluzek K, Bialkowska A, Swift S, et al. Deficiency in the 
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30. Gottipati P, Vischioni B, Schultz N, Solomons J, Bryant HE, Djureinovic T, et al. 
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31. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib 
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34. Rustin GJS, Vergote I, Eisenhauer E, Pujade-Lauraine E, Quinn M, Thigpen T, et al. 
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37. Popova T, Manie E, Rieunier G, Caux-Moncoutier V, Tirapo C, Dubois T, et al. Ploidy and 
Large-Scale Genomic Instability Consistently Identify Basal-like Breast Carcinomas with 
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38. Wang ZC, Birkbak NJ, Culhane AC, Drapkin R, Fatima A, Tian R, et al. Profiles of 
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39. US Cancer Statistics Working Group. United States Cancer Statistics: 1999–2009 
Incidence and Mortality Web-based Report: Atlanta (GA): Department of Health and 
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40. Morgan RJ, Jr., Alvarez RD, Armstrong DK, Boston B, Burger RA, Chen LM, et al. 
NCCN Clinical Practice Guidelines in Oncology: epithelial ovarian cancer. J Natl Compr 
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41. Cannistra SA. Cancer of the ovary. N Engl J Med. 2004;351(24):2519-29. 
42. Salvador S, Rempel A, Soslow RA, Gilks B, Huntsman D, Miller D. Chromosomal 
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55. Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Br J 
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15 APPENDICES 
Appendix A. 
List of Homologous Recombination Genes for HRD Stratification by the ICTA 
Appendix B. 
Response Evaluation Criteria in Solid Tumors Criteria 
Appendix C. 
Gynecological Cancer Intergroup (GCIG) Guidelines  
Appendix D. 
Eastern Cooperative Oncology Group (ECOG) Performance Status Scale 
Appendix E. 
Quality of Life Questionnaires 
Appendix F. 
Examples of CYP Substrates with Narrow Therapeutic Range 
 
 


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15.1 
Appendix A 
List of Homologous Recombination Genes for HRD Stratification by the ICTA 
tBRCA 
nbHRD 
Biomarker-negative 
BRCA1 
BRCA2 
ATM 
ATR 
ATRX 
BARD1 
BLM 
BRIP1 
CHEK1 
CHEK2 
FANCA 
FANCC 
FANCD2 
FANCE 
FANCF 
FANCG 
FANCI 
FANCL 
FANCM 
MRE11A 
NBN 
PALB2 
RAD50 
RAD51 
RAD51B 
RAD51C 
RAD51D 
RAD52 
RAD54L 
RPA1 
Genes not included in 
the tBRCA or nbHRD 
groups 
 
 
 


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15.2 
Appendix B 
Response Evaluation Criteria in Solid Tumors Criteria 
The RECIST guidelines (v1.1) are described in Eisenhauer (2009)33 and at 
http://www.eortc.be/Recist/Default.htm. A short summary is given below. 
Measurable Disease: 
Tumor lesions: measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) with the following: 
• A minimum size of 10 mm by CT scan (CT scan thickness no greater than 5 mm). 
• A minimum size of 10 mm caliper measurement by clinical exam (lesions that cannot be 
accurately measured with calipers should be recorded as nonmeasurable). 
• A minimum size of 20 mm by chest X-ray. 
All tumor measurements must be recorded n millimeters (or decimal fractions of centimeters). 
Malignant lymph nodes: to be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be not greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed.  
Nonmeasurable Disease: 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis), as well as truly nonmeasurable 
lesions, are considered nonmeasurable disease. Lesions considered truly nonmeasurable include 
leptomeningeal disease, ascites, pleural/pericardial effusions, inflammatory breast disease, 
lymphangitic involvement of skin and lung, and abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques.  
Bone Lesions 
Bone lesions, cystic lesion, and lesions previously treated with local therapy require particular 
comment. Bone scan, PET scan, or plain films are not considered adequate imaging techniques 
to measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
Lytic bone lesions or mixed lytic–blastic lesions with identifiable soft tissue components that can 
be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability described 
above. 
Blastic bone lesions are nonmeasurable. 


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Cystic Lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor nonmeasurable) because they are, by definition, 
simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered as measurable lesions if 
they meet the definition of measurability described above. However, if noncystic lesions are 
present in the same patient, these are preferred as target lesions. 
Lesions with Prior Local Treatment 
Tumor lesions situated in a previous irradiated area or in an area subjected to other locoregional 
therapy are usually not considered measurable unless there has been demonstrated progression in 
the lesion. 
Target Lesions 
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference 
by which to characterize the objective tumor response.  
Non target Lesions 
RECIST criteria require unequivocal quantification of the changes in tumor size for adequate 
interpretation of the sum of target lesions. Consequently, when the boundaries of the primary are 
difficult to delineate, this tumor should not be considered a target lesion. 
Guidelines for Evaluation of Measurable Disease 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. 


Clovis Oncology, Inc. 
 
Clinical Protocol CO-338-014 
Oral rucaparib (CO-338) 
06 July 2020 
Amendment 5 
103 
 
Evaluation of Target Lesions 
Complete Response 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or nontarget) must have reduction in short axis to <10 
mm. 
Partial Response 
At least a 30% decrease in the sum of the LD of target lesions, taking as 
reference the baseline sum LD. 
Stable Disease 
Neither sufficient shrinkage to qualify for partial response nor sufficient 
increase to qualify for progressive disease (PD), taking as reference the 
smallest sum LD since the treatment started. 
Progressive Disease 
At least a 20% increase in the sum of the LD of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, 
the sum must also demonstrate an absolute increase of at least 5 mm. 
The appearance of one or more new lesions is also considered 
progression. 
Evaluation of Nontarget Lesions 
Complete Response 
Disappearance of all nontarget lesions and normalization of tumor 
marker level. 
Stable Disease/Incomplete 
Response 
Persistence of one or more nontarget lesion(s) or/and maintenance of 
tumor marker level above the normal limits. 
Progressive Disease 
Appearance of one or more new lesions and/or unequivocal progression 
of existing nontarget lesions. 
If tumor markers are initially above the institutional ULN, they must normalize for a patient to 
be considered a complete responder.  
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). The patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria.  
Evaluation of Best Overall Response 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not 
evaluated 
No 
PR 
SD 
Non-PD or not 
evaluated 
No 
SD 


Clovis Oncology, Inc. 
 
Clinical Protocol CO-338-014 
Oral rucaparib (CO-338) 
06 July 2020 
Amendment 5 
104 
 
Evaluation of Best Overall Response 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
Not Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
NE = 
Not evaluable. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
symptomatic deterioration. Every effort should be made to document the objective progression, 
even after discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response (CR) depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspiration/biopsy) prior to 
confirming the CR status. 
Confirmatory Measurement/Duration of Response 
Confirmation 
CT scans are required at screening and at the end of every 3rd cycle of treatment. 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded since the treatment 
started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
SD is measured from the start of the treatment until the criteria for progression are met, taking as 
reference the smallest measurements recorded since the treatment started. 
 
 


Clovis Oncology, Inc. 
 
Clinical Protocol CO-338-014 
Oral rucaparib (CO-338) 
06 July 2020 
Amendment 5 
105 
 
15.3 
Appendix C 
Modified Gynecological Cancer Intergroup (GCIG) Guidelines  
GCIG Guidelines for Response Using CA-12534 (adapted for use in this trial) 
GCIG CA-125 definitions are available at http://gcig.igcs.org/CA-125.html.  
To be evaluable for response by CA-125 requires at least one pre-treatment sample >2 x ULN 
and two post-treatment samples confirming a response 
A response to CA-125 has occurred if there is at least a 50% decrease as the result of the 
treatment. The pre / post treatment samples must satisfy the following criteria: 
1. There must be at least one sample that is >2 x ULN prior to initiation of treatment 
2. The second sample (post-treatment) must be ≤ 50% of the pre-treatment sample; 
3. The confirmatory third sample must be ≥21 days after the second sample and ≤ 110% of 
the second sample; 
4. Any intervening samples between samples 2 and 3 must be ≤ 110% of the previous 
sample unless considered to be increasing because of tumor lysis. 
Per inclusion criteria #5, CA-125 must =be <ULN prior to study entry. This requirement applies 
to all patients, including those who achieved a best response of PR by serologic CA-125 
response criteria. Thus, patients must have achieved a >50% reduction in CA-125 level and also 
have CA-125 <ULN. 
Patients are not evaluable by CA-125 if they have received mouse antibodies or if there has been 
medical or surgical interference with their peritoneum or pleura during the previous 28 days.  
 
 


Clovis Oncology, Inc. 
 
Clinical Protocol CO-338-014 
Oral rucaparib (CO-338) 
06 July 2020 
Amendment 5 
106 
 
15.4 
Appendix D 
Eastern Cooperative Oncology Group (ECOG) Performance Status Scale 
ECOG Performance Status 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature (eg, light house work or office work). 
2 
Ambulatory and capable of all self care but unable to carry out any work activities. Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self care; confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self care. Totally confined to bed or chair. 
5 
Dead. 
 
In the event performance status is assessed by the Karnofsky Performance Status scale, the 
following conversion chart applies. 
Karnofsky Performance Status 
ECOG Performance 
Status 
General Description 
Score 
Specific Description 
Score 
Able to carry on 
normal activity and to 
work; no special care 
needed 
100 
Normal; no complaints; no 
evidence of disease 
0 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease 
1 
80 
Normal activity with effort; 
some signs or symptoms of 
disease 
Unable to work; able 
to live at home and 
care for most personal 
needs; varying 
amount of assistance 
needed 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work 
2 
60 
Requires occasional assistance, 
but is able to care for most of 
personal needs 
50 
Requires considerable assistance 
and frequent medical care 
3 


Clovis Oncology, Inc. 
 
Clinical Protocol CO-338-014 
Oral rucaparib (CO-338) 
06 July 2020 
Amendment 5 
107 
 
Karnofsky Performance Status 
ECOG Performance 
Status 
General Description 
Score 
Specific Description 
Score 
Unable to care for 
self; requires 
equivalent of 
institutional or 
hospital care; disease 
may be progressing 
rapidly 
40 
Disabled; requires special care 
and assistance 
30 
Severely disabled; hospital 
admission is indicated although 
death not imminent 
4 
20 
Very sick; hospital admission 
necessary; active supportive 
treatment necessary 
10 
Moribund; fatal processes 
progressing rapidly 
0 
Dead 
5 
 
 
 


Clovis Oncology, Inc. 
 
Clinical Protocol CO-338-014 
Oral rucaparib (CO-338) 
06 July 2020 
Amendment 5 
108 
 
15.5 
Appendix E  
National Comprehensive Cancer Network – Functional Assessment of Cancer Therapy 
(NCCN-FACT) FACT - Ovarian Symptom Index (FOSI-18) instrument (NCCN-FACT 
FOSI-18) – English Version 
Sample form and background available at: http://www.facit.org/FACITOrg/Questionnaires.  
Patients will complete the instrument on an electronic device. This device is a Class 1 listed (i.e., 
approved) device. 
Below is a list of statements that other people with your illness have said are important.  
Please circle or mark one number per line to indicate your response as it applies to  
the past 7 days. 


Clovis Oncology, Inc. 
 
Clinical Protocol CO-338-014 
Oral rucaparib (CO-338) 
06 July 2020 
Amendment 5 
109 
 
 
 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GP1 
I have a lack of energy
 .....................................................................  
0 
1 
2 
3 
4 
GP4 
I have pain
 .....................................................................  
0 
1 
2 
3 
4 
GP6 
I feel ill
 .....................................................................  
0 
1 
2 
3 
4 
O3 
I have cramps in my stomach area
 .....................................................................  
0 
1 
2 
3 
4 
HI7 
I feel fatigued
 .....................................................................  
0 
1 
2 
3 
4 
Cx6 
I am bothered by constipation
 .....................................................................  
0 
1 
2 
3 
4 
O1 
I have swelling in my stomach area
 .....................................................................  
0 
1 
2 
3 
4 
C3 
I have control of my bowels
 .....................................................................  
0 
1 
2 
3 
4 
GF5 
I am sleeping well
 .....................................................................  
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse
 .....................................................................  
0 
1 
2 
3 
4 
GP2 
I have nausea
 .....................................................................  
0 
1 
2 
3 
4 
B5 
I am bothered by hair loss
 .....................................................................  
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment
 .....................................................................  
0 
1 
2 
3 
4 
O2 
I have been vomiting
 .....................................................................  
0 
1 
2 
3 
4 
BMT15 
I am bothered by skin problems
 .....................................................................  
0 
1 
2 
3 
4 
BMT5 
I am able to get around by myself
 .....................................................................  
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life
 .....................................................................  
0 
1 
2 
3 
4 
D
R
S-
P 
T
S
E 
F 
W 
B 
D
R
S-
E 


Clovis Oncology, Inc. 
 
Clinical Protocol CO-338-014 
Oral rucaparib (CO-338) 
06 July 2020 
Amendment 5 
110 
 
GF7 
I am content with the quality of my life 
right now
 .....................................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
 
Euro-QoL5D (EQ-5D) – English Version for the US 
By placing a checkmark in one box in each group below, please indicate which statements best 
describe your own health state today. 
Mobility 
I have no problems in walking about 
 
 
I have some problems in walking about 
 
 
I am confined to bed 
 
 
Self-Care 
I have no problems with self-care 
 
 
I have some problems washing or dressing myself 
 
 
I am unable to wash or dress myself 
 
 
Usual Activities (e.g. work, study, housework, family or leisure activities) 
I have no problems with performing my usual activities 
 
 
I have some problems with performing my usual activities 
 
 
I am unable to perform my usual activities 
 
 
Pain/Discomfort 
I have no pain or discomfort 
 
 
I have moderate pain or discomfort 
 
 
I have extreme pain or discomfort 
 
 
Anxiety/Depression 
I am not anxious or depressed 
 
 


Clovis Oncology, Inc. 
 
Clinical Protocol CO-338-014 
Oral rucaparib (CO-338) 
06 July 2020 
Amendment 5 
111 
 
I am moderately anxious or depressed 
 
 
I am extremely anxious or depressed 
 
 
 


Clovis Oncology, Inc. 
 
Clinical Protocol CO-338-014 
Oral rucaparib (CO-338) 
06 July 2020 
Amendment 5 
112 
 
 


Clovis Oncology, Inc. 
 
Clinical Protocol CO-338-014 
Oral rucaparib (CO-338) 
06 July 2020 
Amendment 5 
113 
 
15.6 
Appendix F 
Examples of CYP Substrates with Narrow Therapeutic Range  
CYP Enzyme 
Substrates with Narrow Therapeutic Rangea 
CYP1A2 
Tizanidine, theophylline 
CYP2C9 
Warfarin, phenytoin  
CYP3A 
Alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, 
terfenadine 
The table is based on the Draft FDA Guidance on Drug Interaction Studies — Study Design, Data Analysis, 
Implications for Dosing, and Labeling Recommendations, 2012.50  
a CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship indicates that 
small increases in their exposure levels by the concomitant use of CYP inhibitors may lead to serious safety 
concerns (eg, Torsades de Pointes). 

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STATISTICAL ANALYSIS PLAN 
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 Ovarian Cancer 
PROTOCOL:  
CO-338-014 
VERSION:  
Version 1.0 
DATE FINAL:  
21 April 2017 
SPONSOR:  
Clovis Oncology 
5500 Flatiron Parkway, Suite 100 
Boulder, CO 80301 
(303) 625-5000 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or 
regulations. Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them. 




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TABLE OF CONTENTS 
APPROVAL PAGE ...................................................................................................................2 
ABBREVIATIONS AND ANALYSIS POPULATION DEFINTION ....................................6 
Analysis Population Definitions ..........................................................................................7 
1 
INTRODUCTION ...........................................................................................................8 
2 
OVERALL STUDY DESIGN, OBJECTIVES, AND ENDPOINTS .............................9 
2.1 
Study Objectives and Endpoints Outlined in Original Protocol ..............................9 
2.2 
Trial Design ...........................................................................................................10 
2.3 
Sample Size ............................................................................................................11 
2.4 
Data Cut-off Used ..................................................................................................11 
3 
GENERAL ANALYSIS CONVENTIONS ..................................................................12 
3.1 
Populations Definitions ..........................................................................................12 
3.2 
Definition of HRD Subgroups ...............................................................................12 
3.3 
Step-down Procedure .............................................................................................14 
3.4 
BRCA Subgroups...................................................................................................14 
4 
PATIENT DISPOSITION .............................................................................................15 
5 
PROTOCOL DEVIATIONS .........................................................................................15 
6 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ....................................15 
6.1 
Demographics ........................................................................................................15 
6.2 
Baseline Clinical Characteristics ...........................................................................16 
6.3 
Medical History .....................................................................................................17 
7 
STUDY DRUG EXPOSURE AND COMPLIANCE ...................................................17 
8 
PRIOR AND CONCOMITANT MEDICATIONS ......................................................17 
9 
EFFICACY VARIABLES ............................................................................................17 
9.1 
Primary Efficacy Variable .....................................................................................17 
9.2 
Secondary Efficacy Variables Included in the Step Down Analysis .....................17 
9.3 
Secondary Efficacy Variables Not Included in the Step Down Analysis ..............18 
10 
EFFICACY ANALYSIS ...............................................................................................18 
10.1 
Primary Efficacy Analysis .....................................................................................18 
10.1.1 
Sensitivity Analyses for PFS .......................................................................18 
10.1.1.1 
Censoring Distribution .......................................................................18 
10.1.1.2 
Interaction Between Treatment and HRD Status ...............................19 
10.2 
Secondary Efficacy Analyses Included in the Step Down Procedure ...................19 
10.2.1 
Disease Related Symptoms – Physical Subscale of the FOSI-18 ................19 
10.2.2 
Total Score of the FOSI-18 ..........................................................................19 
10.2.3 
Independent Radiologic Review of PFS (irrPFS) ........................................20 
10.3 
Secondary Efficacy Analyses Not Included in the Step Down Procedure ............20 


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10.3.1 
Overall Survival ...........................................................................................20 
10.3.2 
Population PK: Individual Model Parameter Estimates of Rucaparib and 
Covariates Identification. .............................................................................20 
10.4 
Exploratory Endpoints ...........................................................................................20 
10.4.1 
Change from Baseline in CA-125 Measurement .........................................21 
10.4.2 
Progression Free Survival 2 (PFS2) .............................................................21 
10.4.3 
ORR per RECIST v1.1 as Assessed by the Investigator .............................21 
10.4.4 
Duration of Response (DOR) per RECIST v1.1 as Assessed by the 
Investigator ..................................................................................................21 
10.4.5 
Change from Baseline in Sum of the Diameters of Target Lesions as 
Assessed by the Investigator ........................................................................22 
10.4.6 
Patient Reported Outcome of EQ-5D ..........................................................22 
10.4.7 
Exploratory Endpoint: Association Between the Change from Baseline in 
CA-125 Measurement and invPFS ..............................................................22 
10.4.8 
Exploratory Endpoint: Chemo-Free Interval ...............................................22 
10.4.9 
Exploratory Endpoint: Time to Start of First Subsequent Anti-cancer 
Treatment .....................................................................................................23 
10.4.10 Exploratory Endpoint: Time to Start of Second Subsequent Anti-cancer 
Treatment .....................................................................................................23 
10.4.11 Exposure- Response PK Report: Rucaparib PK, invPFS, irrPFS, CA-125, 
AEs, Clinical Laboratory Abnormalities, and Dose Modifications .............23 
11 
STATISTICAL / ANALYTICAL ISSUES ..................................................................23 
11.1 
Statistical Hypothesis .............................................................................................23 
11.2 
Handling of Dropouts or Missing Data ..................................................................24 
11.3 
Multiple Comparison / Multiplicity .......................................................................24 
11.4 
Examination of Efficacy in Subgroups ..................................................................25 
12 
SAFETY ANALYSIS ...................................................................................................27 
12.1 
Adverse Events ......................................................................................................27 
12.2 
Clinical Laboratory Evaluations ............................................................................28 
12.3 
Vital Signs ..............................................................................................................29 
12.4 
Examination of Safety in Subgroups .....................................................................29 
13 
REFERENCES ..............................................................................................................29 
APPENDICES .........................................................................................................................30 
 
LIST OF IN-TEXT TABLES 
Table 1. Primary, Secondary, and Exploratory Objectives and Endpoints .............................9 
Table 2. Sample Size and Power Calculations ......................................................................11 
Table 3. Algorithm for Determine Origin of BRCA Mutation - Germline versus Somatic – 
in the tBRCA Population ........................................................................................15 


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LIST OF IN-TEXT FIGURES 
Figure 1. Ordered Step-down Procedure ................................................................................25 
 
LIST OF APPENDICES 
Appendix A 
List of Homologous Recombination Repair Genes for HRD Stratification 
by the CTA .......................................................................................................30 
Appendix B 
 
 
............................................................................................................31 
Appendix C 
 
 .......................................................................33 
 


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ABBREVIATIONS AND ANALYSIS POPULATION DEFINTION 
AE(s) 
adverse event(s) 
ATC 
Anatomical Therapeutical Chemical (coding) 
BRCA 
breast cancer gene 
CA-125 
cancer antigen 125 
CDx 
companion diagnostic  
CI 
confidence interval  
Cm 
Centimeter 
CR 
complete response 
CRF 
case report form 
CSR 
clinical study report 
CTA 
Clinical Trial Assay (also referred to as ICTA) 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
duration of response 
DRS-P 
disease related symptoms-physical subscale 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
FACT 
Functional Assessment of Cancer Therapy 
FMI 
Foundation Medicine, Inc. 
FOSI-18 
FACT-Ovarian Symptom Index-18 
gBRCA 
germline BRCA1/2 mutation  
GCIG 
Gynecologic Cancer InterGroup 
HGSOC 
high grade serous ovarian cancer 
HR 
hazard ratio 
HRD 
homologous recombination deficiency 
HRR 
homologous recombination repair 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
invPFS 
progression-free survival, investigator assessed 
IRR 
independent radiology review 
irrPFS 
progression-free survival, independent radiology review 
ITT 
intent-to-treat 
LOH 
loss of heterozygosity 
MedDRA 
Medical Dictionary for Regulatory Activities 
nbHRD 
non-tBRCA HRD 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NGS 
next generation sequencing 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival  


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PK 
pharmacokinetic(s) 
PR 
partial response 
PRO 
patient reported outcome 
PT 
Preferred Term 
QoL 
quality of life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP  
statistical analysis plan 
SD 
stable disease 
sNDA 
supplemental New Drug Application 
SOC 
System Organ Class 
tBRCA 
BRCA1/2 mutation in tumor tissue 
TEAE(s) 
treatment-emergent adverse event(s) 
ULN 
upper limit of normal 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization 
 
Analysis Population Definitions 
tBRCA 
Patients with BRCA mutation in their tumor 
HRD 
Patients with HRD+ tumors (a NGS HRD assay result), composed of 
tBRCA and non-tBRCA LOH+ 
non-tBRCA LOH+ 
Patients without a tBRCA mutation and with percent of tumor genome 
LOH ≥ 16% 
non-tBRCA LOH- 
Patients without a tBRCA mutation and with percent of tumor genome 
LOH < 16% 
non-tBRCA LOH unknown Patients who do not have a tBRCA mutation and where the LOH result is 
unknown. 
Intent-to-Treat (ITT) 
All randomized patients  
Safety Population  
The safety population will consist of all patients who received at least one 
dose of protocol-specified treatment 
 


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1 
INTRODUCTION 
This document describes the statistical analyses and data presentations to be performed for the 
clinical study report (CSR) of Clovis Oncology protocol CO-338-014 “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.” 
This statistical analysis plan (SAP) provides a comprehensive and detailed description of the 
strategy, rationale, and statistical techniques to be used to assess the efficacy and safety of 
rucaparib (CO-338) compared with placebo in patients with platinum-sensitive high-grade serous 
ovarian or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer who 
achieved a response to platinum-based therapy. 
The purpose of the SAP is to ensure the credibility of the study findings by specifying the 
statistical approaches to the analysis of study data prior to snapshot and unblinding of treatment 
codes. This SAP provides additional details around the statistical analyses that are outlined in the 
original protocol dated 9 Sep 2013, and three protocol amendments (Amendment 1 dated 4 Nov 
2014, Amendment 2 dated 9 Mar 2015, and Amendment 3 dated 7 Jul 2016). 
All statistical analyses detailed in this SAP will be conducted using SAS® Version 9.3 or higher. 


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2 
OVERALL STUDY DESIGN, OBJECTIVES, AND ENDPOINTS 
2.1 
Study Objectives and Endpoints Outlined in Original Protocol 
Table 1. 
Primary, Secondary, and Exploratory Objectives and Endpoints 
Primary Objectives 
Primary Endpoints 
To evaluate progression-free survival (PFS) by 
Response Evaluation Criteria in Solid Tumors 
(RECIST) Version 1.1, as assessed by the 
investigator (invPFS), in molecularly-defined 
homologous recombination deficiency (HRD) 
subgroups 
Disease progression according to RECIST 
v.1, as assessed by the investigator (invPFS), 
or death from any cause, in molecularly-
defined HRD subgroups 
Secondary Objectives 
Secondary Endpoints 
To evaluate PFS by RECIST, as assessed by 
independent radiology review (IRR), in 
molecularly-defined HRD subgroups 
Disease progression according to RECIST 
v1.1, as assessed by independent radiology 
review (irrPFS), or death from any cause, in 
molecularly-defined HRD subgroups 
To evaluate patient-reported outcome (PRO) of 
disease-related symptoms utilizing the disease-
related symptoms – physical (DRS-P) subscale 
of the National Comprehensive Cancer 
Network-Functional Assessment of Cancer 
Therapy (NCCN-FACT) FACT-Ovarian 
Symptom Index 18 (FOSI-18) 
Time to a 4-point decrease in the DRS–P 
subscale of the FOSI-18 
To evaluate PRO utilizing the complete FOSI-
18 instrument 
Time to a 8-point decrease in the total score of 
the FOSI-18 
To evaluate survival benefit 
Overall survival (OS) 
To evaluate safety 
The incidence of adverse events (AEs), 
clinical laboratory abnormalities, and dose 
modifications 
To determine the population pharmacokinetics 
(PK) of rucaparib  
Individual model parameter estimates of 
rucaparib and covariates identification 
Exploratory Objectives 
Exploratory Endpoints 
To evaluate the relationship between cancer 
antigen 125 (CA-125) levels and invPFS 
Association between the change from baseline 
in CA-125 measurements and invPFS 
To evaluate PFS2 (PFS on the subsequent line 
of treatment) 
Time to the next event of disease progression 
or death, as assessed by the investigator 
To evaluate overall response rate (ORR) 
ORR per RECIST v1.1, as assessed by both 
the investigator and IRR, in patients who have 
measureable disease at study entry 
 


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Table 1 continued. Primary, Secondary, and Exploratory Objectives and 
Endpoints 
To evaluate duration of response (DOR)  
DOR per RECIST v1.1, as assessed by both 
the investigator and IRR 
To evaluate PRO utilizing the Euro-QoL 5D 
(EQ-5D) instrument 
PRO as measured by the total score on the 
EQ-5D 
To explore the relationship between rucaparib 
exposure, efficacy, and safety 
Rucaparib PK, invPFS, irrPFS, CA-125, AEs, 
clinical laboratory abnormalities, and dose 
modifications 
2.2 
Trial Design 
This double-blind, randomized, multicenter, Phase 3 study will compare rucaparib with placebo 
in patients with platinum-sensitive, high-grade serous or endometrioid epithelial ovarian, primary 
peritoneal, or fallopian tube cancer who have achieved a response to platinum-based therapy 
(ARIEL3).  
The initial clinical trial assay (CTA) will be utilized to stratify patients for randomization at 
study entry into 1 of 3 HRD subgroups (tBRCA, nbHRD, and biomarker negative). The CTA 
sequences DNA extracted from tumor tissue and identifies mutations in 30 genes involved in 
HRD: BRCA1/2 (stratify into the tBRCA) and 28 other HRR genes (stratify into nbHRD) (see 
Appendix A for the specific list of genes). Patients with no mutations identified in the 30 HRD 
genes are stratified into the biomarker negative subgroup. Eligible patients will be randomized 
(2:1) using Interactive Response Technology to receive either rucaparib or placebo. 
The primary efficacy endpoint for this study is to evaluate PFS, as assessed by the investigator, 
in molecularly-defined HRD subgroups. Investigational centers will interpret tumor scans locally 
for the purpose of making treatment decisions. IRR will also be performed to support analyses by 
investigator assessment. Secondary endpoints include patient-reported outcome as assessed by 
the FOSI-18 instrument using an electronic PRO tool and overall survival.  
For the efficacy analyses, patients will be assigned to molecularly-defined HRD subgroups based 
on the CTA results. Results from study CO-338-017 (ARIEL2) Part 1 demonstrated that genomic 
loss of heterozygosity (LOH) was a good predictor of rucaparib sensitivity. Based on these 
ARIEL2 results, an optimized rucaparib sensitivity algorithm, which includes a pre-specified 
LOH cut-off of 16% percent genomic LOH along with tBRCA mutation status, has been 
established and documented, and will be prospectively applied to the primary analysis of 
ARIEL3 
 That is, all analyses will be performed using the optimized definition 
of HRD. Section 3.2 details the full development for the LOH cut-off used for HRD 
classification of all patients without a tBRCA mutation for the purpose of ARIEL3 efficacy 
analyses.  
A separate analysis plan will be created for the clinical validation of the companion diagnostic 
(CDx) test. This report will evaluate the primary endpoint of invPFS based on the CDx results 
and will also compare the CTA and CDx results. A multiple imputation analysis will also be 
performed in order to evaluate the effect of patients with an unknown CDx result. 


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Safety analyses are based on adverse event, vital signs, and physical exam collection and central 
laboratories measurements.  
2.3 
Sample Size 
Approximately 540 patients will be randomized (2:1) to receive either rucaparib or placebo in 
this study. A minimum of 180 and a maximum of 200 patients with a deleterious tBRCA 
mutation will be enrolled. Enrollment of patients with a known deleterious germline BRCA1/2 
mutation (gBRCA) documented in their medical record will not exceed 150. There is no 
minimum number of patients required for each of the nbHRD and biomarker negative subgroups; 
however, no more than 360 total patients will be randomized for stratification into these 
subgroups combined. 
Tumor HRD status by the CTA (see Section 3.2) will be determined after randomization, but 
before the final efficacy analysis, so that the primary endpoint (PFS in molecularly-defined HRD 
subgroups) can be assessed prospectively. 
Table 2. 
Sample Size and Power Calculations 
Group 
Hazard 
Ratio 
Cumulative 
N  
Minimum 
Number of 
Events (70%) 
Median PFS 
Placebo vs 
Rucaparib 
(months) 
Power 
One-
sided 
Alpha 
tBRCA  
0.50 
180 
126 
6 vs 12 
90% 
0.025 
HRD  
0.60 
300 
210 
6 vs 10 
90% 
0.025 
ITT  
0.70 
540 
378 
6 vs 8.5 
90% 
0.025 
The study will end after 70% of the patients in the tBRCA subgroup have an observed event of 
investigator-determined disease progression or death. If the minimum number of tBRCA patients 
are enrolled, then the study will end following the 126th event of investigator-determined disease 
progression or death. Similarly, if the maximum number of tBRCA patients are enrolled then the 
study will end following the 140th event of investigator-determined disease progression or death. 
The Independent Data Monitoring Committee (IDMC) will inform the sponsor when the required 
number of PFS events have been observed in order to ensure the sponsor remains blinded to 
which patients are in the tBRCA subgroup. 
2.4 
Data Cut-off Used  
The IDMC will inform the sponsor when the required number of PFS events have been observed 
and when treatment blind can be broken for the study. All data up to and including this date will 
be cleaned and collected before the treatment blind can be broken. In addition, key vendor data 
such as HRD classification from the Foundation Medicine CTA, central laboratory 
measurements, and Independent Radiology Review up to this date will also need to be collected. 
This process can take up to 4-8 weeks after the established visit cut-off for the primary analysis. 
The dataset will include all data that are collected and dated prior to or on the date of the visit 
cut-off date.   


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3 
GENERAL ANALYSIS CONVENTIONS 
The summary tables will be presented by randomized treatment group (rucaparib vs placebo) 
within the nested populations outlined in the step-down procedure in Section 3.2 and other 
subgroups of interest.  
Quantitative variables will typically be summarized using frequencies and percentages for 
appropriate categorizations and may also be summarized using descriptive statistics. For 
variables summarized with descriptive statistics, the following will be presented: N, mean, 
standard deviation, median, minimum, and maximum. Categorical variables will be presented 
using frequencies and percentages. The Kaplan-Meier methodology will be used to summarize 
time-to-event variables. If estimable, the 25th, 50th (median), and 75th percentiles will be 
presented along with the Kaplan-Meier estimates of event rates at 6-month intervals. The number 
of patients with events and the number of censored patients will also be presented. The stratified 
log rank test will be used to compare the PFS distributions between the randomized treatment 
groups. In addition, the Cox proportional hazards model will be used to estimate the hazard ratio 
between the randomized treatment groups. Months will be calculated as number of days divided 
by 30.4375. 
All data will be used to their maximum possible extent, but without any imputations for missing 
data. 
Unless otherwise indicated, baseline is defined as the last measurement on or prior to 
randomization. 
3.1 
Populations Definitions 
Intent-to-Treat Population: The intent-to-treat (ITT) population will consist of all randomized 
patients.  
Safety Population: The safety population will consist of all patients who received at least one 
dose of protocol-specified treatment. 
In addition to the population definitions above, further analysis subgroups within the ITT 
population based on tumor HRD status by the CTA are outlined in Section 3.2 below.  
3.2 
Definition of HRD Subgroups 
The CTA is a tumor tissue-based next generation sequencing (NGS) test that has been developed 
in collaboration with Foundation Medicine, Inc. (FMI). Tumors with potential deficiency in 
homologous recombination repair (HRR) may be identified by a gene mutation analysis 
approach or using a phenotypic genomic instability indicator such as loss of heterozygosity 
(LOH). The FMI CTA test is capable of both types of analyses, i.e., it can identify gene 
mutations for the purpose of classifying patients into 1 of 3 molecularly defined HRD subgroups 
for stratification at randomization (i.e., tBRCA, nbHRD, or biomarker negative as described in 
Appendix A), and can also assess the percentage of the tumor genome with LOH in order to 


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classify patients as tBRCA, non-tBRCA LOH+, non-tBRCA LOH-, or non-tBRCA LOH 
unknown. 
Clovis is blinded to  treatment assignment for the efficacy data and also blinded to the percent 
genomic LOH results from ARIEL3, and thus no results from ARIEL3 were used to inform the 
pre-specification of the LOH cut-off used for HRD determination. 
The purpose of the ARIEL2 study has always been to generate rucaparib efficacy data to identify 
the optimal % LOH cut-off for prospective testing in study ARIEL3. ARIEL2 Part 1 is a Phase 2, 
open-label study of rucaparib in patients with platinum-sensitive, relapsed, high-grade epithelial 
ovarian, fallopian tube, or primary peritoneal cancer. 
The 14% LOH cut-off prospectively tested in ARIEL2 Part 1 was based on analysis of the public 
TCGA dataset in high-grade serous ovarian tumors. In this dataset, clinical outcome data were 
only available for platinum-based therapy and not for PARP inhibitor therapy. Therefore, 
platinum sensitivity was used as a surrogate of rucaparib sensitivity. This analysis of the TCGA 
dataset demonstrated that 14% was the LOH cut-off that best differentiated overall survival 
outcome associated with platinum-based therapy. Therefore 14% was used as the pre-specified 
LOH cut-off to distinguish between the LOH-high and LOH-low populations in ARIEL2 Part 1 
and to test the hypothesis that LOH-high tumors would be more sensitive to rucaparib than LOH-
low tumors. This was documented in a Clovis internal memo signed on February 18, 2014. 
While the 14% pre-specified LOH cut-off determined from TCGA platinum data significantly 
discriminated patient benefit in LOH-high and LOH-low tumors, initial analysis of ARIEL2 
Part 1 suggested that a range of potential LOH cut-offs (16-18%) could potentially better identify 
tumors that were sensitive to rucaparib, based on efficacy endpoints of investigator assessed 
confirmed response rate by RECIST v1.1. or investigator assessed Progression-Free Survival 
(invPFS). The LOH cut-off of 18% was pre-specified for ARIEL2 Part 2 because it enrolled only 
fourth or fifth line patients, whose tumors may have accumulated more genomic scars and 
therefore have higher genomic LOH (Clovis internal memo signed on August 21, 2015). 
The pre-specified LOH cut-off of 16% for prospective testing of ARIEL3 was selected following 
an analysis of mature clinical data from ARIEL2 Part 1, which enrolled platinum-sensitive 
patients similar to ARIEL3. Based on an analysis of invPFS for the subgroup of non-tBRCA 
patients in ARIEL2 Part 1, it was found that the greatest separation in PFS distribution between 
LOH-high vs LOH-low to be optimal using the 16% LOH cut-off (HR=0.455, p<0.0001). The 
pre-specification of 16% LOH cut-off for prospective testing in ARIEL3
 
  
Patients with a percent genomic LOH ≥ 16% will be classified as LOH high (LOH+). Therefore 
the HRD defined nested populations used in the step-down procedure is as follows:  
1. tBRCA: Patients with a tBRCA mutation per the CTA. 
2. HRD (tBRCA or non-tBRCA LOH+): Patients who are found to have a BRCA mutation 
per the CTA and/or to have LOH ≥ 16% 
3. ITT Population 


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In addition, non-nested subgroups as noted below will also be explored for efficacy: 
• Non-tBRCA LOH+: Patients without a tBRCA mutation and with percent of tumor genome 
LOH ≥ 16% 
• Non-tBRCA LOH-: Patients without a tBRCA mutation and with percent of tumor genome 
LOH < 16% 
• Non-tBRCA LOH unknown: Patients without a tBRCA mutation and with percent of tumor 
genome LOH unknown 
3.3 
Step-down Procedure  
All efficacy evaluations will be conducted using the ITT population in the 3 nested HRD 
subgroups, unless otherwise specified: 
1. tBRCA: Patients with a tBRCA mutation per the CTA.  
2. HRD (tBRCA or non-tBRCA LOH+): Patients who are found to have a BRCA mutation 
per the CTA or do not have a BRCA mutation, but have tumor genomic LOH ≥ 16% 
3. ITT Population 
The primary and key secondary endpoints will be tested among the tBRCA, HRD, and ITT 
subgroups using an ordered step-down multiple comparisons procedure. invPFS in the tBRCA 
subgroup will be tested first at a one-sided 0.025 significance level. If invPFS in the tBRCA 
subgroup is statistically significant then invPFS will be tested in the all HRD subgroup followed 
by invPFS in the ITT population. Continuing in an ordered step-down manner, the remaining 
secondary endpoints will be tested at the one-sided 0.025 significance level in the tBRCA, HRD, 
and ITT subgroups. Once statistical significance is not achieved for one test, the statistical 
significance will not be declared for all subsequent analyses in the ordered step-down procedure. 
The primary and secondary efficacy endpoints will be evaluated in the non-nested, non-
overlapping subgroups of tBRCA, non-tBRCA LOH+, non-tBRCA LOH-, and non-tBRCA LOH 
unknown in order to ensure that the results in the HRD and ITT subgroups are not solely driven 
by the results in the tBRCA subgroup. In order to claim a significant result in the HRD subgroup, 
the size of the estimated effect in the non-tBRCA LOH+ subgroup should be clinically relevant 
and should be at least as large as what would be needed to achieve ‘‘statistical significance’’ in 
an analysis conducted in the entire HRD population. Similarly, for the ITT results to be 
considered significant and not solely driven by the results of the tBRCA or HRD subgroups, the 
size of the estimated effect in the non-tBRCA LOH- and non-tBRCA LOH unknown subgroups 
should be clinically relevant and should be at least as large as what would be needed to achieve 
‘‘statistical significance’’ in an analysis conducted in the entire ITT population. 
3.4 
BRCA Subgroups 
The tumor tissue-based CTA used in this study identifies sequence variants in the BRCA1 and 
BRCA2 genes; however, it does not distinguish between the mutation type, i.e., germline or 
somatic. In order to determine whether a BRCA mutation detected by the CTA is germline or 


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somatic, a central laboratory will sequence DNA extracted from blood. The germline and 
somatic designation for a tBRCA mutation will be based on the results of the central germline 
BRCA testing as described in Table 3. 
Table 3. 
Algorithm for Determine Origin of BRCA Mutation - Germline versus 
Somatic – in the tBRCA Population 
CTA Result 
Central Germline Blood Test Result 
Designation 
BRCA Positive 
BRCA Positive 
Germlinea 
BRCA Positive 
BRCA Negative 
Somatic 
BRCA Positive 
Not tested 
Unknown 
a 
The same BRCA mutation should be detected in the CTA and central germline blood test result for a mutation 
to be considered germline. 
 
4 
PATIENT DISPOSITION 
Patient disposition (analysis population allocation, randomized, discontinued, and primary reason 
for discontinuation) will be summarized using frequency counts, and the corresponding 
percentages. 
5 
PROTOCOL DEVIATIONS 
Major protocol deviations will be identified via use of both central lab data and EDC data. The 
categories for major protocol deviations are in accordance with the ICH E3 guidelines1 and will 
be identified prior to database lock. The deviations that will be deemed major fall under the 
following categories: 
• Incorrect IP treatment compared to randomization  
• Inclusion or exclusion criteria deviations 
• Over-dose or under-dose of study drug 
• Prohibited medications such as other anti-cancer medications 
• Any other significant deviation that had the potential to affect the primary efficacy or safety 
of the patients  
 
A listing with all the major protocol deviations will be presented.  
6 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
All demographic and baseline characteristics will be summarized for the ITT population. 
6.1 
Demographics 
The demographic variables will be summarized with frequency tabulations that will focus on 
identifying differences between treatment groups in the extreme values of the distributions. 


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Descriptive statistics may also be used to summarize the quantitative variables. The demographic 
variables presented will include age, height, weight, gender, race, and ECOG performance status 
using the following categorizations: 
• Age (years): ≤ 50, 51-60, 61-70, 71-80, 81-90, > 90; 
• Height (cm): ≤ 75, > 75-100, > 100-125, > 125-150, > 150-175, > 175; 
• Weight (kg): ≤ 50, > 50-75, > 75-100, > 100-125, > 125-150, > 150; 
• Race: American Indian or Alaska Native, Asian, Black, Native Hawaiian or Other Pacific 
Islander, White, Other 
• ECOG performance status: 0, 1 
• Region: North America, Western Europe, Australia/New Zealand, and Israel 
These categorizations may be adjusted if the majority of the data lies in only 2 or 3 of the 
categories. 
6.2 
Baseline Clinical Characteristics 
The following variables will be summarized with frequency tabulations 
• Time since diagnosis (months): > 12-24, > 24  
• Type of Cancer (Epithelial Ovarian Cancer, Fallopian Tube Cancer, Primary Peritoneal 
Cancer, Other)  
• Histological Classification (Serous, Endometrioid, Mixed, Other).  
• Stratification subgroups used in the treatment randomization: 
• tBRCA, nbHRD, biomarker negative 
• Best response to most recent platinum-based regimen (complete response [CR], partial 
response [PR])  
• Interval between completion of the penultimate platinum-based regimen and disease 
progression (6 to 12 months or > 12 months) 
• Subgroups based on data recorded on eCRFs: 
• Best response to most recent platinum-based regimen 
• Interval between completion of the penultimate platinum-based regimen and disease 
progression (6 to 12 months or > 12 months) 
• tBRCA and LOH subgroups based on the CTA 
• tBRCA 
• non-tBRCA LOH+ 
• non-tBRCA LOH- 
• non-tBRCA LOH unknown 
• tBRCA mutation (BRCA1, BRCA2) based on the CTA 
• BRCA mutation origin (germline, somatic, or unknown) based on central laboratory and 
CTA results 


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Descriptive statistics may also be used to summarize these variables. 
6.3 
Medical History 
Medical history events will be classified using the Medical Dictionary for Regulatory Activities 
(MedDRA) classification system version 19.1. Medical history data will be summarized using 
frequency tabulations by System Organ Class (SOC) and Preferred Term (PT). 
7 
STUDY DRUG EXPOSURE AND COMPLIANCE 
The following variables will be summarized:  
• Duration of treatment 
• Number of patients with at least one dose reduction or interruption 
The duration of treatment will be calculated as the number of days from the first dose of study 
drug to the day of the last dose of study drug +1. The number of patients with at least one dose 
reduction or interruption based on the dispensation log will be summarized with frequencies and 
percentages.  In addition, the number of patients at each dose level will be summarized (i.e., 
600 mg BID, 480 mg BID, 360 mg BID) in order to assess patients with multiple levels of dose 
reductions.  
8 
PRIOR AND CONCOMITANT MEDICATIONS 
All concomitant treatments documented during the study period will be summarized in frequency 
tabulations for each randomized treatment group and overall. Prior/concomitant medication 
coding will utilize the World Health Organization (WHO) Drug Dictionary version 
2016SEP01DDE (Enhanced). 
Prior medications will only be presented in listings. Prior medications will be defined as those 
medications with both a start and a stop date that is before the day of the first dose of study drug 
administration. If either the start date and/or the stop date of the medication is missing so that it 
is unclear whether the medication was stopped prior to first dose of study drug administration 
then the medication will be included in the summary of the concomitant medications. 
9 
EFFICACY VARIABLES 
9.1 
Primary Efficacy Variable 
The primary efficacy variable is investigator determined PFS (invPFS). 
9.2 
Secondary Efficacy Variables Included in the Step Down Analysis 
• DRS-P subscale of the FOSI-18 instrument 
• Total score of the FOSI-18 instrument 
• Final Overall Survival (OS)  


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9.3 
Secondary Efficacy Variables Not Included in the Step Down Analysis 
• Interim OS 
• Independent Radiology Review Determination of PFS  
 
10 EFFICACY ANALYSIS 
10.1 Primary Efficacy Analysis 
The primary efficacy endpoint is PFS as assessed by the investigator (invPFS). The time to 
invPFS will be calculated in months as the time from randomization to disease progression +1 
day, as determined by RECIST v1.1 criteria2 or death due to any cause, whichever occurs first. 
Only scans and deaths prior to the start of any subsequent anti-cancer treatment or within 90 days 
of treatment end date will be included in the analysis. Patients without a documented event of 
progression will be censored on the date of their last tumor assessment (i.e., radiologic 
assessment) prior to the start of any subsequent anti-cancer treatment or within 90 days of 
treatment end date. Patients who withdrew without a disease progression event and do not have 
any post-baseline tumor assessment will be censored at date of randomization. 
The stratified log rank test will be considered the primary analysis for invPFS comparing 
rucparib to placebo. In addition, a stratified Cox proportional hazard model will be used to 
calculate the hazard ratio (HR) between the treatment groups. The following randomization 
strata are used to estimate the treatment effect: 
• HRD classification by the CTA (tBRCA, nbHRD, biomarker negative) 
• Best response to most recent platinum-based regimen (CR, PR)  
• Interval between completion of the penultimate platinum-based regimen and disease 
progression (6 to 12 months or > 12 months) 
 
10.1.1 
Sensitivity Analyses for PFS 
10.1.1.1 
Censoring Distribution 
Sensitivity analyses for invPFS will be performed to evaluate the impact of censored patients. 
The following analyses will be performed: 
• According to the study protocol, tumor scans were to continue to be performed during follow 
up for patients who discontinued without a documented disease progression event by 
RECIST v1.1. As such, a sensitivity analysis will be performed in which all tumor scans or 
death events will be included for assessment of PFS even if the patient discontinued study 
treatment or initiated a subsequent anticancer therapy.  
• Patients who discontinued the study due to clinical progression will be considered to have a 
PFS event on the date of their last dose of  treatment  


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Additional sensitivity analyses may also be performed to evaluate the robustness of the study 
results. These analyses will be considered exploratory and will likely be motivated by the 
observed results. 
10.1.1.2 
Interaction Between Treatment and HRD Status 
In order to further evaluate the effectiveness of rucaparib in the HRD subgroups, the interaction 
between treatment and HRD status will be tested using the Cox proportional hazards model for 
the primary endpoint of invPFs. The model will include: 
• Indicator variable for treatment with rucaparib; 
• Categorical variable for HRD status; and  
• Interaction between treatment and HRD status. 
 
The HRD status is defined as the following mutually exclusive subgroups: tBRCA, non-tBRCA 
LOH+, non-tBRCA LOH-, and non-tBRCA LOH unknown. In addition, further exploratory 
analyses may be performed using the HRD definitions based on the mutation in Appendix A.  
10.2 Secondary Efficacy Analyses Included in the Step Down Procedure 
Secondary efficacy analyses will be based on nested populations (tBRCA, HRD, ITT). The 
multiple comparisons procedure presented in Section 10.1 will be used to control the type 1 error 
rate for the key secondary endpoints. 
10.2.1 
Disease Related Symptoms – Physical Subscale of the FOSI-18 
The time to an event of worsening in the DRS-P subscale of the FOSI-18 will be defined as the 
time from randomization to a 4 point reduction in the DRS-P subscale. Patients without a 
documented event of a 4 point reduction will be censored on the date of their last adequate FOSI-
18 assessment or date of randomization if no FOSI-18 assessments have been completed. For 
patients without a baseline FOSI-18 assessment their values will be censored at date of 
randomization.  
The same statistical test used for the primary endpoint (i.e., stratified log rank test and a stratified 
Cox proportional model) will be used to compare rucaparib to placebo for this endpoint. 
10.2.2 
Total Score of the FOSI-18 
The time to an event of worsening in the total score of the FOSI-18 will be defined as the time 
from randomization to an 8 point reduction in the total score. Patients without a documented 
event of an 8 point reduction will be censored on the date of their last adequate FOSI-18 
assessment or date of randomization if no FOSI-18 assessments have been completed. For 
patients without a baseline FOSI-18 assessment their values will be censored at date of 
randomization.  
The same statistical test used for the primary endpoint (i.e., stratified log rank test and a stratified 
Cox proportional model) will be used to compare rucaparib to placebo for this endpoint. 


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10.2.3 
Independent Radiologic Review of PFS (irrPFS) 
The time to irrPFS will be calculated in months as the time from randomization to disease 
progression + 1 day, as determined by the IRR or death due to any cause, whichever occurs first.  
Only scans and deaths prior to the start of any subsequent anti-cancer treatment or within 90 days 
of treatment end date will be included in the analysis. Patients without a documented event of 
progression will be censored on the date of their last tumor assessment (i.e., radiologic 
assessment) prior to the start of any subsequent anti-cancer treatment or within 90 days of 
treatment end date. Patients who withdrew without a disease progression event and do not have 
any post-baseline tumor assessment will be censored at date of randomization.  
The same statistical test used for the primary endpoint (i.e., stratified log rank test and a stratified 
Cox proportional model) will be used to compare rucaparib to placebo for this endpoint. 
10.3 Secondary Efficacy Analyses Not Included in the Step Down 
Procedure 
10.3.1 
Overall Survival 
The time to overall survival will be calculated in months as the time from randomization to date 
of death due to any cause. Patients who are still alive will be censored on the date of their last 
available visit or last date known to be alive.  
It is anticipated that the data for overall survival will be heavily censored at the time of the 
primary endpoint analysis. In order to adjust for multiple analyses of overall survival at a later 
stage, a stopping rule will be applied. The Haybittle-Peto3, 4 stopping rule will be applied where 
an overall survival result with a p-value <0.001 can be used to claim superiority of rucaparib 
compared to placebo. This means that a p-value <0.05 can be utilized at the final analysis which 
is projected to be once 70% of the death events has been collected.  
The same statistical test used for the primary endpoint (i.e., stratified log rank test and a stratified 
Cox proportional model) will be used to compare rucaparib to placebo for this endpoint. 
10.3.2 
Population PK: Individual Model Parameter Estimates of Rucaparib and Covariates 
Identification.  
A population PK analysis will be performed and documented in a separate report.  
10.4 Exploratory Endpoints 
Exploratory endpoints will be presented separately for the three nested analysis populations (i.e., 
tBRCA, HRD, and ITT population). The exploratory endpoints include change in CA-125 level,  
tumor response, and DOR in patients who had measurable disease per the investigator at 
baseline. The purpose of the exploratory endpoint is to further explore the efficacy. No multiple 
adjustment is performed for these analyses.  


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10.4.1 
Change from Baseline in CA-125 Measurement 
Analyses of changes and/or percent changes from baseline for CA-125 measured by the central 
laboratory will be analyzed for each scheduled post-baseline visit and for the final visit. Patients 
who do not have both a baseline measurement and at least one post-baseline measurement will 
not be included in these analyses.  
At a given visit, the change and/or percent change from baseline for CA-125 will be compared 
between the randomized treatment groups using an ANCOVA using the treatment as a 
categorical factor and baseline measurement for the parameter as a continuous covariate.  
10.4.2 
Progression Free Survival 2 (PFS2)  
The second event of PFS (referred to as PFS2) is defined as the time from randomization to the 
second event of disease progression as assessed by the investigator, or death due to any cause. 
The first event of disease progression will be captured as the primary endpoint in this study and 
thus the second event will be the next event of disease progression as assessed by the 
investigator. This second event of PFS may be a documented event per RECIST guidelines or 
may be an event of symptomatic/clinical or CA-125 progression.  
10.4.3 
ORR per RECIST v1.1 as Assessed by the Investigator 
The Overall Response Rate (ORR) as assessed by the investigator will be analyzed in the 
subgroup of patients who have measurable disease (i.e., measurable target lesions) at baseline. 
Both unconfirmed and confirmed response rate by RECIST v1.1 will be summarized. The 
confirmed response rate is defined as the proportion of patients with a confirmed CR or PR on 
subsequent tumor assessment at least 28 days after first response documentation. The ORR will 
be summarized with frequencies and proportion together with 95% confidence interval (CI) and 
compared between treatments by using a stratified Cochran-Mantel-Haenszel (CMH) test. In 
addition, the frequency and proportion of patients will be summarized for each of the 
unconfirmed and confirmed response categories:  
• CR 
• PR 
• Stable disease (SD) 
• Progressive disease (PD) 
• Not evaluable (for example, discontinuation or death before first tumor assessment) 
 
10.4.4 
Duration of Response (DOR) per RECIST v1.1 as Assessed by the 
Investigator 
The Duration of Response (DOR) as assessed by investigator will be analyzed in the subgroup of 
patients who have measurable disease (i.e., measurable target lesions) at baseline and have a 
confirmed response by RECIST v1.1. DOR for any confirmed RECIST CR or PR will be 
measured from the date of the first response until the first date that PD is documented. DOR will 


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be summarized as a time to event variable. For patients who continue treatment post-progression, 
the first date of progression will be used for the analysis. Any patients with an ongoing response 
will be censored at the date of the last post-baseline scan.  
The Kaplan-Meier methodology will be used to summarize DOR. If able to be estimated, the 
50th (median) together with a 95% CI, will be presented. The stratified log rank test comparing 
the treatment groups will also be presented. The number of patients with PD events and the 
number of censored patients will also be presented.  
10.4.5 
Change from Baseline in Sum of the Diameters of Target Lesions as Assessed 
by the Investigator  
The change from baseline in sum of diameters of target lesions as assessed by the investigator 
will be analyzed in the subgroup of patients who have measurable disease (i.e., measurable target 
lesions) at baseline. The largest percent decrease from baseline in the sum of the diameters of 
target lesions as identified by RECIST v1.1 will be displayed graphically using a waterfall plot. 
This analysis will be based on the investigator assessed tumor responses and only presented for 
patients with measurable disease at baseline and one valid post-baseline evaluation of the target 
lesions. 
10.4.6 
Patient Reported Outcome of EQ-5D 
Analyses of changes and/or percent changes from baseline will be analyzed for each scheduled 
post-baseline visit and for the final visit for EQ-5D VAS. Patients that do not have both a 
baseline measurement and at least one post-baseline measurement will not be included.  
At a given visit, the change and/or percent change from baseline will be compared between the 
randomized treatment groups using an ANCOVA using the treatment as a categorical factor and 
baseline measurement for the parameter as a continuous covariate. 
10.4.7 
Exploratory Endpoint: Association Between the Change from Baseline in 
CA-125 Measurement and invPFS 
The association between the change from baseline in CA-125 and invPFS will be analyzed by 
adding the maximum decrease from baseline in CA-125 to the stratified Cox proportional model 
as a covariate in the model. The change or percent change will be analyzed both as a continuous 
variable and as a categorical variable depending on the data distribution.  
10.4.8 
Exploratory Endpoint: Chemo-Free Interval 
The chemo-free interval will be calculated in months as the time since the last dose of the most 
recent chemotherapy regimen to the date of the first dose of a subsequent chemotherapy after 
study drug + 1 day. Patients without a documented start of a subsequent chemotherapy after 
study drug will be censored on the date of their last available assessment.  
The same statistical test used for the primary endpoint (i.e., stratified log rank test and a stratified 
Cox proportional model) will be used to compare rucaparib to placebo for this endpoint.   


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10.4.9 
Exploratory Endpoint: Time to Start of First Subsequent Anti-cancer Treatment 
The time to start of the first subsequent anti-cancer treatment will be calculated in months as the 
time from randomization to the date of the first dose of the first subsequent anti-cancer treatment 
regimen after study drug + 1 day. Patients without a documented start of a subsequent anti-
cancer treatment after study drug will be censored on the date of their last available assessment.  
The same statistical test used for the primary endpoint (i.e., stratified log rank test and a stratified 
Cox proportional model) will be used to compare rucaparib to placebo for this endpoint.   
10.4.10 Exploratory Endpoint: Time to Start of Second Subsequent Anti-cancer 
Treatment 
The time to start of the second subsequent anti-cancer treatment will be calculated in months as 
the time from randomization to the date of the first dose of the second subsequent anti-cancer 
treatment regimen after study drug + 1 day. Patients without a documented start of a second 
subsequent anti-cancer treatment after study drug will be censored on the date of their last 
available assessment.  
The same statistical test used for the primary endpoint (i.e., stratified log rank test and a stratified 
Cox proportional model) will be used to compare rucaparib to placebo for this endpoint.   
10.4.11 Exposure- Response PK Report: Rucaparib PK, invPFS, irrPFS, CA-125, AEs, 
Clinical Laboratory Abnormalities, and Dose Modifications 
An Exposure-Response PK analysis will be performed and documented in a separate report.  
11 STATISTICAL / ANALYTICAL ISSUES 
11.1 Statistical Hypothesis  
The primary statistical hypothesis for this study is to test for differences in PFS within each of 
the nested populations (tBRCA, HRD and ITT)  using a stratified log-rank test. 
H0: HR (rucaparib/placebo) ≥ 1. 
Ha: HR (rucaparib /placebo) < 1. 
 
Stratification factors include: 
• HRD classification tBRCA or nbHRD or biomarker negative) as determined by CTA 
• Interval between completion of the penultimate platinum-based regimen and disease 
progression (6 to 12 months or >12 months) 
• Best response (RECIST CR or PR [RECIST and/or GCIG CA-125] response) to platinum 
regimen received immediately prior to initiation of rucaparib maintenance therapy 


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All efficacy analyses will be based on the randomization strata given at randomization, however, 
a sensitivity analysis of invPFS may be performed using the actual strata if patients have been 
allocated incorrectly.  
11.2 Handling of Dropouts or Missing Data 
All patients with a deleterious tBRCA mutation based on the CTA will be included in the HRD 
positive subgroup even if the percent of genomic LOH is unknown. Patients without a 
deleterious tBRCA mutation and without a genomic LOH result will only be included in the 
analyses in the ITT and Safety Populations.  
Imputation of missing baseline values for the FOSI-18 will be performed as supportive analyses. 
For patients without a baseline value, the baseline value will be imputed by using the FOSI-18 
assessment performed closest to randomization and may include assessments performed up to 
and including Cycle 2 Day 1. 
11.3 Multiple Comparison / Multiplicity 
The primary and key secondary endpoints will be tested among the subgroups of tBRCA, HRD, 
and ITT using the ordered step-down procedure as illustrated in Figure 1 below. 


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Figure 1. 
Ordered Step-down Procedure 
 
 
11.4 Examination of Efficacy in Subgroups 
Subgroup analyses of the primary endpoint (invPFS) will be presented for the following:  
• Randomization stratification factors 
o tBRCA, nbHRD, or biomarker negative as determined by CTA for randomization 
(per gene list, as defined in Appendix A) 
o Interval between completion of the penultimate platinum-based regimen and 
disease progression (6 to 12 months or > 12 months) 
o Best response (RECIST CR or PR [RECIST and/or GCIG CA-125 response]) to 
platinum regimen received immediately prior to initiation of rucaparib 
maintenance therapy 
invPFS 
invPFS 
FOSI-18 
DRS-P  
FOSI-18 
DRS-P  
FOSI-18 
DRS-P 
invPFS 
FOSI-18 
Total 
score  
FOSI-18 
Total 
score  
FOSI-18 
Total 
score 
tBRCA 
HRD  
 
ITT  
final OS  
final OS  
final OS  


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• HRD definition used for analysis (tBRCA, non-tBRCA LOH+, non-tBRCA LOH-, non-
tBRCA LOH unknown), as further described in Section 3.3 
• Age groups (< 65, 65-74, ≥ 75) 
• Race (white, non-white) 
 
Subgroups by Disease Burden at Baseline:  
In addition, the primary endpoint (invPFS) will be further explored based on the disease burden 
at baseline in the following subgroups of patients:  
• Measurable Disease: All patients who have measurable disease (i.e., target lesion of any 
size) at baseline as assessed by the investigator and/or independent radiology reviewer). 
• No Disease: All patients who have no target lesions or non-target disease at baseline as 
assessed by the investigator and/or independent radiology reviewer). 
• No Bulky Disease: All patients with any/all lesions < 2 cm in the shortest axis (lymph nodes) 
or longest axis (all other lesions) as assessed by the independent reviewer. A reassessment of 
baseline scans was conducted by independent radiology reviewer in order to define this 
subgroup. The shortest axis is used as the diameter for malignant lymph nodes, and the 
longest axis is used for all other measurable lesions, in accordance with RECIST 1.1. 
 
Subgroups Based on Gene Mutation and Type:  
In addition, the primary endpoint (invPFS) will be further explored based on mutation and 
mutation type.  
• BRCA mutation (BRCA1, BRCA2) 
• BRCA mutation origin (germline, somatic, unknown) 
• Patients with tumors harboring a deleterious mutation within the pre-specified list of non-
BRCA HRR genes 
 This pre-specified list of non-BRCA HRR genes was 
derived based on biomarker analysis of ARIEL2, and is more specific than the nbHRD gene 
list used for stratification. 
• Combining the somatic tBRCA subgroup with the non-tBRCA LOH+ subgroup. 
• Comparing germline tBRCA vs all others (i.e., all non-germline tBRCA and non-tBRCA 
patients) 
 
In addition, a sensitivity analysis of invPFS will be performed for all BRCA patients, including 
those identified as BRCA by the CTA and those identified by a local or central BRCA test. 


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12 SAFETY ANALYSIS 
The safety analyses will be performed using the safety population.  
12.1 Adverse Events 
AEs will be classified using the MedDRA version 19.1 classification system. The severity of the 
toxicities will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) whenever possible. Treatment-emergent adverse 
events (TEAEs) are defined as AEs with onset date on or after the date of first dose of study 
medication until the date of the last study medication dose plus 28 days. AEs will be considered 
treatment-emergent if all or part of the date of onset of the adverse event is missing and it cannot 
be determined if the AE meets the definition for treatment-emergent. 
The number and percentage of patients who experienced TEAEs for each SOC and PT will be 
presented. Multiple instances of the TEAE in each SOC and multiple occurrences of the same PT 
are counted only once per patient. The number and percentage of patients with at least one TEAE 
will also be summarized.  
Separate tables will be presented as follows: 
• All TEAEs; 
• TEAEs by CTCAE grade; 
• Grade 3 or greater TEAEs; 
• Treatment-related TEAEs; 
• Serious TEAEs; 
• TEAEs with an outcome of death; 
• TEAEs leading to discontinuation of study medication; 
• TEAEs resulting in reduction study medication; 
• TEAEs resulting in interruption of study medication; 
• TEAEs resulting in reduction or interruption of study medication; 
• Time to the first TEAE that results in a reduction or interruption of study drug. 
 
The incidence of TEAEs will be summarized by relationship to study drug according to the 
following categories: “treatment-related,” or “not treatment-related”. If a patient experiences 
multiple occurrences of the same AE with different relationship categories, the patient will be 
counted once, as a relationship category of treatment related. 
If a patient experiences multiple occurrences of the same AE with different toxicity grades, the 
patient will be counted once for the maximum (most severe) toxicity grade. AEs with a missing 
toxicity grade will be presented in the summary table with a toxicity grade of “Missing.” For 
each toxicity grade, the number and percentage of patients with at least one TEAE of the given 
maximum grade will be summarized. 


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The time to the first TEAE and first treatment-related TEAE that results in a dose reduction, 
delay, interruption, or discontinuation of study drug is defined as 1+ the number of days from the 
first dose of study drug to the start of the first adverse event. The cumulative incidence is 
presented in a 1-KM graph for just the patients with an event and the median time to onset will 
be calculated together with the 95% CI. 
Non-TEAEs (pre-treatment and post-treatment) will be presented in the by patient data listings 
for the safety population.  
MedDRA PTs were combined for the following similar terms: 
• Asthenia/Fatigue  
• Alanine Aminotransferase (ALT)/ Aspartate Aminotransferase (AST) Increased  
• Anaemia and/or Low/Decreased Haemoglobin  
• Thromobocytopenia and/or Low/Decreased Platelets  
• Neutropenia and/or Low/Decreased Absolute Neutrophil Count (ANC)  
 
In addition, the analysis of combined terms for anemia is explored as a time to first event 
analysis as described above. Transfusions (blood or plasma) and concomitant medications / 
growth factor support are provided in patient listings. The number of transfusions and the time to 
fist transfusion is also summarized.  
12.2 Clinical Laboratory Evaluations 
Clinical laboratory evaluations include the continuous variables for hematology, serum 
chemistry, and urinalysis. The laboratory values will be presented in SI units. The on-treatment 
period will be defined as the time from randomization to 28 days after the last dose of study 
drug. Laboratory values collected during the on-treatment period will be included in the 
summary tables. The laboratory values collected after the on-treatment period will only be 
presented in the data listings.  
The summary of laboratory data will include descriptive statistics (N, mean, SD, minimum, 
median, and maximum) of the maximum, minimum, and last value during the on-treatment 
period. Summaries using descriptive statistics of the change from baseline to the maximum, 
minimum, and last value during the on-treatment period will also be given. 
Summary tables from baseline to the maximum on-treatment toxicity grade (CTCAE Version 
4.03) for each lab parameter will be summarized. In addition, the number and percent of patients 
who has at least one worsening in toxicity grade on-treatment compared to baseline toxicity 
grade will be summarized by treatment group.  
Laboratory data including normal ranges and flagged abnormal laboratory findings will be 
provided using by-patient listings. 


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12.3 Vital Signs 
The on-treatment period will be defined as the time from randomization to 28 days after the last 
dose of study drug. Vital sign measurements collected during the on-treatment period will be 
included in the summary tables. The vital sign measurements collected after the on-treatment 
period will only be presented in the data listings.  
The summary of vital sign data will include descriptive statistics (N, mean, SD, minimum, 
median, third quartile and maximum) of the maximum, minimum and last value during the on-
treatment period. Summaries using descriptive statistics (N, mean, SD, minimum, median, and 
maximum) of the change from baseline to the maximum, minimum, and last value during the on-
treatment period will also be given. The data will be presented separately for each randomized 
treatment group, and overall.  
12.4 Examination of Safety in Subgroups 
Safety will be further explored in the following subgroups:  
• HRD subgroups per efficacy nested populations (tBRCA, HRD) 
• tBRCA subgroups (germline, somatic) 
• Age groups (< 65, 65-74, ≥ 75) 
• Race (white, non-white) 
 
13 REFERENCES 
1. International Conference on Harmonisation E3 Implementation Working Group/ICH E3 
Guideline: Structure and Content of Clinical Study Reports/Questions & Answers (version 
7Jun2012). 2012. 
2. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). 
European Journal of Cancer. 2009;45(2):228-47. 
3. Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Br J 
Radiol. 1971;44(526):793-7. 
4. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis 
of randomized clinical trials requiring prolonged observation of each patient. I. Introduction 
and design. Br J Cancer. 1976;34(6):585-612. 


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APPENDICES 
Appendix A 
List of Homologous Recombination Repair Genes for HRD 
Stratification by the CTA 
tBRCA 
nbHRD 
Biomarker-negative 
BRCA1 
BRCA2 
ATM 
ATR 
ATRX 
BARD1 
BLM 
BRIP1 
CHEK1 
CHEK2 
FANCA 
FANCC 
FANCD2 
FANCE 
FANCF 
FANCG 
FANCI 
FANCL 
FANCM 
MRE11A 
NBN 
PALB2 
RAD50 
RAD51 
RAD51B 
RAD51C 
RAD51D 
RAD52 
RAD54L 
RPA1 
Genes not included in 
the tBRCA or nbHRD 
groups 
 
 


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Appendix B 
 
 
 
 


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Appendix C