Conditions: Ovarian Cancer Epithelial Ovarian Cancer Fallopian Tube Cancer Peritoneal Cancer
Keywords: ovarian cancer fallopian tube cancer primary peritoneal cancer peritoneal cancer platinum sensitive relapsed disease PARP Inhibitor rucaparib homologous recombination homologous recombination deficiency genomic scarring loss of heterozygosity 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 ARIEL2 ARIEL 2 ARIEL3 ARIEL 3
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 491
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine which patients with ovarian, fallopian tube, and primary peritoneal cancer will best respond to treatment with rucaparib.

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). The safety and efficacy of rucaparib has been evaluated in several Phase 1 and Phase 2 studies. An oral formulation is the focus of current development efforts. Rucaparib is currently being investigated as monotherapy in patients with cancer associated with breast cancer susceptibility gene 1 (BRCA1) or BRCA2 mutations.

Clinical data with PARP inhibitors indicate there is an ovarian cancer patient population beyond just those with germline BRCA (gBRCA) mutations that may benefit from treatment with a PARP inhibitor. This study will define a molecular signature of HRD in ovarian cancer that correlates with response to rucaparib and enables selection of appropriate ovarian cancer patients for treatment with rucaparib. The HRD signature will be based on an association between the extent of genomic scarring (a downstream consequence of HRD) in a patient's tumor and observed clinical benefit from rucaparib treatment. Genomic scarring can be assessed by quantifying the extent of loss of heterozygosity across the tumor genome (tumor genomic 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 genetic and other mechanisms.

Once determined, this signature will be prospectively applied to ARIEL2 PART 2 and ARIEL3. This Phase 2 study (ARIEL2) will also compare archival versus recently collected tumor tissue in order to validate the use of archival tumor tissue for assessment of HRD status in ARIEL3.

This study will include 2 parts:

PART 1 (completed enrollment): Evaluation of HRD status and rucaparib efficacy in patients who received ≥1 prior platinum-based regimen and had platinum-sensitive disease

PART 2 (completed enrollment): Evaluation of HRD status and rucaparib efficacy in patients who received at least 3 prior chemotherapy regimens

Arms:
arm 1: rucaparib

Interventions: intervention 1: Oral rucaparib
Intervention descriptions: intervention 1: 600 mg BID

Protocol document:
Prot_000.pdf: 
Clovis Oncology, Inc. 
 
Clinical Protocol 
Oral rucaparib (CO-338) 
CO-338-017 
Amendment 6 
17 July 2019 
 
 
1 
Confidential 
A Phase 2, Open-Label Study of Rucaparib in Patients with 
Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian 
Tube, or Primary Peritoneal Cancer 
Protocol Number: 
CO-338-017 
Investigational Product: 
Oral rucaparib (CO-338) 
Eudra CT Number: 
 
IND Number: 
 
Development Phase: 
Phase 2 
Indication Studied: 
Relapsed, high-grade epithelial ovarian, fallopian tube, or 
primary peritoneal cancer 
Sponsor Name and Address: 
Clovis Oncology, Inc. 
  
  
 
 
 
 
Responsible Medical Officer: 
 
Compliance Statement: 
This study will be conducted in accordance with the ethical 
principles that have their origin in the Declaration of 
Helsinki, clinical research guidelines established by the Code 
of Federal Regulations (Title 21, CFR Parts 50, 56, and 312), 
and International Council for Harmonization (ICH) Good 
Clinical Practice (GCP) Guidelines ICH E6(R2). Essential 
study documents will be archived in accordance with 
applicable regulations. 
 
 
 
 
 
 
 
  
 
Amendment 6 Date: 
17 July 2019 
CONFIDENTIALITY STATEMENT 
The information in this document contains commercial information and trade secrets that are privileged 
or confidential and may not be disclosed unless such disclosure is required by applicable laws and 
regulations. In any event, persons to whom the information is disclosed must be informed that the 
information is privileged or confidential and may not be further disclosed by them. These restrictions on 
disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential. 


Clovis Oncology, Inc. 
 
Clinical Protocol 
Oral rucaparib (CO-338) 
CO-338-017 
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Protocol Approval Signature Page 
Protocol: 
CO-338-017 
 
Title: 
 
 
A Phase 2, Open-Label Study of Rucaparib in Patients with  
Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian 
Tube, or Primary Peritoneal Cancer 
Date: 
17 July 2019 
 
 
Amendment: 
6 
DocuSign Envelope ID: 29E87828-DC1E-46E2-90E0-1CB6C17AB849


Clovis Oncology, Inc. 
 
Clinical Protocol 
Oral rucaparib (CO-338) 
CO-338-017 
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Protocol Acceptance Form 
Protocol: 
CO-338-017 
Title: 
A Phase 2, Open-Label Study of Rucaparib in Patients with  
Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian 
Tube, or Primary Peritoneal Cancer 
Date: 
17 July 2019 
 
 
I have carefully read this protocol and agree that it contains all of the necessary information 
required to conduct this study.  I agree to conduct this study as described and according to the 
Declaration of Helsinki, ICH Guidelines for GCP, and all applicable regulatory requirements. 
 
 
 
  
Investigator’s Signature 
 Date 
 
 
 
  
Name (printed) 
  
 


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Clinical Protocol 
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Table of Contents  
Description 
Page 
1 SYNOPSIS ............................................................................................................................ 11 
2 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................. 21 
3 INTRODUCTION................................................................................................................ 24 
3.1 
Ovarian Cancer ............................................................................................................... 24 
3.1.1 
General Overview ................................................................................................... 24 
3.1.2 
Treatment of Ovarian Cancer .................................................................................. 24 
3.1.3 
Role of BRCA and HRD in Ovarian Cancer .......................................................... 25 
3.2 
PARP Inhibitors .............................................................................................................. 26 
3.3 
Rucaparib ........................................................................................................................ 28 
3.3.1 
Nonclinical Experience ........................................................................................... 28 
3.3.1.1 
Rucaparib Absorption, Distribution, Metabolism, and Excretion ............... 28 
3.3.1.2 
Multiple-Dose Toxicity Studies .................................................................. 30 
3.3.1.3 
Additional Observations .............................................................................. 31 
3.3.2 
Clinical Experience ................................................................................................. 32 
3.3.2.1 
Rucaparib Monotherapy .............................................................................. 32 
3.3.2.1.1 
Safety ............................................................................................. 33 
3.3.2.1.2 
Efficacy .......................................................................................... 34 
3.3.2.1.3 
Pharmacokinetics ........................................................................... 36 
3.3.2.2 
Studies A4991002 and A4991005, and A4991014 ..................................... 37 
3.4 
Rationale for Study ......................................................................................................... 37 
4 STUDY OBJECTIVES ........................................................................................................ 39 
4.1 
Objectives and Endpoints ............................................................................................... 39 
5 STUDY DESIGN .................................................................................................................. 41 
5.1 
Overall Study Design and Plan ....................................................................................... 41 
5.1.1 
Screening Phase ...................................................................................................... 41 
5.1.2 
Treatment Phase ...................................................................................................... 42 
5.1.3 
Post-Treatment Phase.............................................................................................. 43 
5.2 
Study Schema ................................................................................................................. 44 
5.3 
End of Study ................................................................................................................... 45 
6 STUDY POPULATION ...................................................................................................... 46 


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6.1 
Number of Patients and Sites .......................................................................................... 46 
6.2 
Inclusion Criteria ............................................................................................................ 46 
6.3 
Exclusion Criteria ........................................................................................................... 48 
6.4 
Patients or Partners of Patients of Reproductive Potential ............................................. 49 
6.5 
Waivers of Inclusion/Exclusion Criteria ......................................................................... 49 
7 DESCRIPTION OF STUDY TREATMENTS AND DOSE MODIFICATIONS ......... 50 
7.1 
Description of Investigational Product ........................................................................... 50 
7.2 
Method of Assigning Patients to Treatment Groups ...................................................... 50 
7.3 
Preparation and Administration of Protocol-Specified Treatment ................................. 50 
7.3.1 
Dietary Restrictions ................................................................................................ 51 
7.4 
Starting Dose and Dose Modifications of Protocol-Specified Treatment ...................... 51 
7.4.1 
Starting Dose ........................................................................................................... 51 
7.4.2 
Dose Modification Criteria ..................................................................................... 51 
7.4.3 
Criteria for Re-Treatment ....................................................................................... 53 
7.4.4 
Treatment Beyond Progression ............................................................................... 53 
7.5 
Accountability of Protocol-Specified Treatment ............................................................ 53 
7.6 
Blinding/Masking of Treatment ...................................................................................... 53 
7.7 
Treatment Compliance .................................................................................................... 54 
8 PRIOR AND CONCOMITANT THERAPIES................................................................. 55 
8.1 
Anticancer or Experimental Therapy .............................................................................. 55 
8.2 
Hematopoietic Growth Factors and Blood Products ...................................................... 55 
8.3 
CYP450 Isoenzyme Inhibitors, Inducers, and Substrates ............................................... 55 
8.4 
Bisphosphonates ............................................................................................................. 55 
8.5 
Anticoagulants ................................................................................................................ 56 
8.6 
Other Concomitant Medications ..................................................................................... 56 
8.7 
General Restrictions ........................................................................................................ 56 
9 STUDY PROCEDURES ..................................................................................................... 57 
9.1 
Schedule of Assessments ................................................................................................ 57 
9.2 
Screening Phase .............................................................................................................. 59 
9.3 
Treatment Phase .............................................................................................................. 60 
9.3.1 
Day 1 of Cycle 1 ..................................................................................................... 60 
 


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9.3.2 
Day 15 of Cycle 1 ................................................................................................... 61 
9.3.3 
Cycles 2 and Beyond .............................................................................................. 61 
9.4 
End of Treatment Visit ................................................................................................... 62 
9.5 
28 Day Follow-up Visit .................................................................................................. 62 
9.6 
Methods of Data Collection ............................................................................................ 63 
9.6.1 
Pharmacokinetic Evaluations and AAG Measurement ........................................... 63 
9.6.2 
Biomarker Analysis – FFPE Tumor Tissue ............................................................ 63 
9.6.3 
Biomarker Analysis – Blood ................................................................................... 64 
9.6.4 
Safety Evaluations .................................................................................................. 64 
9.6.4.1 
Adverse Event Assessment ......................................................................... 64 
9.6.4.2 
Clinical Laboratory Investigations .............................................................. 64 
9.6.4.3 
Vital Signs ................................................................................................... 64 
9.6.4.4 
12-Lead Electrocardiograms ....................................................................... 65 
9.6.4.5 
Body Weight and Height ............................................................................. 65 
9.6.4.6 
Physical Examinations ................................................................................ 65 
9.6.4.7 
ECOG Performance Status .......................................................................... 65 
9.6.5 
Efficacy Evaluations ............................................................................................... 65 
9.6.5.1 
Tumor Assessments .................................................................................... 65 
9.6.5.2 
Tumor Markers ............................................................................................ 65 
10 ADVERSE EVENT MANAGEMENT .............................................................................. 66 
10.1 Definition of an Adverse Event ...................................................................................... 66 
10.2 Definition of a Serious Adverse Event ........................................................................... 66 
10.3 Definition of an Adverse Event of Special Interest (AESI) ............................................ 67 
10.4 Exceptions to Serious Adverse Event Reporting ............................................................ 67 
10.5 Pregnancy or Drug Exposure During Pregnancy ............................................................ 67 
10.6 Recording of Serious Adverse Events, and Adverse Events of Special Interest ............ 68 
10.6.1 Intensity of Serious Adverse Events ....................................................................... 68 
10.6.2 Causal Relationship of Serious Adverse Events to Investigational Product........... 69 
10.6.3 Outcome .................................................................................................................. 69 
10.7 Follow-Up of Serious Adverse Events, and Adverse Events of Special Interest ........... 69 
10.8 Potential Drug-Induced Liver Injury .............................................................................. 70 
10.9 Regulatory Aspects of Serious Adverse Event Reporting .............................................. 70 


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11 STATISTICAL METHODS ............................................................................................... 71 
11.1 Analysis Populations ....................................................................................................... 71 
11.2 Statistical Methods .......................................................................................................... 71 
11.2.1 General Considerations ........................................................................................... 71 
11.2.2 Patient Disposition .................................................................................................. 71 
11.2.3 Baseline Characteristics .......................................................................................... 72 
11.2.4 Efficacy Analyses ................................................................................................... 72 
11.2.4.1 Primary Efficacy Analyses .......................................................................... 72 
11.2.4.2 Secondary Efficacy Analyses ...................................................................... 72 
11.2.4.2.1 Objective Response Rate (ORR) (Part 1) ...................................... 72 
11.2.4.2.2 Duration of Response ..................................................................... 73 
11.2.4.2.3 ORR Assessed by RECIST and GCIG CA-125 Criteria ............... 73 
11.2.4.2.4 Overall Survival (Part 2) ................................................................ 74 
11.2.4.3 Exploratory Efficacy Analyses ................................................................... 74 
11.2.4.4 Diagnostic Test ............................................................................................ 74 
11.2.5 Pharmacokinetic Analyses ...................................................................................... 74 
11.2.6 Safety Analyses ....................................................................................................... 74 
11.2.6.1 Adverse Events ............................................................................................ 75 
11.2.6.2 Clinical Laboratory Evaluations ................................................................. 76 
11.2.6.3 Vital Sign Measurements ............................................................................ 76 
11.3 Interim Analyses ............................................................................................................. 76 
11.4 Sample Size Considerations ............................................................................................ 77 
12 PATIENT DISPOSITION................................................................................................... 79 
12.1 Patient Discontinuations ................................................................................................. 79 
13 STUDY ADMINISTRATION ............................................................................................ 80 
13.1 Regulatory and Ethical Considerations ........................................................................... 80 
13.1.1 Regulatory Authority Approvals ............................................................................. 80 
13.1.2 Independent Ethics Committee/Institutional Review Board................................... 80 
13.2 Confidentiality of Information ........................................................................................ 81 
13.3 Patient Informed Consent ............................................................................................... 81 
13.4 Study Monitoring ............................................................................................................ 82 
13.5 Case Report Form ........................................................................................................... 82 


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13.6 Study Termination and Site Closure ............................................................................... 83 
13.7 Modification of the Study Protocol ................................................................................ 84 
13.8 Study Documents ............................................................................................................ 84 
13.9 Clinical Study Report ...................................................................................................... 85 
13.10 Study Publication ............................................................................................................ 85 
13.11 Quality Assurance Audits ............................................................................................... 85 
13.12 Investigator Oversight ..................................................................................................... 85 
14 REFERENCES ..................................................................................................................... 87 
15 APPENDICES ...................................................................................................................... 92 
15.1 Appendix A ..................................................................................................................... 93 
15.2 Appendix B ..................................................................................................................... 94 
15.3 Appendix C ..................................................................................................................... 98 
15.4 Appendix D ..................................................................................................................... 99 
15.5 Appendix E ................................................................................................................... 100 
 


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List of Tables 
Description 
Page 
Table 1 
Response Rates by HRD Subgroup in Part 1 of Study CO-338-017 
(ARIEL2) ............................................................................................................. 36 
Table 2 
Primary, Secondary, and Exploratory Objectives and Endpoints ........................ 39 
Table 3 
Dose Reduction Steps .......................................................................................... 52 
Table 4 
Revised Schedule of Assessments as of Implementation of Protocol 
Amendment 6 ....................................................................................................... 58 
Table 5 
Overall Response by RECIST54 and GCIG CA-125 Criteria55 ............................ 74 
Table 6 
Estimated HRD Subgroup Sizesa ......................................................................... 77 
 


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List of Figures 
Description 
Page 
Figure 1 
Best Target Lesion Response – Study CO-338-010 Phase 2 ............................... 34 
Figure 2 
Best Target Lesion Response – Study CO-338-017 (ARIEL2) Part 1 ................ 35 
Figure 3 
Study Schema....................................................................................................... 44 
 


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Oral rucaparib (CO-338) 
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1 
SYNOPSIS 
Protocol Number 
CO-338-017 
Title 
A Phase 2, Open-Label Study of Rucaparib in Patients with Platinum-Sensitive, 
Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal 
Cancer 
Study Phase 
Phase 2 
Introduction 
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 DNA repair 
deficiency.  The safety and efficacy of rucaparib has been evaluated in 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 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 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 repaired by homologous recombination repair (HRR) 
of DNA, a complex process involving multiple proteins, including those encoded 
by breast cancer susceptibility gene 1 and 2 (BRCA1 and BRCA2), as well as 
RAD51, Fanconi anemia core complex, ataxia telangiectasia mutated (ATM), 
and ataxia telangiectasia and RAD3-related (ATR) protein, among others. 
HRR 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.  The Cancer Genome Atlas (TCGA), which completed an analysis 
of molecular changes associated with high-grade serous ovarian cancer 
(HGSOC), estimated that approximately 50% of patients with HGSOC have 
homologous recombination deficiency (HRD).3  Germline mutations in the 
BRCA1 and BRCA2 genes (gBRCA) are the strongest known hereditary factors 
for epithelial ovarian cancer (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”).  Approximately 6 – 8% of HGSOC patients have somatic 
mutations in BRCA1 or BRCA2 (sBRCA).3, 6  HRD is not limited to mutations of 
BRCA1/2, however.  Approximately 27% of HGSOC patients are estimated to 


Clovis Oncology, Inc. 
 
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have HRD due either to an alteration in a HRR gene other than BRCA1/2 or due 
to other molecular alteration or modification (e.g., epigenetic silencing). 
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.  Inhibition of multiple 
pathways, such as BER with a PARP inhibitor, in the context of tumor with 
intrinsic HRD, 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.  This 
concept of synthetic lethality has been demonstrated in key in vitro and in 
vivostudies, as well as in several clinical trials with PARP inhibitors.7-12   
While up to 15% of patients may have a hereditary form of ovarian cancer 
(based on germline mutations), the majority of cases are sporadic (based on 
somatic mutations).3, 13-15  Both gBRCA and sBRCA mutations result in HRD, and 
patients whose tumors harbor these mutations derive clinical benefit from PARP 
inhibitor therapy.16  Collectively, these mutations comprise a group known as 
tissue BRCA (tBRCA).  Patients without evidence of a gBRCA or sBRCA 
mutation also derive benefit from PARP inhibitor treatment.16, 17  The molecular 
signature associated with PARP inhibitor response in a non-BRCA setting is not 
yet fully understood, but may be linked to other mechanisms of HRD, termed 
non-BRCA HRD (nbHRD).  This molecular signature, as well as sBRCA 
mutations, cannot be characterized by a blood-based diagnostic test.  
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 patients for treatment with rucaparib.  Through a 
series of experiments and data analyses, the Sponsor has determined that 
measuring the extent of genomic scarring, a downstream consequence of HRD, 
is a potential method for identifying patients who may be sensitive to rucaparib. 
Genomic scarring can be assessed by quantifying the extent of loss of 
heterozygosity across the tumor genome (tumor genomic 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 genetic and other mechanisms.  In this 
study, patients will be prospectively placed into 1 of 3 HRD subgroups prior to 
primary efficacy analysis.  HRD subgroups include: tBRCA (HRD related to a 
deleterious BRCA1 or BRCA2 gene mutation in tumor tissue), nbHRD (no 
BRCA1 or BRCA2 mutation; LOH+ - meets or exceeds a pre-specified tumor 
genomic LOH cutoff), or biomarker negative (no BRCA1 or BRCA2 mutation; 
LOH- - tumor genomic LOH below the prespecifed cutoff).   
Additional sensitivity analyses will be performed to determine the optimal tumor 
genomic LOH cutoff to determine rucaparib sensitivity.  Once the optimal 
response signature is defined, it will be prospectively applied in the final analysis 
of the planned Phase 3 pivotal study (CO-338-014), which will evaluate 
rucaparib as switch maintenance treatment following a response to platinum-
based chemotherapy in a similar patient population.  This Phase 2 study will also 
compare archival versus recently collected tumor tissue in order to validate the 
use of archival tumor tissue for assessment of HRD status in the planned Phase 3 


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study. 
Study Overview 
This is a two-part study that will enroll patients with relapsed, platinum-
sensitive, high-grade epithelial ovarian, fallopian tube, or primary peritoneal 
cancer who have disease that can be biopsied and is measurable.  Part 1 will 
enroll patients who received ≥1 prior platinum-based regimen and have 
platinum-sensitive disease.  Part 2 will enroll patients who have received at least 
3, but no more than 4, prior chemotherapy regimens.  In Part 1, patients <55 
years of age at diagnosis, or with prior history of breast cancer, or who have a 
close relative (first or second degree) with ovarian cancer or early onset (<age 
50) breast cancer are required to have been previously tested for gBRCA 
mutation.  Enrollment of patients known a priori to harbor a gBRCA mutation 
classified as deleterious (pathogenic), suspected deleterious, or favor deleterious 
(or the equivalent interpretation of any of these) on the most recent assessment 
by a testing laboratory will be limited to 15 in Part 1 in order to enrich for 
patients that have HRD associated with a defect other than germline BRCA1/2.  
Patients with a tBRCA mutation but no gBRCA mutation do not count toward this 
cap and will be eligible to receive treatment with rucaparib, provided all other 
eligibility criteria are met.  In Part 2, at least 80 patients with a tBRCA mutation 
will be enrolled. 
All patients, with the exception of Part 2 patients known to harbor a deleterious 
gBRCA mutation, will be required to undergo a pre-dose biopsy for collection of 
tumor tissue.  Archival tumor tissue will also be collected.  tBRCA mutation 
and/or tumor genomic LOH analysis will be performed using Foundation 
Medicine’s next generation sequencing (NGS) test. Analysis of tumor genomic 
LOH is expected to identify tumors with HRD regardless of the underlying 
mechanism(s).  tBRCA mutation and/or the extent of tumor genomic LOH will 
be correlated with the clinical outcome with rucaparib. 
The NGS test also targets a large panel of other cancer-related genes and other 
HRR pathway genes.  Results of the Foundation Medicine panel test will be 
provided to all patients who consent to receive this information.  In the event a 
BRCA1 or BRCA2 mutation is identified in tumor tissue, the patient may be 
referred by the investigator for genetic counseling and potential germline testing 
per institutional guidelines.  If the patient chooses to have germline testing, this 
result will be entered in the clinical trial database for this study.  
Alterations 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 at screening and stored.  Prior to final efficacy analysis, 
genomic DNA may be subjected to exploratory analysis in order to determine 
whether the mutation is germline or somatic.  These data will be generated in a 
research setting and will not be provided to the investigator or patient. 
The following correlative translational studies are planned: 
1. Tumor genomic LOH and gene sequence alterations in archival and 
screening tumor tissue will be compared to assess the changes in a tumor’s 
genomic LOH and genetic profile over time and determine if archival tumor 
tissue carries sufficient predictive utility and obviates the need for a 
contemporaneous biopsy.  The frequency and nature of secondary BRCA 
mutations will also be assessed.  Acquired secondary BRCA mutations (also 


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known as reversions) may result in functional protein and restored HRR 
capability, leading to PARP inhibitor resistance.18-20 
2. An alternative NGS test known as BROCA will be used to potentially 
identify mutations in other DNA repair genes that may confer sensitivity or 
resistance to rucaparib.21 
3. Gene expression profiling on extracted RNA will be analyzed to potentially 
identify a signature associated with efficacy.  A gene expression signature 
has been developed to identify BRCA and BRCA-like (also referred to as 
"BRCAness") tumors.  Such a signature may predict response to platinum 
and PARP inhibitors.22 
4. Immunohistochemistry (IHC) of non-homologous end joining (NHEJ) 
proteins will be investigated to assess whether NHEJ pathway integrity 
modulates efficacy.  It has been hypothesized that cells with HRD must have 
functional NHEJ DNA repair in order to generate sufficient genomic 
instability for synthetic lethality with a PARP inhibitor.23 
5. Circulating cell-free tumor DNA (ctDNA) will be analyzed as a potential 
molecular marker of efficacy. Tagged-amplicon deep sequencing (TAm-
Seq) will be utilized to sequence ctDNA and identify mutations, including 
but not limited to, those in the tumor suppressor gene TP53, which is present 
in greater than 95% of high-grade serous ovarian tumors.3, 24  Similar to 
CA-125, the fraction of TP53 mutant alleles in plasma of ovarian cancer 
patients has been shown to track with the clinical course of the disease.24 
Number of 
Patients 
Part 1: Approximately 180 patients will be enrolled.  Patients known a priori to 
harbor a gBRCA mutation classified as deleterious (pathogenic), suspected 
deleterious, or favor deleterious (or the equivalent interpretation of any of these) 
on the most recent assessment by a testing laboratory will be limited to 15.  
Patients who do not harbor a known gBRCA mutation but are found to have a 
tBRCA mutation after their tumor tissue is analyzed by the Foundation Medicine 
NGS test are not subject to this cap and will be eligible to receive treatment with 
rucaparib. 
Part 2: Up to 300 patients will be enrolled, including at least 80 patients with a 
tBRCA mutation, as identified by the Foundation Medicine NGS test.  
Patients will enroll into either Part 1 or Part 2 of the study.  Part 2 will begin 
once enrollment of Part 1 has been completed. 
Number of Sites 
This is a multicenter, multinational study.  Patients will be enrolled from 
approximately 60 study sites. 
Study Duration 
Q4 2013 – Q4 2021 (estimated, LPLV) 
Study Objectives 
Unless otherwise specified, the objectives apply to both parts of the study. 
The primary objectives of this study are: 
• 
To determine progression-free survival (PFS) in patients with relapsed 
platinum-sensitive ovarian cancer classified into molecularly-defined 
subgroups by a prospectively defined HRD signature (Part 1) 
• 
To estimate objective response rate (ORR) in heavily pre-treated patients 
with relapsed ovarian cancer classified into molecularly-defined 


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subgroups by a prospectively defined HRD signature (Part 2) 
The secondary objectives of this study are: 
• 
To estimate ORR (Part 1) 
• 
To estimate ORR including cancer antigen 125 (CA-125) response 
criteria 
• 
To evaluate duration of response (DOR) 
• 
To determine PFS (Part 2) 
• 
To evaluate survival (Part 2) 
• 
To evaluate the safety and tolerability of rucaparib 
• 
To evaluate steady state trough level pharmacokinetics (PK) 
 
The exploratory objectives of this study are: 
• 
To assess efficacy in molecularly-defined HRD subgroups as defined by 
HRR gene alterations 
• 
To optimize the tumor LOH algorithm by testing additional signatures of 
interest based on higher or lower genomic LOH 
• 
To assess changes in HRD status over time 
• 
To assess whether the BROCA panel can identify mutations in 
additional HRR genes that may be associated with efficacy 
• 
To assess if a gene expression signature for HRD correlates with 
efficacy  
• 
To assess NHEJ pathway integrity and correlate it with efficacy 
• 
To assess ctDNA as a molecular marker of efficacy 
Study Population 
 
Unless otherwise specified, the criteria below apply to both parts of the study. 
Inclusion Criteria 
Eligible patients must meet 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 serous or Grade 2 
or Grade 3 endometrioid epithelial ovarian, fallopian tube, or primary 
peritoneal cancer  
− 
If mixed histology, > 50% of the primary tumor must be confirmed to 
be high-grade serous or endometrioid upon re-review by local 
pathology 
− 
Patients with a histology of other than serous or endometrioid are also 
eligible for Part 2 of the study if they are known to harbor a deleterious/ 
pathogenic BRCA mutation (germline or somatic) 
4. 
Have relapsed/progressive disease as confirmed by radiologic assessment 
5. 
Part 1: Received prior platinum-based therapy and have platinum-sensitive 
disease  
a. Received ≥1 prior platinum-based treatment regimen; AND 


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b. Received a platinum-based regimen as their last treatment; continuous 
or switch maintenance treatment as part of this regimen is permitted 
(hormonal treatment may be permitted following the last platinum 
regimen with advance approval from the Sponsor); AND 
c. Was sensitive to the last platinum regimen.  Platinum-sensitive disease 
is defined as documented radiologic progression ≥ 6 months after the 
last dose of platinum administered in the treatment setting. 
Part 2:  Received at least 3, but no more than 4, prior chemotherapy 
regimens and had documented treatment-free interval of ≥ 6 months 
following 1st chemotherapy regimen received 
a. Hormonal agents (e.g., tamoxifen, letrozole, etc), anti-angiogenic agents 
(e.g., bevacizumab, pazopanib, cediranib, nintedanib, trebananib, etc), 
and other non-chemotherapy agents administered as single agent 
treatment will not be counted as a chemotherapy regimen for the 
purpose of determining patient eligibility 
b. Agents administered in the maintenance setting will not be counted as a 
separate regimen 
6. 
Part 1 only: If < 55 years of age at diagnosis, or has prior history of breast 
cancer, or has close relative (first or second degree) with ovarian cancer or 
early onset (<age 50) breast cancer, must have been previously tested for 
gBRCA mutation; after 15 patients harboring the gBRCA mutation are 
enrolled, no additional patients with a known gBRCA mutation will be 
allowed to enroll. 
7. 
Have undergone a biopsy of tumor tissue prior to first dose of study drug 
and had the tumor tissue confirmed by the central laboratory as being of 
adequate quality (at least 20% tumor content with a minimum of 80% 
nucleated cellular content).  Note: biopsy is optional for Part 2 patients 
known to harbor a deleterious gBRCA mutation 
− If tumor tissue obtained from the biopsy is deemed inadequate, and the 
patient is unwilling or unable to have another biopsy, the patient may be 
considered for enrollment if archival tumor tissue is provided and 
deemed of adequate quality.  This must occur prior to any treatment with 
rucaparib. 
a. Biopsy must be of solid tumor tissue; ascites is not acceptable 
b. Biopsy must be of sufficient yield for planned analyses  
8. 
Have sufficient archival formalin-fixed paraffin-embedded (FFPE) tumor 
tissue  available for planned analyses; cytospin blocks from ascites are not 
acceptable 
− The most recently obtained tumor tissue that is of adequate quality (at 
least 20% tumor content with a minimum of 80% nucleated cellular 
content) should be submitted 
9. 
Have measurable disease as defined by Response Evaluation Criteria in 
Solid Tumors (RECIST) Version 1.1 (Appendix B) in addition to the lesion 
planned for biopsy; a single RECIST target lesion will suffice if, in the 
investigator’s opinion, it is of sufficient size that the biopsy will not affect 
postdose RECIST evaluations.   
10. Have adequate organ function confirmed by the following laboratory values 


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obtained within 14 days prior to the first dose of rucaparib: 
a. Bone Marrow Function 
i. 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
ii. 
Platelets > 100 × 109/L  
iii. 
Hemoglobin ≥ 9 g/dL  
b. Hepatic Function 
i. 
Aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN); 
if liver metastases, then ≤ 5 × ULN  
ii. 
Bilirubin ≤ 1.5 × ULN; < 2 × ULN if hyperbilirubemia is due 
to Gilbert’s syndrome 
iii. 
Serum albumin ≥ 30 g/L (3.0 g/dL) (Part 2 only) 
c. Renal Function 
i. 
Serum creatinine ≤ 1.5 x ULN or estimated glomerular 
filtration rate (GFR) ≥ 45 mL/min using the Cockcroft Gault 
formula 
11. Have an Eastern Cooperative Oncology Group (ECOG) performance status 
of 0 to 1 (Appendix C) 
Exclusion Criteria 
Patients will be excluded from participation if any of the following criteria 
apply: 
1. Active second malignancy, i.e., patient known to have potentially fatal 
cancer present for which she may be (but not necessarily) currently receiving 
treatment 
a. Patients with a history of malignancy that has been completely treated, 
with no evidence of that cancer currently, are permitted to enroll in the 
trial provided all chemotherapy was completed > 6 months prior and/or 
bone marrow transplant (BMT) > 2 years prior to first dose of rucaparib 
2. Prior treatment with any PARP inhibitor, including oral or intravenous 
rucaparib.  Patients who previously received iniparib are eligible. 
3. 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. 
4. Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that 
would, in the opinion of the Investigator, interfere with absorption of 
rucaparib 
5. Known human immunodeficiency virus (HIV) or acquired 
immunodeficiency syndrome (AIDS)-related illness, or history of chronic 
hepatitis B or C   
6. Pregnant or breast feeding.  Women of childbearing potential must have a 
negative serum pregnancy test < 3 days prior to first dose of rucaparib. 
7. 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 rucaparib and/or ongoing 
adverse effects from such treatment > National Cancer Institute (NCI) 


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Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 
(ongoing Grade 2 non-hematologic toxicity related to most recent treatment 
regimen may be permitted with prior advanced approval from sponsor) 
8. Received administration of strong CYP1A2 or CYP3A4 inhibitors ≤7 days 
prior to first dose of rucaparib or have on-going requirements for these 
medications 
9. Non-study related minor surgical procedure ≤ 5 days, or major surgical 
procedure ≤ 21 days, prior to first dose of rucaparib; in all cases, the patient 
must be sufficiently recovered and stable before treatment administration 
10. 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 
11. Diagnosis of low-grade serous or Grade 1 endometrioid ovarian cancer 
Part 2 Only 
12. Hospitalization for bowel obstruction within 3 months prior to enrollment 
 
Pregnancy is an exclusion criterion and women of childbearing potential must 
not be considering getting pregnant during the study.  Patients of childbearing 
potential and their male partners must practice a highly effective method of 
contraception during treatment and for 6 months following the last rucaparib 
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 
Patients will take 600 mg rucaparib orally twice daily (BID; as close to 12 hours 
apart as possible, preferably at the same times every day) with at least 8 oz 
(240 mL) of water starting on Day 1.  Rucaparib may be taken with an empty 
stomach or with food. Rucaparib will be provided as 200 and 300 mg [as free 
base] dose strength tablets. 
Patients will take rucaparib BID for continuous 28-day cycles until disease 
progression as assessed by the investigator, or other reason for discontinuation. 
Dose reductions are permitted in the event of unacceptable toxicity. 
Interim Safety 
Monitoring 
A formal safety data review will occur after the first 20 patients have been 
enrolled, then quarterly until Part 1 of the study is fully enrolled, and then every 
6 months thereafter until all patients are enrolled and have participated in the 
study for at least 6 months or have discontinued prior to 6 months, at which point 
safety reviews will occur on an as-needed basis.  The review committee will 
include external experts and Sponsor personnel.  The protocol will be amended 
as appropriate to incorporate additional patient safety monitoring if new safety 
signals are noted at any review.  In the event that the recommended Phase 2 dose 
of 600 mg BID rucaparib is determined to be unsuitable for chronic dosing, the 
starting dose may be decreased to Dose Level -1 (480 mg / 500 mg BID 
rucaparib) for all subsequent patients if agreed upon between the Sponsor and 
the Principal Investigators.   


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Withdrawal 
Criteria 
A patient must be discontinued from protocol-prescribed therapy 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 cancer 
• 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 may include tumor assessments using computed tomography 
(CT) scans of the chest, abdomen, and pelvis with appropriate slice thickness per 
RECIST, CA-125 measurement, and clinical examination; other studies 
(magnetic resonance imaging [MRI], X-ray, positron emission tomography 
[PET], and ultrasound) may be performed if required.  As of implementation of 
Protocol Amendment 6, disease assessments should be performed according to 
local standard of care per Investigator during and at the end of treatment.  
Statistical 
Procedures 
Currently, there are few clinical studies that have prospectively evaluated 
response to treatment beyond the 3rd-line setting; however, retrospective analysis 
of patients in 3rd relapse and beyond indicate they have a short PFS 
(approximately 4-6 months) and OS (approximately 5-6 months).25  Overall, 
there is a need for new treatments and alternatives to chemotherapy for heavily 
pre-treated ovarian cancer patients with advanced, relapsed disease to be 
explored in prospectively designed trials.  
The table below provides 95% CIs for observed response rates ranging from 10 
to 60% assuming a total of 80 patients within each HRD subgroup. 
Confidence Intervals for Objective Response Rates (ORR) 
ORR(%) 
 [95% CI] 
10 
4.4, 18.8 
20 
11.8, 30.4 
30 
20.3,41.3 
40 
29.2,51.6  
50 
38.6, 61.4 
60 
48.4, 70.8 
CI=Confidence intervals of ORR using Clopper-Pearson methodology.26 
An ORR ≥ 20% in any subgroup would be worthy of further exploration in that 
population. 
Efficacy Analyses 
Kaplan-Meier methodology will be used to summarize time to event variables.  
Response will be determined using RECIST Version 1.1 and Gynecologic 
Cancer InterGroup (GCIG) CA-125 criteria.  The overall response rate will be 
summarized with frequencies and percentages.  The duration of response will be 
summarized with descriptive statistics (N, mean, standard deviation, median, 
minimum, and maximum) as well as categorically. The efficacy analyses will be 


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evaluated for all patients treated in the study as well as for each of the HRD 
subgroups.  
Safety Analyses 
Adverse events (AEs), clinical laboratory results, vital signs, ECOG performance 
status, body weight, and concomitant medications/procedures will be tabulated 
and summarized.  AEs will be summarized overall and separately for serious 
AEs, AEs leading to discontinuation, AEs leading to death, and NCI CTCAE 
Version 4.0 Grade 3 or higher AEs.  Body weight and vital signs will be 
summarized descriptively (N, mean, standard deviation, median, minimum, and 
maximum).  ECOG will be summarized categorically.    


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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 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
AST 
aspartate transaminase 
AUC 
area under the curve 
BER 
base excision repair 
BID 
twice a day 
BMT 
bone marrow transplant 
BRCA1 
breast cancer susceptibility gene 1 
BRCA2 
breast cancer susceptibility gene 2 
BRCAmut 
BRCA1 and/or BRCA2 gene(s) harboring a deleterious mutation 
BRCAunk 
BRCA1 and BRCA2 genes with unknown mutation status 
BRCAwt 
wild-type BRCA1 and BRCA2 gene sequences 
BUN 
blood urea nitrogen 
CA-125 
cancer antigen 125 
ctDNA 
circulating cell-free tumor DNA 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CK 
creatinine kinase 
Cmax 
maximum concentration 
CNS 
central nervous system 
CPK 
creatine phosphokinase 
CR 
complete response  
CRO 
contract research organization  
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events (version 4.0) 
CYP 
cytochrome P450 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity  
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DSB 
double-strand break 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOC 
epithelial ovarian cancer 


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EOS 
end of study 
EOT 
end of treatment 
FFPE 
formalin-fixed paraffin-embedded 
FSH 
follicle stimulating hormone 
FTC 
fallopian tube cancer 
GALT 
gut-associated-lymphoid tissue 
gBRCA 
germline BRCA 
GCIG 
Gynecologic Cancer InterGroup 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GS 
genomic scarring 
h 
hour 
H & E 
hematoxylin and eosin 
HDL 
high-density lipoprotein 
hERG 
human ether-a-go-go-related gene 
HGSOC 
high-grade serous ovarian cancer 
HIPAA 
Health Information Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRR 
homologous recombination repair 
HRD 
homologous recombination deficiency 
HNSTD 
highest non-severely toxic dose 
ICxx 
concentration where maximum response is inhibited by XX% 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemistry 
INR 
international normalized ratio 
IRB 
Institutional Review Board  
irr 
independent radiology review 
irrORR 
objective response rate assessed by independent radiology review 
IVRS/IWRS 
Interactive Voice Response System/Interactive Web Response System 
LDL 
low-density lipoprotein 
LOH 
loss of heterozygosity 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
Min 
minute 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
nbHRD 
non-BRCA homologous recombination deficiency 
NCCN-FACT  
National Comprehensive Cancer Network-Functional Assessment of Cancer  
NCI 
National Cancer Institute 
NGS 
next generation sequencing 


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NHEJ 
non-homologous end-joining  
NOAEL 
no-observed-adverse-effect level 
ORR 
objective response rate 
OS 
overall survival 
PARP 
poly(adenosine diphosphate [ADP]-ribose) polymerase 
PBL 
peripheral blood lymphocytes 
PD 
progressive disease 
PET 
positron emission tomography 
PLD 
PEGylated liposomal doxorubicin 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PPC 
primary peritoneal cancer 
PR 
partial response 
PT 
prothrombin time 
QD 
once a day 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase II dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
statistical analysis software 
SD 
stable disease and standard deviation 
SI 
international units 
SNP 
single-nucleotide polymorphism 
SOA 
schedule of assessments 
SOC 
system organ class 
SSB 
single-strand break 
STD 
severely toxic dose 
SUSAR 
suspected unexpected serious adverse reaction 
TAm-Seq 
tagged-amplicon deep sequencing 
t1/2 
half-life 
tBRCA 
tumor tissue mutation in BRCA1 or BRCA2, includes gBRCA and sBRCA  
TCGA 
The Cancer Genome Atlas 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum concentration 
TMZ 
temozolomide 
TP53 
tumor protein p53 
ULN 
upper limit of normal 
UV 
ultraviolet 
WBC 
white blood cell 
WOCBP 
women of childbearing 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.27, 28  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.29  Relapse still occurs, however, in the 
majority of cases, and only 10−30% of women experience long-term survival.29  Advanced stage 
disease is associated with a 5-year survival rate of only 30−40%.27 
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.29  The site of origin of epithelial ovarian cancer remains unclear.  Some studies suggest 
that serous epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC) arise from the 
fallopian tube epithelium; however, other studies suggest an origin within stem cells of the 
ovarian surface epithelium.29-33  EOC, PPC and fallopian tube cancer behave very similarly and 
are therefore treated in the same way. 
The median age at presentation of EOC is 60 years.  Due to the non-specific nature of symptoms, 
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 high-grade serous ovarian cancer (HGSOC) is 
cytoreductive surgery (either at time of diagnosis or interval debulking), 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).29, 34 
The choice of treatment for relapsed disease is based on the treatment-free interval relative to last 
therapy administered and chemotherapy agents used. Platinum-based regimens dominate ovarian 
cancer therapy and define treatment groups.35  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; and patients whose disease 
relapses more than 6 months after last platinum-based therapy was administered are considered 
to have platinum-sensitive disease. However, these classifications are somewhat arbitrary as 
resistance to platinum-based therapy is a time continuum, not a categorical variable, and a status 
of ‘platinum-resistant’ is not absolute as it can be partially overcome. In addition, ‘platinum-
sensitivity’ was defined when there was no alternative to platinum-based treatment and in 


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clinical practice typically only refers to second-line treatment. These definitions also do not take 
into account the molecular characteristics of a patient’s tumor (i.e. HRD such as BRCA 
mutations).  In later lines of therapy, treatment choice is often restricted according to the 
individual patient situation (e.g., performance status, organ function, residual toxicities from 
prior treatment, other comorbidities, and patient choice). 
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.  Patients who have received several prior lines of 
treatment are known to have strongly diminished treatment-free intervals and response rates and 
the benefits of continued treatment with conventional chemotherapy often does not outweigh the 
risk of additional toxicity. This patient population is a group with limited treatment options that 
could benefit from treatment with a targeted agent that takes the molecular characteristics of their 
disease into account.25, 36 
3.1.3 Role of BRCA and HRD in Ovarian Cancer 
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.   
Single-strand breaks are normally quickly repaired by a process known as base excision repair 
(BER).  The BER process is initiated by the activity of the poly (adenosine diphosphate [ADP]-
ribose) polymerase (PARP) enzyme.  In normal cells, an additional DNA repair process known 
as homologous recombination repair (HRR) can repair DSBs.  Homologous recombination is a 
complex, multistep process, in which two key components are the proteins encoded by the breast 
cancer susceptibility 1 and 2 genes (BRCA1 and BRCA2). 
Germline mutations in BRCA1 and BRCA2 genes are the strongest known hereditary factors for 
breast and EOC, accounting for up to 5% of all breast cancers and 15% of all EOCs.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”).  Approximately 
6 – 8% of patients with HGSOC have somatic mutations in BRCA1 or BRCA2.3, 6   
If either the BER or HRR 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 HRR 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 HRR) 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, this state of dual non-functionality can be 


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achieved by enzymatic inhibition of PARP in the context of a genetic mutation in the BRCA1 or 
BRCA2 genes. 
Two key in vitro and in vivo studies demonstrated the concept of synthetic lethality in DNA 
repair.  Bryant and colleagues showed that cell lines and a tumor xenograft deficient in BRCA2  
were highly sensitive to PARP inhibition.7  In a parallel set of experiments, Farmer and 
colleagues illustrated that chemical inhibition of PARP-1 was more potent in homozygous 
BRCA1/2-deficient cell lines than in heterozygous mutant or wild-type cell lines.8  These 
findings were also supported by a BRCA2-deficient murine model.  Taken together, these studies 
provide support for the treatment of patients with a BRCA-deficient tumor with a PARP 
inhibitor. 
However, defects in the HRR pathway are not limited solely to mutations of BRCA1/2.  Genetic 
alterations of many different HRR pathway genes are associated with human cancers, with the 
percentage of tumors affected by homologous recombination deficiency (HRD) varying 
considerably across different tumor types.  The Cancer Genome Atlas (TCGA), which completed 
an analysis of molecular changes in HGSOC, estimated that approximately 50% of patients with 
HGSOC have alterations in genes involved in the HRR DNA repair.3  Of those, approximately 
27% are estimated to have HRD due to a gene mutation or other genomic alteration or 
modification (e.g., epigenetic silencing) that is not associated with a BRCA1/2 mutation.3  
Approximately 15% of patients are estimated to have a gene mutation in a HRR pathway gene 
other than BRCA1/2.3  
An alternative approach in identifying 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.37, 38  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 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.39, 40 
3.2 PARP Inhibitors 
Refer to the current Investigator’s Brochure for comprehensive information on rucaparib.  
PARP inhibitors have been evaluated in the clinic for the past decade. Iniparib (BSI-201) was 
initially the furthest advanced, with a Phase 3 randomized study in combination with 
gemcitabine and carboplatin conducted in patients with triple-negative metastatic breast cancer. 
Data from this study showed that patients receiving iniparib with chemotherapy did not 
experience significant improvements in overall survival (OS) or progression free survival (PFS) 
compared to patients receiving just the chemotherapy regimen.41  Since then, several groups have 
determined that the primary mechanism of action for iniparib is not via inhibition of PARP 
activity.42, 43 
Rucaparib has demonstrated compelling activity in ovarian cancer patients with a BRCA 
mutation as well as in patients without a BRCA mutation (see Section 3.3). Durable responses 
have been observed in both platinum-sensitive and platinum-resistant disease.  


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Olaparib (AZD-2281), another PARP inhibitor, has also demonstrated Phase 2 clinical activity, 
both in treatment and maintenance settings, in metastatic breast cancer patients with a germline 
BRCA (gBRCA) mutation and in relapsed HGSOC patients (both BRCA mutant and wild-type). 
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 included women with and without a gBRCA mutation.10, 11 In these 
patients, who had received a median of three prior chemotherapy regimens, encouraging overall 
response rates of 33% and 41%, were observed, in ovarian and 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-BRCA 
associated cohort (41% vs 24%, respectively).12  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.44  
More recently, olaparib demonstrated good clinical activity (31% ORR) in gBRCAmut ovarian 
cancer patients (n=193) with platinum-resistant disease who received a mean of 4.3 prior 
treatment regimens.45 
Activity in HGSOC has also been observed with switch maintenance therapy following response 
to platinum-based chemotherapy.46  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).46  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).16  It should be noted that outcomes were the same in patients who had a gBRCA 
mutation and those who had a somatic BRCA (sBRCA) mutation, suggesting that 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).16   
Niraparib (MK-4827), another PARP inhibitor with a similar mechanism of action to olaparib, 
exhibited clinical activity in both BRCA-mutated ovarian cancer (8 RECIST PRs) and sporadic 
ovarian cancer (2 RECIST PRs and/or GCIG CA-125 responses) patients in a Phase 1 study.47, 48  
In a Phase 1 evaluation of BMN 673, also a PARP inhibitor, 11 of 17 BRCA-mutated ovarian 
cancer patients treated at doses ≥100 µg/day exhibited a RECIST and/or CA-125 response.49 
It is worth noting that 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.12, 44, 48  This indicates that using platinum-
sensitivity alone as a selection marker for PARP inhibitor therapy is not an effective tool.  
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 in the non-BRCA cohort 
described above and the benefit of maintenance PARP inhibitor treatment in patients without a 
BRCA mutation suggest that the clinical utility of PARP inhibitors can be extended to a larger 
patient group with HRD based on HRR alterations other than BRCA,  i.e., nbHRD.12, 16  


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Assessing tumor genomic LOH in this trial provides a mechanism to identify patients with HRR 
alterations who may benefit from treatment with rucaparib but do not harbor a deleterious 
BRCA1 or BRCA2 mutation. 
Emerging data with PARP inhibitors also support evaluation of rucaparib in relapsed ovarian 
cancer patients with advanced disease who have received multiple prior lines of treatment, a 
patient population for whom there are limited treatment options currently. 
3.3 Rucaparib 
Rucaparib (CO-338; formerly known as PF-01367338 and AG-014447) is an orally available, 
small molecule inhibitor of PARP-1 and PARP-2.  Rucaparib is specific for PARP-1 and PARP-
2 based on results of direct biochemical assays and an off-target receptor panel. Rucaparib 
(Rubraca®) is approved in the United States (US) as monotherapy treatment for adult patients 
with deleterious 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 
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.   
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 camsylate 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). 
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 


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exposure was observed in the 1-month dog toxicity study when rucaparib was administered in 
capsules.      
Rucaparib PK, following IV administration of salts of rucaparib, were evaluated in mice, rats, 
dogs, and monkeys.  IV dosing with the glucuronate or phosphate salt of rucaparib resulted in 
moderate to rapid clearance and a large volume of distribution, indicating this compound is well 
distributed in the body.  The half-life (t1/2) ranged from 2.3 to 5.2 hours. 
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%.   
In in vitro studies, rucaparib reversibly inhibited CYP1A2, CYP2C19, CYP2C9, CYP3A, 
CYP2C8, and CYP2D6 (in the order of decreasing potency), as well as moderately inhibited 
uridine-diphosphate glucuronosyletransferase (UGT) 1A1.  In hepatocyte incubation, rucaparib 
showed concentration-dependent induction of CYP1A2 and down regulation of CYP3A4 and 
CYP2B6 at clinically relevant concentrations.  No time-dependent CYP inhibition was observed.  
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 
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, the downregulation could further 
increase AUCR for CYP3A and result in elevated exposures of drugs that are CYP3A substrates. 
Based on bi-directional experiments of digoxin transport carried out using Caco-2 cells, it was 
determined that rucaparib is a moderate P-glycoprotein (P-gp) inhibitor. The inhibition potential 
for rucaparib on P-gp will likely be low at clinical oral doses ≤200 mg. At doses >200 mg, 
patients taking digoxin should have their digoxin levels monitored regularly via standard clinical 
practice. 
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 
these 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 Studies 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 (n=2; first day of recovery phase).  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 severely 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 Studies 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 


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all treatment groups.  Lymphoid atrophy occurred in both sexes and in all treatment groups.  
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 
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 nonprogressive 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 7-fold and 2-fold higher, respectively, than the highest (unbound) 
steady state plasma concentrations observed to date in humans (3710 ng/mL x 0.298 Fu = 
1106 ng/mL) 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 Cmax=13629 ng/mL) resulted in a significant reduction in 


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motor activity compared with vehicle-treated animals; however, there were no effects on 
neurofunctional or reflex testing at this dose.  The plasma concentration measured at this dose is 
3.7-fold above the highest steady state plasma concentration (3710 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. 
Additional information may be found in the current Investigator’s Brochure. 
3.3.2 Clinical Experience   
The early clinical program assessed safety and efficacy in patients with malignancies commonly 
treated with chemotherapeutic agents, initially with the IV formulation of rucaparib administered 
in combination with a variety of chemotherapies, and later with the oral formulation of rucaparib 
administered as a monotherapy.  The latter 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 
Rucaparib monotherapy is currently being evaluated as treatment for relapsed ovarian cancer  in 
two Clovis-sponsored clinical studies (Study CO-338-010 and this study, CO-338-017 
[ARIEL2].  Over 200 patients have been treated with the oral formulation of monotherapy 
rucaparib in open-label trials; over 150 patients have been treated with the recommended Phase 2 
dose of 600 mg BID. 
Study CO-338-010 
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 was a Phase 1 portion in 
patients with any solid tumor, including lymphoma, who have progressed on standard treatment.  
The primary objective of this portion of the study was to determine the optimal monotherapy 
dose for orally administered rucaparib.  Measurable disease was not required and tumor marker 
assessments are optional.  Part 2 is the ongoing Phase 2 portion in patients (up to n=41) 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 this portion of 
the study is to assess the overall objective response rate by RECIST v1.1 in this ovarian cancer 
patient population.  
Study CO-338-010 was initiated in Q4 2011.  In the Phase 1 portion, a total of 56 patients 
(median age 50 years [range 21−71]; 51 female; 27 breast cancer, 20 ovarian/peritoneal cancer, 2 
pancreatic cancer; 7 other tumor) were treated at dose levels of 40, 80, 160, 300, and 500 mg 
QD, and 240, 360, 480 and 600 mg BID rucaparib administered continuously.  Two patients are 


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still receiving treatment as of November 2014.  One patient treated with 360 mg BID rucaparib 
experienced a dose-limiting toxicity (DLT) of Common Toxicity 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 mg BID and 600 mg BID cohorts however, similar to other 
PARP inhibitors, non-DLT myelosuppression was observed beyond Cycle 1, therefore the dose 
of 600 mg BID rucaparib was selected as the recommended dose for future Phase 2 and Phase 3 
studies. 
In the ongoing Phase 2 portion, 20 ovarian cancer patients (median age 56 [range 44-84]; ECOG 
performance status 0/1=12/8; median number of anticancer regimens=2 [range 2-4]; median 
number of platinum-based regimens=2 [range 2-3]) were enrolled as of September 2014. 
Study CO-338-017 (ARIEL2) 
In this ongoing trial, 143 ovarian cancer patients (median age 65 [range 31-86]; ECOG 
performance status 0/1/pending=95/47/1; median number of anticancer regimens=1 [range 1-6); 
median number of platinum-based regimens=1 [range 1-5]) have enrolled into Part 1 of the study 
as of October 2014.  Full enrollment into Part 1 of the study is anticipated to be completed in 
December 2014.   
3.3.2.1.1 Safety 
As of November 2014, safety data are available for n=163 ovarian cancer patients treated with 
600 mg BID rucaparib monotherapy in the ongoing Phase 2 studies, including Part 1 of this trial. 
Treatment-related adverse events (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 ALT and/or AST are also commonly observed.  The ALT/AST elevations occur 
early (within first 2-4 weeks of treatment), are generally mild to moderate (Gr 1-2), are not 
accompanied by any changes in bilirubin levels, and often transient and resolved to within 
normal ranges, or stabilize.  No patient has 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.  Grade 3/4 adverse events assessed as treatment-
related and occurring in >5% of patients include: anemia/decreased hemoglobin and increased 
ALT. All treatment-related adverse events have been successfully managed with concomitant 
medications, supportive care, and treatment interruption and/or dose reduction.  No patient has 
discontinued rucaparib treatment due to a treatment-related adverse event.  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 1 
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.  


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No patient experienced a ≥60 msec increase in QTcF over baseline.  A total of 11 patients 
experienced a QTcF increase ≥30 msec over baseline.  Further analyses suggest a lack of 
relationship between QTcF increase ≥30 msec and dose or exposure.  In addition, there were no 
adverse events suggestive of cardiac arrhythmia (e.g., presyncope, syncope, sudden death) in any 
patient.  ECG and adverse event data to date in patients receiving monotherapy rucaparib at 
doses up to 840 mg BID suggest there is a minimal risk of QTc prolongation. 
3.3.2.1.2 Efficacy 
Study CO-338-010 
In the Phase 1 portion, 2 patients (breast cancer and ovarian cancer, both gBRCAmut) achieved a 
RECIST CRs and 7 patients (3 ovarian cancer, 4 breast cancer, 1 pancreatic cancer; all 
gBRCAmut) achieved a RECIST PR during the dose escalation phase (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).  Response were durable across 
tumor types.  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 weeks) in evaluable ovarian cancer patients treated at doses ≥360 mg BID 
was 92% (11/12).  Responses were observed in platinum-resistant as well as platinum-sensitive 
ovarian cancer patients.  In platinum-resistant ovarian cancer patients treated with ≥360 mg BID 
rucaparib, 50% (4/8) achieved either a RECIST (25%, 2/8) or GCIG CA-125 response (25%, 
2/8).  The disease control rate (CR, PR, or SD>24 weeks) in this group was 75% (6/8) and 
median time on treatment was approximately 9 months (range 1.5-14.5). 
In the Phase 2 portion of Study CO-338-010, compelling activity has been observed in patients 
who had received 2-4 prior chemotherapy regimens and a deleterious BRCA mutation, with 15 of 
20 (75%) achieving a RECIST PR and 17 of 20 (85%) achieving a RECIST PR and/or a GCIG 
CA-125 response.  The vast majority of patients had some level of target lesion measurement 
reduction as shown in Figure 1. 
Figure 1 
Best Target Lesion Response – Study CO-338-010 Phase 2 
 
 


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Study CO-338-017 (ARIEL2) 
In Part 1 of this study, preliminary efficacy data as of October 2014 indicate target lesion 
reduction in the majority of patients currently evaluable for efficacy, as indicated in Figure 2.  
ORRs of 38% (RECIST) and 44% (RECIST & GCIG CA-125) have been observed in n=61 
patients who had a baseline scan and at least one post-treatment scan, and who were able to be 
classified into 1 of 3 HRD subgroups based on analysis of their screening biopsy sample.  The 
disease control rate (CR, PR or SD>24 weeks) in this group of patients is 78% and 61% of 
patients were continuing treatment with rucaparib at the time of this data analysis. 
Figure 2 
Best Target Lesion Response – Study CO-338-017 (ARIEL2) Part 1 
 
Response and disease control rate data were also analyzed by HRD subgroup as shown in 
Table 1.  Activity was enhanced, as expected, in the subset of patients with a BRCA mutation 
(n=23), with ORRs of 61% (RECIST) and 70% (RECIST and/or GCIG CA-125).  Responses 
were observed in patients with germline as well as somatic mutations, indicating the importance 
of assessing tumor tissue rather than relying on a blood test that assesses germline mutation 
status only.  Clinical activity was also observed in patients without a tBRCA mutation.  In these 
patients, the nbHRD group (patients whose tumors had a high level of genomic LOH) (n=25) had 
ORRs of 32% (RECIST) and 40% (RECIST and/or GCIG CA-125), while the biomarker 
negative group (patients whose tumors had a low level of genomic LOH) (n=13) had a best ORR 
(RECIST/RECIST & GCIG CA-125) of 8%.  The disease control rates across the 3 HRD 
subgroups displayed very similar differential results. While these preliminary results are very 
encouraging and indicate that the current analysis approach of assessing BRCA mutation status 
in tumor tissue and also assessing level of genomic LOH in tumors without a BRCA mutation 
does differentially identify patients likely respond to rucaparib, the individual group sizes are 
still small and more data is still required to complete the analysis and determine the optimal 
HRD signature, particularly with regards to the BRCAwt groups. 


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Table 1 
Response Rates by HRD Subgroup in Part 1 of Study CO-338-017 
(ARIEL2) 
Efficacy Parameter 
HRD Subgroup 
tBRCAmut 
nbHRD 
(tBRCAwt / high 
LOH) 
Biomarker 
Negative 
(tBRCAwt / low 
LOH) 
RECIST ORR, % (n) 
61 (14/23) 
32 (8/25) 
8 (1/13) 
RECIST & GCIG CA-125 ORR, % (n) 
70 (16/23) 
40 (10/25) 
8 (1/13) 
Disease Control Rate* 
(CR, PR, or SD>12 wks), % (n) 
94 (15/16) 
75 (9/12) 
50 (3/6) 
*Patients with SD who are ongoing with <12 weeks on study are not included in denominator 
 
SUMMARY 
Refer to the current Investigator’s Brochure for comprehensive information on rucaparib. 
Monotherapy rucaparib has demonstrated clinical activity in ovarian cancer patients with and 
without a BRCA mutation.  Overall, response to rucaparib occurs rapidly, with the majority of 
patients achieving a PR at the first disease assessment scan (weeks 6-8).  Responses have been 
durable and most responders are continuing to receive treatment with rucaparib.   
In addition to the data presented by study, the efficacy of rucaparib in BRCAmut ovarian cancer 
patients who received ≥3 prior chemotherapy regimens and were treated with 600 mg BID 
rucaparib has been evaluated.  In this group, which included both patients with platinum-
sensitive and platinum-resistant disease, ORRs of 47% (RECIST) and 73% (RECIST & GCIG 
CA-125) have been observed, suggesting that rucaparib may be a suitable treatment alternative in 
this patient population with advanced disease and limited treatment options. 
3.3.2.1.3 Pharmacokinetics 
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% CV). 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. 


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3.3.2.2 Studies A4991002 and A4991005, and A4991014 
Further details of these rucaparib combination studies are provided in the Investigator’s 
Brochure. 
3.4 
Rationale for Study 
Clinical data with PARP inhibitors indicate there is an ovarian cancer patient population beyond 
just those with gBRCA mutations and/or platinum-sensitive disease that may benefit from 
treatment with a PARP inhibitor.  The purpose of this study is to test and optimize a molecular 
signature of HRD in ovarian cancer that is hypothesized to correlate with response to rucaparib 
and will enable selection of appropriate ovarian cancer patients for treatment with rucaparib.  
The HRD signature has been defined based on the presence of a deleterious BRCA1 or BRCA2 
mutation and/or genomic tumor LOH. This study will test the ability of the signature to 
discriminate good from poor outcome on rucaparib.  It is anticipated that patients with a BRCA1 
or BRCA2 mutation and those with tumors exhibiting tumor genome LOH will derive the 
greatest clinical benefit from rucaparib treatment.   
After optimization (if needed), this signature will be prospectively applied in the final analysis of 
the planned Phase 3 pivotal study (CO-338-014), which will evaluate rucaparib as switch 
maintenance treatment following a response to platinum-based chemotherapy in a similar patient 
population.  This Phase 2 study will also compare archival versus recently collected tumor tissue 
in order to validate the use of archival tumor tissue for assessment of HRD status in the Phase 3 
study. 
This 2-part study will enroll patients with relapsed, platinum-sensitive, high-grade epithelial 
ovarian, fallopian tube, and primary peritoneal cancer who have disease that can be biopsied and 
is measurable.  Part 1 of the study will enroll approximately 180 patients who received ≥1 prior 
platinum-based regimen and have platinum-sensitive disease.  Enrollment of patients known to 
harbor a deleterious / pathogenic gBRCA mutation will be limited to 15 in Part 1 in order to 
enrich for patients that have HRD associated with a defect other than BRCA1/2.  Part 2 will 
enroll up to 300 patients who received at least 3, but no more than 4, prior chemotherapy 
regimens, including at least 80 patients with a tBRCA mutation.  Patients will enroll into either 
Part 1 or Part 2 of the study.  Part 2 will begin once enrollment of Part 1 has been completed. 
Tumor tissue collected at screening and/or an archival tumor tissue sample will be sequenced 
using Foundation Medicine’s next generation sequencing (NGS) test, which analyzes a large 
panel of cancer-related genes, including tumor genome LOH, BRCA, and other HRR pathway 
genes.  Genetic alterations, which include mutations and homozygous deletions, in specific HRR 
pathway genes may also be associated with clinical outcome on treatment with rucaparib. 
The following correlative translational studies are also planned: 
1. Tumor genomic LOH and gene sequence alterations in archival and screening tumor 
tissue will be compared to assess the changes in a tumor’s genomic LOH and genetic 
profile over time and determine if archival tumor tissue carries sufficient predictive utility 
and obviates the need for a contemporaneous biopsy.  The frequency and nature of 


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secondary BRCA mutations will also be assessed.  Acquired secondary BRCA mutations 
(also known as reversions) may result in functional protein and restored HRR capability, 
leading to PARP inhibitor resistance.18-20 
2. An alternative NGS test known as BROCA will be used to potentially identify additional 
mutations in other DNA repair genes that may confer sensitivity or resistance to 
rucaparib.21 
3. Gene expression profiling on extracted RNA will be analyzed to potentially identify a 
signature associated with efficacy. A gene expression signature has been developed to 
identify BRCA and BRCA-like (also referred to as “BRCAness”) tumors.  Such a 
signature may predict response to platinum and PARP inhibitors.22 
4. Immunohistochemistry (IHC) of non-homologous end joining (NHEJ) proteins will be 
investigated to assess whether NHEJ pathway integrity modulates efficacy.  It has been 
hypothesized that cells with HRD must have functional NHEJ DNA repair in order to 
generate sufficient genomic instability for synthetic lethality with a PARP inhibitor.23 
5. Circulating cell-free tumor DNA (ctDNA) will be analyzed as a potential molecular 
marker of efficacy.  Tagged-amplicon deep sequencing (TAm-Seq) will be utilized to 
sequence ctDNA and identify mutations, including but not limited to, those in the tumor 
suppressor gene TP53, which is present in greater than 95% of HGSOC tumors.3, 24  
Similar to CA-125, the fraction of TP53 mutant alleles in plasma of ovarian cancer 
patients has been shown to track with the clinical course of the disease.24 
Taken together, the analyses planned in this trial will provide valuable information on genomic 
abnormalities that may be associated with response or resistance to rucaparib and will identify a 
broader ovarian cancer patient population that may benefit from treatment than has previously 
been explored in most other PARP inhibitor studies. 


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4 
STUDY OBJECTIVES 
4.1 Objectives and Endpoints 
This is a two-part, open-label efficacy study of oral rucaparib in patients with platinum-sensitive, 
relapsed, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer to define a 
signature of HRD that correlates with efficacy. 
Primary, secondary, and exploratory objectives and endpoints are shown in Table 2.  Unless 
otherwise specified, the objectives below apply to both parts of the study. 
Table 2 
Primary, Secondary, and Exploratory Objectives and Endpoints 
Primary Objectives 
Primary Endpoints 
1. To determine PFS in patients with relapsed 
platinum-sensitive ovarian cancer classified 
into molecularly-defined subgroups by a 
prospectively defined HRD signature 
(Part 1) 
1. Disease progression (RECIST v1.1) 
(Appendix B) as assessed by investigator, or 
death from any cause, in molecularly-defined 
subgroups identified by a prospectively defined 
HRD signature 
2. To estimate ORR in heavily pre-treated 
patients with relapsed ovarian cancer 
classified into molecularly-defined 
subgroups by a prospectively defined HRD 
signature (Part 2) 
2. ORR by RECIST v1.1 in molecularly-defined 
subgroups identified by a prospectively defined 
HRD signature 
Secondary Objectives 
Secondary Endpoints 
1. To estimate ORR (Part 1) 
1. ORR by RECIST v1.1  
2. To estimate ORR including CA-125 
response criteria 
2. ORR by RECIST v1.1 and GCIG CA-125 criteria 
3. To evaluate duration of response (DOR) 
3. DOR by RECIST v1.1 
4. To determine PFS (Part 2) 
4. Disease progression (RECIST v1.1) 
(Appendix B) as assessed by investigator, or 
death from any cause  
5. To evaluate survival (Part 2) 
5. Overall survival 
6. To evaluate the safety and tolerability of 
rucaparib 
6. The incidence of adverse events (AEs), clinical 
laboratory abnormalities, and dose modifications 
7. To evaluate steady state trough level PK 
7. Trough (Cmin) level rucaparib concentrations 


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Table 2 
Primary, Secondary, and Exploratory Objectives and Endpoints 
Exploratory Objectives 
Exploratory Endpoints 
1. To assess efficacy in molecularly-defined 
HRD subgroups as defined by HRR gene 
alterations 
1. PFS and/or ORR by RECIST v1.1 and GCIG 
CA-125 criteria. HRD subgroups as defined by 
HRR gene alterations 
2. To optimize the tumor LOH algorithm by 
testing additional signatures of interest 
based on higher or lower genomic LOH 
2. PFS and/or ORR by RECIST v1.1 and GCIG 
CA-125 criteria. Additional signatures of interest 
based on higher or lower genomic LOH. 
3. To assess changes in HRD status over time 
3. Changes in HRD status (LOH and gene 
alterations) between fresh biopsy versus archival 
tumor tissue samples 
4. To assess whether the BROCA panel can 
identify mutations in additional HRR genes 
that may be associated with efficacy 
4. ORR by RECIST v1.1 and GCIG CA-125 criteria 
in relation to HRR gene mutations identified in 
BROCA 
5. To assess if a gene expression signature for 
HRD correlates with efficacy 
5. PFS and/or ORR by RECIST v1.1 and GCIG 
CA-125 criteria in relation to gene signature 
defined by a gene expression profiling assay 
6. To assess NHEJ pathway integrity and 
correlate it with efficacy  
6. NHEJ protein expression by 
immunohistochemistry (IHC) and PFS and/or 
ORR by RECIST v1.1 and GCIG CA-125 criteria  
7. To assess ctDNA as a molecular marker of 
efficacy 
7. Levels of ctDNA in relation to PFS and/or ORR 
by RECIST v1.1 and GCIG CA-125 criteria 


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5 
STUDY DESIGN 
5.1 Overall Study Design and Plan 
This is a two-part, open-label efficacy study of rucaparib in patients with platinum-sensitive, 
relapsed, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer to 
characterize the relationship between HRD status and rucaparib efficacy in patients who received 
≥1 prior platinum-based regimen and have platinum-sensitive disease (Part 1) and patients who 
received at least 3, but no more than 4, prior chemotherapy regimens (Part 2).  Patients will 
enroll into either Part 1 or Part 2 of the study.  Part 2 will begin once enrollment of Part 1 has 
been completed. 
5.1.1 Screening Phase 
All patients will undergo screening assessments within 28 days prior to the first dose of 
rucaparib.  AEs that occur after signing of the informed consent form and before administration 
of the first rucaparib dose will also be collected during this period. 
Screening assessments will include demographics and medical history, prior treatments for 
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, hematology, serum chemistry, serum pregnancy for women of 
childbearing potential, urinalysis, blood sample for ctDNA analysis, physical examination, vital 
signs, weight and height measurements, adverse events, radiological assessment by CT or MRI, 
and CA-125 measurement.  All patients, with the exception of Part 2 patients known to harbor a 
deleterious gBRCA mutation, will be required to have a screening biopsy to collect fresh tumor 
tissue for determination of HRD status at study entry within 28 days prior to the first dose of 
rucaparib.  The screening biopsy will be optional for Part 2 patients known to harbor a gBRCA 
mutation.  This biopsy should be performed at least 7 days prior to the planned start of treatment 
to allow sufficient time for the sample to be sent to Foundation Medicine, the central laboratory 
for confirmation the tissue is of adequate quality for the planned analyses.  If a biopsy was 
recently performed as standard of care prior to this patient consenting to this study or after study 
informed consent but outside the 28 day screening window this may be acceptable with advance 
approval from the Sponsor.  In addition, archival tumor tissue samples must be confirmed as 
being available for all patients.  While archival tumor tissue is not required to be shipped prior to 
initiation of treatment, it is highly recommended that the tissue be sent as close as possible to the 
time of sending the screening biopsy to enable timely enrollment in the event that the screening 
biopsy is deemed inadequate by Foundation Medicine. 
In Part 1, patients <55 years of age at diagnosis, or with prior history of breast cancer, or who 
have a close relative (first or second degree) with ovarian cancer or early onset (<age 50) breast 
cancer are required to have been previously tested for gBRCA mutation.  Germline BRCA test 
results must 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 favor deleterious (or the 
equivalent interpretation of any of these) on the most recent assessment by a testing laboratory 


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will be limited to 15 in Part 1.  Patients not required to have been previously tested, or who 
tested negative for a gBRCA mutation, or who were found to have a mutation that was classified 
as other than deleterious, suspected deleterious, or favor deleterious or the equivalent of any of 
these, are eligible to enroll in Part 1 provided all other criteria are met.  Patients with a BRCA 
mutation detected in tumor tissue (tBRCA), but who do not have a germline mutation, will not 
count toward the cap and will be eligible to receive treatment with rucaparib, provided all other 
eligibility criteria are met. 
At least 80 patients with a deleterious / pathogenic tBRCA mutation will be enrolled into Part 2 
of the study.  There is no requirement for a patient enrolling into Part 2 to have been previously 
tested for a germline BRCA mutation, even if she meets the clinical criteria for testing being 
applied to patients entering Part 1 of the study. 
Results of the Foundation Medicine panel test will be provided to all patients who consent to 
receive this information.  In the event a BRCA1 or BRCA2 mutation is detected in tumor tissue, 
the patient may be referred by the investigator for genetic counseling and potential germline 
testing per institutional guidelines. If the patient chooses to have germline testing, this result will 
be entered into the clinical trial database.  
Mutations detected in tumor tissue may be somatic or germline; however, the central laboratory’s 
NGS test will not distinguish between the two.  A blood sample will therefore be collected for all 
patients at screening and stored.  Prior to final efficacy analysis, genomic DNA may be subjected 
to exploratory analysis in order to determine whether the mutation is germline.  These data will 
be generated in a research setting and will not be provided to the investigator or patient. 
Enrollment will require Clovis review of eligibility, including information on prior cancer 
therapies and dates administered, local gBRCA test result if patient has previously been tested, 
and, with the exception of Part 2 patients known to harbor a deleterious gBRCA mutation, 
confirmation that the screening biopsy sample has been submitted to the central laboratory and 
deemed adequate for the planned genetic analyses. Confirmation that an adequate amount of 
archival tumor tissue is available for analysis is also required. 
5.1.2 Treatment Phase 
For patients remaining on treatment as of implementation of Protocol Amendment 6, 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 (SOA) is provided in Section 9.1, which replaces 
all prior SOAs and should be followed for all patients who remain on treatment. 
During the treatment phase (continuous 28-day treatment cycles), patients will be monitored for 
safety and efficacy.  Assessments during the treatment phase will include AEs, complete blood 
count (monthly assessment advised), serum pregnancy test for women of childbearing potential, 
and study drug accountability; in addition, disease assessments (imaging/CA-125), 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.  Patients experiencing disease 
progression, as assessed by the investigator, will be discontinued from treatment. 


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A formal safety data review will occur after the first 20 patients have been enrolled, then every 
quarter until Part 1 enrollment is completed, and then every 6 months thereafter until all patients 
are enrolled and have participated in the study for at least 6 months or have discontinued prior to 
6 months, at which point safety reviews will occur on an as-needed basis. The review committee 
will include external experts and Sponsor personnel.  The external experts will include, but not 
be limited to, the coordinating PIs of the study (Dr. Elizabeth Swisher at Univ. of Washington 
and Dr. Iain McNeish at Imperial College London). Clovis reviewers will include the Medical 
Monitor, Chief Medical Officer, Head of Medical Safety (Pharmacovigilance), and 
Biostatistician.  The protocol will be amended as appropriate to incorporate additional patient 
safety monitoring if new safety signals are noted at any review. 
5.1.3 Post-Treatment Phase 
As of implementation of Protocol Amendment 6, more limited post-treatment assessments 
will be performed while maintaining appropriate safety monitoring. A revised SOA is 
provided in Section 9.1, which replaces prior SOAs. 
Upon discontinuation of treatment with rucaparib or study closure by the Sponsor, all patients 
will return to the clinic for an End of Treatment visit.  Assessments at this visit will include AEs, 
complete blood count, serum pregnancy for women of childbearing potential, and study drug 
accountability; in addition, disease assessments (imaging/CA-125), clinical chemistry, urinalysis, 
and vital signs may be performed per local standard of care practices.  An optional tumor biopsy 
sample, if available, will be collected from patients who experience disease progression and 
provide appropriate consent. Disease assessments should also be done at the time of treatment 
discontinuation if it has been ≥ 8 weeks since the last assessment.  
All patients will be assessed for AEs at 28 (±3) days following the last dose of rucaparib at the 
28-Day Follow-up visit.  All serious adverse events (SAEs) and adverse events of special interest 
(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.   
All patients who discontinued treatment for any reason other than radiologically confirmed 
disease progression will continue to have scans according to local standard of care per 
investigator until radiologically confirmed disease progression, death, initiation of subsequent 
treatment, or study closure by the sponsor. 


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5.2 Study Schema 
The study schema in Figure 3 summarizes the treatment design of the study.  
Figure 3 
Study Schema 
Screening Phase
(Day -28 to Day -1)
Screening 
Assessments
Within 28 days 
before first 
dose of 
rucaparib
D
A
Y
1
D
A
Y 
1
5
D
A
Y
1
Tumor Scans
Per local 
standard of 
care
EOT Visit
After last dose of 
rucaparib
28-day Follow-up
(28 ± 3 days after 
last dose of 
rucaparib)
Disease progression, unacceptable toxicity, study closure by 
sponsor, or other reason for discontinuation of rucaparib
Cycle 1
(28-day cycle)
Cycle 2 and subsequent cycles
(28-day cycles)
Rucaparib Treatment Phase
Post-treatment Phase


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5.3 End of Study 
The study will close when all patients have discontinued the study, or by sponsor decision as 
stated in Section 13.6.  If the study is closed by the sponsor, individual patients who are 
continuing to benefit from rucaparib treatment, and who do not meet any of the criteria for 
withdrawal, may have the option of entering an extension protocol, receiving rucaparib through 
compassionate use, or other acceptable study or option in which they can continue to receive 
rucaparib.   


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6 
STUDY POPULATION 
6.1 Number of Patients and Sites 
Approximately 480 patients with platinum-sensitive, relapsed high-grade epithelial ovarian, 
fallopian tube, or primary peritoneal cancer will be enrolled into either Part 1 (n=180) or Part 2 
(n=300) of the study at approximately 60 study sites.  Enrollment of patients known a priori to 
have a deleterious / pathogenic gBRCA mutation will be limited to 15 in Part 1.  At least 80 
patients with a tBRCA mutation will be enrolled into Part 2. 
6.2 Inclusion Criteria 
Eligible patients must meet the following inclusion criteria.  Unless otherwise specified, the 
criteria below apply to patients enrolling in either Part 1 or Part 2 of the study. 
1. Have signed an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-
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 serous or Grade 2 or Grade 3 
endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer 
− If mixed histology, >50% of the primary tumor must be confirmed to be high-grade 
serous or endometrioid upon re-review by local pathology 
− Patients with a histology other than serous or endometrioid are also eligible for Part 2 
of the study if they are known to harbor a deleterious / pathogenic BRCA mutation 
(germline or somatic) 
4. Have relapsed/progressive disease as confirmed by radiologic assessment 
5. Part 1: Received prior platinum-based therapy and have platinum-sensitive disease 
a. Received ≥1 prior platinum-based treatment regimen; AND 
b. Received a platinum-based regimen as their last treatment; continuous or switch 
maintenance treatment as part of this regimen is permitted (hormonal treatment 
may be permitted following the last platinum regimen with advance approval 
from the Sponsor); AND 
c. Was sensitive to the last platinum regimen.  Platinum-sensitive disease is defined 
as documented radiologic progression ≥6 months after the last dose of platinum 
administered in the treatment setting. 
Part 2:  Received at least 3, but no more than 4, prior chemotherapy regimens and had 
documented treatment-free interval of ≥6 months following 1st chemotherapy 
regimen received 
a. Hormonal agents (e.g., tamoxifen, letrozole, etc), anti-angiogenic agents (eg. 
bevacizumab, pazopanib, cediranib, nintedanib, trebananib, etc), and other non-
chemotherapy agents administered as single agent treatment will not be counted 
as a chemotherapy regimen for the purpose of determining patient eligibility 
b. Agents administered in the maintenance setting will not be counted as a separate 
regimen 


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6. Part 1 only: If <55 years of age at diagnosis, or has prior history of breast cancer, or has 
close relative (first or second degree) with ovarian cancer or early onset (<age 50) breast 
cancer, must have been previously tested for gBRCA mutation ; after 15 patients 
harboring the gBRCA mutation are enrolled, no additional patients with a known gBRCA 
mutation will be allowed to enroll. 
7. Have undergone a biopsy of tumor tissue prior to first dose of study drug and had the 
tumor tissue confirmed by the central laboratory as being of adequate quality (at least 
20% tumor content with a minimum of 80% nucleated cellular content). Note: biopsy is 
optional for Part 2 patients known to harbor a deleterious gBRCA mutation 
− If tumor tissue obtained from the biopsy is deemed inadequate, and the patient is 
unwilling or unable to have another biopsy, the patient may be considered for 
enrollment if archival tumor tissue is provided and deemed of adequate quality.  This 
must occur prior to any treatment with rucaparib. 
a. Biopsy must be of solid tumor tissue; ascites is not acceptable. 
b. Biopsy must be of sufficient yield for planned analyses 
8. Have sufficient archival FFPE tumor tissue available for planned analyses; cytospin 
blocks from ascites are not acceptable 
− The most recently obtained tumor tissue that is of adequate quality (at least 20% 
tumor content with a minimum of 80% nucleated cellular content) should be 
submitted 
9. Have measurable disease as defined by RECIST v1.1 (Appendix B) in addition to the 
lesion planned for biopsy; a single RECIST target lesion will suffice if, in the 
Investigator’s opinion, it is of sufficient size that the biopsy will not affect post-dose 
RECIST evaluations. 
10. Have adequate organ function confirmed by the following laboratory values obtained 
within 14 days prior to the first dose of rucaparib: 
a. Bone Marrow Function 
i. Absolute neutrophil count (ANC) ≥1.5 × 109/L 
ii. Platelets >100 × 109/L  
iii. Hemoglobin ≥9 g/dL 
b. Hepatic Function 
i. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)  
≤3 × upper limit of normal (ULN); if liver metastases, then ≤5 × ULN  
ii. Bilirubin ≤1.5 × ULN (<2 × ULN if hyperbilirubemia is due to Gilbert’s 
syndrome) 
iii. Serum albumin ≥30 g/L (3 g/dL) (Part 2 only) 
c. Renal Function  
i. Serum creatinine ≤1.5 × ULN or estimated glomerular filtration rate 
(GFR) ≥45 mL/min using the Cockcroft Gault formula 
11. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 
(Appendix C) 


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6.3 Exclusion Criteria 
Patients will be excluded from participation if any of the following criteria apply.  Unless 
otherwise specified, the criteria below apply to patients enrolling in either Part 1 or Part 2 of the 
study. 
1. Active second malignancy, i.e., patient known to have potentially fatal cancer present for 
which she may be (but not necessarily) currently receiving treatment 
a. Patients with a history of malignancy that has been completely treated, with no 
evidence of that cancer currently, are permitted to enroll in the trial provided all 
chemotherapy was completed >6 months prior and/or bone marrow transplant 
(BMT) >2 years prior to first dose of rucaparib 
2. Prior treatment with any PARP inhibitor, including oral or intravenous rucaparib.  
Patients who previously received iniparib are eligible 
3. 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 
4. Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that would, in 
the opinion of the Investigator, interfere with absorption of rucaparib 
5. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS)-related illness, or history of chronic hepatitis B or C 
6. Pregnant or breast feeding.  Women of childbearing potential must have a negative serum 
pregnancy test <3 days prior to first dose of rucaparib 
7. 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 rucaparib and/or ongoing adverse effects from such 
treatment > NCI CTCAE Grade 1 (ongoing Grade 2 non-hematologic toxicity related to 
most recent treatment regimen may be permitted with prior advanced approval from 
sponsor). 
8. Received administration of strong CYP1A2 or CYP3A4 inhibitors ≤7 days prior to first 
dose of rucaparib or have on-going requirements for these medications 
9. Non-study related minor surgical procedure ≤5 days, or major surgical procedure 
≤ 21 days, prior to first dose of rucaparib; in all cases, the patient must be sufficiently 
recovered and stable before treatment administration 
10. 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 
11. Diagnosis of low-grade serous or Grade 1 endometrioid ovarian cancer 
12. Part 2 Only: Hospitalization for bowel obstruction within 3 months prior to enrollment 
 


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6.4 Patients or Partners of Patients of Reproductive Potential 
Pregnancy is an exclusion criterion and women of childbearing potential must not be considering 
getting pregnant during the study.  Female patients are considered to be of childbearing potential 
unless 1 of the following applies: 
• Is 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 childbearing potential must have a negative serum pregnancy test result 
≤ 3 days prior to administration of the first dose of rucaparib.  In addition, a serum pregnancy 
test must be performed ≤ 3 days prior to Day 1 of every cycle from Cycle 2 and beyond during 
the treatment phase.  A serum pregnancy test will be performed at the End of Treatment visit.  
Pregnancy testing will be conducted locally. 
Female patients of reproductive potential and their male partners must practice a highly effective 
method (failure rate < 1% per year) of contraception during treatment and for 6 months 
following the last dose of rucaparib. 
Highly effective contraception includes: 
• Ongoing use of progesterone-only injectable or implantable contraceptives (e.g., 
Depo Provera, Implanon, Nexplanon); 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS); 
• 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 (e.g., 
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 rucaparib.   
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 (formerly known as PF-01367338 and AG-014447) is an oral formulation 
with a molecular weight of 555.67 Daltons.  Rucaparib tablets for oral administration will be 
supplied to the study sites by the sponsor.  A brief description of the investigational product is 
provided below. 
Drug Name: 
Rucaparib camsylate (CO-338) 
INN: 
Rucaparib 
 
 
Formulation: 
Tablet; film coated; 200 mg – blue, 300 mg – yellow  
How Supplied: 
200 and/or 300 mg (as free base) strength in high-density polyethylene 
bottles or equivalent with child-resistant caps . Patients may receive one or 
more strengths.  
Storage Conditions: 
15–30 °C 
 
Study drug containers containing rucaparib tablets will be labeled according to national 
regulations for investigational products.  Where accepted, the expiry date 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 
All patients enrolled in the study will receive rucaparib. 
7.3 Preparation and Administration of Protocol-Specified Treatment 
The investigator or designee will be responsible for distributing rucaparib tablets to all patients.  
Study sites should follow local guidelines for the handling of oral cytotoxic drugs. 
All patients will ingest rucaparib twice a day.  Patients may take rucaparib on an empty stomach 
or with food.  Each dose should be taken with at least 8 oz (240 mL) of room temperature water.  
Tablets should be swallowed whole.   
Patients should take rucaparib 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 rucaparib with her 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 rucaparib tablets and all containers (empty, partially 
used, and/or unopened) to the next scheduled visit for reconciliation by site personnel. 


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Patients enrolled into Part 1 of the study will initially receive 120 mg tablets, and once available 
supplies are exhausted, patients receiving this dose strength will be transitioned to 300/200 mg 
tablets or combination of dose strengths at a dose agreed upon between the investigator and 
sponsor.  Patients enrolled into Part 2 of the study will initially receive 300 mg tablets.  (Tablets 
of 200 mg dose strength will also be available for patients in Part 2 to enable dose reductions in 
100 mg increments – see Table 3). 
7.3.1 Dietary Restrictions 
All patients participating in the study should be instructed to use caution with CYP1A2, 
CYP2C9, CYP2C19, and CYP3A substrates noted in Appendix D.  
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 BID.  This dose was selected as the 
recommended dose for future Phase 2 and Phase 3 studies based on safety, tolerability, overall 
PK, and preliminary efficacy profile observed in the CO-338-010 study, which evaluated 
monotherapy rucaparib in patients with advanced solid tumors.  A summary of that study is 
provided in Section 3.3.2.1.  In the event that the recommended Phase 2 dose of 600 mg BID 
rucaparib is determined to be unsuitable for chronic dosing, the starting dose may be decreased 
to Dose Level -1 (480 mg BID rucaparib) for all subsequent patients if agreed upon between the 
Sponsor and the Principal Investigators.   
7.4.2 Dose Modification Criteria  
Treatment with rucaparib 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 alopecia, 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 rucaparib may be held and/or 
reduced for Grade 2 toxicity not adequately controlled by concomitant medications and/or 
supportive care. 
MANAGEMENT OF RUCAPARIB TREATMENT-EMERGENT ALT/AST ELEVATIONS  
• Grade 4 ALT/AST elevations: hold rucaparib until values have returned to Grade 2 or 
better, then resume rucaparib with a dose reduction.  Monitor liver function tests weekly 
for 3 weeks after rucaparib has been restarted. 


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• 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 rucaparib 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 rucaparib, and levels do not 
decline within 2 weeks or they continue to rise, treatment interruption and 
resolution to ≤ Grade 2 will be required before rucaparib can be resumed, either at 
the current dose or at a reduced dose. 
Treatment with rucaparib 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 
the patient continues to experience toxicity, additional dose reduction steps are permitted.  If a 
patient continues to experience toxicity despite multiple dose reduction steps, or if dosing with 
rucaparib is interrupted for >14 consecutive days due to toxicity, treatment should be 
discontinued, unless otherwise agreed between the investigator and the sponsor. 
Dose reduction steps are presented in Table 3. 
Dose re-escalation upon resolution of toxicity to ≤ CTCAE Grade 1 is permitted upon agreement 
between the investigator and sponsor. 
Table 3 
Dose Reduction Steps 
Tablets 
300/200 mg 
Starting Dose 
600 mg BID  
Dose Level -1 
500 mg BID 
Dose Level -2 
400 mg BID 
Dose Level -3* 
300 mg BID 
*Consult with medical monitor before reducing to this dose 
 


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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) 
7.4.4 Treatment Beyond Progression 
If the patient has met criteria for radiologic progression by RECIST, but the patient is still 
receiving benefit from rucaparib (e.g., patient has mixed radiologic response or is continuing to 
have symptomatic benefit) according to the Investigator, then continuation of treatment will be 
considered.  In such cases, the decision to continue will be made jointly between the Investigator 
and the Sponsor, and must be documented prior to continuing treatment with rucaparib.  Patients 
will continue to have all protocol-required assessments specified in Table 4 and may have the 
option of entering an extension protocol, receiving rucaparib through compassionate use, or other 
acceptable study or option in which they can continue to receive rucaparib either at the 
investigator’s discretion at any time or if this study is closed by the sponsor. 
7.5 Accountability of Protocol-Specified Treatment 
Study personnel will maintain accurate records of study drug receipt, dispensation, use, return, 
destruction, and reconciliation.  A web/phone-based drug management system will be used to 
manage study drug inventory at all sites.  In order to function properly, the system will require 
real-time entry of study drug receipt, dispensation, destruction, etc. by study personnel at the 
study center. 
The site is responsible for the return or destruction of study drug as required.  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.  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 
This is an open-label study; the investigational product will not be blinded or masked.  All 
patients enrolled will receive rucaparib. 


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7.7 Treatment Compliance 
As of implementation of Protocol Amendment 6, drug dosing diaries will be discontinued. 
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.  Patients (or legally authorized 
representative) will be instructed to bring all unused tablets with them to scheduled clinic visits.  
A compliance check and tablet count will be performed by study personnel during clinic visits. 
Every effort should be made to ensure patients return their study drug containers at the end of 
each cycle of treatment.  Study site personnel should conduct a verbal review of dosing with the 
patient and document the discussion in the patient’s medical record. 


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8 
PRIOR AND CONCOMITANT THERAPIES 
Patients who have received prior treatment with a PARP inhibitor including intravenous 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 (e.g., antiemetics; analgesics for pain control) may be used at 
the investigator’s discretion and in accordance with institutional procedures. Supportive care 
must be recorded for each patient in the appropriate section of the eCRF. 
All procedures performed (e.g., thoracentesis, etc.) and medications used during the study must 
be documented on the eCRF. 
8.1 Anticancer or Experimental Therapy 
No other anticancer therapies (including chemotherapy, radiation, 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 hormonal treatment.  Prior treatment with anticancer therapies must have been 
completed >14 days prior to the first dose of study drug. 
 
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 results of in vivo CYP interaction study (CO-338-044), rucaparib is a moderate 
inhibitor of CYP1A2, and a weak inhibitor of CYP2C9, CYP2C19, and CYP3A.  Caution should 
be used in patients on rucaparib taking concomitant medicines that are sensitive clinical 
substrates of CYP1A2, CYP2C9, CYP2C19, and/or CYP3A (Appendix D). 
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 rucaparib and concomitant warfarin (Coumadin). Patients taking warfarin should have 
international normalized ratio (INR) monitored regularly per standard clinical 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 drug interactions, 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 decrease 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 50% 
inhibitory concentration (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 4 summarizes the procedures and assessments to be performed for all patients 
remaining on treatment or in follow-up as of implementation of Protocol Amendment 6. 
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 (SOA) shown below in Table 4 replaces all prior 
SOAs. 
All procedures and assessments are to be completed within ±3 days of the scheduled time point, 
unless otherwise specified. 
The purpose of the revised SOA 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 4 
Revised Schedule of Assessments as of Implementation of Protocol Amendment 6 
Procedurea 
Treatment Phase 
(±3 days) 
Cycle X Day 1 
Post-Treatment Phase 
End of Treatment 
28 Day Follow-up (FU) 
(±3 days after last dose) 
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 Testc (WOCBP only)  
(local lab) 
X 
X 
 
Disease Assessments (Imaging/CA-125) 
Local standard of care practices per Investigator 
 
Tumor Tissue Biopsyd 
 
X 
 
Rucaparib 
Dispensation/Administration/Accountability 
X 
X 
 
Abbreviations: AE = adverse event, AESI = adverse event of special interest, FU = follow up, SAE = serious adverse event, WOCBP = women of childbearing 
potential. 
a 
= 
Treatment cycles are 28 days.  Unless otherwise specified, all assessments are to be completed within ± 3 days of scheduled time point. 
b 
= 
AEs will be monitored but 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. 
c 
= 
Women of childbearing potential must have a negative serum pregnancy test result ≤3 days prior to the first dose of rucaparib. A serum pregnancy test  must 
be performed ≤3 days prior to Day 1 of every cycle from Cycle 2 and beyond during the treatment phase.  A serum pregnancy test must be performed at the 
End of Treatment visit. 
d 
= 
An optional post-treatment tumor biopsy sample may be collected from patients who progress on rucaparib.  If the progression is due to new lesions, the 
preference is to obtain the biopsy from the new lesion(s). Additional consent is required. Refer to the Pathology Charter for detailed sample handling 
instructions. 


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9.2 Screening Phase 
Following written informed consent, and unless otherwise specified, the following assessments 
will be performed during the 28-day period prior to the first dose of study drug.  Assessments 
performed within this window, but prior to patient signing informed consent, are acceptable only 
if confirmed to have been standard of care. 
• Medical/oncology history, including demographic information (birth date, race, gender, etc.) 
and smoking status, including date of cancer diagnosis, and any surgical procedures 
• Physical examination by body system, height, and weight 
• ECOG performance status (Appendix C) 
• Vital signs (blood pressure, pulse, and temperature) 
• Prior and concomitant medications and any procedures 
• 12-lead ECG  
• Hematology (hemoglobin, hematocrit, WBC and differential [with ANC], and platelet count) 
≤14 days prior to the first dose of study drug (all patients in Parts 1 and 2; patients in Part 2 
will also have MCH, MCV, MCHC, and reticulocyte count measurements) 
• Serum chemistry (total protein, albumin, creatinine or estimated GFR using the Cockcroft 
Gault formula, blood urea nitrogen [BUN] or urea, total bilirubin, ALP, ALT, AST, glucose, 
sodium, potassium, chloride, CO2, calcium, and phosphorus) and total cholesterol for all 
patients in Parts 1 and 2; patients in Part 2 will also have a lipid panel that includes LDL, 
HDL and triglycerides in addition to the total cholesterol measurement) ≤14 days prior to the 
first dose of study drug. Note: fasting is not required for the lipid panel. 
• Serum pregnancy test for women of childbearing potential (within 3 days of first dose of 
study drug) 
• Cancer antigen 125 (CA-125) measurements per GCIG criteria provided in Appendix E  
- To be evaluable for response by CA-125, at least 2 pretreatment samples must be 
collected at least 1 day, but not more than 3 months, apart.  At least one pretreatment 
sample should be within 1 week prior to the first dose of rucaparib.  Both must be at least 
twice the upper limit of normal. 
• Urinalysis performed on freshly voided clean sample (dipstick for protein, glucose, blood, 
pH, and ketones).  If dipstick findings are abnormal based on investigator judgment, then a 
microscopic evaluation will be performed to assess the abnormal findings. 
• 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 (MRI, X-ray, positron emission tomography [PET], and 
ultrasound) may be performed if required.  The same methods used to detect lesions at 


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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.   
• Tumor tissue biopsy / sample collection (If a biopsy was recently performed as standard of 
care prior to this patient consenting to this study or after study informed consent but outside 
the 28 day screening window this may be acceptable with advance approval from the 
Sponsor).  Tumor specimen must be processed locally as FFPE tissue.  Sample must be sent 
to the central laboratory for review and confirmed as adequate (at least 20% tumor content 
with a minimum of 80% nucleated cellular content; 30% or greater tumor content is 
preferred) for planned analyses prior to enrollment.  Refer to the Pathology Charter for 
detailed sample requirements and handling instructions.  
- To ensure sufficient viable tumor tissue is obtained, image-guided biopsies should be 
achieved with 14 to 18 gauge cutting needles to provide 1 to 3 cores measuring 1 to 
1.5 cm in length. 
- Biopsy must be of solid tumor tissue; ascites is not acceptable. 
- If tumor tissue obtained from the biopsy is deemed not adequate, and the patient is 
unwilling or unable to have another biopsy, the patient may be considered for enrollment 
if archival tumor tissue is provided and deemed of adequate quality.  This must occur 
prior to any treatment with rucaparib. 
- Note: screening biopsy sample is optional for Part 2 patients known to harbor a 
deleterious gBRCA mutation 
• FFPE archival tumor tissue sample.  Sufficient archival FFPE tumor tissue for planned 
analyses should be provided.  Cytospin blocks from ascites are not acceptable.  Refer to the 
Pathology Charter for detailed sample requirements and handling instructions.  
− The most recently obtained tumor tissue that is of adequate quality (at least 20% tumor 
content with a minimum of 80% nucleated cellular content) should be submitted 
- Sample need not be submitted prior to enrollment; however, confirmation that such tissue 
is available must be provided prior to enrollment approval. 
• AE monitoring (after signing informed consent) 
• Blood sample for ctDNA analysis 
• Blood sample for storage (may be collected at a subsequent visit, if not collected during this 
visit) 
9.3 Treatment Phase 
9.3.1 Day 1 of Cycle 1 
The following procedures will be completed before rucaparib is administered: 
• Physical examination (abbreviated) 
• Weight 
• ECOG performance status (Appendix C) 


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• Vital signs 
• Concomitant medications and procedures 
• Hematology 
• Serum chemistry 
• CA-125 measurement 
• AE monitoring 
• Blood sample for ctDNA analysis 
Rucaparib tablets will be dispensed to the patient in sufficient quantity to last until the next 
treatment cycle.  Patients will ingest rucaparib twice daily at about the same times every day, at 
close to 12 hours apart as possible.  Each dose of rucaparib should be taken with at least 8 oz 
(240 mL) of room temperature water.  Patients may take rucaparib on an empty stomach or with 
food.  Patients will record dosing information in their dosing diary. 
9.3.2 Day 15 of Cycle 1 
Patients will be instructed to refrain from taking their first dose of rucaparib at home on the day 
of their clinic visit because certain assessments should be performed prior to dosing.  
• Hematology 
• Serum chemistry 
• A single plasma PK sample (as close to 12 hours after the last dose taken as possible and 
prior to the next dose) 
• A single serum sample for AAG measurement (as close to 12 hours after the last dose taken 
as possible and prior to the next dose) 
• Concomitant medications and procedures 
• AE monitoring 
9.3.3 Cycles 2 and Beyond 
The revised Schedule of Assessments shown in Table 4 replaces all prior schedules of 
assessments as of implementation of Protocol Amendment 6. 
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 
• CA-125 measurement according to local standard of care per Investigator 


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• Serum pregnancy test ≤ 3 days prior to start of cycle (for women of childbearing potential 
only) 
• Tumor scans according to local standard of care per Investigator. 
• AE monitoring 
• Study drug accountability 
Rucaparib tablets will be dispensed to the patient in sufficient quantity to last until the next clinic 
visit.  A single dose of rucaparib will be administered with at least 8 oz (240 mL) of room 
temperature water during the current clinic visit.  Patients may take rucaparib on an empty 
stomach or with food.   
Patients will continue dosing with rucaparib at home on an empty stomach or with food, taking 
doses twice daily at about the same times every day.  Rucaparib should be taken with at least 8 
oz (240 mL) of room temperature water.   
9.4 End of Treatment Visit 
The revised Schedule of Assessments shown in Table 4 replaces all prior schedules of 
assessments as of implementation of Protocol Amendment 6. 
The following procedures are advised as soon as possible after the last dose of rucaparib: 
• Hematology (complete blood count) 
• Clinical chemistry, urinalysis, and vital signs according to local standard of care per 
Investigator 
• Serum pregnancy test for women of childbearing potential 
• CA-125 measurement according to local standard of care per Investigator 
• Optional tumor tissue biopsy sample collection at time of disease progression/treatment 
discontinuation (requires additional consent).  If disease progression is caused by appearance 
of a new lesion(s), this lesion should be prioritized for biopsy. Tumor tissue will be 
processed locally as FFPE tissue.  Refer to the Pathology Charter for detailed sample 
handling instructions 
• AE monitoring 
• Study drug accountability 
• Disease assessments according to local standard of care per Investigator  
9.5 28 Day Follow-up Visit 
The following procedures will be performed for all patients at 28 (±3) days after the last dose of 
rucaparib: 


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• AE monitoring (ongoing SAEs and AEs of special interest [AESI]; Section 10.3) should be 
followed until resolution, stabilization, or lost to follow-up even if the duration extends 
beyond the 28-day follow-up period). 
After the 28-day window, only SAEs assessed as related to study drug and all AESIs, 
irrespective of causality, should be reported. 
9.6 Methods of Data Collection 
Hematology, serum CA-125, and serum pregnancy will be performed locally.  Central/core 
laboratories will conduct all other assays described below.  Please refer to the Pathology Charter 
and/or Laboratory Manual for details on collecting and processing all samples that will be sent to 
central/core laboratories. 
9.6.1 Pharmacokinetic Evaluations and AAG Measurement 
As of implementation of Protocol Amendment 6, samples will no longer be collected for PK 
and AAG analyses. 
9.6.2 Biomarker Analysis – FFPE Tumor Tissue  
A tumor tissue biopsy sample is required to be collected during screening from all patients, 
except for Part 2 patients known to harbor a deleterious gBRCA mutation; the screening biopsy 
sample in this group of patients is optional.  A tumor tissue biopsy sample at the time of disease 
progression/treatment discontinuation is optional; patients must provide additional consent for 
this optional tumor tissue biopsy sample.  If disease progression is caused by appearance of a 
new lesion(s), this lesion should be prioritized for the optional biopsy. 
Sufficient archival FFPE tumor tissue (See Pathology Charter for details) must be available and 
located during the screening process and submitted to the central laboratory as soon as possible.  
Submission of archival tumor tissue is not required for enrollment; however, confirmation that 
such tissue is available is required. 
Analysis of the tumor tissue samples may include, but not be limited to: 
• DNA extraction and sequencing of single nucleotide polymorphisms (SNPs) to identify 
tumor genomic LOH and to determine whether tumor genomic LOH can be used as a 
predictor of efficacy 
• DNA extraction and sequencing in order to identify: 
• If the patient has a mutation in BRCA1, BRCA2, or another gene in the HRR pathway 
(Appendix A) 
• If a patient has a BRCA reversion or other mutation(s) that may be associated with efficacy 
• Gene expression profiling on extracted RNA to potentially identify a signature associated 
with efficacy 
• Immunohistochemistry analysis to assess NHEJ pathway integrity  


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9.6.3 Biomarker Analysis – Blood 
As of implementation of Protocol Amendment 6, blood samples will no longer be collected 
for biomarker analyses. 
9.6.4 Safety Evaluations 
9.6.4.1 Adverse Event Assessment 
The investigator has the responsibility 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 at the time informed consent is obtained) and until 28 days after the last 
dose of rucaparib.  Any ongoing SAEs and AESIs will be recorded and followed until resolution, 
stabilization, or lost to follow-up.  Only treatment-related SAEs and all AESIs, irrespective of 
causality, need to be reported after the 28-day window.  SAEs will be graded according to the 
NCI CTCAE grading system (Version 4.0) and recorded on the eCRF. 
Complete details for monitoring AEs, including the definition of drug-related AEs, are provided 
in Section 10. 
9.6.4.2 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 6, monthly hematology 
assessment, consisting of a complete blood count, is advised.  
Clinical Chemistry:  As of implementation of Protocol Amendment 6, clinical chemistry 
assessments may be performed according to local standard of care per Investigator.  
Urinalysis:  As of implementation of Protocol Amendment 6, urinalysis may be performed 
according to local standard of care per Investigator.  
Serum ß-hCG  Pregnancy Test:  For women of childbearing potential only.  Serum pregnancy 
to be performed ≤ 3 days prior to first dose of rucaparib, ≤ 3 days prior to Day 1 of every cycle 
from Cycle 2 and beyond, and at End of Treatment.   
Laboratory reports should be reviewed by the investigator or delegated physician who will assess 
clinical significance. 
9.6.4.3 Vital Signs 
As of implementation of Protocol Amendment 6, vital signs may be performed according to local 
standard of care per Investigator.   


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9.6.4.4 12-Lead Electrocardiograms 
As of implementation of Protocol Amendment 6, ECGs will no longer be performed. 
9.6.4.5 Body Weight and Height 
As of implementation of Protocol Amendment 6, body height and weight assessments will no 
longer be performed. 
9.6.4.6 Physical Examinations 
As of implementation of Protocol Amendment 6, physical examinations will no longer be 
performed.  
9.6.4.7 ECOG Performance Status 
As of implementation of Protocol Amendment 6, ECOG performance status assessments will no 
longer be performed. 
9.6.5 Efficacy Evaluations 
9.6.5.1 Tumor Assessments 
As of implementation of Protocol Amendment 6, tumor assessments will be performed per 
institutional standard of care during treatment and post-treatment (if patient discontinued 
treatment for any reason other than radiologically confirmed disease progression) until 
radiologically confirmed disease progression, death, initiation of subsequent treatment, or study 
closure by the sponsor.  Tumor assessments should be done according to local standard of care 
per Investigator.  Tumor response will be interpreted using RECIST Version 1.1 (Appendix B).  
Tumor assessments may consist of 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.  Investigators should perform scans of the anatomical sites that, in their 
judgment, are appropriate to assess based on each patient’s tumor status.   
Copies of CT scans will be collected from all patients in Part 2 of the study and may be collected 
from selected patients in Part 1 of the study.  Independent radiology review may be conducted on 
all or a subset of CT scans. 
9.6.5.2 Tumor Markers 
CA-125 will be collected at Screening, on Day 1 of every cycle, at the End of Treatment visit, 
and as clinically indicated.  


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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.  An AE can, therefore, be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an investigational product, whether or not related to 
the investigational medicinal product. This includes an exacerbation of pre-existing conditions or 
events, intercurrent illnesses, drug interaction, or the significant worsening of the indication 
under investigation that is not recorded elsewhere on the eCRF under specific efficacy 
assessments.  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. 
Events of progression of the patient’s underlying cancer, as well as events clearly related to 
progression of the patient’s cancer (signs and symptoms of progression) should not be reported 
as an AE/SAE.  
It is the responsibility of the investigator to monitor all AEs that occur during the study.  AEs 
should be elicited by asking the patient a nonleading question (e.g., “Have you experienced any 
new or changed symptoms since we last asked/since your last visit?”).  SAEs/AESIs will be 
reported on the AE eCRF.  Symptoms reported spontaneously by the patient that meet 
seriousness criterion 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 (including after informed 
consent is given and prior to dosing if deemed related to a protocol-mandated procedure) that: 
• Results in death.  Any event resulting in death during the reporting period (from date of first 
dose of study drug through 28 days after last dose) must be treated as an SAE and reported as 
such. 
• 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. 
• Is an important medical event based upon appropriate medical judgment; it may jeopardize 
the patient or may require intervention to prevent one of the other outcomes noted above. 


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10.3 Definition of an Adverse Event of Special Interest (AESI) 
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 
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 (e.g., 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 Investigator’s Brochure.  These AESIs are to be reported to the sponsor within 24 
hours (see Section 10.8 for reporting instructions).  
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 (e.g., 
respite care). 
• Hospital visits of less than 24 hours duration (e.g., patient presents to the emergency room, 
but is not admitted to a ward).  
• Overdose of study drug or concomitant medication, unless there is an associated SAE (e.g., 
hospitalization), as a direct consequence of the overdose. The accompanying SAE should be 
reported and overdose should be described in the report. 
• Events of progression of the patient’s underlying cancer, as well as events clearly related to 
progression of the patient’s cancer (signs and symptoms of progression) should not be 
reported as an AE/SAE. 
10.5 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 in a study 
patient 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. 


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10.6 Recording of Serious Adverse Events, and Adverse Events of Special Interest 
All 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 through 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. After the 28-day window, only SAEs 
assessed as related to study drug and all AESI, 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. 
In order to avoid vague, ambiguous, or colloquial expressions, the SAE should be recorded in 
standard medical terminology rather than the patient’s own words. Whenever possible, the 
investigator should combine signs and symptoms that constitute a single disease entity or 
syndrome into a final diagnosis, if appropriate. For example, fever, cough, and shortness of 
breath may be reported as pneumonia, if that is a reasonable diagnosis. 
Each SAE is to be evaluated for duration, severity, seriousness, and causal relationship to the 
investigational drug. The action taken and the outcome must also be recorded. 
All SAEs/AESIs, regardless of relationship to study drug, must be reported to the 
Sponsor/designee within 24 hours of the Investigator’s knowledge. 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. 
Investigators must follow patients with SAEs/AESIs until the event has resolved or the condition 
has stabilized.  If the patient is lost to follow-up with an ongoing SAE, this should be captured 
accordingly on a follow-up SAE report.   
10.6.1 Intensity of Serious Adverse Events 
Severity refers to the intensity of an SAE.  The severity of each SAE will be categorized using 
the NCI CTCAE, Version 4.0 (http://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf).53 
Severity is not the same as Serious 
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 


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• Life threatening (Grade 4): life-threatening consequences; urgent intervention indicated 
• Fatal (Grade 5): results in death 
10.6.2 Causal Relationship of Serious Adverse Events to Investigational Product 
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. 
Not Related 
To Study Drug 
An SAE that is clearly due to extraneous causes (e.g., concurrent disease, 
concomitant medication, disease under study, etc.) 
An SAE that does not follow a reasonable temporal sequence from administration of 
the study drug. 
An SAE that does not reappear or worsen when study drug is restarted. 
An SAE for which an alternative explanation is likely, but not clearly identifiable. 
Related to 
Study Drug 
An SAE that is difficult to assign to alternative causes. 
An SAE that follows a strong or reasonable temporal sequence from administration 
of study drug. 
An SAE that could not be reasonably explained by the patient’s clinical state, 
concurrent disease, or other concomitant therapy administered to the patient. 
An SAE that is confirmed with a positive rechallenge or supporting laboratory data. 
 
10.6.3 Outcome 
The investigator will record the outcome for each SAE/AESI according to the following criteria: 
Outcome 
• Recovered/Resolved 
• Recovered/Resolved with sequelae 
• Improving 
• Ongoing 
• Death 
• Unknown/Lost to follow-up 
10.7 Follow-Up of Serious Adverse Events, and Adverse Events of Special Interest 
All 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 through 28 days after the last dose of study drug. Any SAE or AESI 
must be followed until resolution or stabilization, or until lost to follow-up. After the 28-day 
window, treatment-related SAEs and all AESIs, irrespective of causality, need to be reported. 


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10.8 Potential Drug-Induced Liver Injury 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential drug-induced liver injury (DILI) event. All occurrences 
of potential DILIs, meeting the defined criteria,52 must be reported as SAEs (see Section 10.9 for 
reporting details). 
Potential drug induced liver injury is defined as: 
1. 
ALT or AST elevation > 3 × ULN 
AND 
2. 
Total bilirubin > 2 × ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 
AND 
3. 
No other immediately apparent possible causes of ALT/AST elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic. 
10.9 Regulatory Aspects of Serious Adverse Event Reporting 
All SAEs and AESIs, regardless of relationship to study drug, and pregnancy must be reported to 
the Sponsor’s SAE designee within 24 hours of knowledge of the event, according to the 
procedures below.  After the 28-day specified window, only SAEs considered to be 
treatment-related and all AESIs, regardless of treatment relationship, should be reported.  It is 
important that the investigator provide an assessment of relationship of the SAE to study 
treatment at the time of the initial report.  The  SAE/AESI Report Form must be used for 
reporting SAEs and AESIs. The contact information for reporting of SAEs can be found on the 
SAE/AESI Report Form.  The Pregnancy Report Form must be used for reporting pregnancies. 
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 FDA, according 
to 21 Code of Federal Regulations (CFR) 312.32, to the 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. 


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11 STATISTICAL METHODS 
11.1 Analysis Populations 
The following analysis populations are defined for the study: 
Safety Population – The safety population will consist of all patients who received at least one 
dose of protocol-specified treatment. 
Efficacy Population – The efficacy population will consist of all patients evaluable for response 
by RECIST (Appendix B) and/or GCIG CA-125 criteria (Appendix E).  Patients evaluable for a 
RECIST response must have at least one measureable target lesion at baseline and at least one 
post-baseline tumor assessment.  Patients evaluable for GCIG CA-125 response must have 2 
pretreatment CA-125 values at least twice the upper limit of normal and at least 2 post-baseline 
values. 
11.2 Statistical Methods 
11.2.1 General Considerations 
Data will be summarized separately for Parts 1 and 2 and may also be pooled as appropriate. 
The summary tables will be presented for all treated patients and by the subgroups defined by 
HRD status.   
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.      
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, version 9.3 or higher.    
Unless otherwise specified, baseline is defined as the last measurement on or prior to the first 
day of study drug administration. 
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. 


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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):  > 6-12, > 12-24, > 24;  
• Baseline laboratory parameters:  graded based on CTCAE; 
Descriptive statistics may also be used to summarize these variables.   
11.2.4 Efficacy Analyses  
All primary and secondary efficacy evaluations will be presented by HRD status and study part 
(Part 1 or Part 2).  Data may also be pooled across HRD status or Parts 1 and 2 as appropriate.  
Analyses of PFS will be presented for the safety population and ORR and CA-125 response rates 
will be presented for the appropriate subset of the efficacy evaluable population. 
11.2.4.1 Primary Efficacy Analyses 
Part 1: The primary efficacy endpoint of PFS will be calculated as 1+ the number of days from 
the first dose of study drug to disease progression, as determined by the investigator or death due 
to any cause, whichever occurs first, in molecularly defined subgroups. Patients without a 
documented event of progression will be censored on the date of their last adequate tumor 
assessment (i.e., radiologic assessment) or date of first dose of study drug if no tumor 
assessments have been performed. 
Part 2: The primary efficacy endpoint of ORR is defined as the proportion of patients with a 
best response of CR or PR using RECIST v1.1 (Appendix B) as assessed by the Investigator.  
The ORR will be summarized with frequencies and percentages in the efficacy population. 
Independent radiology review may also be performed as a supportive analysis for all or a subset 
of patients.  The supportive analysis of ORR by independent radiology review (irrORR) is 
defined as the proportion of patients with a best response of CR or PR using RECIST v1.1 
(Appendix B) as assessed by independent radiology review.   
11.2.4.2 Secondary Efficacy Analyses 
11.2.4.2.1 Objective Response Rate (ORR) (Part 1) 
ORR is defined as the proportion of patients with a best response of CR or PR using RECIST 
v1.1 (Appendix B) as assessed by the Investigator.  The ORR will be summarized with 
frequencies and percentages.   
As a supportive analysis, the ORR will also be evaluated in the safety population.  Patients who 
are not evaluable for a RECIST response will be considered to have experienced disease 
progression. 


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Independent radiology review may also be performed as a supportive analysis.  The supportive 
analysis of ORR by independent radiology review (irrORR) is defined as the proportion of 
patients with a best response of CR or PR using RECIST v1.1 (Appendix B) as assessed by 
independent radiology review.  The irrORR will be evaluated in the efficacy population for 
patients with measurable disease per the independent radiology review. 
11.2.4.2.2 Duration of Response 
The duration of response is measured from the time measurement criteria are met for CR/PR per 
RECIST or a 50% response in CA-125 (whichever is first recorded) until the first date that 
recurrent or PD is objectively documented using the earliest of the RECIST or CA-125 response. 
The duration of response will also be evaluated separately for CR/PR RECIST responses and for 
CA-125 responses.  In addition, the duration of overall CR will be measured from the time 
measurement criteria are first met for CR until the first date that recurrent disease is objectively 
documented. 
The duration of response will be summarized with descriptive statistics.  Only patients with a 
response will be included in the summary. 
11.2.4.2.3 ORR Assessed by RECIST and GCIG CA-125 Criteria 
The endpoint of ORR defined as a best response of CR or PR using RECIST (Appendix B) will 
be summarized with frequencies and percentages in the appropriate efficacy population. 
The endpoint of CA-125 response rate defined as a 50% reduction in CA-125 as assessed by 
GCIG criteria will be summarized with frequencies and percentages in the safety population.  As 
a supportive analysis, the CA-125 response rate will also be evaluated in the patients evaluable 
for a CA-125 response as defined in Appendix E. 
ORR will be reported separately and together for RECIST and GCIG.  The combined ORR will 
be assessed as indicated in Table 5. 


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Table 5 
Overall Response by RECIST54 and GCIG CA-125 Criteria55 
RECIST Response 
GCIG CA-125 Response 
RECIST + GCIG CA-125 
Combined  
CR 
(requires normalization of CA-125) 
CA-125 within normal range 
Response 
PR 
Response 
Response 
PR 
No Response 
Response 
SD 
Response 
Response 
SD 
No Response 
No Response 
PD 
Response 
No Response 
PD 
No Response 
No Response 
 
11.2.4.2.4 Overall Survival (Part 2) 
Overall survival (OS) is defined as the number of days from the date of first dose of study drug 
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. 
11.2.4.3 Exploratory Efficacy Analyses 
Statistical analysis of exploratory endpoints will be detailed in the Statistical Analysis Plan. 
11.2.4.4 Diagnostic Test 
The predictive utility of the HRD diagnostic test will be evaluated by comparing the primary and 
secondary endpoints in the tBRCA subgroup to that of nbHRD subgroup and the biomarker 
negative subgroup. 
11.2.5 Pharmacokinetic Analyses 
As a secondary endpoint of the study, trough (Cmin) concentrations of rucaparib will be 
summarized with descriptive statistics overall and by cycle in all patients with at least one PK 
sample collected. 
11.2.6 Safety Analyses  
The safety analyses will be performed using the safety population (all patients who have received 
at least one dose of rucaparib).   


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11.2.6.1 Adverse Events 
Adverse events 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. 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.  Adverse events 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 
adverse event meets the definition for treatment-emergent. 
The number and percentage of patients who experienced TEAEs for each system organ class and 
preferred term will be presented.  Multiple instances of the TEAE in each system organ class 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; 
• Treatment-related TEAEs; 
• Serious TEAEs; 
• TEAEs with an outcome of death; 
• TEAEs leading to discontinuation of study medication; 
• TEAEs resulting in interruption/delay of study medication; and 
• TEAEs resulting in reduction of study medication. 
The incidence of TEAEs will be summarized by relationship to study drug according to the 
following categories:  “treatment-related,” or “not treatment-related”.  The category of treatment-
related contains the TEAEs with a missing relationship.  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 
grade will be summarized.    
Non-TEAEs (pre-treatment and post-treatment) will be presented in the by patient data listings 
for the safety population.  


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11.2.6.2 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 enrollment 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.     
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 
Version 4.0). 
11.2.6.3 Vital Sign Measurements 
The on-treatment period will be defined as the time from enrollment 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. 
11.3 Interim Analyses 
No formal statistical interim efficacy analyses for the purpose of stopping early or altering the 
the sample size will be performed in this open-label study. 
A formal safety data review will occur after the first 20 patients have been enrolled, then 
quarterly until Part 1 of the study is fully enrolled, and then every 6 months thereafter until all 
patients are enrolled and have participated in the study for at least 6 months or discontinued prior 
to 6 months, at which point safety reviews will occur on an as-needed basis.  The review 
committee will include external experts and Sponsor personnel.  The external experts will 
include, but not be limited to, the coordinating PIs of the study (Dr. Elizabeth Swisher at Univ. 
of Washington and Dr. Iain McNeish at Imperial College London). Clovis reviewers will include 
the Medical Monitor, Chief Medical Officer, Head of Pharmacovigilance, and Biostatistician.  
The protocol will be amended as appropriate to incorporate additional patient safety monitoring 
if new safety signals are noted at any review. 


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11.4 Sample Size Considerations 
The total enrollment planned for this study is approximately 480 patients, N=180 in Part 1 and 
up to N=300 in Part 2.   
Part 1: It is anticipated that approximately 180 patients will be required in order to ensure each 
subgroup of patients (tBRCA, nbHRD, and biomarker negative) will contain an adequate number 
of patients.  Other than the cap on patients with a known deleterious gBRCA mutation, (n=15), 
there will be no specific requirement to enroll defined numbers of patients into each planned 
subgroup.  The likely size of each subgroup has been estimated based on: a) frequencies of 
HRD-associated genetic abnormalities at initial diagnosis as reported in the literature and b) the 
hypothesis that the inclusion criterion of sensitivity to platinum following the most recent line of 
platinum therapy will enrich the population for patients with tumors harboring mutations of HRD 
pathway genes (i.e., that the frequency will be greater than that described in the newly-diagnosed 
population).  Table 6 provides estimated HRD subgroup sizes in Part 1 of this trial. 
Table 6 
Estimated HRD Subgroup Sizesa 
HRD Subgroup  
Expected 
Frequency at 
Diagnosis 
Estimated 
Frequency with 
Enrichment for 
Platinum 
Sensitivity 
Estimated Number of Patients 
tBRCA 
21% 
30% 
15 with known deleterious gBRCA 
mutation (fixed) 
plus 
20 – 25 with somatic BRCA mutation 
plus 
5 – 25 additional with newly diagnosed 
gBRCA mutation 
nbHRD 
22 – 32% 
30 – 50% 
50 – 90 
Biomarker 
Negative 
60 – 70% 
20 – 40% 
36 – 72 
aExpected frequency estimates are from TCGA3 
 
Enrollment of patients known a priori to harbor a gBRCA mutation classified as deleterious 
(pathogenic), suspected deleterious, or favor deleterious (or the equivalent interpretation of any 
of these) on the most recent assessment by a testing laboratory will be limited to 15 in Part 1.  
Fifteen patients with a known gBRCA mutation are sufficient to establish that the frequency of 
gBRCA mutation reversions is low.  In particular, if none of the 15 patients with a known gBRCA 
mutation is shown to have a reversion between archival tissue and tumor tissue collected at 
screening, then the frequency of gBRCA reversions is likely less than 20% as the upper bound on 
the 90% confidence interval (CI) is 18%.  Additional patients, previously untested or tested and 
found to be gBRCAwt, may be identified as having a BRCA mutation in tumor tissue, therefore 
the BRCA subgroup will likely contain at least 40 patients.    


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The benefit of rucaparib is expected to be the greatest in patients in the tBRCA subgroup, 
followed by patients in the nbHRD subgroup, and lowest in patients in the biomarker negative 
subgroup.  This study will provide evidence as to whether the benefit of rucaparib is clinically 
meaningful in each of these subgroups, and particularly in the nbHRD subgroup.   
With a total of 180 patients enrolled in Part 1 of the study, the comparison of any 2 subgroups 
will likely contain about 100 patients.  Therefore with 100 patients, there is 80% power at a 2-
sided 10% significance level to detect a difference in PFS distributions assuming the hazard ratio 
between 2 subgroups is 0.50.   
Part 2: The objective of Part 2 is to estimate the ORR in each of the HRD subgroups in a more 
heavily pre-treated patient population (at least 3, but no more than 4, prior chemotherapy 
regimens).  Up to 300 patients will be enrolled in Part 2 of the study in order to enroll at least 80 
patients in each HRD subgroup.  A total of 300 patients should be sufficient assuming an 
approximate 33.3% allocation to each HRD subgroup in the enrollment population. 
Currently, there are few clinical studies that have prospectively evaluated response to treatment 
beyond the 3rd-line setting; however, retrospective analyses of patients in 3rd relapse and beyond 
indicate they have a short PFS (approximately 4-6 months) and OS (approximately 
5-6 months).25  Overall, there is a need for new treatments and alternatives to chemotherapy for 
heavily pre-treated ovarian cancer patients with advanced, relapsed disease to be explored in 
prospectively designed trials.  
The table below provides 95% CIs for observed response rates ranging from 10 to 60% assuming 
a total of 80 patients within each HRD subgroup. 
Confidence Intervals for Objective Response Rates (ORR) 
ORR(%) 
 [95% CI] 
10 
4.4, 18.8 
20 
11.8, 30.4 
30 
20.3,41.3 
40 
29.2,51.6  
50 
38.6, 61.4 
60 
48.4, 70.8 
CI=Confidence intervals of ORR using Clopper-Pearson methodology.26 
 
An ORR ≥20% in any subgroup would be worthy of further exploration in that population. 


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12 
PATIENT DISPOSITION 
12.1 Patient Discontinuations 
A patient must be discontinued from protocol-prescribed therapy 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 
• 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 
• In addition, the sponsor may discontinue the trial early for any of the reasons noted in 
Section 13.6. 
The sponsor (or designee) should be notified of all study terminations as soon as possible.  The 
date and reason for cessation of rucaparib must be documented in the eCRF and source 
documents.  To the extent possible, the End of Treatment visit procedures should be performed 
on all patients who receive rucaparib as soon as possible following the last dose of rucaparib.  
Patients will be followed for 28 (±3) days after the last dose of rucaparib for safety; those with 
ongoing SAEs will be followed until either resolution or stabilization has been determined.  
Patients that discontinue treatment due to anything other than disease progression or death will 
be followed for tumor assessments until radiologic disease progression is confirmed, death or the 
initiation of new treatment. 


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13 STUDY ADMINISTRATION 
13.1 Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and applicable Standard Operating 
Procedures, and in compliance with: ICH E6(R2), the Code of Federal Regulations (21 CFR 
Parts 50, 54, 56, and 312), EU Directives 2001/20/EC, 2005/28/E, all applicable local 
requirements, and in accordance with the ethical principles of the Declaration of Helsinki. 
13.1.1 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 be admitted 
to the study until appropriate regulatory approval of the study protocol has been received. 
Each investigator must complete a Form FDA 1572 (or equivalent) and provide the completed 
form according to written instructions to the sponsor (or designee).  Each investigator must 
submit to the sponsor (or designee) financial disclosure information according to national law 
and/or local regulations. 
The study will be registered on regionally relevant registries, including www.clinicaltrials.gov, 
EudraCT, and the Spanish Clinical Studies Registry using the Protocol Registration System.  
Data generated from this study must be handled in accordance with any laws, rules, and 
regulations related to the privacy of personal data or medical information applicable in the 
jurisdiction where the data is processed, including without limitation, the United States Health 
Information Portability and Accountability Act of 1996 (HIPAA), and its implementing 
regulations, and the European Union General Data Protection Regulation 2016/679 (GDPR). 
13.1.2 Independent Ethics Committee/Institutional Review Board 
This protocol and any material to be provided to the patient (such as advertisements, patient 
information sheets, drug dosing diaries, or descriptions of the study used to obtain informed 
consent) will be submitted by the investigator to an IEC/IRB.  This also applies to protocol 
amendments.   
Clovis Oncology will supply relevant data for the investigator to submit the study protocol and 
additional study documents to the IEC/IRB.  The principal investigator will submit the study 
protocol for review and approval by an IEC/IRB, according to national law and/or local 
regulations, and will provide the IEC/IRB with all appropriate materials.   
Verification of the IEC’s/IRB’s unconditional approval of the study protocol and the written 
informed consent form will be transmitted to Clovis Oncology.  This approval must refer to the 
study by exact study protocol title and number, identify the documents reviewed, and state the 
date of the review. 


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No patient will be admitted to the study until appropriate IEC/IRB approval of the study protocol 
has been received, the investigator has obtained the signed and dated informed consent form, and 
the sponsor is notified.   
The principal 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 and sponsor.   
The IEC/IRB must be informed by the principal investigator of all subsequent study protocol 
amendments and of SAEs or SUSARs occurring during the study that are likely to affect the 
safety of the patients or the conduct of the study. 
13.2 Confidentiality of Information 
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., not names) should be recorded on any form submitted to the sponsor and the IEC/IRB.  The 
investigator must record all screened and enrolled patients in the eCRF. The investigator must 
maintain a list with the identity of all treated patients, but not intended for use by the sponsor.  
The investigator agrees that all information received from Clovis Oncology or designee, 
including, but not limited to, the Investigator’s Brochure, this protocol, eCRFs, the protocol-
specified treatment, and any other study information, 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. 
13.3 Patient Informed Consent 
All information about the clinical study, including the patient information and the informed 
consent form, is prepared and used for the protection of the human rights of the patient according 
to ICH GCP guidelines and the Declaration of Helsinki. 
It is the responsibility of the investigator to obtain signed informed consent forms from each 
patient participating in this study after adequate explanation of the aims, methods, objectives, 
and potential hazards of the study and prior to undertaking any study-related procedures.   
The informed consent form, prepared by the investigator with the assistance of the sponsor, must 
be approved along with the study protocol by the IEC/IRB and be acceptable to the sponsor. 
The patient must be provided with the patient information and informed consent form consistent 
with the study protocol version used and approved by the relevant IEC/IRB.  The informed 
consent form must be in a language fully comprehensible to the prospective patient.  Patients 
(and/or relatives, guardians, or legal representatives, if necessary) must be given sufficient time 
and opportunity to inquire about the details of the study and to discuss and decide on their 


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participation in the study with the investigator concerned.  The patient and the person explaining 
about the study and with whom they discuss the informed consent will sign and date the 
informed consent form.  A copy of the signed informed consent form will be retained by the 
patient and the original will be filed in the investigator file unless otherwise agreed. 
The patient will have the option to provide additional consent to allow or not allow the 
sponsor to retain residual samples for future unspecified research. 
13.4 Study Monitoring 
On behalf of Clovis Oncology, a CRO monitor will contact and visit the investigator at the study 
center prior to the entry of the first patient (unless Clovis or the CRO has worked with the center 
recently, in which case this initial visit maybe 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.  Visits may also be conducted by Clovis Oncology personnel. 
In accordance with ICH GCP guidelines, 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 verifying adherence to the study protocol and the completeness, consistency, 
and accuracy of data entered on the eCRF and other documents.   
The investigator will make all source data (i.e., the various study records, the eCRFs, laboratory 
test reports, other patient records, drug accountability forms, and other pertinent data) available 
for the monitor and allow access to them throughout the entire study period.  Monitoring is done 
by comparing the relevant site records of the patients with the entries on the eCRF (i.e., source 
data verification).  It is the monitor’s responsibility to verify the adherence to the study protocol 
and the completeness, consistency, and accuracy of the data recorded on the eCRFs; however, 
the investigator retains ultimate responsibility for the quality and integrity of data generated by 
the site.   
By agreeing to participate in the study, the investigator agrees to cooperate with the monitor to 
ensure that any problems detected in the course of the monitoring visits are resolved.  Contact 
information for the study monitor is located in the investigator file.  Representatives from Clovis 
Oncology may also contact and visit the investigators and monitor data during the study.   
13.5 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 to ensure accurate interpretation of data. Data recorded in the eCRF should 
be consistent with the data recorded on the source documents. 


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Prior to study start, the investigator will prepare a list showing the signature and handwritten 
initials of all individuals authorized to make or change entries on eCRFs.  This “study center 
personnel and delegation list” must be kept current throughout the study. 
Clinical data, including AEs, concomitant medications, and laboratory data will be entered into 
INFORM, a 21 CFR Part 11-compliant data capture system. The data system includes password 
protection and internal quality checks, such as automatic range checks, to identify data that 
appear inconsistent, incomplete, or inaccurate. This also applies to records for those patients who 
fail to complete the study. If a patient withdraws from the study, the reason must be noted on the 
eCRF. If a patient is withdrawn from the study because of a treatment-limiting AE, thorough 
efforts should be made to clearly document the outcome. 
All laboratory data and investigator observations on the results and any other clinically 
significant test results must be documented on eCRFs. 
Full information regarding EDC and completing eCRFs is included in the investigator files.  All 
questions or comments related to electronic capture should be directed to the assigned monitor. 
Clinical data will be entered directly from the source documents.  
13.6 Study Termination and Site Closure 
Both the sponsor and the investigator reserve the right to terminate the study at any time.  Should 
this be necessary, both parties will arrange discontinuation procedures.  In terminating the study, 
Clovis Oncology and the investigator will assure that adequate consideration is given to the 
protection of the patients’ interests. 
Clovis Oncology reserves the right to discontinue 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: 
• 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. 
• The sponsor discontinues the development of rucaparib. 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded 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).  
13.7 Modification of the Study Protocol 
Protocol amendments, except when necessary to eliminate an immediate hazard to patients, must 
be made only with the prior approval of Clovis Oncology.  Agreement from the investigator must 
be obtained for all protocol amendments and amendments 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 concerned 
regulatory authorities for approval and keep the investigator(s) updated as detailed in the ICH 
GCP guidelines. 
13.8 Study Documents 
The study site will maintain a study file, which should contain all documents defined in the ICH 
E6(R2) Guideline for Good Clinical Practice. The investigator should have control of all 
essential documents generated by the site. Source documents must be maintained, ALCOA-C 
(attributable, legible, contemporaneous, original, accurate, and complete) used. Any changes to 
source data should be traceable, should not obscure the original entry, and should 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, source worksheets, all original signed and dated informed 
consent forms, copies of all eCRFs, query responses, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities and Clovis Oncology or its designees. 
The investigator should have control of and continuous access to the eCRF data. 
The investigator shall retain records required to be maintained for a period of 5 years following 
the date a marketing application in an ICH region is approved for the drug for the indication for 
which it is being investigated 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 should be retained for a longer period if required by the applicable 
regulatory requirement(s) 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 that are used for source document verification should 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. 


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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. 
13.9 Clinical Study Report 
A clinical study report 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, or a designee, thereby indicating their agreement with the analyses, results, 
and conclusions of the clinical study report.  The CSR will be provided to the regulatory 
agency(ies) as required by the applicable regulatory requirements. 
13.10 Study Publication 
All data generated from this study are the property of Clovis Oncology and shall be held in strict 
confidence along with all information furnished by Clovis Oncology.  Independent analysis 
and/or publication of these data by the investigator(s) or any member of their staff are not 
permitted without the prior written consent of Clovis Oncology.  Written permission to the 
investigator will be contingent on the review by Clovis Oncology.  Any collaborative 
publications will be authored in accordance with the applicable guidelines (eg, International 
Committee of Medical Journal Editors [ICMJE]). Written permission to the investigator will be 
contingent on the review of the statistical analysis and manuscript/abstract by the sponsor, and 
will provide for nondisclosure of the confidential or proprietary information.  In all cases, the 
parties agree to submit all manuscripts or abstracts to all other parties 60 days prior to 
submission.  This will enable all parties to protect proprietary information and to provide 
comments based on information that may not yet be available to other parties. 
13.11 Quality Assurance Audits 
An audit visit to clinical centers may be conducted by a quality control auditor appointed by 
Clovis Oncology.  The purpose of an audit, which is independent of and separate from routine 
monitoring or quality control functions, is to evaluate trial conduct and compliance with the 
protocol, SOPs, ICH GCPs, and the applicable regulatory requirements.  The investigator and the 
sponsor may also be subject to an inspection by FDA, EMA, other European Regulatory 
authorities, or other applicable regulatory authorities at any time.  The auditor and regulatory 
authorities will require authority from the investigator to have direct access to the patients’ 
medical records.  It is important that the investigator(s) and their staff cooperate with the auditor 
or regulatory authorities during this audit or inspection. 
13.12 
Investigator Oversight 
The investigator has a responsibility for supervising any individual or party to whom they 
delegate study-related duties or functions conducted at the trial site.  This includes the 
services of any party or individual retained by the investigator for this purpose. All staff 
delegated study responsibilities must be documented on an approved Delegation of Authority 
log for the study and this filed with the essential documents. In addition, the investigator must 
ensure that delegated staff are qualified by training, experience and licensure (as applicable). 


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The investigator should implement procedures to ensure integrity of the study-related duties, 
functions performed, and any data generated.  
 
 
 


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26. Clopper C. The use of confidence or fiducial limits illustrated in the case of the binomia. 
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genomic instability in high-grade serous ovarian cancer predict treatment outcome. Clinical 
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40. Abkevich V, Timms KM, Hennessy BT, Potter J, Carey MS, Meyer LA, et al. Patterns of 
genomic loss of heterozygosity predict homologous recombination repair defects in 
epithelial ovarian cancer. British journal of cancer. 2012;107(10):1776-82. 
41. O'Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, et al. Iniparib plus 
chemotherapy in metastatic triple-negative breast cancer. The New England Journal of 
Medicine. 2011;364(3):205-14. 
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modifies cysteine-containing proteins in tumor cells and is not a Bona Fide PARP inhibitor. 
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Label, Randomized, Multicenter Study Comparing the Efficacy and Safety of Olaparib, a 
Poly (ADP-Ribose) Polymerase Inhibitor, and Pegylated Liposomal Doxorubicin in 
Patients With BRCA1 or BRCA2 Mutations and Recurrent Ovarian Cancer. J Clin Oncol. 
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Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer. The New England 
Journal of Medicine. 2012. 
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and PARP2 by Clinical PARP Inhibitors. Cancer Research. 2012;72(21):5588-99. 
48. Sandhu SK, Schelman WR, Wilding G, Moreno V, Baird RD, Miranda S, et al. The 
poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers 
and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol. 
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49. De Bono JS, Mina LA, Gonzalez M, Curtin NJ, Wang E, Henshaw JW, et al. First-in-
human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors. Journal 
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51. Fahmi OA, Hurst S, Plowchalk D, Cook J, Guo F, Youdim K, et al. Comparison of 
different algorithms for predicting clinical drug-drug interactions, based on the use of 
CYP3A4 in vitro data: predictions of compounds as precipitants of interaction. Drug Metab 
Dispos. 2009;37(8):1658-66. 


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52. US Food and Drug Administration. Guidance for Industry: Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation 2009 [15 December 2014]. Available from: 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf. 
53. National Cancer Institute. Common Terminology Criteria for Adverse Events, Version 4.03 
14 June 2010 [cited 19 November 2014]. Available from: 
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54. 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. 
55. Rustin GJS, Vergote I, Eisenhauer E, Pujade-Lauraine E, Quinn M, Thigpen T, et al. 
Definitions for Response and Progression in Ovarian Cancer Clinical Trials Incorporating 
RECIST 1.1 and CA 125 Agreed by the Gynecological Cancer Intergroup (GCIG). Int J 
Gynecol Cancer. 2011;21(2):419-23. 
56. US Department of Health and Human Services, Food and Drug Administration, CDER. 
Draft Guidance for Industry: Clinical Drug Interaction Studies - Study Design, Data 
Analysis, and Clinical Implications October 2017. Available from: 
https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf. 


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15 
APPENDICES 
Appendix A. List of Candidate Genes That May Comprise an HRD Signature 
Appendix B. Response Evaluation Criteria in Solid Tumors Criteria 
Appendix C. Eastern Cooperative Oncology Group (ECOG) Performance Status Scale 
Appendix D. Examples of Sensitive Clinical CYP Substrates 
Appendix E. Gynecological Cancer Intergroup (GCIG) Guidelines for Response by CA-125 


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15.1 Appendix A 
List of Candidate Genes That May Comprise an HRD Signature 
Note: this list may be revised prior to initiation of the trial and/or prior to final analysis. 
BRCA 
nbHRD 
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 


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15.2 Appendix B 
Response Evaluation Criteria in Solid Tumors Criteria 
The RECIST guidelines (Version 1.1) are described in Eisenhauer (2009) and at 
http://www.eortc.be/Recist/Default.htm.54  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 in 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.   
Nontarget 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. 


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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 PR nor sufficient increase to qualify 
for 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 
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. 


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Patients with 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 evaluation of CR depends on this determination, it is recommended that the residual lesion 
be investigated (fine needle aspiration/biopsy) prior to confirming the complete response status. 
Confirmatory Measurement/Duration of Response 
Confirmation 
CT scans are required at screening and every 8 weeks (± 4 days) thereafter.  Patients who have 
been on study at least 18 months, may decrease the frequency of disease assessments to every 16 
(±2) weeks.  If an initial CR or PR is noted , confirmatory scans must be performed at least 
4 weeks later.   
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. 


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15.3 Appendix C 
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 (e.g., 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 
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 no imminent 
4 
20 
Very sick; hospital admission 
necessary; active supportive 
treatment necessary 
10 
Moribund; fatal processes 
progressing rapidly 
0 
Dead 
5 
 


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15.4 Appendix D 
Examples of Sensitive Clinical CYP Substrates 
CYP Enzyme 
Sensitive Substrates 
CYP1A2 
tizanidine, theophylline, alosetron, caffeine, duloxetine, 
melatonin, ramelteon, tasimelteon 
CYP2C9 
celecoxib 
CYP2C19 
S-mephenytoin, omeprazole  
CYP3A 
alfentanil, sirolimus, tacrolimus, avanafil, buspirone, 
conivaptan, darifenacin, darunavir, ebastine, everolimus, 
ibrutinib, lomitapide, lovastatin, midazolam, naloxegol, 
nisoldipine, saquinavir, simvastatin, tipranavir, triazolam, 
vardenafil, budesonide, dasatinib, dronedarone, eletriptan, 
eplerenone, felodipine, indinavir, lurasidone, maraviroc, 
quetiapine, sildenafil, ticagrelor, tolvaptan 
a Sensitive substrates are drugs that demonstrate an increase in AUC of ≥5-fold with strong index inhibitors 
of a given metabolic pathway in clinical Drug-drug interaction (DDI) studies. 
Source: Draft FDA Guidance on Clinical Drug Interaction Studies - Study Design, Data Analysis, and 
Clinical Implications, 2017.56 More example drugs can be found at the FDA’s website: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin
g/ucm093664.htm#table3-1 


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15.5 Appendix E 
Modified Gynecological Cancer Intergroup (GCIG) Guidelines for Response Using CA-125  
Adapted from Rustin et al., Int J Gynecol Cancer. 201155  
GCIG CA 125 definitions are available at http://gcig.igcs.org/CA-125.html.   
To be evaluable for response by CA-125 requires an elevated baseline value of at least twice the 
upper limit of normal and at least two additional samples after the start of treatment.   
A response to CA-125 has occurred if there is at least a 50% decrease from baseline: 
1. in a sample collected after initiation of study treatment AND  
2. that is confirmed in a subsequent sample collected ≥21 days after the prior sample.  
The absolute value of this confirmatory sample must be ≤110% of the prior sample. 
The date when the first sample with a 50% decrease from baseline is observed is the date of the 
CA-125 response. 
In patients who have measureable disease by RECIST v1.1 and CA-125, the date of response 
will be the date of the earlier of the two events.  When assessing progression, the objective 
change in tumor size should be used for treatment decisions.  For example, if a patient has a 
reduction in measurable disease, but an increase in CA-125 that suggests progression, treatment 
should continue. 

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
A Phase 2, Open-Label Study of Rucaparib in Patients with 
Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian 
Tube, or Primary Peritoneal Cancer 
PROTOCOL NUMBER: 
 
CO-338-017 
: 
 
  
DATE FINAL: 
 
16 May 2019  
SPONSOR: 
 
Clovis Oncology 
 
 
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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Approval Page  
The document is hereby signed and approved by: 
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Signature 
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DocuSign Envelope ID: 85C029C2-1560-42E3-A06C-836AC2F90071


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TABLE OF CONTENTS 
ABBREVIATIONS AND SPECIALIST TERMS ....................................................................5 
1 
INTRODUCTION ...........................................................................................................7 
2 
OVERALL STUDY DESIGN, OBJECTIVES, AND ENDPOINTS .............................7 
2.1 
Study Objectives and Endpoints ..............................................................................7 
2.2 
Trial Design .............................................................................................................9 
2.3 
Sample Size Justification .......................................................................................10 
2.4 
Data Cutoff used for Final CSR .............................................................................12 
3 
GENERAL ANALYSIS CONVENTIONS ..................................................................12 
3.1 
Definition of HRD Subgroups ...............................................................................13 
4 
ANALYSIS POPULATIONS .......................................................................................13 
5 
PATIENT DISPOSITION .............................................................................................13 
6 
PROTOCOL VIOLATIONS .........................................................................................14 
7 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ....................................14 
7.1 
Demographics ........................................................................................................14 
7.2 
Baseline Clinical Characteristics ...........................................................................14 
7.3 
Medical History .....................................................................................................15 
8 
STUDY DRUG EXPOSURE AND COMPLIANCE ...................................................15 
9 
PRIOR, CONCOMITANT MEDICATIONS AND SUBSEQUENT 
TREATMENT ...............................................................................................................15 
10 
EFFICACY VARIABLES ............................................................................................15 
10.1 
Primary Efficacy Variable .....................................................................................15 
10.2 
Secondary Efficacy Variables ................................................................................16 
10.3 
Exploratory Efficacy Variables ..............................................................................16 
11 
EFFICACY ANALYSIS ...............................................................................................16 
11.1 
Primary Efficacy Analysis .....................................................................................16 
11.2 
Secondary Efficacy Analyses ................................................................................18 
11.2.1 
ORR for Study Part 1 ...................................................................................18 
11.2.2 
Duration of Response ...................................................................................18 
11.2.3 
ORR by RECIST and GCIG CA-125 Criteria .............................................18 
11.2.4 
Progression-free Survival in Part 2 ..............................................................19 
11.2.5 
Overall Survival in Part 2 ............................................................................19 
11.2.6 
Pharmacokinetic Analyses ...........................................................................20 
11.3 
Exploratory Efficacy Analyses ..............................................................................20 
11.3.1 
Efficacy by HRR Gene Subgroups ..............................................................20 
11.3.2 
Efficacy Based on Lower/Higher Genomic LOH Cutoff in Part 1 ..............20 
11.3.3 
Time to First Response RECIST Version 1.1 ..............................................20 


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11.3.4 
Change from Baseline in Sum of Diameters of Target Lesions ..................21 
12 
STATISTICAL / ANALYTICAL ISSUES ..................................................................21 
12.1 
Handling of Dropouts or Missing Data ..................................................................21 
12.2 
Pooling of Centers in Multi-Center Studies ...........................................................21 
12.3 
Multiple Comparison / Multiplicity .......................................................................21 
13 
SAFETY ANALYSIS ...................................................................................................21 
13.1 
Adverse Events ......................................................................................................21 
13.2 
Clinical Laboratory Evaluations ............................................................................23 
13.3 
Vital Signs ..............................................................................................................23 
13.4 
Electrocardiograms (ECG).....................................................................................23 
14 
CHANGES IN THE PLANNED ANALYSES.............................................................24 
15 
REFERENCES ..............................................................................................................25 
16 
APPENDIX A ...............................................................................................................26 
17 
APPENDIX B................................................................................................................31 
 
LIST OF IN-TEXT TABLES 
Table 1 
Primary, Secondary, and Exploratory Objectives and Endpoints .............................7 
Table 2 
Estimated HRD Subgroup Sizesa ............................................................................11 
Table 3  Confidence Intervals for Objective Response Rates (ORR) ...................................12 
Table 4 
Overall Response by RECIST v1.1 and GCIG CA-125 Criteria2 ...........................19 
 
LIST OF IN-TEXT FIGURES 
Figure 1 The Study Schema...................................................................................................10 
 


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ABBREVIATIONS AND SPECIALIST TERMS 
AE 
Adverse event 
ATC 
Anatomical Therapeutical Chemical (coding) 
BRCA 
breast cancer susceptibility genes 
CA-125 
Cancer antigen 125 
ctDNA 
circulating cell-free tumor DNA 
CI 
Confidence interval  
Cmin  
minimum concentration 
CR 
Complete response 
CRF 
Case report form 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
GCIG 
Gynecologic Cancer Intergroup 
HGSOC 
High Grade Serous Ovarian Cancer 
HRD 
homologous recombination deficiency 
HRR 
Homologous recombination repair 
IRR 
Independent Radiology Review  
LOH 
loss of heterozygosity 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
nbHRD 
Non-BRCA HRD 
NGS 
Next generation sequencing 
NJEJ 
non-homologous end-joining 
ORR 
Objective response rate 
OS 
Overall survival 
PFS 
Progression-free survival  
PR 
Partial response 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious adverse event 
SAP  
Statistical analysis plan 
SAS  
statistical analysis software 
SD 
Stable Disease  


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tBRCA 
Tumor tissue alteration in BRCA1 or BRCA2, includes gBRCA and 
sBRCA 
TCGA 
The Cancer Genome Atlas  
TEAEs 
Treatment-emergent adverse events 
ULN 
Upper limit of normal 
Wt 
Wild type 


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1 
INTRODUCTION 
This document describes the statistical analyses and data presentations to be performed for 
Clovis Oncology’s protocol CO-338-017. 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) in patients with relapsed 
high-grade serious ovarian cancer (HGSOC), fallopian tube cancer or primary peritoneal 
cancer  
The Statistical Analysis Plan (SAP) provides further detail of the statistical analyses, which 
were originally outlined in the original protocol 
 and subsequent 
amendments
 
 
  
All statistical analyses detailed in this SAP will be conducted using SAS® Version 9.4 or 
higher. 
2 
OVERALL STUDY DESIGN, OBJECTIVES, AND ENDPOINTS 
2.1 
Study Objectives and Endpoints 
Table 1 
Primary, Secondary, and Exploratory Objectives and Endpoints 
Primary Objectives 
Primary Endpoints 
1. To determine PFS in patients with 
relapsed platinum-sensitive ovarian 
cancer classified into molecularly-
defined subgroups by a prospectively 
defined HRD signature (Part 1) 
1. Disease progression (RECIST v1.1) as 
assessed by investigator, or death from 
any cause, in molecularly-defined 
subgroups identified by a prospectively 
defined HRD signature 
2. To estimate ORR in heavily pre-treated 
patients with relapsed ovarian cancer 
classified into molecularly-defined 
subgroups by a prospectively defined 
HRD signature (Part 2) 
2. ORR by RECIST v1.1 in molecularly-
defined subgroups identified by a 
prospectively defined HRD signature 


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Secondary Objectives 
Secondary Endpoints 
1. To estimate ORR (Part 1) 
1. ORR by RECIST v1.1  
2. To estimate ORR including CA-125 
response criteria 
2. ORR by RECIST v1.1 and GCIG CA-
125 criteria 
3. To evaluate duration of response (DOR) 
3. DOR by RECIST v1.1 
4. To determine PFS (Part 2) 
4. Disease progression (RECIST v1.1) as 
assessed by investigator, or death from 
any cause  
5. To evaluate survival (Part 2) 
5. Overall survival 
6. To evaluate the safety and tolerability of 
rucaparib 
6. The incidence of adverse events (AEs), 
clinical laboratory abnormalities, and 
dose modifications 
7. To evaluate steady state trough level PK 
7. Trough (Cmin) level rucaparib 
concentrations 
Exploratory Objectives 
Exploratory Endpoints 
1. To assess efficacy in molecularly-defined 
HRD subgroups as defined by HRR gene 
alterations 
1. PFS and/or ORR by RECIST v1.1 and 
GCIG CA-125 criteria. HRD subgroups 
as defined by HRR gene alterations 
2. To optimize the tumor LOH algorithm by 
testing additional signatures of interest 
based on higher or lower genomic LOH 
2. PFS and/or ORR by RECIST v1.1 and 
GCIG CA-125 criteria. Additional 
signatures of interest based on higher or 
lower genomic LOH. 
3. To assess changes in HRD status over 
time 
3. Changes in HRD status (LOH and gene 
alterations) between fresh biopsy versus 
archival tumor tissue samples 
4. To assess whether the BROCA panel can 
identify mutations in additional HRR 
genes that may be associated with 
efficacy 
4. ORR by RECIST v1.1 and GCIG CA-
125 criteria in relation to HRR gene 
mutations identified in BROCA 
5. To assess if a gene expression signature 
for HRD correlates with efficacy 
5. PFS and/or ORR by RECIST v1.1 and 
GCIG CA-125 criteria in relation to gene 
signature defined by a gene expression 
profiling assay 
6. To assess NHEJ pathway integrity and 
correlate it with efficacy  
6. NHEJ protein expression by 
immunohistochemistry (IHC) and PFS 
and/or ORR by RECIST v1.1 and GCIG 
CA-125 criteria  
7. To assess ctDNA as a molecular marker 
of efficacy 
7. Levels of ctDNA in relation to PFS 
and/or ORR by RECIST v1.1 and GCIG 
CA-125 criteria 
 


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2.2 
Trial Design 
This is a two-part open-label study that enrolled patients with relapsed, high-grade, epithelial 
ovarian, fallopian tube, or primary peritoneal cancer who had disease that could be biopsied 
and was measurable. Part 1 enrolled patients who had received ≥1 prior platinum-based 
regimen and had platinum-sensitive disease. Part 2 enrolled patients who had received at 
least 3, but no more than 4, prior chemotherapy regimens.  
The purpose of Part 1 of this study was to define a molecular signature of HRD in ovarian 
cancer that correlates with response to rucaparib and enables selection of appropriate ovarian 
cancer patients for treatment with rucaparib. The HRD signature was based on an association 
between genomic scarring, as defined by a BRCA mutation or high level of loss of genomic 
heterozygosity (LOH), observed in a patient’s tumor and observed clinical benefit from 
rucaparib treatment (see Section 3.1).  
The objective of Part 2 of this study was to further explore the safety and efficacy in more 
heavily pre-treated ovarian cancer patients. 
All patients, with the exception of Part 2 patients known to harbor a deleterious gBRCA 
mutation, were required to undergo a screening biopsy for collection of tumor tissue. 
Archival tumor tissue was also collected. tBRCA mutation and/or tumor genomic LOH 
analysis was performed using Foundation Medicine’s next generation sequencing (NGS) test. 
Analysis of tumor genomic LOH was expected to identify tumors with HRD regardless of the 
underlying mechanism(s). tBRCA mutation and/or the extent of tumor genomic LOH was 
correlated with the clinical outcome experienced with rucaparib treatment.  
Patients took 600 mg rucaparib orally twice daily for continuous 28-day cycles until disease 
progression as assessed by the investigator, or other reason for discontinuation. If the patient 
met criteria for radiologic progression by RECIST Version 1.12, but the patient was still 
receiving benefit from rucaparib (e.g., patient had mixed radiologic response or was 
continuing to have symptomatic benefit) according to the investigator, then continuation of 
treatment was considered. In such cases, the decision to continue was made jointly between 
the investigator and the sponsor and had to be documented prior to continuing treatment with 
rucaparib. 
Tumor scans were performed at the end of every 8 weeks (± 4 days) while on study. A 
confirmatory scan should have been performed ≥4 weeks after an initial response of PR or 
CR was observed. Patients who had been on study at least 18 months were permitted to 
decrease the frequency of disease assessments to every 16 (±2) weeks. Disease assessment 
was to be ongoing/completed for all patients who discontinued treatment for reason other 
than disease progression or death. 
Patients in Part 2 were followed for survival, subsequent therapy, and secondary malignancy 
every 12 weeks until death, loss to follow-up, withdrawal of consent from study or study 
closure, whichever happened first. Tumor response was interpreted using RECIST 
Version 1.1. Figure 1 shows a schema for this study. 


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Copies of CT/MRI scans were collected from all patients in Part 2 of the study and for 
selected patients in Part 1 of the study and sent to an independent radiology review (IRR) 
vendor. The protocol specified that the IRR would be conducted on all or a subset of CT 
scans. Clovis elected to only have IRR reads for scans that were collected from the subset of 
patients who had a BRCA mutation as this population was the molecular subgroup that had 
the highest degree of benefit and the IRR-assessed ORR was supportive of the Investigator-
assessed ORR that supported regulatory filings in the US and Europe. As only a subset of 
scans had a central read by IRR, no IRR analyses will be performed or summarized in this 
final CSR. Please refer to Section 14 of this SAP for changes to protocol-specified analyses 
for this final CSR.  
Figure 1 
The Study Schema 
EOT Visit
 After last 
dose of 
rucaparib
Screening 
Assessments
Within 28 days 
of first dose of 
rucaparib
Rucaparib Treatment Phase
Screening Phase
(Day -28 to Day -1)
Post-Treatment Phase
Tumor Scans
At the end of 
every 8 weeks  
(±4 days) 
Disease progression, unacceptable toxicity, or other reason for 
discontinuation of rucaparib
D
A
Y 
1
D
A
Y 
1
Cycle 1
(28-day cycle)
Cycle 2 and subsequent cycles
(28-day cycles)
28 Day 
Follow-up
(28 ± 3 days 
after last 
dose of 
rucaparib)  
D
A
Y 
15
Long-term 
Follow-up
   
Part 1: Disease assessments will continue every 8 weeks for 
patients who discontinued treatment for reason other than PD
Part 2: All patients will be followed for survival, subsequent 
therapies, and development of secondary malignancy every 12 
weeks 
 
 
2.3 
Sample Size Justification 
The total enrollment planned for this study was approximately 480 patients, N=180 in Part 1 
and up to N=300 in Part 2.  
Part 1: It was anticipated that approximately 180 patients were required in order to ensure 
each subgroup of patients (tBRCA, nbHRD, and biomarker negative) contained an adequate 
number of patients. Other than the cap on patients with a known deleterious gBRCA mutation 
(n=15), there were no specific requirement to enroll defined numbers of patients into each 
planned subgroup. The likely size of each subgroup was estimated based on: a) frequencies 
of HRD-associated genetic abnormalities at initial diagnosis as reported in the literature and 
b) the hypothesis that the inclusion criterion of sensitivity to platinum following the most 
recent line of platinum therapy will enrich the population for patients with tumors harboring 
mutations of HRD pathway genes (i.e., that the frequency will be greater than that described 
in the newly-diagnosed population). Table 2 provides estimated HRD subgroup sizes in 
Part 1 of this trial. 


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Table 2 
Estimated HRD Subgroup Sizesa 
HRD 
Subgroup  
Expected 
Frequency at 
Diagnosis 
Estimated 
Frequency 
with 
Enrichment 
for Platinum 
Sensitivity 
Estimated Number of Patients 
tBRCA 
21% 
30% 
15 with known deleterious gBRCA 
mutation (fixed) 
plus 
20 – 25 with somatic BRCA mutation 
plus 
5 – 25 additional with newly diagnosed 
gBRCA mutation 
nbHRD 
22 – 32% 
30 – 50% 
50 – 90 
Biomarker 
Negative 
60 – 70% 
20 – 40% 
36 – 72 
a 
Expected frequency estimates are from TCGA1 
 
Enrollment of patients known a priori to harbor a gBRCA mutation classified as deleterious 
(pathogenic), suspected deleterious, or favor deleterious (or the equivalent interpretation of 
any of these) on the most recent assessment by a testing laboratory was limited to 15 in 
Part 1. Fifteen patients with a known gBRCA mutation was considered sufficient to establish 
that the frequency of gBRCA mutation reversions is low. In particular, if none of the 15 
patients with a known gBRCA mutation was shown to have a reversion between archival 
tissue and tumor tissue collected at screening, then the frequency of gBRCA reversions was 
likely less than 20% as the upper bound on the 90% confidence interval (CI) is 18%. 
Additional patients, previously untested or tested and found to be gBRCAwt, may be identified 
as having a BRCA mutation in tumor tissue, therefore the BRCA subgroup will likely contain 
at least 40 patients.   
The benefit of rucaparib is expected to be the greatest in patients in the tBRCA subgroup, 
followed by patients in non-tBRCA LOH+ subgroup, and lowest in patients in the biomarker 
negative subgroup (i.e., non-tBRCA LOH-). This study will provide evidence as to whether 
the benefit of rucaparib is clinically meaningful in each of these subgroups.  
With a total of 180 patients enrolled in Part 1 of the study, the comparison of any 2 
subgroups will likely contain about 100 patients. Therefore with 100 patients, there is 80% 
power at a 2-sided 10% significance level to detect a difference in PFS distributions 
assuming the hazard ratio between 2 subgroups is 0.50.  
Part 2: The objective of Part 2 is to estimate the ORR in each of the HRD subgroups in a 
more heavily pre-treated patient population (at least 3, but no more than 4, prior 
chemotherapy regimens). Up to 300 patients were to be enrolled in Part 2 of the study in 
order to enroll at least 80 patients in each HRD subgroup. A total of 300 patients should be 


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sufficient assuming an approximate 33.3% allocation to each HRD subgroup in the 
enrollment population.  
Table 3 below provides 95% CIs for observed response rates ranging from 10 to 60% 
assuming a total of 80 patients within each HRD subgroup. 
Table 3  
Confidence Intervals for Objective Response Rates (ORR) 
ORR(%) 
[95% CI] 
10 
4.4, 18.8 
20 
11.8, 30.4 
30 
20.3,41.3 
40 
29.2,51.6  
50 
38.6, 61.4 
60 
48.4, 70.8 
CI=Confidence intervals of ORR using Clopper-Pearson methodology. 
 
An ORR ≥20% in any subgroup would be worthy of further exploration in these subgroups. 
2.4 
Data Cutoff used for Final CSR  
A visit cutoff of 01 Feb 2019 was applied in order to clean the data and do a snapshot for the 
final CSR. Part 1 was fully enrolled in Dec 2014 and Part 2 was fully enrolled by August 
2016. At the time of the visit cutoff (01 Feb 2019), there were still 14 patients receiving 
rucaparib treatment in this study. However, all data are mature enough to fully evaluate the 
primary study objectives; therefore, the sponsor has deemed the study completed.  
3 
GENERAL ANALYSIS CONVENTIONS 
Data will be summarized for each study part separately. The summary tables will be 
presented for all treated patients and by the subgroups defined by HRD status (tBRCA 
[somatic and germline], non-tBRCA LOH+, non-tBRCA LOH-, and unknown).  
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 for any time to event endpoint. If estimable, the 
50th (median) together with a 95% Confidence Interval (CI) will be presented. The number 
of patients with events and the number of censored patients will also be presented.  
All data will be used to their maximum possible extent but without any imputations for 
missing data. 


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Unless otherwise specified, baseline is defined as the last measurement on or prior to the first 
day of study drug administration. 
3.1 
Definition of HRD Subgroups 
Clovis is collaborating with Foundation Medicine, Inc. (FMI) to develop a tumor tissue-
based NGS test. The HRD status group definition is based on BRCA mutations and the 
percentage of the genome with Loss of Heterozygosity (LOH). All analyses will be 
performed separately for the subgroups defined by HRD status (tBRCA, non-tBRCA LOH+, 
non-tBRCA LOH-, and non-tBRCA unknown) defined as follows:  
• tBRCA: Patients with deleterious BRCA mutation detected in their tumor  
• Non-tBRCA LOH+:  Patients who are found to not have the a BRCA mutation in 
their tumor, but where the percent of LOH is ≥14% (in Part 1) or ≥18% (in Part 2). 
For further rationale around this definition see Appendix A.  
• Non-tBRCA LOH-: Patients who are found to not have a BRCA mutation in their 
tumor, but where the percent of LOH is <14% (in Part 1) or <18% (in Part 2). For 
further rationale around this definition see Appendix A.  
• Non-tBRCA Unknown: Patients who are found to not have a BRCA mutation in 
their tumor, but where the percent of LOH is unknown due to missing results and/or 
failed test result(s)  
 
The proposed FMI test identifies sequence variants in the BRCA1 and BRCA2 genes for all 
tBRCA patients.  
4 
ANALYSIS POPULATIONS 
Safety Population:  The safety population will consist of all patients who received at least 
one dose of rucaparib.  
Efficacy Population: The efficacy population consist of all patients who received at least 
one dose of rucaparib, have tumor measurable disease at baseline, and have at least one post-
baseline tumor scan assessment by RECIST v1.1. Efficacy population is not used for the PFS 
analysis, but only for assessing tumor response.  
GCIG CA-125 evaluable Population: The efficacy population of patient evaluable for 
GCIG CA-125 response will consist of all patients who received at least one dose of 
rucaparib, with an elevated tumor marker of CA-125 at baseline (i.e., values at least twice the 
upper limit of normal), and who had at least two post-baseline CA-125 measurements.  
5 
PATIENT DISPOSITION 
Patient disposition (analysis population allocation, ongoing status, discontinued, along with 
primary reason for discontinuation) will be summarized using frequency counts, and the 
corresponding percentages. 


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6 
PROTOCOL VIOLATIONS 
The number of patients with major protocol deviations (e.g., inclusion or exclusion criteria) 
will be determined prior to data base lock and will provided in a patient listing. 
7 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
All demographic and baseline characteristics will be summarized for the safety population. 
7.1 
Demographics 
The demographic variables will be summarized with frequency tabulations that will focus on 
identifying the extreme values of the distributions. Descriptive statistics may also be used to 
summarize the quantitative variables. The demographic variables presented will include age, 
height, weight, BMI, gender, race, region, 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, ≥2 
• Region:  North America, Europe, and Other 
 
7.2 
Baseline Clinical Characteristics 
The following variables were to be summarized with frequency tabulations: 
• Time since diagnosis of HGSOC (months):  > 6-12, > 12-24, > 24;  
• Baseline laboratory parameters:  graded based on CTCAE; 
• HRD status; tBRCA, non-tBRCA LOH+, non-tBRCA LOH- or non-tBRCA unknown;  
• Number of prior anti-cancer regimens: 0,1,2,3,4,5, >5; 
• Number of prior chemotherapy regimens 0,1,2,3,4,5, >5;  
• Number of prior platinum therapies 0,1,2,3, >3; 
• Progression-free interval following the last platinum regimen received (months): <6,  ≥6-
12, >12-24, > 24; 
• (Platinum-response status (sensitive, resistant, refractory) relative to most recent platinum 
containing regimen., where status is defined as 
• Refractory: Best response of PD and PD occurs during or up to 2 months after 
regimen 
• Resistant: PD 0-<6 months after last platinum with best response other than PD 


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• Sensitive: PD ≥6 months after last platinum  
 
Descriptive statistics could also be used to summarize these variables.  
7.3 
Medical History 
Medical history events will be classified using the Medical Dictionary for Drug Regulatory 
Activities (MedDRA) classification system version 19.1. Medical history data will be 
summarized using frequency tabulations by system organ class and preferred term. 
8 
STUDY DRUG EXPOSURE AND COMPLIANCE 
The following variables will be summarized:  
• Number of cycles initiated 
• Duration of treatment 
• Number of dose reductions per patient and by dose level  
• Dose intensity (i.e., actual dose received divided by the assigned dose amount) 
 
The duration of treatment initiated will be investigated by summarizing the number of days 
from treatment start date to treatment end date +1 or if the subject is ongoing then we use the 
date of the visit cutoff.   
9 
PRIOR, CONCOMITANT MEDICATIONS AND SUBSEQUENT 
TREATMENT  
All concomitant treatments documented during the study period will be summarized in 
frequency tabulations. Prior/concomitant medication coding will utilize World Health 
Organization (WHO) Drug version 2016DEC01DDE (Enhanced). 
Separate data summaries of prior medications will be provided. 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. 
In Part 2 of the study the subsequent anti-cancer treatment information for all patients that 
were in follow up was collected. This data will be presented in a patient listing.  
10 
EFFICACY VARIABLES 
10.1 Primary Efficacy Variable 
The primary efficacy variables for each of the study parts are as follows:  


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Part 1: The primary efficacy endpoint is progression-free survival (PFS) according to 
RECIST v1.1, as assessed by the investigator or death from any cause in molecularly-defined 
HRD subgroups.  
Part 2: ORR by RECIST v1.1 in molecularly-defined subgroups identified by a 
prospectively defined HRD signature. 
10.2 Secondary Efficacy Variables 
Secondary variables include: 
• ORR assessed by RECIST v1.1 in Part 1 
• ORR assessed by GCIG CA-125 response criteria 
• DOR by RECIST v1.1 
• Progression-Free Survival (PFS) in Part 2 
• Overall Survival in Part 2  
• AEs, clinical lab abnormalities, and dose modifications 
• Steady State Trough (Cmin) level rucaparib concentrations 
 
10.3 Exploratory Efficacy Variables 
The following are the exploratory variables described in this SAP and planned for the final 
CSR:  
• Efficacy as defined by homologous recombination repair (HRR) gene alterations   
• Efficacy based on lower / higher genomic LOH cutoff (optimization)  
• Time to first response by RECIST v1.1. 
• Change from baseline in sum of diameter of target lesions 
 
There are some exploratory endpoints that have been explored and summarized within 
publications. Due to the exploratory nature of those endpoints, they will not be re-analyzed 
within the context of this SAP nor described within the final CSR. The exploratory endpoints 
that were protocol specified, but not performed as part of this SAP, are listed in Section 14. 
 
11 
EFFICACY ANALYSIS 
11.1 Primary Efficacy Analysis 
Part 1: Progression-free Survival in HRD group 
The primary efficacy endpoint of PFS will be calculated as 1+ the number of days from the 
first dose of study drug to disease progression by RECIST, as determined by the investigator 
or death due to any cause, whichever occurs first. Patients without a documented event of 


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progression will be censored on the date of their last adequate tumor assessment (i.e., 
radiologic assessment) or date of first dose of study drug if no tumor assessments have been 
performed.  
The Kaplan-Meier methodology will be used to summarize PFS by HRD group. If able to be 
estimated, the 50th (median) together with a 95% Confidence Interval (CI), will be presented. 
The number of patients with PD events and the number of censored patients will also be 
presented. In addition, cox proportional hazard methodology will be used to compare the PFS 
by HRD group. The hazard ratio with 95% CI and p-value will be presented for the 
comparison of the tBRCA group compared to non-tBRCA LOH-, and for the non-tBRCA 
LOH+ compared to non-tBRCA LOH- subgroup. The primary endpoint of PFS will be 
analyzed for the safety population.  
Part 2: ORR by RECIST v1.1 in HRD group  
The primary efficacy endpoint of ORR is defined as best confirmed response according to 
RECIST v1.1 as assessed by investigator. The primary efficacy endpoint will be analyzed for 
the efficacy population, but also summarized for the safety population as supportive analysis.  
The tumor assessment is summarized by confirmed response by RECIST v1.1 criteria as 
outlined below in each HRD group. No statistical test will be performed between the HRD 
groups.  
Confirmatory Response Rate 
The confirmed response rate by RECIST v1.1 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% CI of the proportion using Clopper-Pearson methodology. In addition, the frequency 
and proportion of patients will be summarized for each of the confirmed response assessment 
in the following categories:  
• Complete Response 
• Partial Response 
• Stable disease, including the following classifications 
o Patients with confirmed SD  
o CR/PR/SD followed by PD if the CR/PR/SD is at least 49 days from treatment start 
date.  
o Patients ongoing with a single response 
o Ongoing without a response  
• Progressive Disease 
• Not evaluable (for example discontinuations or deaths before first tumor assessment) 
 


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11.2 Secondary Efficacy Analyses 
11.2.1 
ORR for Study Part 1 
The ORR is a secondary endpoint for Part 1 of the study. The ORR is defined as best 
confirmed response according to RECIST v1.1 as assessed by investigator as outlined in 
Section 11.1. The ORR for Part 1 will be analyzed for the efficacy population, but also 
summarized for the safety population as supportive analysis within each of the HRD 
subgroups. No statistical test will be performed between the HRD groups. 
11.2.2 
Duration of Response 
Duration of response (DOR) for any confirmed RECIST CR or PR will be measured from the 
date of the first occurrence of a response until the first occurrence of PD per RECIST. DOR 
will be summarized as a time to event variable for each HRD subgroup. 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 number of 
patients with PD events and the number of censored patients will also be presented.  
11.2.3 
ORR by RECIST and GCIG CA-125 Criteria 
The endpoint of ORR defined as a best response of CR or PR using RECIST v 1.1 or a 
response per GCIG CA-125 criteria1. The ORR will be summarized with frequencies and 
percentages in the efficacy population.  
The endpoint of CA-125 response rate defined as a 50% reduction in CA-125 as assessed by 
GCIG criteria will be summarized with frequencies and percentages in the safety population. 
As a supportive analysis, the CA-125 response rate will also be evaluated in the patients 
evaluable for a CA-125 response as defined in Appendix B. 
ORR will be reported separately and together for RECIST and GCIG. The combined ORR 
will be assessed as indicated in Table 4. 


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Table 4 
Overall Response by RECIST v1.1 and GCIG CA-125 Criteria2 
RECIST Response 
GCIG CA-125 
Response 
RECIST + GCIG CA-125 
Combined  
CR 
(requires normalization of CA-125) 
CA-125 within 
normal range 
Response 
PR 
Response 
Response 
PR 
No Response 
Response 
SD 
Response 
Response 
SD 
No Response 
No Response 
PD 
Response 
No Response 
PD 
No Response 
No Response 
 
The ORR will be summarized with frequencies and proportion together with 95% 
Confidence Interval (CI) of the proportion using Clopper-Pearson methodology. 
11.2.4 
Progression-free Survival in Part 2 
PFS will be calculated as 1+ the number of days from the first dose of study drug to disease 
progression by RECIST, as determined by the investigator or death due to any cause, 
whichever occurs first. Patients without a documented event of progression will be censored 
on the date of their last adequate tumor assessment (i.e., radiologic assessment) or date of 
first dose of study drug if no tumor assessments have been performed.  
The Kaplan-Meier methodology will be used to summarize PFS by HRD group. If able to be 
estimated, the 50th (median) together with a 95% Confidence Interval (CI), will be presented. 
The number of patients with PD events and the number of censored patients will also be 
presented. In addition, cox proportional hazard methodology will be used to compare the PFS 
by HRD group. The hazard ratio with 95% CI and p-value will be presented for the 
comparison of the tBRCA group compared to non-tBRCA LOH-, and for the non-tBRCA 
LOH+ compared to non-tBRCA LOH- subgroup.  
11.2.5 
Overall Survival in Part 2 
Overall survival (OS) is defined as the number of days from the date of first dose of study 
drug 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. 
The Kaplan-Meier methodology will be used to summarize OS by HRD group. If able to be 
estimated, the 50th (median) together with a 95% Confidence Interval (CI), will be presented. 
The number of patients with a death events and the number of censored patients will also be 
presented. In addition, cox proportional hazard methodology will be used to compare the OS 
by HRD group. The hazard ratio with 95% CI and p-value will be presented for the 
comparison of the tBRCA group compared to non-tBRCA LOH-, and for the non-tBRCA 
LOH+ compared to non-tBRCA LOH- subgroup.  


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11.2.6 
Pharmacokinetic Analyses 
As a secondary endpoint of the study, trough (Cmin) concentrations of rucaparib will be 
summarized with descriptive statistics overall and by cycle in all patients with at least one 
PK sample collected. 
11.3 Exploratory Efficacy Analyses 
11.3.1 
Efficacy by HRR Gene Subgroups 
Results of HRR genes testing by FMI NGS in this study will be summarized in a patient 
listing. FMI sequences 28 genes that are associated with homologous recombination repair 
(HRR): BRCA1, BRCA2, ATM, ATR, ATRX, BARD1, BLM, BLIP1, CHECK1, CHECK2, 
FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, 
MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD52, 
RAD54L, and RPA1.  
Five (BRCA1, BRCA2, RAD51C, RAD51D, and PALB2) of the above 28 HRR genes have 
been identified as genes more strongly linked to possible rucaparib sensitivity as compared to 
the other genes. PFS and ORR will therefore be summarized in the following HRR 
subgroups:  
- BRCA1  
- BRCA2 
- RAD51C or RAD51D or PALB2  
- Any of the 5 HRR genes (BRCA1, BRCA2, RAD51C, RAD51D, or PALB2)  
 
The analyses for these mutation subgroups will be performed in the same manner as that 
described for each of the primary efficacy endpoints (Section 11.1). 
11.3.2 
Efficacy Based on Lower/Higher Genomic LOH Cutoff in Part 1  
The objective of Part 1 was to give guidance for an optimal LOH cutoff ARIEL3 
CO-338-014 study “A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 
Study of Rucaparib as Switch Maintenance Therapy Following Platinum-Based 
Chemotherapy in Patients with Platinum-Sensitive, Relapsed High-Grade Serous Ovarian 
Cancer”. The primary endpoint of PFS in Part 1 will be explored in all non-tBRCA patients 
with known LOH at different cutoff of LOH. A Cox proportional hazard model of primary 
endpoint of PFS will be done testing the patients with a LOH+ vs LOH- at different cutoffs 
(e.g., 10% to 35%) and LOH as a continuous variable in the model. 
11.3.3 
Time to First Response RECIST Version 1.1 
The frequency and percentages of patients with a response (CR or PR) will be summarized 
by the first occurrence using the following time points; ≤ 9 weeks (Cycle 2), ≤ 17 weeks 
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11.3.4 
Change from Baseline in Sum of Diameters of Target Lesions 
The largest percent decrease from baseline in the sum of diameters of target lesions as 
identified by RECIST v1.1 will be displayed graphically using a waterfall plot. This 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.  
12 
STATISTICAL / ANALYTICAL ISSUES 
12.1 Handling of Dropouts or Missing Data 
All data will be used to their maximum possible extent but without any imputations for 
missing data. All time-to-events are censored, and the rules for deriving the censoring value 
is described in more detail under each one of the time to event endpoints.  
12.2 Pooling of Centers in Multi-Center Studies 
The centers will be pooled. 
12.3 Multiple Comparison / Multiplicity 
No adjustments for multiple comparisons will be made.  
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SAFETY ANALYSIS 
The safety analyses will be performed using the safety population. 
13.1 Adverse Events 
Adverse events will be classified using the Medical Dictionary for Drug Regulatory 
Activities (MedDRA) classification system version 19.1. The severity of the toxicities will be 
graded according to the 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. Adverse events 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 adverse event meets the definition for treatment-
emergent. 
The number and percentage of patients who experienced TEAEs for each system organ class 
and preferred term will be presented. Multiple instances of the TEAE in each system organ 
class 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; 


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• 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 interruption of study medication; and 
• TEAEs resulting in reduction of study medication 
• TEAEs resulting in reduction, interruption of study medication. 
• Time to the first TEAE that results in a reduction, delay, interruption or discontinuation 
of study drug. 
• Time to the first Treatment-related TEAE that results in a reduction, delay, interruption 
or discontinuation 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 grade will be summarized.   
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% Confidence interval.  
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  
• Anemia 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 


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support are provided in patient listings. The number of transfusions and the time to first 
transfusion is also summarized. Patient listing of any secondary malignancies may also be 
presented.  
13.2 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.    
Shift summary tables from baseline to the maximum on-treatment toxicity grade (CTCAE 
Version 4.03 or higher) for each lab parameter will be summarized. 
Laboratory data including normal ranges and abnormal laboratory flags will be provided 
using by-patient listings. 
Laboratory parameters of mean corpuscular volume (MCV), mean corpuscular hemoglobin 
(MCH), and reticulocytes were only captured for Part 2 patients, hence, summary statistics 
and proportion of patient above the normal range is summarized for Part 2 only.   
13.3 Vital Signs 
The on-treatment period will be defined as the time from enrolment 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.  
13.4 Electrocardiograms (ECG) 
Local reads of ECG were collected at screening and end of study. 
The QT interval was corrected by using both Fridericia’s (QTcF) and Bazett’s (QTcB) 
formula. The QTcF and QTcB intervals will be stratified into categories indicative of 


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potential clinical significance. Each patient’s maximum QTc intervals from baseline to end 
of treatment visits will be classified into the following:  ≤450 msec, >450 to ≤480 msec, 
>480 to ≤500 msec, and >500 msec. For each patient’s maximum change from the 
pretreatment ECG visit for QT and QTc, intervals will be classified into <30 msec, ≥30 to 
<60 msec, and ≥60 msec. Patients will also be classified according to the CTCAE grade 3 
criteria of at least 2 on treatment QTc values >500 ms. The number and percentage of 
patients in each classified category will be presented.  
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CHANGES IN THE PLANNED ANALYSES 
The following analyses were planned in the protocol, but will not be performed as part of this 
SAP:  
Exploratory Objectives 
• Changes in HRD (LOH and gene alterations) in fresh biopsy versus archival tumor tissue 
samples. 
• ORR by RECIST v1.1 and GCIG CA-125 criteria in relation to HRR gene mutations 
identified by BROCA analysis 
•  PFS and/or ORR by RECIST v1.1 and GCIG CA-125 criteria in relation to gene 
signature defined by a gene expression profiling assay 
• NHEJ protein expression by immunohistochemistry (IHC) and PFS and/or ORR by 
RECIST v1.1 and GCIG CA-125 criteria  
• Levels of ctDNA in relation to PFS and/or ORR by RECIST v1.1 and GCIG CA-125 
criteria 


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15 
REFERENCES 
1. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian 
carcinoma, Nature, 2011; 474(7353):609-15 
2. Rustin GJS, Vergote I, Eisenhauer E, et al. Definitions for Response and Progression in 
Ovarian Cancer Clinical Trials Incorporating RECIST 1.1 and CA 125 Agreed by the 
Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer 2011;21:419-23 


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16 
APPENDIX A 


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17 
APPENDIX B 
Modified Gynecological Cancer Intergroup (GCIG) Guidelines for Response Using  
CA-125  
 
Adapted from Rustin et al., Int J Gynecol Cancer. 2011  
GCIG CA 125 definitions are available at http://gcig.igcs.org/CA-125.html.  
 
To be evaluable for response by CA-125 requires an elevated baseline value of at least twice 
the upper limit of normal (i.e., > 70 iU/L) and at least two additional samples after the start of 
treatment.  
A response to CA-125 has occurred if there is at least a 50% decrease from baseline: 
• in a sample collected after initiation of study treatment AND  
• is confirmed in a subsequent sample collected ≥21 days after the prior sample. The 
absolute value of this confirmatory sample must be ≤110% of the prior sample. 
The date when the first sample with a 50% decrease from baseline is observed is the date of 
the CA-125 response.