Conditions: Epithelial Ovarian Cancer Fallopian Tube Cancer Primary Peritoneal Carcinoma High Grade Serous Carcinoma Endometrioid Adenocarcinoma
Keywords: PARP PARPi PARP inhibitor ARIES Opdivo Rucaparib Nivolumab PD-1 BRCA LOH CO-338 Immunotherapy BMS-936558 Clovis Clovis Oncology Rubraca
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
This is an open label Phase 2, 2-stage, 2-cohort study to evaluate rucaparib in combination with nivolumab in patients with high-grade serous or endometroid ovarian cancer.

Patients entering the following cohorts must have BRCA mutational status confirmed by a central lab:

* Cohort A1: No BRCA mutation in tumor; high level of LOH (loss of heterozygosity)
* Cohort A2: BRCA mutation in tumor

Detailed description:

Arms:
arm 1: Oral rucaparib and Intravenous (IV) nivolumab (combination therapy)

* Cohort A1
* Cohort A2

Interventions: intervention 1: Rucaparib intervention 2: Nivolumab
Intervention descriptions: intervention 1: Oral rucaparib will be administered twice daily intervention 2: IV nivolumab will be administered once every 4 weeks

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
CLINICAL STUDY PROTOCOL: CO-338-097 
Study Title: 
A Phase 2, open-label study to evaluate rucaparib in combination with 
nivolumab in patients with selected solid tumors (ARIES) 
Study Number: 
CO-338-097 
Study Phase: 
Phase 2 
Product Name: 
Rucaparib (CO-338); Nivolumab (BMS-936558-01) 
IND Number: 
 
EUDRA CT 
Number 
 
Indication: 
Selected solid tumors 
Investigators: 
Multicenter 
Sponsor Name: 
Clovis Oncology, Inc. 
Sponsor Address: 
 
 
 
 
 
 
Responsible 
Medical Officer: 
 
 
Protocol Version 
Date 
 
Amendment 1 
30 July 2019 
Confidentiality Statement 
This document contains confidential information belonging to Clovis Oncology, Inc. Except as 
otherwise agreed to in writing, by accepting or reviewing this document, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by 
applicable law) or use it for unauthorized purposes. In the event of any actual or suspected 
breach of this obligation, Clovis Oncology, Inc., must be promptly notified 


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PROTOCOL APPROVAL SIGNATURE PAGE 
Protocol: 
CO-338-097 
Title: 
A Phase 2, open-label study to evaluate rucaparib in combination with 
nivolumab in patients with selected solid tumors (ARIES) 
Date: 
30 July 2019 
Version: 
Amendment 1 
DocuSign Envelope ID: CDA8C095-D951-45B6-9644-DAC6E6F9899A


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PROTOCOL ACCEPTANCE FORM 
Protocol: 
CO-338-097 
Title: 
A Phase 2, open-label study to evaluate rucaparib in combination with 
nivolumab in patients with selected solid tumors (ARIES) 
Date: 
30 July 2019 
Version: 
Amendment 1 
 
 
I have carefully read this protocol and agree that it contains all the necessary information 
required to conduct this study. I agree to conduct this study as described and according to the 
Declaration of Helsinki, ICH E6(R2) Guidelines for GCP, and all applicable regulatory 
requirements. 
 
 
 
 
 
Investigator’s Signature 
 
Date 
(DD-MMM-YYYY) 
 
 
 
 
 
Name (printed) 
 
 
 


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SPONSOR’S MEDICAL EXPERT FOR THE STUDY 
Medical Expert: 
 
 
 
 
 
Clinical Investigators, Study Sites, and Laboratories: 
This is a multicenter study. Information on investigators, institutions, and laboratories involved 
in the study are maintained in the clinical study file and can be provided upon request. 


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SYNOPSIS 
Sponsor 
Clovis Oncology, Inc. 
Name of Finished Product 
Rucaparib tablets; 
Nivolumab injection 
Name of Active Ingredient 
Rucaparib camsylate (CO-338); 
Nivolumab (BMS-936558-01) 
Study Title 
A Phase 2, open-label study to evaluate rucaparib in combination with nivolumab in 
patients with selected solid tumors (ARIES) 
Study Number 
CO-338-097 (ARIES) 
Study Phase 
Phase 2 
Background and Study Rationale 
Study CO-338-097 will evaluate the combination of rucaparib and nivolumab as treatment 
for patients with either high-grade serous or endometrioid epithelial ovarian (EOC), 
fallopian tube (FTC), or primary peritoneal (PPC) cancer, referred to collectively as 
ovarian cancer. 
Rucaparib is an inhibitor of poly (adenosine diphosphate [ADP]-ribose) polymerase 
(PARP) enzymes, which play a critical role in base excision repair (BER) of 
deoxyribonucleic acid (DNA).1 When PARP function and effective BER are impaired, 
double-stranded DNA breaks accumulate. In cells deficient in homologous recombination, 
these breaks cannot be accurately repaired, resulting in synthetic lethality.2 While mutated 
breast cancer genes (BRCA)1 and BRCA2 are most commonly associated with 
homologous recombination deficiency (HRD), other essential homologous recombination 
repair (HRR) proteins may be mutated or functionally deficient in ovarian and other 
cancers. Recently, it has also been determined that measuring genomic loss of 
heterozygosity (LOH) is a phenotypic approach that can be utilized to identify HRD 
regardless of underlying mechanism.3 
Rucaparib monotherapy has demonstrated preclinical and clinical activity in cancers 
associated with a deleterious mutation in BRCA1/2 or other HRR gene, and different 
levels of genomic LOH (LOH High, Low, or Unknown). Rucaparib (Rubraca®) has been 
approved in the United States (US) and in the European Union (EU) as monotherapy 
treatment and maintenance treatment for ovarian cancer.4,5 
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody (HuMAb; 
IgG4-S228P) that binds to the programmed death-1 (PD-1) cell surface membrane receptor 


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and blocks receptor interaction with programmed-death ligand 1 (PD-L1) and PD-L2, 
releasing PD-1 pathway-mediated inhibition of the immune response, including anti-tumor 
immune response. Nivolumab monotherapy has shown anti-tumor activity preclinical 
models6 and in patients with ovarian cancer.7-9 Nivolumab (OPDIVO®) monotherapy is 
approved in multiple regions, including the US8 and EU,9 and for multiple indications, 
including unresectable or metastatic melanoma, previously treated advanced renal cell 
carcinoma (RCC), and previously treated advanced or metastatic urothelial carcinoma.  
The rationale for combining rucaparib with nivolumab as treatment for patients with 
ovarian cancer derives from emerging data that demonstrate an important association 
between high neoantigen load (increased mutational burden) and high expression of PD-1 
and/or its ligand, PD-L1, in ovarian tumors with gene mutations in the HRR pathways 
compared to ovarian cancers without these mutations.10-13 BRCA1 and BRCA2 mutations 
have been reported to increase the number of tumor infiltrating lymphocytes (TILs), and 
BRCA mutations are associated with improved overall survival (OS).13-15 It is estimated 
that approximately 50% of patients with high-grade serous ovarian cancer (HGSOC)10 
have HRD (Clovis Oncology, Inc. [Clovis], data on file). In addition, internal data (Clovis) 
indicate a significant association between percentage of genomic LOH and level of tumor 
mutational burden (TMB). A high TMB (TMBhigh) increases the likelihood of the 
development of tumor-specific neoepitopes that could confer clinical benefit from PD-1 
blockade. Thus, it is hypothesized that increased DNA damage by PARP inhibition will 
increase the number of tumor neoantigens, creating a more antigenic environment in which 
to stimulate the immune microenvironment.  
Cohorts A1 and A2 will investigate the efficacy and safety of rucaparib in combination 
with nivolumab, with the hypothesis that this drug combination may benefit patients with 
either (Cohort A1) germline BRCA wild-type (gBRCAwt) ovarian cancer or (Cohort A2)  
germline BRCA-mutant (gBRCAmut) ovarian cancer, who have previously received 1 or 
2 prior regimens of standard treatment. The gBRCAwt population in Cohort A1 will be 
comprised of predominantly BRCA wild-type (BRCAwt) patients, as well as patients with a 
deleterious somatic BRCA mutation (sBRCAmut). Rucaparib in combination with 
nivolumab represents a potential new therapy for the treatment of ovarian cancer patients 
with relapsed disease. In addition, the combination will be evaluated in the gBRCAmut 
ovarian cancer population16 included in the exploratory Cohort A2, for translational 
research to examine the impact of rucaparib on immune response in the tumor. 
Study Objectives 
All objectives (unless otherwise specified) will be assessed for Cohorts A1 and A2. 
Assessments will be conducted separately per Cohort A1 and A2.  
Primary Objective: 
• To evaluate the objective response rate (ORR) by Response Evaluation Criteria in 
Solid Tumors Version 1.1 (RECIST v1.1) as assessed by the investigator 
(Cohort A1 only) 
• To study the effect of rucaparib on the immune microenvironment (Cohort A2 
only) 


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Secondary Objectives: 
• To evaluate the ORR by RECIST v1.1 and Gynecological Cancer InterGroup 
(GCIG) cancer antigen 125 (CA-125 criteria (Cohort A1 only) 
• To evaluate the ORR by RECIST v1.1 as assessed by the investigator, according to 
molecularly-defined HRD subgroups: BRCAwt/LOHhigh; BRCAwt/LOHlow; 
BRCAwt/LOHunknown; and sBRCA (Cohort A1 only) 
• To estimate progression-free survival (PFS) (Cohort A1 only) 
• To evaluate duration of response (DOR) (Cohort A1 only)  
• To evaluate safety and tolerability of rucaparib in combination with nivolumab 
Exploratory Objectives: 
• To evaluate the ORR by RECIST v1.1 as assessed by the investigator (Cohort A2 
only) 
• To evaluate the ORR by RECIST v1.1 and GCIG CA-125 criteria (Cohort A2 only) 
• To estimate PFS (Cohort A2 only) 
• To evaluate DOR (Cohort A2 only)  
• To assess mutations in BRCA1, BRCA2, and other HRR genes as molecular 
markers of efficacy 
• To assess PD-L1 expression as a molecular marker of efficacy 
• To assess LOH, TMB, and other genomic and transcriptional signatures as 
molecular markers of efficacy 
• To study variants in circulating tumor DNA (ctDNA) as markers of response and 
resistance 
• To characterize pharmacokinetics (PK) of rucaparib and nivolumab in combination  
• To evaluate immunogenicity of nivolumab when administered in combination with 
rucaparib  
• To explore exposure-response (ER) relationship between selected exposure 
measures of rucaparib and nivolumab, and safety and efficacy endpoints 
• To study the effect of rucaparib on the immune microenvironment (Cohort A1 only) 
Study Design 
This is an open label, 2-stage, 2-cohort study to evaluate rucaparib in combination with 
nivolumab in patients with high-grade serous or endometrioid ovarian cancer: 
Cohort A1: gBRCAwt 
Cohort A2: gBRCAmut 
 
For both Cohort A1 and A2, the study will enroll patients with either high-grade serous or 
endometrioid EOC, FTC, or PPC, measurable disease per RECIST v1.1, who received 1 or 
2 prior regimens (including at least 1 prior platinum-containing regimen), who were 
sensitive to their last platinum regimen, and who had radiologic progression during or after 
the most recent regimen. 


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The study will use a Simon 2-stage design in Cohort A1. Patients who meet eligibility 
criteria will be entered into the applicable study cohort. Refer to detailed information on 
the Simon 2-stage calculation under the description of Statistical Methods below and 
Determination of Sample Size in Section 9.2. In Cohort A2, exploratory endpoints 
including efficacy will be evaluated. 
This study consists of a Screening Phase, a Treatment Phase, and a Post-treatment Phase. 
Screening Phase 
General (All patients) 
All patients will undergo screening assessments within 28 days prior to enrollment (see 
exception for mandatory tumor tissue below). Patients must provide written informed 
consent prior to any screening procedures and must meet all inclusion and exclusion 
criteria as specified in the protocol prior to enrollment in the study. Patients undergoing 
repeated screening assessment(s) must also meet all inclusion and exclusion criteria prior 
to enrollment. 
Screening assessments will include demographics and medical history, prior anticancer 
treatments, prior and current medications and procedures, 12-lead electrocardiogram 
(ECG), Eastern Cooperative Oncology Group (ECOG) performance status, local 
laboratory hematology and clinical chemistry measurements, serum pregnancy test (for 
women of childbearing potential only), urinalysis, physical examination, height, weight, 
and vital signs measurements, new adverse events (AEs) during screening, and tumor 
assessment by computed tomography (CT) scan. Other complementary assessments 
(magnetic resonance imaging [MRI], X-ray, positron emission tomography [PET], and 
ultrasound) may be performed if required. Blood sampling for ctDNA in plasma will also 
be collected for central laboratory analysis. 
Submission of tumor tissue at screening is mandatory as described below for each cohort. 
Tumor tissue will be analyzed by the central laboratory for tumor mutation classification 
as described below for each cohort. In addition, the tumor tissue will be analyzed by the 
central laboratory for baseline assessment of molecular markers associated with efficacy 
and the immune microenvironment. 
Collection of adequate tumor tissue at screening is mandatory. Tissue must be sent to and 
analyzed by the central laboratory for all patients enrolled. 
Tumor tissue samples should be from primary or metastatic tissue and must be collected 
within 42 days of the first dose of rucaparib. Alternatively, tumor tissue collected 
> 42 days prior to the first dose of rucaparib may be submitted, provided there have been 
no intervening anticancer treatments during this period and the tissue is of adequate 
quality. Patients may be enrolled prior to tumor tissue being analyzed by the central 
laboratory, provided there is confirmation that tumor tissue has been received by the 
central laboratory. 
Sequencing of BRCA1/2 and analysis of genomic LOH in the tumor sample will be 
performed by the central laboratory (Foundation Medicine, Inc. [FMI]). A prior test result 
for gBRCAmut is required to determine eligibility for patients enrolled into Cohort A1 and 
A2. 


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Treatment Phase 
Dosing Procedures: 
Patients will commence treatment with oral rucaparib, beginning on Cycle 1 Day 1. Oral 
study drug will be taken twice a day (BID) continuously thereafter.  
Dosing with intravenous (IV) nivolumab will commence on Cycle 2 Day 1; IV nivolumab 
will be administered every 4 weeks (Q4W).  
Study Visits and Procedures:  
General (All patients) 
Patients will come into the study site for a visit on Day 1 and Day 15 of Cycles 1 and 2, 
and on Day 1 of every cycle thereafter. A blood sample will be collected from all patients 
at Cycle 1 Day 1 and stored for subsequent genomic DNA testing and determination of 
germline status. 
Study treatment will continue in 28-day cycles until 24 months from the start of the oral/IV 
combination treatment (ie, 25 months for Cohorts A1 and A2), disease progression, or 
unacceptable toxicity, whichever occurs first. Patients will undergo procedures and 
assessments, including regular safety, PK, and efficacy evaluations, during the entire 
conduct of the study. 
Tumor assessments by CT scan will be performed every 8 calendar weeks (±7 days) from 
the start of the oral/IV combination treatment on Cycle 2 Day 1 for Cohorts A1 and A2, up 
to 18 months and then every 12 calendar weeks (±7 days) thereafter and at the End of 
Treatment Visit, if applicable, until confirmed objective radiological disease progression, 
as assessed by the investigator. Tumor assessments are to be performed prior to the next 
scheduled IV nivolumab treatment. 
Patients experiencing confirmed disease progression by RECIST v1.1 will be discontinued 
from treatment and enter follow-up. If the patient has met criteria for confirmed radiologic 
progression by RECIST, but the patient is still receiving benefit from the study drug(s) 
according to the investigator (eg, patient has mixed radiologic response or is continuing to 
have symptomatic benefit), then continuation of treatment will be considered for a 
maximum cumulative duration of 24 months following initiation of combination treatment. 
In such cases, the decision to continue receiving treatment with study drug(s) must be 
documented in source documents, and the patient must provide additional consent at their 
next routine study visit. Patients will continue to have all protocol-required assessments 
specified in the Schedule of Assessments (Table 6) and Pharmacokinetic and 
Immunogenicity Sample Collections (Table 7). 
Safety and efficacy data will be periodically reviewed by the study Data Monitoring 
Committee (DMC).  
Within 5 days and prior to commencement of IV nivolumab treatment on Cycle 2 Day 1, 
collection of a primary or metastatic tumor sample is mandatory for patients in Cohorts A1 
and A2, unless tumor biopsy procedure is contraindicated (eg, unacceptable risk in the 
opinion of the investigator). The tumor sample will be analyzed by the central laboratory 


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to assess molecular markers of efficacy or resistance, as well as the effect of rucaparib on 
the immune microenvironment.  
Post-Treatment Follow-up Phase for Both Cohorts  
All patients will be followed for at least 100 days (+7 days) after the last dose of IV 
nivolumab treatment. There will be 2 follow-up visits: the 28-day Follow-up Visit (FU-28) 
should occur 28 days (±3 days) after last dose of the oral and/or IV study drug (whichever 
occurs later), and the 100-day Follow-up Visit (FU-100) should occur at least 100 days 
(+7 days) after the last dose of IV study drug treatment. If a patient remains on oral study 
drug after discontinuation of IV study drug, FU-100 can be performed at a cycle visit, 
provided it has been at least 100 days (+7 days) since the last IV study drug dose.  
Patients who discontinued treatment for reason other than disease progression or death 
should continue to have tumor scans performed at 12-week intervals from Cycle 2 Day 1 
for the first 18 months after initiation of oral/IV combination study drug treatment and then 
every 24 weeks thereafter until objective radiological disease progression by RECIST 
v1.1, as assessed by the investigator, is documented. An optional tumor biopsy will be 
collected from patients who experience disease progression and provide appropriate 
consent. 
Patients will also be followed long-term for survival, subsequent treatments, disease 
progression (if treatment discontinuation was for reason other than disease progression or 
death), and monitoring for secondary malignancy every 12 weeks (±14 days) until death, 
loss to follow-up, withdrawal of consent, or study closure. 
Number of Patients 
Approximately 28 to 53 patients will be enrolled. A maximum of 43 patients (Cohort A1), 
and 10 patients (Cohort A2) will be enrolled. 
Number of Sites 
Patients will be enrolled at approximately 15 sites in the US. 
Inclusion Criteria 
Eligible patients must meet the following applicable inclusion criteria: 
General Inclusion Criteria (All patients) 
1. Have signed an Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)-approved Informed Consent Form (ICF) prior to any study-specific 
evaluation. 
2.  ≥ 18 years of age at the time the ICF is signed. 
3. Have adequate organ function confirmed by the following laboratory values 
obtained at screening (within 14 days prior to the first dose of study drug): 
a. Bone Marrow Function 
- 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
- 
Platelets ≥ 100 × 109/L  
- 
Hemoglobin ≥ 9 g/dL  


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b. Hepatic Function 
- 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤ 1.5 × upper limit of normal (ULN) 
- 
Bilirubin ≤ 1.5 × ULN; < 2 × ULN if hyperbilirubinemia is due to Gilbert's 
syndrome 
- 
Serum albumin ≥ 30 g/L (3.0 g/dL) 
c. Renal Function 
- 
Serum creatinine ≤ 1.5 × ULN unless estimated glomerular filtration rate 
(GFR) ≥ 30 mL/min using the Cockcroft Gault formula 
4. Have life expectancy ≥ 16 weeks, in the opinion of the investigator. 
5. Women of childbearing potential must have a negative serum pregnancy test 
≤ 3 days prior to administration of the first dose of study drug. 
6. Have a histologically confirmed diagnosis of high-grade serous or 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. 
7. Have measurable disease as defined by RECIST v1.1 (Cohort A1 only). 
8. A mandatory biopsy or resection of tumor tissue must be collected ≤ 42 days prior 
to first dose of rucaparib. Alternatively, tumor tissue collected > 42 days prior to 
the first dose of rucaparib may be submitted, provided there have been no 
intervening anticancer treatments during this period and the tissue is of adequate 
quality. See Section 7.5.6.1. Patients may be enrolled prior to tumor tissue being 
analyzed by the central laboratory, provided there is confirmation that the tumor 
tissue has been received by the central laboratory. 
9.  (Cohort A1) Have gBRCAwt ovarian cancer (ie, patients with a deleterious 
germline mutation in BRCA1 or BRCA2, as determined by a local laboratory that 
has received an international or country-specific quality standards certification, are 
excluded). 
 
OR 
 
(Cohort A2) Have gBRCAmut ovarian cancer (ie, deleterious germline  BRCA1/2 
mutation, as determined by a local laboratory that has received an international or 
country-specific quality standards certification). 
10. Be willing to have a mandatory biopsy of tumor tissue collected at Cycle 1 Day 28 
of treatment. 
11. Have relapsed/progressive disease as confirmed by radiologic assessment.  
12. Received 1 or 2 prior regimens, including ≥ 1 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); 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. 
13. Have an ECOG performance status of 0 to 1 < 14 days prior to first dose of 
rucaparib.  
Exclusion Criteria 
Patients will be excluded from participation if any of the following applicable criteria 
apply: 
General Exclusion Criteria (All patients) 
1. Active second malignancy, ie, patient known to have potentially fatal cancer 
present for which she may be (but not necessarily) currently receiving treatment. 
- 
Patients with a history of malignancy that has been completely treated, with no 
evidence of active cancer for 3 years prior to enrollment, or patients with 
surgically-cured low-risk tumors, such as early-stage cervical or endometrial 
cancer, or non-melanoma skin cancers are allowed to enroll. 
2. Known central nervous system brain metastases. 
3. Has evidence of interstitial lung disease, active pneumonitis, myocarditis, or 
history of myocarditis. 
4. Patients with an active, known or suspected autoimmune disease (eg, autoimmune 
hepatitis). Patients with type I diabetes mellitus, hypothyroidism only requiring 
hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not 
requiring systemic treatment, or conditions not expected to recur in the absence of 
an external trigger are permitted to enroll. 
5. Patients with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications 
within 14 days of enrollment. Inhaled or topical steroids, and adrenal replacement 
steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of 
active autoimmune disease. 
6. Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that 
would, in the opinion of the investigator, interfere with absorption of study 
treatment. 
7. Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). Note: Testing for HIV must be 
performed at all sites where mandated locally. 
8. Any positive test result for hepatitis B virus or hepatitis C virus indicating presence 
of virus, eg, hepatitis B surface antigen (HBsAg, Australia antigen) positive, or 
hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative). 
9. For female patients of childbearing potential, the following are exclusion criteria, 
as applicable: 


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a. Refusal to use highly effective method of contraception or to practice true 
abstinence during treatment and for 6 months after the last dose of rucaparib 
study treatment 
b. Pregnant or breast feeding.  
c. Women of childbearing potential must not be considering getting pregnant 
during the study and for 6 months following the last dose of rucaparib and/or 
nivolumab. 
10. Non-study related minor surgical procedure (eg, placement of a central venous 
access port) ≤ 5 days, or major surgical procedure ≤ 21 days, prior to first dose of 
study drug; in all cases, the patient must be sufficiently recovered and stable before 
treatment administration. 
11. Presence of any other condition that may increase the risk associated with study 
participation or may interfere with the interpretation of study results, and, in the 
opinion of the investigator, would make the patient inappropriate for entry into the 
study. 
12. Hospitalization for bowel obstruction within 12 weeks prior to enrollment. 
13. Prior treatment with a PARP inhibitor (PARPi) or immune checkpoint inhibitor 
(Exception: patient is eligible if they received a prior PARPi as frontline 
maintenance therapy and patient did not have disease progression whilst on the 
PARPi, providing inclusion criterion 11 is also met at time of screening). 
14. Received treatment with chemotherapy, radiation, antibody therapy or other 
immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or 
experimental drugs ≤ 14 days prior to first dose of study drug and/or ongoing 
adverse effects from such treatment > NCI CTCAE v5.0 Grade 1, with the 
exception of Grade 2 non-hematologic toxicity such as alopecia, peripheral 
neuropathy, and related effects of prior chemotherapy that are unlikely to be 
exacerbated by treatment with study drug. 
15. Non-epithelial tumors (pure sarcomas) or ovarian tumors with low malignant 
potential (ie, borderline tumors) or mucinous tumors. Mixed Mullerian 
tumors/carcinosarcomas are allowed. 
No waivers of these inclusion or exclusion criteria will be granted by the investigator and 
the sponsor or its designee for any patient enrolled in the study. 
Enrollment and Study Treatment 
Eligible patients meeting all applicable inclusion/exclusion criteria will be enrolled in the 
applicable open-label treatment cohort by the investigator:  
• Cohorts A1 and A2: rucaparib + nivolumab 
No randomization or blinding will be performed in the study. 
Rucaparib 600 mg, is administered orally BID; as close as possible to 12 hours apart 
(preferably at the same times every day) with water starting on Day 1. Oral study drug may 
be taken with or without food. Rucaparib will be provided as 200, 250, and 300 mg (as free 
base) dose strength tablets.  


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Nivolumab is administered as 480 mg via a 30-minute IV infusion on Day 1 of every 
4-week cycle, starting Cycle 2 Day 1 (Cohorts A1 and A2).Patients will receive both study 
drugs for a maximum of 24 months after initiation of oral/IV combination treatment, or 
until disease progression by RECIST v1.1 as assessed by the investigator, unacceptable 
toxicity, or other reason for discontinuation, whichever occurs first. Treatment interruption 
or dose reduction of oral study drug are permitted in the event of unacceptable toxicity. 
Doses of IV study drug may be interrupted or delayed, but may not be reduced. 
Withdrawal Criteria 
A patient must be discontinued from treatment with study drug if any of the following 
apply: 
• Consent withdrawal at the patient’s own request or at the request of their legally 
authorized representative; 
• Progression of patient’s underlying disease by RECIST v1.1 as assessed by the 
investigator unless the patient is still receiving benefit from the study drug(s) 
according to the investigator, the investigator has consulted with the sponsor’s 
medical officer or designee, and the patient has provided additional consent at her 
next study visit; 
• 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; 
• Noncompliance by the patient with protocol mandated procedures; 
• A positive pregnancy test at any time during the study; and/or 
• Study-specific treatment withdrawal rules for rucaparib and nivolumab (defined in 
Section 5.5.1.2). 
Efficacy Assessments 
Tumor assessment measurements will be performed at screening, at the end of every 
8 weeks of treatment (±7 days) relative to Cycle 1 Day 1 for the first 18 months after 
initiation of oral/ IV study treatment, and then every 12 weeks thereafter until objective 
radiological disease progression, or discontinuation of treatment, and as clinically 
indicated. 
Disease assessment will comprise clinical examination and appropriate imaging techniques 
per RECIST v1.1 (ie, CT scans of the chest, abdomen, and pelvis with appropriate slice 
thickness per RECIST v1.1). Other complementary assessments (MRI, X-ray, PET, and 
ultrasound) may be performed if required. The same methods used to detect lesions at 
baseline are to be used to follow the same lesions throughout the clinical study. Scans of 
the chest, abdomen, and pelvis performed to determine the extent of disease at baseline 
should also be performed at each time of disease assessment, even if the scans were 
negative at baseline. Investigators should perform scans of other anatomical sites that, in 
their judgment, are appropriate to assess based on each patient’s tumor status. Imaging 


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guidelines provided in imaging manual should be followed for the collection of images and 
the radiological assessment of disease. 
Tumor response will be interpreted using RECIST v1.1, as assessed by the investigator. 
Disease progression will primarily be determined by RECIST v1.1.  
Blood samples to assess CA-125 will be collected at screening and throughout the study 
(Table 6) and assessed by a local laboratory. Cohort A1 and A2 patients who meet GCIG 
CA-125 criteria for disease progression should have a radiologic assessment and be 
assessed by RECIST v1.1 If the radiologic assessment does not confirm disease 
progression, patients should continue on treatment and continue to be assessed by 
RECIST v1.1 per the protocol schedule of assessments. 
Patients who discontinued study treatment for a reason other than disease progression or 
death should continue to have tumor scans performed at 12-week intervals (±7 days) for 
the first 18 months after initiation of oral/IV combination study treatment and every 
24 weeks thereafter until objective radiologic disease progression by RECIST v1.1, as 
assessed by the investigator, is documented, or initiating subsequent anticancer treatment. 
Safety Assessments 
Safety and tolerability will be assessed based on the following: 
• Incidence, type, seriousness, and severity of adverse events (AEs) reported (CTCAE 
v5.0); 
• Clinical laboratory investigations (hematology, clinical chemistry, urinalysis); 
• Vital signs (blood pressure, heart rate, and body temperature); 
• 12-lead electrocardiograms (ECGs); 
• Physical examinations; and 
• ECOG performance status. 
Statistical Methods 
Sample Size 
Approximately 28 to 53 patients will be enrolled in this open-label, 2-stage, 2-cohort 
study. 
A maximum of 43 patients (Cohort A1) and 10 patients (Cohort A2) will be enrolled. 
Study Design 
A Simon 2-stage design to evaluate ORR by RECIST v1.1 criteria per investigator will be 
used for Cohort A1. Enrollment in the study will continue while the interim analysis 
(Stage 1 criteria) occurs for Cohort A1. The DMC will review data for the interim analysis 
and provide recommendation if Stage 1 criteria are not met for Cohort A1. If Stage 1 
criteria are not met, the DMC will evaluate the overall benefit:risk for study treatment, and 
make a recommendation whether further enrollment should be discontinued. If Stage 1 
criteria in the Simon 2-stage design are met, the enrollment will continue with additional 
patients in Stage 2. Further details on the Simon 2-stage design is outlined below:  


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Cohort A1 (gBRCAwt) 
With an optimal design, a minimum of 18 patients and a maximum of 43 patients will be 
enrolled in this cohort. 
Stage 1 evaluation will be performed after the first 18 patients have either: 
a) completed 16 weeks of treatment, or b) discontinued treatment prior to completing. If 
≥ 3/18 patients have a confirmed objective response, then enrollment will continue with 
additional patients in Stage 2. With 43 total patients, characteristics of the Simon 2-stage 
design include: 
• 5% probability of accepting a minimally effective drug (ie, ORR of 10%) 
• 80% probability of accepting an effective drug (ie, ORR of 25%) 
Cohort A2 (gBRCAmut) 
Cohort A2 is an exploratory cohort that will enroll approximately 10 ovarian cancer 
patients classified as gBRCAmut. Due to the exploratory nature of this cohort, a sample size 
of 10 patients is considered sufficient in order to study the effect of rucaparib on the 
immune microenvironment in this cohort for comparison to the immune microenvironment 
in the cohort of patients harboring gBRCAwt tumors (Cohort A1). No stopping rule in 
enrollment will be used for Cohort A2.  
Data Monitoring Committee 
A study DMC will be established and comprise the coordinating investigator and sponsor 
representatives. The DMC composition, responsibilities, and procedures for this study will 
be documented in the DMC Charter, which will be endorsed by the DMC members and 
signed by the DMC chair prior to the first data review meeting.  
The DMC will review on an ongoing basis the study progress and clinical data to ensure 
the study remains beneficial to patients. The DMC will review the overall safety and 
efficacy data of rucaparib in combination with nivolumab, and by study cohort, to 
determine whether the study benefit: risk remains positive during the study. 
The DMC will meet after the first 10 patients (Cohort A1) have either a) received at least 
1 cycle of study treatment with rucaparib and nivolumab, b) discontinued study treatment 
or c) died of any cause. The DMC will perform continuous safety review at least every 
6 months. The DMC chairperson or sponsor may convene an unscheduled DMC meeting if 
there are any emergent significant safety concerns.  
Following data review, the DMC will recommend continuation, revision, or termination of 
the study and/or continuing or suspending enrollment into the study or a particular study 
cohort.  
Date of Amendment 1 Approval 
30 July 2019 


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TABLE OF CONTENTS 
PROTOCOL APPROVAL SIGNATURE PAGE ...........................................................................2 
PROTOCOL ACCEPTANCE FORM .............................................................................................3 
SPONSOR’S MEDICAL EXPERT FOR THE STUDY .................................................................4 
SYNOPSIS .......................................................................................................................................5 
TABLE OF CONTENTS ...............................................................................................................17 
LIST OF IN-TEXT TABLES ........................................................................................................22 
LIST OF IN-TEXT FIGURES.......................................................................................................22 
LIST OF APPENDICES ................................................................................................................22 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................23 
1 
INTRODUCTION .................................................................................................................28 
1.1 
Background ..................................................................................................................28 
1.1.1 
Ovarian Cancer ..................................................................................................28 
1.1.2 
Rucaparib ...........................................................................................................30 
1.1.2.1 
Mechanism of Action ...............................................................................30 
1.1.2.2 
Nonclinical Experience ............................................................................31 
1.1.2.3 
Clinical Experience ..................................................................................32 
1.1.3 
Nivolumab..........................................................................................................37 
1.1.3.1 
Mechanism of Action ...............................................................................38 
1.1.3.2 
Nonclinical Experience ............................................................................39 
1.1.3.3 
Clinical Experience ..................................................................................39 
1.1.4 
PARP Inhibitors and Checkpoint Inhibitors ......................................................41 
1.1.4.1 
Nonclinical Overview ..............................................................................41 
1.1.4.2 
Clinical Overview ....................................................................................41 
1.1.5 
Rationale for the Study and Benefit: Risk Assessment .....................................43 
1.1.5.1 
Rationale for Ovarian Cancer ..................................................................43 
1.1.5.2 
Rationale for Rucaparib and Nivolumab Combination in Ovarian 
Cancer ......................................................................................................43 
1.2 
Dose Rationale .............................................................................................................44 
1.2.1 
Dose Rationale for Nivolumab ..........................................................................44 
1.2.1.1 
Rationale for Nivolumab 30-minute Infusion ..........................................45 
1.2.2 
Dose Rationale for Nivolumab and Rucaparib Combination ............................45 
1.3 
Rationale for Duration of Treatment ............................................................................46 
1.3.1 
Nivolumab..........................................................................................................46 
1.3.2 
Rucaparib ...........................................................................................................46 
2 
STUDY OBJECTIVES ..........................................................................................................47 
2.1 
Primary Objective ........................................................................................................47 
2.2 
Secondary Objectives ...................................................................................................47 
2.3 
Exploratory Objectives ................................................................................................47 


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3 
STUDY DESIGN...................................................................................................................49 
3.1 
Overall Study Design and Plan ....................................................................................49 
3.1.1 
Screening Phase .................................................................................................50 
3.1.2 
Treatment Phase .................................................................................................51 
3.1.3 
End of Treatment ...............................................................................................52 
3.1.4 
Post-treatment Follow-up Phase ........................................................................52 
3.2 
Removal of Patients From Therapy or Assessment .....................................................53 
3.3 
Study Schema...............................................................................................................53 
3.4 
End of Study ................................................................................................................55 
3.5 
Discussion of Study Design .........................................................................................55 
4 
STUDY POPULATION SELECTION .................................................................................56 
4.1 
Number of Patients and Sites .......................................................................................56 
4.2 
Inclusion Criteria .........................................................................................................56 
4.3 
Exclusion Criteria ........................................................................................................57 
4.4 
Patients or Partners of Patients of Reproductive Potential ..........................................59 
4.5 
Waivers of Inclusion/Exclusion Criteria ......................................................................60 
5 
STUDY TREATMENT(S) ....................................................................................................61 
5.1 
Description of Treatment(s) and Storage .....................................................................61 
5.1.1 
Investigational Drug Product – Rucaparib .........................................................61 
5.1.2 
Investigational Drug Product – Nivolumab .......................................................61 
5.2 
Packaging and Labeling ...............................................................................................61 
5.2.1 
Rucaparib Tablets ..............................................................................................61 
5.2.2 
Nivolumab..........................................................................................................62 
5.3 
Method of Assigning Patients to Treatment Groups ....................................................62 
5.4 
Preparation and Administration of Protocol-specified Treatment ...............................62 
5.4.1 
Rucaparib ...........................................................................................................62 
5.4.2 
Nivolumab..........................................................................................................63 
5.5 
Dose Modification Criteria ..........................................................................................63 
5.5.1 
Dose Reduction ..................................................................................................69 
5.5.1.1 
Rucaparib .................................................................................................69 
5.5.1.2 
Nivolumab ................................................................................................69 
5.6 
Management Algorithms for Immuno-oncology Agents .............................................69 
5.7 
Treatment of Infusion-related Reactions .....................................................................70 
5.8 
Treatment Compliance .................................................................................................71 
5.8.1 
Rucaparib Treatment Compliance .....................................................................71 
5.8.2 
Nivolumab Treatment Compliance ....................................................................71 
5.9 
Accountability of Protocol-specified Treatment ..........................................................72 
5.10 
Treatment of Study Drug beyond Disease Progression ...............................................72 


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6 
PRIOR AND CONCOMITANT THERAPY ........................................................................73 
6.1 
Supportive Care ...........................................................................................................73 
6.2 
Radiotherapy ................................................................................................................73 
6.3 
Anticancer or Experimental Therapy ...........................................................................73 
6.4 
CYP450 Isoenzyme Inhibitors, Inducers, and Substrates ............................................73 
6.5 
Anticoagulants .............................................................................................................74 
6.6 
Immunosuppressive Agents .........................................................................................74 
6.7 
Other Concomitant Medications ..................................................................................74 
6.8 
Imaging Restrictions and Precautions ..........................................................................75 
6.9 
General Restrictions .....................................................................................................75 
7 
STUDY PROCEDURES AND METHODS .........................................................................76 
7.1 
Schedule of Assessments .............................................................................................76 
7.2 
Informed Consent.........................................................................................................85 
7.3 
Screening Phase ...........................................................................................................85 
7.3.1 
Up to 42 Days Prior to Start of Treatment .........................................................85 
7.3.2 
Up to 28 Days Prior to Start of Treatment .........................................................86 
7.3.3 
Up to 14 Days Prior to Start of Treatment .........................................................86 
7.4 
Treatment Phase ...........................................................................................................86 
7.4.1 
Cycle 1 Day 1.....................................................................................................86 
7.4.2 
Cycle 1 Day 15...................................................................................................87 
7.4.3 
Cycle 1 Day 28...................................................................................................88 
7.4.4 
Cycle 2 Day 1.....................................................................................................88 
7.4.5 
Cycle 2 Day 15...................................................................................................89 
7.4.6 
Cycle 3 Day 1 and Every Cycle Thereafter .......................................................89 
7.4.7 
Post-treatment Follow-up Phase ........................................................................91 
7.4.7.1 
End of Treatment .....................................................................................91 
7.4.7.2 
28-day Safety Follow-up (FU-28)............................................................91 
7.4.7.3 
100-day Safety Follow-up (FU-100) .......................................................92 
7.4.8 
Long-term Follow-up .........................................................................................93 
7.5 
Methods of data collection ...........................................................................................93 
7.5.1 
Medical History and Demographic/ Baseline Characteristics ...........................93 
7.5.2 
Prior and Concomitant Medication Assessments ..............................................94 
7.5.3 
Efficacy Evaluations ..........................................................................................94 
7.5.3.1 
Disease/ Tumor Assessments ...................................................................94 
7.5.3.2 
Tumor Markers ........................................................................................95 
7.5.4 
Safety Evaluations .............................................................................................95 
7.5.4.1 
Adverse Event Assessment ......................................................................95 
7.5.4.2 
Clinical Laboratory Investigations ...........................................................95 
7.5.4.3 
Vital Signs ................................................................................................96 
7.5.4.4 
12-Lead Electrocardiogram......................................................................96 


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7.5.4.5 
Body Weight and Height .........................................................................96 
7.5.4.6 
Physical Examinations .............................................................................97 
7.5.4.7 
ECOG Performance Status ......................................................................97 
7.5.5 
Pharmacokinetic and Immunogenicity Evaluations ...........................................97 
7.5.5.1 
Rucaparib Pharmacokinetic Sample Collection .......................................97 
7.5.5.2 
Nivolumab Pharmacokinetic Sample Collection .....................................97 
7.5.5.3 
Nivolumab Immunogenicity Assessments ...............................................98 
7.5.6 
Biomarker Analysis ...........................................................................................98 
7.5.6.1 
Biomarker Analysis – Mandatory Tumor Tissue Collection ...................98 
7.5.6.2 
Biomarker Analysis – ctDNA ..................................................................99 
7.5.6.3 
Biomarker Analysis - Genomic DNA from Blood ..................................99 
7.5.6.4 
Other Peripheral Blood Biomarker Analyses ..........................................99 
7.5.6.5 
Additional Research .................................................................................99 
8 
ADVERSE EVENT MANAGEMENT ...............................................................................100 
8.1 
Definition of an Adverse Event .................................................................................100 
8.2 
Definition of a Serious Adverse Event ......................................................................100 
8.3 
Definition of an Adverse Events of Special Interest ..................................................101 
8.4 
Immune-mediated Adverse Events ............................................................................101 
8.5 
Events or Outcomes Not Qualifying as Serious Adverse Events ..............................101 
8.6 
Clinical Laboratory Assessments as Adverse Events and Serious Adverse 
Events .........................................................................................................................102 
8.7 
Pregnancy or Drug Exposure during Pregnancy ........................................................102 
8.8 
Recording of Adverse Events, Serious Adverse Events, and Adverse Events of 
Special Interest ...........................................................................................................102 
8.8.1 
Onset date of Adverse Events ..........................................................................103 
8.8.2 
Resolution date of Adverse Events ..................................................................103 
8.8.3 
Intensity of Adverse Events .............................................................................103 
8.8.4 
Causal Relationship of Adverse Events to Study Drug ...................................103 
8.9 
Follow-Up of Adverse Events, Serious Adverse Events, and Adverse 
Events of Special Interest...........................................................................................104 
8.10 
Potential Drug-Induced Liver Injury .........................................................................104 
8.11 
Regulatory Aspects of Serious Adverse Event and Adverse Events of Special 
Interest Reporting.......................................................................................................105 
8.12 
Data Monitoring Committee ......................................................................................105 
9 
PLANNED STATISTICAL METHODS ............................................................................106 
9.1 
General Considerations ..............................................................................................106 
9.2 
Determination of Sample Size ...................................................................................106 
9.2.1 
Cohort A1.........................................................................................................106 
9.2.2 
Cohort A2.........................................................................................................107 
9.3 
Analysis Populations ..................................................................................................107 
9.4 
Patient Disposition .....................................................................................................107 


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9.5 
Demographics and Baseline Characteristics ..............................................................107 
9.6 
Efficacy Analyses ......................................................................................................108 
9.6.1 
Primary Efficacy Analyses ..............................................................................108 
9.6.2 
Secondary Efficacy Analysis ...........................................................................108 
9.6.2.1 
ORR Assessed by RECIST and GCIG CA-125 Criteria .......................108 
9.6.2.2 
ORR by RECIST v1.1 as Assessed by the Investigator and GCIG 
CA-125 Response According to Molecularly-defined HRD 
Subgroups ..............................................................................................109 
9.6.2.3 
Progression-free Survival (PFS) ............................................................109 
9.6.2.4 
Duration of Confirmed Response (DOR) ..............................................109 
9.6.3 
Exploratory Efficacy Analysis .........................................................................110 
9.7 
ctDNA and immunogenicity Analyses ......................................................................110 
9.8 
Safety Analyses ..........................................................................................................110 
9.8.1 
Adverse Events ................................................................................................110 
9.8.2 
Clinical Laboratory Evaluations ......................................................................112 
9.8.3 
Vital Sign Measurements .................................................................................112 
9.9 
Pharmacokinetic Analysis ..........................................................................................112 
9.9.1 
Rucaparib Pharmacokinetic Analysis ..............................................................112 
9.9.2 
Nivolumab Pharmacokinetic Analysis .............................................................113 
9.9.3 
Anti-Nivolumab Antibodies.............................................................................113 
9.10 
Interim Analysis .........................................................................................................113 
10 STUDY ADMINISTRATION ............................................................................................114 
10.1 
Regulatory and Ethical Considerations ......................................................................114 
10.1.1 
Regulatory Authority Approvals......................................................................114 
10.1.2 
Institutional Review Board or Independent Ethics Committee 
Approval ..........................................................................................................114 
10.2 
Patient Information and Consent ...............................................................................115 
10.3 
Patient Confidentiality ...............................................................................................115 
10.4 
Study Monitoring .......................................................................................................116 
10.5 
Case Report Forms and Study Data ...........................................................................116 
10.6 
Study Termination and Site Closure ..........................................................................117 
10.7 
Modification of the Study Protocol............................................................................118 
10.8 
Retention of Study Documents ..................................................................................118 
10.9 
Quality Control and Assurance ..................................................................................119 
10.9.1 
Changes to the Protocol and Deviations ..........................................................119 
10.9.2 
Study Site Training and Ongoing Monitoring .................................................119 
10.9.3 
Direct Access to Source Data/ Documents for Audits and Inspections ...........119 
10.10 Clinical Study Report .................................................................................................120 
10.11 Publication and Disclosure Policy .............................................................................120 
10.12 Investigator Oversight ................................................................................................120 


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11 REFERENCE LIST .............................................................................................................121 
12 APPENDICES .....................................................................................................................127 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Investigator-assessed Tumor Response by HRD Classification in Study 
CO-338-017 Part 1 .................................................................................................35 
Table 2. 
Description of Rucaparib Tablets ..........................................................................61 
Table 3. 
Description of Nivolumab for Injection .................................................................61 
Table 4. 
Dose Modification and Re-treatment Criteria for Oral and IV Study Drugs .........64 
Table 5. 
Oral Study Drug Dose Reduction Steps .................................................................69 
Table 6. 
Study CO-338-097 Schedule of Assessments ........................................................77 
Table 7. 
Pharmacokinetic and Immunogenicity Sample Collections ..................................83 
Table 8. 
Peripheral Blood Biomarker Sample Collection ....................................................84 
Table 9. 
Blood Sample Collection for ctDNA .....................................................................84 
Table 10. 
Causal Relationship of Adverse Events to Study Drug .......................................104 
Table 11. 
RECIST and GCIG CA-125 Criteria ...................................................................108 
 
LIST OF IN-TEXT FIGURES 
Figure 1. 
Study Design and Plan ...........................................................................................49 
Figure 2. 
Study Schema.........................................................................................................54 
 
LIST OF APPENDICES 
Appendix 1 
Response Evaluation Criteria in Solid Tumors Criteria ......................................127 
Appendix 2 
Modified Gynecological Cancer Intergroup (GCIG) Guidelines for  
Response Using CA-125 ......................................................................................133 
Appendix 3 
ECOG Performance Status Scale .........................................................................134 
Appendix 4 
Examples of CYP Substrates with Narrow Therapeutic Range ...........................135 
Appendix 5 
Example Strong CYP3A Inhibitors or Inducers ..................................................136 
Appendix 6 
Management Algorithms for Immuno-oncology Agents .....................................137 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
2QW 
twice weekly 
ADA 
anti-drug antibody 
ADP 
adenosine diphosphate 
AE 
adverse event 
AESI 
adverse event of special interest 
AIDS 
acquired immunodeficiency syndrome 
ALCOA-C 
attributable, legible, contemporaneous, original, accurate, complete 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
Bcl-xL 
B-cell lymphoma-extra large 
BCRP 
breast cancer resistance protein 
BER 
base excision repair 
BID 
twice a day 
BMS 
Bristol-Myers Squibb 
BRCA 
breast cancer gene 
BRCA1 
breast cancer gene 1 
BRCA2 
breast cancer gene 2 
BRCAwt 
wild-type breast cancer gene 
BRCAwt/LOHhigh 
wild-type breast cancer gene and high loss of heterozygosity (LOH ≥ 16%) 
BRCAwt/LOHlow 
wild-type breast cancer gene and low loss of heterozygosity (LOH < 16%) 
BRCAwt/LOHunknown 
wild-type breast cancer gene and unknown loss of heterozygosity (LOH 
unknown due to missing results and/or failed test result(s)) 
BTLA 
B and T lymphocyte attenuator 
BUN 
blood urea nitrogen 
Cav,ss 
average nivolumab steady-state exposures 
CA-125 
cancer antigen 125 
CD 
cluster of differentiation 
Ceoi 
concentration at the end of infusion 
CFR 
Code of Federal Regulations 
CI 
confidence interval 


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CL 
clearance 
CLcr 
creatinine clearance 
CLss 
steady-state clearance 
Cmax 
maximum concentration 
Cmax,ss 
steady-state maximal concentrations 
Cmin1 
trough concentration after first dose 
Cmin,ss 
steady-state trough concentrations 
CMV 
cytomegalovirus 
CO2/HCO3- 
Bicarbonate 
CR 
complete response  
CRO 
contract research organization  
CT 
computed tomography 
ctDNA 
circulation tumor DNA 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA 
cytotoxic T-lymphocyte-associated protein 4 
CV% 
percent coefficient of variation 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DNA 
deoxyribonucleic acid 
DNAseq 
deoxyribonucleic acid sequencing 
DOR 
duration of response 
DMC 
Data Monitoring Committee 
EC 
European Commission 
EC50 
half-maximal effective concentration 
ECG 
electrocardiogram 
ECL 
electrochemiluminescent 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EMA 
European Medicines Agency 
ENGOT 
European Network for Gynecological Oncological Trial groups 
EOC 
epithelial ovarian cancer 
ER 
exposure-response 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 


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FMI 
Foundation Medicine, Inc. 
FSH 
follicle-stimulating hormone 
fT3 
free thyroxine 
fT4 
free triiodothyronine 
FU-28 
28-day Follow-up Visit after last dose of study drug (oral or IV, whichever is 
later) 
FU-100 
100-day Follow-up Visit after last dose of IV study drug 
FTC 
fallopian tube cancer 
gBRCA 
germline BRCA 
gBRCAmut 
germline BRCA mutation 
gBRCAwt 
germline BRCA wild-type 
GCIG 
Gynecologic Cancer InterGroup 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GFR 
glomerular filtration rate 
GOG 
Gynecologic Oncology Group 
H&E 
hematoxylin and eosin 
HDPE 
high-density polyethylene 
HGSOC 
high-grade serous ovarian cancer 
HIPAA 
Health Information Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRD 
homologous recombination deficiency 
HRR 
homologous recombination repair 
HuMAb 
human monoclonal antibody 
IB 
Investigator’s Brochure 
IC50 
half-maximal inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
ICJME 
International Committee of Medical Journal Editors 
ICOS 
inducible T-cell co-stimulator 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IgG4 
immunoglobulin G4 
IL 
interleukin 
IMAE 
immunotherapy-related adverse event 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
I-O 
immuno-oncology 


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IRB 
Institutional Review Board  
IRR 
independent radiology review 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
LD 
longest diameter 
LDH 
lactate dehydrogenase 
LOH 
loss of heterozygosity 
LOHhigh 
high loss of heterozygosity 
LOHunknown 
unknown loss of heterozygosity, due to missing results and/or failed test 
result(s) 
MATE 
multidrug and toxin extrusion transporter 
mCRPC 
metastatic castration-resistant prostate cancer 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NGS 
next-generation sequencing 
NSCLC 
non-small cell lung cancer 
OCT 
organic cation transporter 
ORR 
objective response rate 
OS 
overall survival 
PARP 
poly (adenosine diphosphate [ADP]-ribose) polymerase 
PARPi 
PARP inhibitor 
PD 
progressive disease 
PD-1 
programmed death-1or programmed death receptor 1 
PD-L1/PD-L2 
programmed-death ligand 1/2  
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic 
PMDA 
Japanese Pharmaceuticals and Medical Devices Agency 


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PO 
oral 
PPC 
primary peritoneal cancer 
PPI 
proton pump inhibitors 
PPK 
population pharmacokinetics 
PR 
partial response 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
QD 
once a day 
RBC 
red blood cell 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
statistical analysis software 
sBRCA 
somatic breast cancer gene 1 or 2 mutation 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease 
StD 
standard deviation 
SmPC 
Summary of Product Characteristics 
SOC 
system organ class 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
half-life 
TAI 
telomeric allelic imbalance 
tBRCAmut 
tumor tissue BRCA1 or BRCA2 mutation, includes gBRCA and sBRCA 
mutations 
TCGA 
The Cancer Genome Atlas 
TEAE 
treatment-emergent adverse event 
TILs 
tumor infiltrating lymphocytes 
TMB 
tumor mutational burden 
TSH 
thyroid stimulating hormone 
UGT 
uridine diphosphate glucuronosyltransferase 
ULN 
upper limit of normal 
US 
United States 
USPI 
United States Prescribing Information 
Vss 
volume of distribution at steady-state 
WBC 
white blood cell 


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1 
INTRODUCTION 
Study CO-338-097 is a Phase 2, open-label study to evaluate rucaparib in combination with 
nivolumab in patients with either high-grade serous or endometrioid epithelial ovarian (EOC), 
fallopian tube (FTC), or primary peritoneal (PPC) cancer, referred to collectively as ovarian 
cancer. 
The ovarian cancer cohorts will include patients who have either: 
• Cohort A1: germline breast cancer gene wild-type (gBRCAwt) , or 
• Cohort A2: a germline breast cancer gene mutation (gBRCAmut). 
Patients in Cohorts A1 and A2 are to have received 1 or 2 prior regimens (including at least 
1 prior platinum-containing regimen), be sensitive to their last platinum regimen, and (for 
Cohort A1) have radiologic progression during or after the most recent regimen. 
The ovarian cancer cohorts planned for this study represent populations of patients who may be 
responsive to the combined therapy given the molecular characteristics of their tumors and 
mechanisms of action of rucaparib and nivolumab. 
1.1 
Background 
1.1.1 
Ovarian Cancer 
Globally, ovarian cancer is the seventh most common cancer and the eighth leading cause of 
cancer death among women, responsible for approximately 150,000 deaths each year.17 The 
median age at presentation of EOC is 60 years. Unfortunately, because of delayed presentation 
and diagnosis, almost 70% of women with ovarian cancer are diagnosed in the later stage of 
disease (Stage III/IV), and these women have particularly poor outcomes.18 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.19 The site of 
origin of EOC remains unclear. Some studies suggest that serous EOC and PPC arise from the 
fallopian tube epithelium; however, other studies suggest an origin within stem cells of the 
ovarian surface epithelium.19-22 EOC, PPC, and FTC behave very similarly and are therefore 
treated in the same way. 
The standard approach to treatment of advanced ovarian cancer 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 8 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 
3 or 4 cycles of primary chemotherapy, followed by 3 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 intrastrand-cross links with deoxyribonucleic acid 
(DNA).19,23 Despite a 70% to 80% initial response rate,18,24,25 most women with advanced 
ovarian cancer will experience disease relapse, usually within 15 months of initial diagnosis.  


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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.26 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. Patients with a ≥ 6 to 12-month interval are considered to 
have partially platinum-sensitive disease, while those with a ≥ 12-month interval are considered 
to have fully platinum-sensitive disease. However, all of 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 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 (such as the presence of a 
BRCA mutation). For the patients enrolled in clinical studies of rucaparib, patients were 
considered sensitive if they had progressive disease (PD) ≥ 6 months after the last dose of 
platinum, resistant if they had PD 0 to < 6 months after the last dose of platinum and with a best 
of response to treatment other than PD, or refractory if they had a best response of PD during 
platinum treatment or PD ≤ 2 months after the last dose of platinum. 
Treatment decisions for relapsed ovarian cancer are driven in part by type of response achieved 
and the duration between completion of treatment and disease relapse. Patients with 
platinum-sensitive disease are typically retreated with platinum-based therapy until they no 
longer respond to or can no longer tolerate such treatment.18,24,25 Patients with platinum-resistant 
disease have more limited treatment options such as bevacizumab in combination with 
chemotherapy (paclitaxel, pegylated liposomal doxorubicin [PLD], or topotecan)27,28 or 
single-agent treatment with PLD, topotecan, gemcitabine, or weekly paclitaxel. However, these 
agents have limited utility due to poor efficacy (objective response rates [ORR] ranging 20% to 
30% with median progression-free survival [PFS]/time to tumor progression < 6 months) and are 
accompanied by significant toxicities that further reduces the ultimate therapeutic benefit. In 
later lines of therapy, treatment choice is often restricted according to the individual patient 
situation (eg, performance status, organ function, residual toxicities from prior treatment, other 
comorbidities, and patient choice). 
Despite advances in treatment, including targeted therapies such as anti-angiogenesis agents and 
PARP inhibitors for advanced treatment settings, there has been little improvement in ovarian 
cancer outcomes, highlighting a clear need for new and more effective treatments for patients 
with recurrent ovarian cancer.29,30 
 
 


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1.1.2 
Rucaparib 
Rucaparib is a potent, oral small molecule inhibitor of poly (adenosine diphosphate [ADP]-
ribose) polymerase (PARP) enzymes, including PARP-1, PARP-2, and PARP-3, that play a 
critical role in base excision repair (BER).1 
In the United States (US), rucaparib received accelerated approval in December 2016 as 
monotherapy treatment for ovarian cancer, followed by a regular approval in April 2018, as both 
monotherapy treatment (Section 1.1.2.3.2.1) and maintenance treatment (Section 1.1.2.3.2.2) for 
ovarian cancer.5 In the European Union (EU), rucaparib was authorized in May 2018 as 
monotherapy treatment (Section 1.1.2.3.2.1), and in January 2019 as maintenance treatment 
(Section 1.1.2.3.2.2) for ovarian cancer.4 The mechanism of action and summary of data from 
nonclinical and clinical studies are provided below, and described in more detail in the rucaparib 
Investigator’s Brochure (IB). A summary of the benefit:risk is also provided in the rucaparib IB. 
1.1.2.1 
Mechanism of Action 
When PARP function is impaired, double-stranded DNA breaks accumulate in the absence of 
effective BER; in cells deficient in homologous recombination, these breaks cannot be accurately 
repaired, resulting in synthetic lethality.2 An analysis of the Cancer Genome Atlas (TCGA), 
which examined molecular changes associated with high-grade serous ovarian cancer (HGSOC), 
estimated that approximately 50% of patients with HGSOC have homologous recombination 
deficiency (HRD).10 Similarly, based on an analysis of TCGA bladder cancer data set 
(http://cancergenome.nih.gov), approximately 60% of bladder cancer tumors may have HRD 
(Clovis Oncology, Inc. [Clovis], data on file). 
While mutations in BRCA1 and BRCA2 are gene mutations most commonly associated with 
HRD, other essential homologous recombination repair (HRR) proteins may be mutated or 
functionally deficient in ovarian and other cancers. Over the past decade, it has been determined 
that patterns of genomic LOH can predict HRD.3 Comprehensive genomic profiling based on 
next generation sequencing (NGS) can be utilized to identify non-BRCA-mutant (ie, BRCAwt) 
patients with HRD. The main advantage of detecting tumor genomic LOH is that it can identify 
HRD tumors regardless of the underlying mechanisms.3,31 An analysis of mature data from 
previous rucaparib clinical studies which enrolled platinum-sensitive patients, suggested that an 
LOH cut-off of 16% or greater for the BRCA wild-type (BRCAwt) subgroup provided the 
optimum discrimination of rucaparib treatment benefit; this group is referred to as LOH high or 
the BRCAwt/LOHhigh subgroup.16,32 In addition, data also support that BRCA wild-type 
(BRCAwt) patients with unknown LOH (BRCAwt/LOHunknown) or low LOH (BRCAwt/LOHlow), 
also benefit from treatment.16,32 
Given the overlap in various DNA repair pathways, inhibition of a single pathway is unlikely to 
have a significant effect on cancer cell death. Inhibition of DNA damage repair in cancer cells 
represents an attractive opportunity for the development of new therapies. In normal cells, 
single-strand breaks (SSBs) in DNA are repaired through BER via PARP enzymes. SSBs that are 
not repaired result in stalled replication forks and the development of double-strand breaks 
(DSBs), which are in turn primarily repaired by HRR of DNA, a complex process involving 
multiple proteins. Homologous recombination pathway defects, either as an initiating event or a 


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late event in the carcinogenetic process, may be responsible for the genetic instability observed 
in many cancers. 
Inhibition of multiple DNA repair pathways may lead to cell death, a concept known as synthetic 
lethality. For example, normal cells treated with a PARP inhibitor still have other intact DNA 
repair pathways and are able to survive, whereas cancer cells, with pre-existing HRD, treated 
with a PARP inhibitor accumulate DNA damage and enter apoptosis. This concept of synthetic 
lethality has been demonstrated in key in vitro and in vivo studies, as well as in several clinical 
studies that evaluated a single-agent PARP inhibitor.33-35 
1.1.2.2 
Nonclinical Experience 
The results from nonclinical studies are consistent with the mechanism of action and 
pharmacological effects of PARP inhibition.  
Pharmacological assessment demonstrated that rucaparib is a potent and selective inhibitor of 
PARP-1, PARP-2, and PARP-3 and has robust and durable in vitro and in vivo activity in 
multiple BRCA1/2-mutant cell lines and xenograft models. Rucaparib was also active in a 
BRCA wild-type model, consistent with in vitro data suggesting that rucaparib is active in cells 
with other defects in HRR through synthetic lethality. In vitro screens suggested that rucaparib 
has a limited potential for off-target effects. Safety pharmacology studies suggest that when 
given orally, rucaparib poses a low risk for causing neurobehavioral and cardiac effects in 
patients. 
In pharmacokinetic (PK) studies, rucaparib demonstrated species-dependent oral bioavailability, 
moderate plasma protein binding, and large volumes of distribution in nonclinical species. As a 
P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) substrate, rucaparib 
demonstrated minimal penetration of rucaparib-derived radioactivity through the blood-brain 
barrier. In vitro data suggested slow metabolism by cytochrome P450 (CYP) enzymes, with 
CYP2D6 and to a lesser extent CYP1A2 and CYP3A4 contributing to the metabolism of 
rucaparib. Rucaparib was mainly excreted in feces in rats and dogs. Rucaparib reversibly 
inhibited CYP1A2, CYP2C9, CYP2C19, and CYP3A, and to a lesser extent CYP2C8, CYP2D6, 
and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). Rucaparib induced CYP1A2, 
and down-regulated CYP2B6 and CYP3A4 in human hepatocytes at clinically-relevant 
exposures. Rucaparib is a potent inhibitor of multidrug and toxin extrusion 1 (MATE1) and 
MATE2-K, a moderate inhibitor of organic cationic transporter 1 (OCT1), and may inhibit P-gp 
and BCRP in the gut. 
Oral dosing of rucaparib in single- and repeat-dose toxicity studies in rats and dogs resulted in 
toxicity to the hematopoietic, lymphopoietic, and gastrointestinal systems. These toxicities were 
generally both reversible upon recovery and predictive of toxicities observed in patients. 
Rucaparib was shown to be clastogenic in an in vitro chromosomal aberration assay suggesting 
potential genotoxicity in humans. Reproductive and development toxicity studies in rat showed 
that rucaparib caused maternal toxicity and was embryo-toxic. Although no rucaparib related 
effects on sperm total count, density, motility, or morphology were identified, based on 
published studies, PARP inhibitors have the potential to impair spermatogenesis and reduce 
fertility.36-38  


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1.1.2.3 
Clinical Experience 
Rucaparib monotherapy is being evaluated in Phase 1, 2, and 3 clinical studies in patients with 
advanced cancer with and without evidence of HRD. Clinical studies evaluating rucaparib as 
monotherapy treatment or maintenance treatment in patients with relapsed, high-grade EOC, 
FTC, or PPC are ongoing. In addition, Phase 2 and Phase 3 studies of rucaparib monotherapy 
treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) are ongoing. 
Clinical pharmacology studies in patients with advanced solid tumors continue to more fully 
characterize rucaparib drug-drug interactions (DDI), mass balance and drug metabolism, as well 
as PK in special populations are ongoing. 
Additional studies of rucaparib as monotherapy and in combination with other anticancer 
therapies, including immune checkpoint inhibitors, are ongoing in ovarian and prostate cancer, as 
well as other tumor types. 
1.1.2.3.1 
OVERVIEW OF PHARMACOKINETICS AND DRUG-DRUG INTERACTIONS 
Assessment of rucaparib PK in cancer patients showed an approximate dose proportional 
exposure after once daily (QD) or twice daily (BID) dosing, rapid absorption with maximum 
concentration (Cmax) achieved within 1.5 to 6 hours, and distribution into tissue. The oral 
bioavailability was 36% and elimination half-life (t1/2) ranged from 11 to 29.8 hours. Rucaparib 
was moderately bound to human plasma proteins in vitro (70%). The steady-state was achieved 
following 1 week of dosing with rucaparib BID, with approximately 4-fold accumulation. 
At a dose of 600 mg BID rucaparib, steady-state was achieved after approximately 1 week. A 
high-fat meal increased the Cmax and area under the curve (AUC)0-24h of rucaparib by 20% and 
38%, respectively, as compared with that under fasted conditions. 
In vitro, rucaparib showed slow enzymatic turnover in human liver microsomes and hepatocytes. 
Recombinant CYP2D6, and to a lesser extent CYP1A2 and CYP3A4, were able to metabolize 
rucaparib.  
Drug interactions with rucaparib as a substrate were assessed in a population PK (PPK) analysis. 
CYP2D6 phenotypes (poor metabolizers, intermediate metabolizers, normal metabolizers, and 
ultrarapid metabolizers) and CYP1A2 phenotypes (normal metabolizers and hyper-inducers) did 
not significantly impact the steady-state exposure of rucaparib at 600 mg BID. Concomitant 
administration of strong CYP1A2 or CYP2D6 inhibitors did not significantly impact rucaparib 
PK. Current smokers had overlapping rucaparib exposures as compared to nonsmokers and 
former smokers. Collectively, the results suggest that CYP1A2 and CYP2D6 play limited role in 
rucaparib metabolism, and no rucaparib dose adjustment is needed when concomitantly 
administered with CYP inhibitors. 
Concomitant treatment with proton pump inhibitors (PPIs) showed no clinically significant effect 
on rucaparib PK. No dose modification of rucaparib is required for patients who are receiving 
concomitant treatment with a PPI. 


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Results from Study CO-338-044 evaluating potential DDI with rucaparib, indicated that 
rucaparib, at 600 mg BID, moderately inhibited CYP1A2, weakly inhibited CYP2C9, CYP2C19, 
and CYP3A, and showed no clinically significant effect on P-gp. Caution should be exercised in 
the concomitant use of drugs that are substrates of the above CYP enzymes with narrow 
therapeutic windows. 
Results from the mass balance and metabolite profiling Study CO-338-045 showed rucaparib 
excretion primarily in feces, followed by urine. The PK profile obtained for the female patients 
enrolled in this study were similar to those reported previously for male patients. M324 derived 
from oxidation of rucaparib was the major metabolite identified. Other metabolic pathways 
included N-demethylation, N-methylation, glucuronidation, and N-formulation.  
1.1.2.3.2 
OVERVIEW OF EFFICACY 
1.1.2.3.2.1 
Rucaparib as Monotherapy Treatment for Ovarian Cancer 
Rucaparib (Rubraca®) received accelerated approval in December 2016, followed by regular 
approval in April 2018, by the US Food and Drug Administration (FDA) for treatment of 
patients with deleterious BRCA mutation (germline and/or somatic)-associated EOC, FTC, or 
PPC who have been treated with 2 or more chemotherapies.5 In May 2018 , the European 
Commission (EC) authorized rucaparib (Rubraca) 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.4 The recommended dose of rucaparib is 600 mg BID. The basis for the approval 
of rucaparib as monotherapy for the treatment of ovarian cancer are the datasets and analyses for 
patients with EOC, FTC, or PPC comprising the primary efficacy analysis population. The 
primary efficacy analysis population included 106 patients, of whom 79 were platinum-sensitive, 
pooled from the open-label, single-arm Phase 2 studies, Study CO-338-010 (Study 10) Part 2A 
and Study CO-338-017 (ARIEL2) Parts 1 and 2, with BRCA-mutant ovarian cancer (EOC, FTC, 
or PPC), who had received ≥ 2 prior chemotherapy regimens, at least 2 of which were 
platinum-based, and who had received at least 1 dose of 600 mg rucaparib.5  
The primary outcome measure on which approval was based is investigator-assessed ORR per 
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), with ORR by central 
independent radiological review conducted as a supportive analysis. ORR by investigator was 
53.8%, while ORR by independent review was 41.5%, confirming the results of investigator 
assessment for this endpoint.39 Responses were durable, indicated by a duration of response 
(DOR) by investigator assessment of approximately 9.2 months.  
In Part 1 of Study CO-338-017, which supported approval of rucaparib as treatment for 
BRCA-mutant ovarian cancer, patients with platinum-sensitive, relapsed ovarian cancer who 
received ≥ 1 prior platinum regimen and the following HRD signatures were enrolled.  
• tBRCA: Patients whose tumor had a BRCA1/2 mutation, irrespective of genomic LOH 
measurement  


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• Non-tBRCA LOH+1: Patients whose tumor did not have a BRCA1/2 mutation and had a 
tumor genomic LOH ≥ 14% 
• Non-tBRCA LOH-: Patients whose tumor did not have a BRCA1/2 mutation and had a 
tumor genomic LOH < 14%. 
• Non-tBRCA LOH Unknown: Patients without a BRCA mutation and indeterminate for 
genomic LOH. 
Response data (from investigator-assessed responses) indicate that rucaparib has activity in 
patients classified into the different HRD subgroups (Table 1). The greatest activity was 
observed in patients with a tBRCA mutation, with a confirmed ORR of 80.0% and median DOR 
of 12.9 months. Confirmed response by RECIST or GCIG CA-125 criteria was 85.0%. Similar 
activity was demonstrated in gBRCA and sBRCA mutations, with confirmed ORRs of 85.0% 
(17/20) and 75.0% (15/20), respectively.16 
The majority (97.5% [39/40]) of tBRCAmut patients had some level of target lesion measurement 
reduction. Rucaparib was also effective in non-tBRCA LOH+ patients, with a confirmed ORR of 
28.0% and median DOR of 11.3 months. 
                                                 
1 Non-BRCA LOH+ is the nomenclature used in Study CO-338-017. This term is consistent with BRCAwt/LOHhigh 
used in the current protocol, although different cut-offs for LOHhigh were applied.  


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Table 1. 
Investigator-assessed Tumor Response by HRD Classification in 
Study CO-338-017 Part 1 
Parameter 
HRD Subgroup 
Total 
(N = 204) 
tBRCA 
(N = 40) 
non-tBRCA 
LOH+ 
(N = 82) 
non-tBRCA 
LOH- 
(N = 70) 
Non-tBRCA 
LOH 
Unknown 
(N = 12) 
Confirmed ORR 
(CR + PR) (n [%]) 
32 (80.0) 
23 (28.0) 
7 (10.0) 
4 (33.3) 
66 (32.4) 
Best Overall Confirmed Response (n [%]) 
CR 
6 (15.0) 
2 (2.4) 
1 (1.4) 
1 (8.3) 
10 (4.9) 
PR 
26 (5.0) 
21 (25.6) 
6 (8.6) 
3 (25.0) 
56 (27.5) 
SD 
7 (7.5) 
38 (46.3) 
43 (61.4) 
6 (50.0) 
94 (46.1) 
PDa 
1 (2.5) 
17 (20.7) 
17 (24.3) 
2 (16.7) 
37 (18.1) 
NE 
0 
4 (4.9) 
3 (4.3) 
0 
7 (3.4) 
Confirmed 
Response by 
RECIST or GCIG 
CA-125 (n [%]) 
34 (85.0) 
36 (43.9) 
14 (20.0) 
4 (33.3) 
91 (44.6) 
DOR (median, 95% 
CI [months])b 
12.9 (7.7-
18.2) 
11.3 (7.4-
16.6) 
5.8 (4.6-8.5) 
ND 
ND 
Abbreviations: CA-125 = cancer antigen 125; CR = complete response; DCR = disease control rate; 
DOR = duration of response; GCIG = Gynecologic Cancer InterGroup; ND = not determined; NE = not 
evaluable; ORR = objective response rate; PD = progressive disease; PR = partial response; RECIST = Response 
Evaluation Criteria in Solid Tumors; SD = stable disease. 
a Progressive Disease by RECIST or if no assessments were done, by reason for discontinuing study. 
b The Kaplan-Meier methodology was used to summarize DOR, based on confirmed responses per RECIST. 
 
1.1.2.3.2.2 
Rucaparib as Monotherapy Maintenance Treatment for Ovarian Cancer  
In both the US (April 2018) and EU (January 2019), rucaparib (Rubraca) is approved for 
maintenance treatment for adult patients with recurrent EOC, FTC, or PPC who are in a 
complete or partial response to platinum-based chemotherapy.4,5 Efficacy and safety data were 
from the Study CO-338-014 (ARIEL3), the pivotal study in support of the approval for the 
maintenance treatment indication.  
Efficacy of rucaparib monotherapy for patients with advanced ovarian cancer in the maintenance 
setting was demonstrated from Study CO-338-014 results showing significant benefit of 
rucaparib compared to placebo across primary, secondary, and exploratory endpoints.40 In this 
study, investigator-assessed PFS (invPFS) was the primary efficacy endpoint, with PFS by 
blinded central independent radiology review (IRR) conducted as a key, stand-alone, secondary 
endpoint. Rucaparib maintenance treatment significantly improved PFS compared with placebo 
in all primary analysis groups of patients with recurrent ovarian cancer after a complete or partial 
response to platinum-based therapy. The median invPFS for rucaparib vs. placebo was 
16.6 months vs. 5.4 months, 13.6 months vs. 5.4 months, and 10.8 months vs. 5.4 months, with 


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hazard ratios of 0.231 (p < 0.0001), 0.317 (p < 0.0001), and 0.365 (p < 0.0001), for the tBRCA, 
HRD, and ITT populations, respectively. The invPFS results were confirmed by the secondary 
endpoint analysis of PFS by independent review (irrPFS), with median irrPFS for rucaparib vs. 
placebo of 26.8 months vs. 5.4 months, 22.9 months vs. 5.5 months, and 13.7 months vs. 
5.4 months, with hazard ratios of 0.201 (p < 0.0001), 0.336 (p < 0.0001), and 0.354 (p < 0.0001), 
for the tBRCA, HRD, and ITT populations, respectively. 
Overall, rucaparib as maintenance treatment reduced the risk of progression by 63.5% (hazard 
ratio 0.365 [95% CI, 0.295 0.451]; p < 0.0001) in the intent-to-treat (ITT) population, 
demonstrating a strong treatment effect over placebo. Analysis of non-nested, non-overlapping 
patient subpopulations indicate that the significant improvement in PFS observed in the ITT 
population was not driven only by the HRD or tBRCA (deleterious tumor mutation in BRCA) 
subpopulations. Nearly half (44.6%) of the patients in the rucaparib group showed benefit at 
1 year compared to 8.8% in the placebo group.40 At 18 and 24 months, 32.0% and 26.0%, 
respectively, of patients who received rucaparib were still progression-free compared to 5.8% 
and 2.6% in the placebo group.40 These investigator-assessed results were confirmed by results 
of central IRR assessment.40 
1.1.2.3.3 
OVERVIEW OF SAFETY 
Results of an integrated safety analysis in over 1,000 patients with ovarian cancer who received 
600 mg BID rucaparib in the treatment or maintenance setting showed that the most common 
treatment-emergent adverse events (TEAEs) reported were primarily mild to moderate 
(Grade 1-2) in severity and include gastrointestinal disorders (nausea, vomiting, diarrhea, 
constipation, and abdominal pain), asthenia/fatigue, decreased appetite, and dysgeusia. The most 
common TEAE ≥ Grade 3 include anemia/decreased hemoglobin, ALT/AST increased, 
neutropenia/decreased absolute neutrophil count (ANC), and asthenia/fatigue. 
The laboratory abnormalities were consistent with the TEAEs, with decreased hemoglobin (and 
associated increase in mean corpuscular volume [MCV] and mean corpuscular hemoglobin 
[MCH]), increased ALT, increased AST, and increased serum creatinine, most commonly 
occurring. Decreased platelets, neutrophils, leukocytes, lymphocytes and increased cholesterol 
were observed to a lesser extent. The transient elevations in ALT/AST with rucaparib treatment 
in either the treatment or maintenance settings were not associated with abnormal increases in 
bilirubin or other criteria for drug-induced hepatotoxicity and generally resolved over time. 
Furthermore, no cases met Hy’s law criteria for drug-induced liver injury (DILI),41,42 and few 
patients discontinued rucaparib due to ALT/AST elevations.32,39 Similarly, elevations in 
creatinine were self-limiting and stabilized over time. The majority of creatinine elevations were 
Grade 1 or Grade 2. Elevated serum creatinine levels resolved upon interruption or 
discontinuation of rucaparib, were not accompanied by changes in blood urea nitrogen (BUN), 
and did not lead to discontinuation of rucaparib treatment. Increased creatinine with rucaparib 
treatment is likely due to the potent inhibition by rucaparib of MATE1 and MATE2-K renal 
transporters (Section 1.1.2.2). 
An updated analyses of safety presented in the US prescribing information5 and the EU 
Summary of Product Characteristics (SmPC)4 for the recent approvals of rucaparib demonstrate 
that safety results in ovarian cancer patients treated with rucaparib have remained consistent with 


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those previously reported, and that the safety profile across both the treatment and maintenance 
indications is consistent.5  
Effects on cardiac channel activity in vitro and a comprehensive assessment of the effects of 
rucaparib on electrocardiogram (ECG) parameters in cancer patients demonstrated a low risk of 
cardiac effects by rucaparib. 
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are considered adverse 
events of special interest (AESI), as these events have been observed in patients exposed to 
cytotoxic chemotherapy (eg, platinum and anthracyclines) used for treatment of ovarian cancer 
as well as with PARP inhibitors, including rucaparib. Patients in rucaparib clinical studies 
diagnosed with MDS or AML had significant confounding risk factors including prior cytotoxic 
chemotherapy, as well as a deleterious BRCA mutation. Based on these confounding factors, 
there is insufficient scientific evidence to conclude that MDS and AML are causally related to 
rucaparib. More information on AESIs experienced by patients in rucaparib clinical studies is 
provided in the rucaparib IB. 
1.1.3 
Nivolumab 
Nivolumab (also referred to as BMS-936558, MDX1106, or ONO-4538) is a human 
immunoglobulin G4 (IgG4) monoclonal antibody (HuMAb; IgG4-S228P) that binds to the PD-1 
cell surface membrane receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 
pathway-medicated inhibition of the immune response, including anti-tumor immune response. 
Nivolumab (OPDIVO®) monotherapy is approved in multiple regions, including the US43 and 
EU9, for unresectable or metastatic melanoma, previously-treated advanced renal cell carcinoma 
(RCC), previously-treated relapsed or refractory classical Hodgkin lymphoma, previously-treated 
recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN), 
previously-treated locally-advanced unresectable/metastatic non-small cell lung cancer 
(NSCLC), and previously-treated advanced or metastatic urothelial carcinoma. Nivolumab is 
also approved for the treatment of previously-treated metastatic colorectal cancer and 
previously-treated hepatocellular carcinoma in the US. In addition, nivolumab has been approved 
for use in combination with ipilimumab for unresectable melanoma in multiple countries, 
including the US and EU. Nivolumab is being investigated both as monotherapy and in 
combination with chemotherapy, targeted therapies, and other immunotherapies for the treatment 
of several types of cancer.  
In the US the approved recommended dose of nivolumab as monotherapy is 240 mg every 
2 weeks (Q2W) or 480 mg every 4 weeks (Q4W) administered as an intravenous (IV) infusion 
over 30 minutes until disease progression or unacceptable toxicity, with the exception of 
microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic 
colorectal cancer, where the recommended dose is 240 mg Q2W.  
In the EU, the approved recommended dose as monotherapy is 240 mg Q2W over 30 minutes or 
480 mg Q4W over 60 minutes in melanoma and renal cell carcinoma. In all other approved 
indications 240 mg Q2W over 30 minutes. 


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Overviews of results/data from nonclinical and clinical studies are provided below and described 
in detail in the nivolumab IB and the current prescribing information for nivolumab (SmPC)9, 
US prescribing information (USPI),43 or country-specific label) for more information. 
1.1.3.1 
Mechanism of Action 
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. 
Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to 
evade immunosurveillance and escape effective innate and adaptive immune responses.44-46 
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by either introducing cancer antigens by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system. T-cell stimulation is a complex 
process involving the integration of numerous positive, as well as negative, co-stimulatory 
signals in addition to antigen recognition by the T-cell receptor.47 Collectively, these signals 
govern the balance between T-cell activation and tolerance. 
PD-1 is a member of the cluster of differentiation 28 (CD28) family of T-cell co-stimulatory 
receptors that also includes CD28, cytotoxic T lymphocyte-associated protein-4 (CTLA-4), 
inducible T-cell co-stimulator (ICOS), and B and T lymphocyte attenuator (BTLA).48 PD-1 
signaling has been shown to inhibit CD-28-mediated upregulation of interleukin 2 (IL-2), IL-10, 
IL-13, interferon-γ (IFN-γ), and B-cell lymphoma-extra large (Bcl-xL). PD-1 expression also has 
been noted to inhibit T-cell activation and expansion of previously activated cells. Evidence for a 
negative regulatory role of PD-1 comes from studies of PD-1-deficient mice, which develop a 
variety of autoimmune phenotypes.49 These results suggest that PD-1 blockade has the potential 
to activate anti-self T-cell responses, but these responses are variable and dependent upon 
various host genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a 
universal loss of tolerance to self-antigens. 
In vitro, nivolumab binds to PD-1 with high affinity (half-maximal effective concentration 
[EC50] 0.39-2.62 nM), and inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 
(half-maximal inhibitory concentration [IC50] ±1 nM). Nivolumab binds specifically to PD-1 and 
not to related members of the CD28 family such as CD28, ICOS, CTLA 4, and BTLA. Blockade 
of the PD-1 pathway by nivolumab results in a reproducible enhancement of both proliferation 
and IFN-γ release in the mixed lymphocyte reaction. Using a cytomegalovirus (CMV) 
re-stimulation assay with human peripheral blood mononuclear cells, the effect of nivolumab on 
antigen-specific recall response indicates that nivolumab augmented IFN-γ secretion from 
CMV-specific memory T-cells in a dose-dependent manner versus isotype-matched control. In 
vivo blockade of PD-1 by a murine analog of nivolumab enhances the anti-tumor immune 
response and result in tumor rejection in several immunocompetent mouse tumor models (MC38, 
SA1/N, and PAN02).6 


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1.1.3.2 
Nonclinical Experience 
No mass balance or metabolism studies with nivolumab have been conducted in animals. The 
expected in vivo degradation of monoclonal antibodies is to small peptides and amino acids via 
biochemical pathways that are independent of drug metabolism enzymes. 
No formal PK DDI studies have been conducted with nivolumab. Nivolumab is not expected to 
have any effect on CYP P450 or other drug metabolizing enzymes in terms of inhibition or 
induction, and is, therefore, not expected to induce these types of PK-based drug interactions.  
In IV repeat-dose toxicology studies in cynomolgus monkeys, nivolumab was well-tolerated at 
doses up to 50 mg/kg, administered weekly for 5 weeks, and at doses up to 50 mg/kg, 
administered twice weekly for 27 doses. While nivolumab alone was well tolerated in 
cynomolgus monkeys, combination studies have highlighted the potential for enhanced toxicity 
when combined with other immunostimulatory agents. 
Administration of nivolumab at up to 50 mg/kg twice weekly (2QW) was well tolerated by 
pregnant monkeys; however, nivolumab was determined to be a selective developmental toxicant 
when administered from the period of organogenesis to parturition at ≥ 10 mg/kg. Specifically, 
increased developmental mortality was noted in the absence of overt maternal toxicity. There 
were no nivolumab-related changes in surviving infants tested throughout the 6-month postnatal 
period. Although the cause of these pregnancy failures was undetermined, nivolumab-related 
effects on pregnancy maintenance are consistent with the established role of PD-L1 in 
maintaining fetomaternal tolerance in mice.50 Human IgG4 is known to cross the placental 
barrier and nivolumab is an IgG4; therefore, nivolumab has the potential to be transmitted from 
the mother to the fetus. 
1.1.3.3 
Clinical Experience 
The PK, clinical activity, and safety of nivolumab have been assessed in patients with NSCLC, 
melanoma, clear-cell RCC, classical Hodgkin Lymphoma, urothelial carcinoma, SCCHN, in 
addition to other tumor types.  
1.1.3.3.1 
OVERVIEW OF PHARMACOKINETICS 
The PK of nivolumab was studied in patients with cancer over a dose range of 0.1 to 20 mg/kg 
administered as a single dose or as multiple doses of nivolumab every 2 or 3 weeks. Nivolumab 
clearance (CL) decreases over time, with a mean maximal reduction (% coefficient of variation 
[CV%]) from baseline values of approximately 24.5% (47.6%) resulting in a geometric mean 
steady-state clearance (CLSS) (CV%) of 8.2 mL/h (53.9%); the decrease in CLss is not considered 
clinically relevant. The geometric mean volume of distribution at steady state (VSS) was 6.8 L 
(27.3%), and geometric mean elimination t1/2 was 25 days (77.5%). Steady-state concentrations 
of nivolumab were reached by 12 weeks when administered at 3 mg/kg Q2W, and systemic 
accumulation was approximately 3.7-fold. The exposure to nivolumab increased dose 
proportionally over the dose range of 0.1 to 10 mg/kg administered Q2W. 
Population PK (PPK) and exposure-response (ER) analyses have been performed to support use 
of nivolumab 240 mg Q2W, 360 mg every 3 weeks (Q3W), and 480 mg Q4W dosing regimens 


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in patients with cancer, in addition to the 3 mg/kg Q2W regimen. A flat dose of nivolumab 
240 mg Q2W was selected since it is identical to a dose of 3 mg/kg for patients weighing 80 kg, 
the observed median body weight in nivolumab-treated cancer patients, while the nivolumab 
360 mg Q3W and 480 mg Q4W regimens allow flexibility of dosing with less frequent visits and 
in combination with other agents using alternative dosing schedules to Q2W. Using a PPK 
model, the overall distributions of nivolumab exposures (Cav,ss, Cmin,ss, Cmax,ss, and Cmin1) are 
comparable after treatment with either nivolumab 3 mg/kg or 240 mg Q2W. Following 
nivolumab 360 mg Q3W and 480 mg Q4W, Cav,ss are expected to be similar to those following 
nivolumab 3 mg/kg or 240 mg Q2W, while Cmin,ss are predicted to be 6% and ~16% lower, 
respectively, and are not considered to be clinically relevant. Following nivolumab 360 mg Q3W 
and 480 mg Q4W, Cmax,ss are predicted to be approximately 23% and 43% greater, respectively, 
relative to that following nivolumab 3 mg/kg Q2W dosing. However, the range of nivolumab 
exposures (median and 90% prediction intervals) following administration of 240 mg Q2W, 
360 mg Q3W, and 480 mg Q4W regimens across the 35 to 160 kg weight range are predicted to 
be maintained well below the corresponding exposures observed with the well-tolerated 
10 mg/kg nivolumab Q2W dosing regimen. 
1.1.3.3.2 
OVERVIEW OF EFFICACY 
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy and in 
combination with ipilimumab in several tumor types, including NSCLC, melanoma, RCC, 
classical Hodgkin Lymphoma, small-cell lung cancer, gastric cancer, SCCHN, urothelial cancer, 
hepatocellular carcinoma, and colorectal cancer. In confirmatory studies, nivolumab as 
monotherapy demonstrated a statistically significant improvement in OS as compared with the 
current standard of care in subjects with advanced or metastatic NSCLC, unresectable or 
metastatic melanoma, advanced RCC, or SCCHN. Nivolumab in combination with ipilimumab 
improved PFS and ORR over ipilimumab alone in subjects with unresectable or metastatic 
melanoma. 
In a small, open-label study conducted in Japan, Hamanishi, et al7 assessed the safety and 
anti-tumor activity of nivolumab in 20 patients with platinum-resistant, recurrent, or advanced 
ovarian cancer. Patients received up to 6 cycles of nivolumab at 1 mg/kg (n = 10) or 3 mg/kg 
Q2W (n = 10) (4 doses per cycle) or until disease progression. The best ORR by RECIST v1.1 
was 15% with 2 patients experiencing a durable complete response, and 4 patients achieving 
prolonged disease control. The activity of nivolumab was similar to what has been observed with 
chemotherapy in the platinum-resistant setting.51-53 However, the durability of the responses was 
an unexpected outcome, but a promising result in a heavily pretreated, difficult to treat, patient 
population. Notably, PD-L1 expression did not significantly correlate with response, highlighting 
the need to identify other markers that may be associated with activity. 
1.1.3.3.3 
OVERVIEW OF SAFETY 
For monotherapy, the safety profile is similar across tumor types. There is no pattern in the 
incidence, severity, or causality of adverse events (AEs) to nivolumab dose level. As 
monotherapy, the most common adverse reactions (≥ 20%) were fatigue, rash, musculoskeletal 
pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back 
pain, arthralgia, upper respiratory tract infection, and pyrexia. 


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The nivolumab IB, the current prescribing information for nivolumab (SmPC, USPI, or 
country-specific label) should be consulted for regarding special warnings and precautions and 
specific guidance on treatment modifications. 
The majority of treatment-related AEs observed with nivolumab treatment of ovarian cancer 
patients, including hypothyroidism and lymphocytopenia, had been reported in previous clinical 
studies of nivolumab in other solid tumors.7 The most frequently observed AEs were those 
related to thyroid function; nearly all events were Grade 1. The frequency and severity of 
treatment-related AEs were not different between the 2 dose cohorts.  
1.1.3.3.4 
IMMUNOGENICITY 
Of 2,085 patients who were treated with OPDIVO as a single agent 3 mg/kg Q2W and evaluable 
for the presence of anti-nivolumab antibodies, 233 patients (11.2%) tested positive for 
treatment-emergent anti-nivolumab antibodies by an electrochemiluminescent (ECL) assay and 
15 patients (0.7%) had neutralizing antibodies against nivolumab. There was no evidence of 
altered PK profile or increased incidence of infusion reactions with anti-nivolumab antibody 
development. Overall, there was no evidence of increased incidence of infusion reactions or 
effects on efficacy with anti-nivolumab antibody development. Clinically-relevant AEs typical of 
stimulation of the immune system were infrequent and manageable by delaying or stopping 
nivolumab treatment and timely immunosuppressive therapy or other supportive care. 
1.1.4 
PARP Inhibitors and Checkpoint Inhibitors 
1.1.4.1 
Nonclinical Overview 
Recent translational data suggest that ovarian cancer patients with a BRCA mutation may have a 
preferential response to immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway.13 
BRCA1- or BRCA2-mutant ovarian cancer patients have a higher number of protein coding 
mutations that can be potentially targeted by the immune system (termed neoantigens), a higher 
expression of PD-1 and PD-L1 in intratumoral immune cells, and an elevated number of 
CD3-positive and CD8-positive tumor infiltrating lymphocytes (TILs).13 These data suggest that 
PD-1/PD-L1-targeting immunotherapies may preferentially benefit BRCA1- or BRCA2-mutant 
ovarian cancer patients. In addition, non-tBRCA patients with HRD that can be identified by a 
NGS HRD test may well preferentially benefit from PD-1/PD-L1-targeting agents.16 Published 
data54 and internal data (Clovis) have demonstrated a significant association between genomic 
LOH and protein coding mutations, which provides an estimate of the tumor mutational burden 
(TMB) that may predict response to immune checkpoint inhibitors.  
1.1.4.2 
Clinical Overview 
The combination of immune checkpoint inhibitors and PARP inhibitors has been recently 
evaluated in 3 early-phase studies.14,15,55 In a Phase 1 dose-escalation study of PD-L1 inhibitor, 
durvalumab, in combination with PARP inhibitor, olaparib, in 12 heavily pretreated patients 
(10 with ovarian cancer and 2 with triple-negative breast cancer), there were 4 patients with 
partial response (duration of response ≥ 15 months and ≥ 11 months) and 8 patients with stable 
disease ≥ 4 months (median, 8 months [4 to 14.5 months]), yielding an 83% disease control 
rate.14 The most common TEAE with durvalumab plus olaparib was hematologic toxicity, with 


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no dose-limiting toxicity reported at the highest dose combination tested (olaparib 300 mg BID 
and durvalumab 1500 mg Q4W).  
In a Phase 1/2 study of niraparib and pembrolizumab in patients with ovarian cancer 
(NCT02657889) who were platinum-resistant/refractory or unable to tolerate further platinum, 
an integrated efficacy analysis of 60 evaluable patients out of 62 patients was performed. The 
objective response rate (ORR) was 18% (11/60) overall. Notably, in platinum-resistant/refractory 
patients, efficacy was observed across the biomarker-selected populations, including BRCA 
wild-type (ORR 18%) and HRD negative patients (ORR 19%).56 This may suggest that in this 
predominantly platinum-resistant ovarian cancer population, response to combination treatment 
was not determined by molecularly-defined HRD subgroups. 
In a Phase 1/1b study, the combination of anti-PD-1 BGB-A317 and PARP inhibitor BGB-290 
was generally well tolerated in 43 patients with advanced solid tumors.55 Liver-related AEs were 
observed in 12 patients; all events were reversible with or without corticosteroid treatment. 
Complete or partial response was observed in 11 patients, 4 of whom had confirmed partial 
response (PR) or complete response (CR); responses were durable and observed in patients with 
wild-type and mutant gBRCA status. Taken together, these studies have not identified any new 
safety signals with the combination of a PARP inhibitor and a PD-L1 inhibitor. 
Preliminary data from an ongoing Phase 2 study of the combination of durvalumab and olaparib 
in an unselected population with mCRPC demonstrated that the combination was well-tolerated 
and there was evidence of durable activity.15 
A Clovis-sponsored Phase 3 study (Study CO-338-087 [ATHENA]) is being conducted in 
collaboration with Bristol-Myers-Squibb (BMS), the Gynecological Oncology Group (GOG), 
and the European Network for Gynecological Oncological Trial group (ENGOT) to evaluate 
rucaparib in combination with nivolumab as a front-line switch maintenance treatment in 
platinum-sensitive relapsed ovarian cancer. This Phase 3 study in ovarian cancer is implementing 
oral rucaparib dosing 1 cycle prior to initiating combination treatment with oral rucaparib/IV 
nivolumab, as planned for the current protocol to explore if immune priming of the tumor 
microenvironment with monotherapy rucaparib will enhance the activity in combination with 
nivolumab. In addition, a BMS-sponsored Phase 2 study (CA2099KD; CheckMate Study) is 
being conducted to evaluate rucaparib in combination with nivolumab as treatment for mCRPC.  
As of 18 May 2018, data are available for 8 patients with Stage IV prostate cancer who have 
been treated with the combination of rucaparib and nivolumab in the Phase 2 CA2099KD study 
(Clovis, data on file). All patients received the full dose of nivolumab (480 mg IV q4 weekly) 
and rucaparib (600 mg BID continuous) in the first 28-day cycle. Overall, the commonly 
observed AEs were mild to moderate, and were consistent with the safety profile of rucaparib 
and nivolumab as single agents. Two of the 8 patients had Grade 1 rash, assessed as 
immune-mediated. The laboratory data were also consistent with what has been observed with 
rucaparib as a single agent. One patient had his rucaparib dose reduced from 600 mg BID to 
500 mg BID at the beginning of Cycle 3, due to Grade 2 ALT elevations. There were no patients 
with Grade 3/4 AEs or serious adverse events (SAEs) assessed as related to study treatment.  


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Overall, the data from the 8 patients treated with nivolumab 480 mg IV Q4W and rucaparib 
600 mg BID showed that the combination was well-tolerated, and there were no new safety 
signals identified.   
1.1.5 
Rationale for the Study and Benefit: Risk Assessment 
The purpose of this Phase 2 study is to evaluate the safety and efficacy of rucaparib in 
combination of nivolumab in patients with selected solid tumors who may be responsive to the 
combined therapy. HRD-related biomarkers associated with efficacy of rucaparib will also be 
explored as a means to further identify patients who may be responsive to rucaparib and as an 
informative tool for clinicians to make treatment decisions.   
1.1.5.1 
Rationale for Ovarian Cancer 
There is a clear and urgent clinical need for novel therapeutic approaches in advanced ovarian 
cancer. Despite the availability of newer and additional therapeutic options, ovarian cancer 
remains a major cause of death, with an estimated quarter of a million new cases per year 
worldwide and only 25% of patients with advanced ovarian cancer surviving long term.17 
Homologous recombination pathway defects may be responsible for the genetic instability 
observed in many cancers, including ovarian cancer. It is estimated approximately 50% of 
high-grade serous ovarian cancer patients have alterations in HRR genes.10 Clinical data with 
rucaparib have shown patients with and without a BRCA (germline or somatic) mutation benefit 
from rucaparib treatment in both the treatment and maintenance settings of ovarian cancer.16,32 
While patients with a BRCA mutation derived the most benefit, patients without evidence of a 
BRCA mutation also derived significant benefit, suggesting an incomplete understanding of 
biomarkers involved in sensitivity to PARP inhibition.57  
1.1.5.2 
Rationale for Rucaparib and Nivolumab Combination in Ovarian Cancer 
The preclinical rationale for combining rucaparib with nivolumab for treatment of ovarian cancer 
is supported by emerging data that demonstrate an association between high neoantigen load and 
high expression of PD-1/PD-L1 in HRD tumors when compared with homologous 
recombinant-proficient ovarian cancers.10-13 BRCA1 and BRCA2 mutations have been reported 
to increase the number of TILs and are associated with improved OS.13 In addition, internal data 
(Clovis) indicate a significant association between genomic LOH and TMB. A high TMB 
increases the likelihood of the development of tumor-specific neoepitopes that would confer 
clinical benefit from CTLA-4 and PD-1 blockade. Thus, it is hypothesized that increased DNA 
damage by PARP inhibition will increase the number of tumor neoantigens, creating a more 
antigenic environment in which to stimulate the immune microenvironment. 
In Cohorts A1 (main cohort) and A2 (exploratory cohort), monotherapy oral study drug will be 
administered in Cycle 1 prior to the initiation of the combination oral and IV study drug 
administration in Cycle 2 within this study to further explore the hypothesis that immune priming 
of the tumor microenvironment will enhance activity of the combination for treatment of ovarian 
cancer associated with either a gBRCAwt (Cohort A1) or a gBRCA mutation (Cohort A2). The 
gBRCAwt population in Cohort A1 represents a broad population of ovarian cancer patients and 
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combination with nivolumab represents a potential new therapy for the treatment of ovarian 
cancer patients with relapsed disease. In addition, the combination will be evaluated in the 
gBRCAmut ovarian cancer population16 included in the exploratory Cohort A2, for translational 
research to examine the impact of rucaparib on immune response in the tumor. The rationale for 
including Cohort A2 is based on preclinical data that suggest the activity of PARP inhibition and 
PD-L1 blockade is predominantly observed in HRD tumors (eg, BRCAmut) and that BRCAmut 
high-grade ovarian cancer tumors have higher tumor mutation burden (TMB), PD-L1 expression, 
and tumor infiltrating lymphocytes (TILs) compared to gBRCAwt tumors.13 Therefore, 
Cohort A2 will serve as a comparator to Cohort A1. 
Overall, the safety profiles of both rucaparib (oral study drug) and nivolumab (IV study drug) are 
manageable and generally consistent across completed and ongoing clinical studies 
(Section 1.1.4.2). Most AEs were low-grade (Grade 1 to 2) with relatively few related high-grade 
(Grade 3 to 4) AEs. A pattern of immunotherapy-mediated adverse events (IMAEs) associated 
with nivolumab has been defined, for which management algorithms have been developed; these 
are provided in Appendix 6. Most high-grade events were manageable with the use of 
corticosteroids or hormone replacement therapy (in the case of endocrinopathy) as instructed in 
these algorithms.  
Additional details on the safety profile of nivolumab and rucaparib, including results from other 
clinical studies, are also available in the respective drug IBs.  
To assure an ongoing favorable benefit:risk assessment for patients enrolled into the present 
study, the following measures will be employed throughout the conduct of the study: 
• A Data Monitoring Committee (DMC) will be established and meet to review safety, efficacy 
and study conduct, including review of data from the first 10 evaluable patients (Cohort A1), 
and subsequent periodic review of data thereafter. 
• Rigorous safety monitoring by the sponsor to ensure patients’ safety, including close 
follow-up of reported safety events, and intensive site and study investigator 
training/education on the implementation of the nivolumab toxicity management algorithms 
and toxicity management of the rucaparib and nivolumab combination.  
In conclusion, the overall benefit:risk of nivolumab in combination with rucaparib is deemed 
acceptable in ovarian cancer. Detailed information about the known and expected benefits and 
risks and reasonably anticipated AEs of nivolumab and rucaparib may be found in their 
respective IBs. 
1.2 
Dose Rationale 
1.2.1 
Dose Rationale for Nivolumab 
Intravenous flat doses of 240 mg Q2W nivolumab, 360 mg Q3W nivolumab, and 480 mg Q4W 
nivolumab have been incorporated in monotherapy and combination oncology studies, and the 
240 mg Q2W and 480 mg Q4W nivolumab dose regimens are now approved in multiple 
indications.8,9 Q4W dosing regimens can reduce the burden to patients of frequent, lengthy IV 
treatments and allow combination of nivolumab with other agents using alternative dosing 


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regimens. Nivolumab 480 mg Q4W is expected to have similar efficacy and safety profiles 
compared to nivolumab 240 mg Q2W and nivolumab 3 mg/kg Q2W.  
Extensive ER analyses of multiple PK measures (maximum serum concentration at Day 1[Cmax1], 
average serum concentration at Day 28 [Cavg28], and trough serum concentration at Day 28 
[Cmin28]) and efficacy and safety endpoints indicated that the efficacy of the flat-dose 480 mg IV 
regimen are similar to that of 3 mg/kg Q2W IV regimen (see nivolumab IB). In ER efficacy 
analyses for OS and ORR conducted in melanoma, RCC, and NSCLC using Cavg28 as the 
exposure measure, probabilities of achieving a response and survival probabilities at 1 year and 
2 years for IV 480 mg Q4W were similar to that of IV 3 mg/kg Q2W. In ER safety analyses, it 
was demonstrated that the exposure margins for safety are maintained following nivolumab 
480 mg Q4W, and the predicted risks of discontinuations due to AEs or death, AE Grade 3 or 
higher, and immune-mediated AEs (IMAEs) Grade 2 or higher are similar following nivolumab 
480 mg Q4W relative to nivolumab 3 mg/kg Q2W across tumor types. In addition, nivolumab 
exposures with 240 mg Q2W and 480 mg Q4W flat-dose IV regimens across tumor types are 
maintained well below the corresponding exposures observed with the well-tolerated 10 mg/kg 
IV nivolumab Q2W dose regimen. 
1.2.1.1 
Rationale for Nivolumab 30-minute Infusion 
Nivolumab is currently approved in the US at doses of 240 mg Q2W and 480 mg Q4W via a 
30-minute IV infusion.8 
1.2.2 
Dose Rationale for Nivolumab and Rucaparib Combination 
The recommended starting dose of rucaparib is 600 mg BID administered orally.58 Dose 
modifications should be implemented as described in Section 5.5. 
The starting dose for the combination of nivolumab plus rucaparib in this study will be the same 
as the monotherapy treatment. Rucaparib will be administered orally at 600 mg BID (as close as 
possible to 12 hours apart) on a 28-day cycle. Nivolumab will be administered at 480 mg via a 
30-minute IV infusion on Day 1 of every 28-day cycle, starting with Cycle 2 for Cohorts A1 and 
A2. The mechanisms of action of the 2 agents are different, and their toxicities are not predicted 
to be cumulative. Extending the dosing interval of IV study drug to Q4W, as described above, 
provides a convenience to patients on a 28-day treatment cycle. 
Further justification for these doses is provided based on previous early phase clinical studies of 
PARP inhibitors plus PD-1/PD-L1 inhibitors as discussed in Section 1.1.4.2. A Phase 1 
dose-escalation study of durvalumab in combination with olaparib in pretreated ovarian and 
triple-negative breast cancer patients was conducted.14 The dose levels for this combination are 
also being evaluated in an ongoing Phase 2 study in patients with mCRPC and appear to be 
well-tolerated, with the most common Grade 3/4 AEs also being hematologic toxicity.15 These 
studies have not identified any new safety signals when giving PARP inhibitor and an 
anti-PD-L1 antibody in combination. Study CA2099KD is an ongoing study in patients with 
prostate cancer to evaluate the combination of rucaparib and nivolumab, using the same doses of 
each agent that are proposed for this study (as described in Section 1.1.4.2). 


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The sponsor has initiated a Phase 3 study (Study CO-338-087 [ATHENA]) to evaluate the 
combination of rucaparib and nivolumab in newly diagnosed patients with advanced ovarian 
cancer as switch maintenance in women who have had a response to first-line platinum-based 
chemotherapy. Rucaparib and nivolumab are being administered at the same dose and regimen as 
proposed in the current protocol. Further, establishment of baseline laboratory values for each 
patient in Cohorts A1 and A2, following monotherapy oral drug and prior to beginning the 
combination therapy will help guide AE management during administration of the oral/IV 
combination therapy. The design is described in Section 3.1, and the analysis is described in 
Section 9.10. 
Please see Section 5.5 regarding appropriate dose modifications of the study drugs. 
1.3 
Rationale for Duration of Treatment 
1.3.1 
Nivolumab 
The optimal duration of immunotherapy is currently unknown. However, because 
immunotherapy engages the immune system to control the tumor, continuous treatment as is 
required with targeted agents or cytotoxic therapy may not be necessary. Accumulating evidence 
from different clinical studies in different tumor types treated with nivolumab indicates that most 
of the responses are generally occurring early, with a median time to response of 2 to 
4 months.59-63 A recent analysis in a melanoma study suggests the majority of patients who 
discontinue nivolumab and/or ipilimumab for toxicity maintain disease control in the absence of 
further treatment. Furthermore, a limited duration of ipilimumab including only 4 induction 
doses resulted in long-term survival in patients with metastatic melanoma, with a sustained 
plateau in survival starting at around year 3.64 For these reasons, in the current study, treatment 
with nivolumab will be given for up to 24 months in the absence of disease progression, 
unacceptable toxicity, withdrawal of patient consent, or the end of the study, whichever occurs 
sooner. 
1.3.2 
Rucaparib 
Rucaparib will be given for up to 25 months, 1 additional cycle over nivolumab) in the absence 
of disease progression, unacceptable toxicity, withdrawal of patient consent, or the end of the 
study, whichever occurs sooner. A total of 25 months was chosen to align with the duration of 
treatment for nivolumab. 


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2 
STUDY OBJECTIVES 
All objectives (unless otherwise specified) will be assessed for Cohorts A1 and A2. All 
endpoints will be summarized separately for each cohort.  
2.1 
Primary Objective  
The primary objectives of this study are: 
• To evaluate the ORR by RECIST v1.1 as assessed by the investigator (Cohort A1 only) 
• To study the effect of rucaparib on the immune microenvironment (Cohort A2 only) 
 
2.2 
Secondary Objectives  
The secondary objectives of this study, using the same comparisons as the primary objective, are: 
• To evaluate the ORR by RECIST v1.1 and Gynecologic Cancer InterGroup (GCIG) 
cancer antigen 125 (CA-125) criteria (Cohort A1only) 
• To evaluate the ORR by RECIST v1.1 as assessed by the investigator, according to 
molecularly-defined HRD subgroups: BRCAwt/LOHhigh; BRCAwt/LOHlow; 
BRCAwt/LOHunknown; and sBRCA (Cohort A1 only) 
• To estimate PFS (Cohort A1only) 
• To evaluate DOR (Cohort A1only)  
• To evaluate safety and tolerability of rucaparib in combination with nivolumab 
 
2.3 
Exploratory Objectives 
Exploratory objectives in this study are:  
• To evaluate the ORR by RECIST v1.1 as assessed by the investigator (Cohort A2 only) 
• To evaluate the ORR by RECIST v1.1 and GCIG CA-125 criteria (Cohort A2 only) 
• To estimate PFS (Cohort A2 only) 
• To evaluate DOR (Cohort A2 only)  
• To assess mutations in BRCA1, BRCA2, and other HRR genes as molecular markers of 
efficacy 
• To assess PD-L1 expression as a molecular marker of efficacy 
• To assess LOH, TMB, and other genomic and transcriptional signatures as molecular 
markers of efficacy 
• To study variants in circulating tumor DNA (ctDNA) as markers of response and 
resistance 


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• To characterize PK of rucaparib and nivolumab in combination 
• To evaluate immunogenicity of nivolumab when administered in combination with 
rucaparib  
• To explore ER relationship between selected exposure measures of rucaparib and 
nivolumab, and safety and efficacy endpoints 
• To study the effect of rucaparib on the immune microenvironment (Cohort A1 only) 
 


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3 
STUDY DESIGN 
3.1 
Overall Study Design and Plan 
The overall study design and plan is presented in Figure 1. 
Figure 1. 
Study Design and Plan 
Stage 1
Stage 2
Cohort A1
(gBRCAwt)
N=18 patients
Cohort A1 (Ovarian)
N=25 patients
≥ 3 responses 
≤ 2 responses 
DMC review benefit: risk if Cohort 
A1 should continue or terminate
Cohort  A2 
Exploratory  
(gBRCAmut)
N=10 patients
Ovarian
 
Abbreviations: DMC = Data Monitoring Committee; gBRCAmut = germline BRCA mutation; gBRCAwt = germline 
breast cancer wild-type gene; 
This is an open label, 2-stage, 2-cohort study to evaluate rucaparib in combination with 
nivolumab in patients with selected solid tumors: 
Cohort A: high-grade serous or endometrioid ovarian cancer 
Cohort A1: gBRCAwt  
Cohort A2: gBRCAmut (exploratory) 
 
The study will enroll patients with high-grade serous or endometrioid EOC, FTC, or PPC, with 
measurable disease per RECIST v 1.1 (in Cohort A1 only), who were sensitive to their last 
platinum regimen, and who received 1 or 2 prior regimens (including at least 1 prior 
platinum-containing regimen). 
For Cohort A1, patients must be gBRCAwt (ie, patients with a deleterious germline mutation in 
BRCA1 or BRCA2, as determined by a local laboratory that has received an international or 
country-specific quality standards certification, are excluded). 
For Cohort A2, patients must be gBRCAmut (as confirmed by local testing result).  
The study will use a Simon 2-stage design for Cohort A1. Patients that meet all eligibility criteria 
will be entered into the applicable study cohort. Refer to detailed information on the Simon 
2-stage calculations under the Determination of Sample Size (Section 9.2). 


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Unless contraindicated, a tumor sample will be collected from patients in Cohorts A1 and A2 
after initiation of rucaparib treatment, but before initiation of nivolumab treatment, and analyzed 
by the central laboratory to assess molecular markers of efficacy or resistance, as well as the 
effect of rucaparib on the immune microenvironment (Section 7.5.6.1). 
This study consists of a Screening Phase, a Treatment Phase, and a Post-treatment Phase.  
3.1.1 
Screening Phase 
A mandatory biopsy or resection of tumor tissue must be collected ≤ 42 days prior to first dose of 
rucaparib. Alternatively, tumor tissue collected > 42 days prior to the first dose of rucaparib may 
be submitted, provided there have been no intervening anticancer treatments during this period 
and the tissue is of adequate quality. Adequate tissue must be available  for analysis by the 
central laboratory for all patients enrolled. Patients may be enrolled prior to tumor tissue being 
analyzed by the central laboratory, provided there is confirmation that tumor tissue has been 
received by the central laboratory. Detailed information is provided in Section 7.5.6.1. 
All patients will undergo screening assessments within 28 days prior to enrollment.  
The study will enroll patients with either high-grade serous or endometrioid ovarian cancer 
(gBRCAwt or gBRCAmut). 
Screening assessments will include demographics and medical history, prior treatments for 
serous or endometrioid EOC, FTC, or PPC (and other malignancies, if applicable) , prior and 
current medications and procedures, 12-lead ECG, Eastern Cooperative Oncology Group 
(ECOG) performance status, local laboratory hematology and clinical chemistry, and CA-125 
measurement, urinalysis, physical examination, height, weight, and vital signs measurements, 
adverse events, radiologic assessment by computed tomography (CT) and/or other 
complementary assessments (MRI, X-ray, PET, and ultrasound) as required, and a blood sample 
for ctDNA analysis. Assessments performed within the specified windows, but prior to patient 
signing informed consent, are acceptable to be used as a study procedure only if confirmed to 
have been standard of care.  
Patients will be required to provide a mandatory screening biopsy for central laboratory analysis 
prior to enrollment. Patients may be enrolled prior to tumor tissue being analyzed by the central 
laboratory, provided there is confirmation that the tumor tissue has been received by the central 
laboratory. Genes of interest will be sequenced using Foundation Medicine, Inc. (FMI) NGS test, 
which examines a panel of cancer-related genes, including BRCA1/2 and other homologous 
recombination pathway genes, as well as those related to response or resistance to 
immunotherapies. The degree of genomic LOH will also be assessed for each tumor.3,31,54,65  
An analysis of mature data from previous rucaparib clinical studies in ovarian cancer that 
enrolled platinum-sensitive patients, showed that patients with a tBRCA mutation responded to 
rucaparib treatment, and also suggested that a cut-off of 16% or greater for the BRCAwt/LOHhigh 
subgroup provided the optimum discrimination of rucaparib treatment benefit.16,32 In addition, 
the data also support that BRCA wild-type (BRCAwt) patients with LOH, which is either 
unknown (BRCAwt/LOHunknown) or low (BRCAwt/LOHlow), also benefit from treatment.16,32 


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Patients participating in Cohort A1 of this study will be gBRCAwt (ie, patients with a deleterious 
germline mutation in BRCA1 or BRCA2, as determined by a local laboratory that has received 
an international or country-specific quality standards certification, are excluded). For ovarian 
cancer patients in Cohort A1, patients will be analyzed by molecularly-defined HRD subgroups 
prospectively (as defined in Section 9). 
The complete results of the NGS-based test will be provided to the physicians of all patients who 
opt to receive this information and provide appropriate consent. Tumor tissue results for the 
BRCA1/2 genes will be provided upon availability to patients who consent to receive this 
information. Note that per eligibility criteria for Cohorts A1 and A2, enrolled patients will be 
required to have adequate tumor tissue available prior to enrollment. Patients may be enrolled 
prior to tumor tissue being analyzed by the central laboratory, provided there is confirmation that 
the tumor tissue has been received by the central laboratory. Results for the remainder of the 
gene panel will be provided to consenting patients upon study treatment discontinuation. Results 
are to be disclosed to consenting patients by the study physician as part of an overall clinical 
discussion. In the event a mutation associated with hereditary cancer or other syndrome is 
detected in tumor tissue, the patient may be referred by the investigator for genetic counseling 
and potential germline testing per institutional guidelines.  
Mutations detected in tumor tissue may be somatic or germline; however, the NGS test will not 
distinguish between the two. A blood sample will therefore be collected for all patients at 
Cycle 1 Day 1 and stored. Prior to final efficacy analysis, genomic DNA may be tested to 
determine whether any mutation identified is of germline or somatic origin. These data may be 
provided to the investigator.  
Enrollment will require sponsor (or designee) review of eligibility, including, but not limited to: 
• The details of prior anticancer therapies; 
• Details of primary surgery and biopsies taken prior enrollment (if applicable); and 
• Confirmation that sufficient tumor tissue was submitted.  
 
3.1.2 
Treatment Phase 
The first dose of oral study treatment will be administered on Day 1 of Cycle 1 and continue BID 
throughout the cycle as monotherapy. Oral study drug administration will begin 28 days 
(1 cycle) prior to IV study drug administration to explore the hypothesis that immune priming of 
the tumor microenvironment with monotherapy rucaparib will enhance the activity in 
combination with nivolumab. Within 5 days and prior to commencement of IV nivolumab 
treatment on Cycle 2 Day 1 (= Cycle 1 Day 28 [window: −5 days), collection of a primary or 
metastatic tumor sample is mandatory, unless tumor biopsy procedure is contraindicated (eg, 
unacceptable risk in the opinion of the investigator). The tumor sample will be analyzed by the 
central laboratory to assess molecular markers of efficacy or resistance, as well as the effect of 
rucaparib on the immune microenvironment. Administration of IV study drug will begin on 
Day 1 of Cycle 2. Details on study drug administration are described in Section 5.4. 


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Patients will come into the study site for a visit on Day 1 and Day 15 of Cycles 1 and 2, and on 
Day 1 of every cycle thereafter. A blood sample will be collected from all patients at Cycle 1 
Day 1 and stored for subsequent genomic DNA testing and determination of germline status. 
Study treatment will continue in 28-day cycles until 24 months from the start of the oral/IV 
combination treatment (ie, 25 months ), disease progression, or unacceptable toxicity, whichever 
occurs first. Patients will undergo procedures and assessments, including regular safety, PK, and 
efficacy evaluations, during the entire conduct of the study. 
Tumor assessments by CT scan will be performed every 8 calendar weeks (±7 days) from the 
start of the oral/IV combination treatment on Cycle 2 Day 1, up to 18 months and then every 
12 calendar weeks (±7 days) thereafter and at the End of Treatment Visit, if applicable, until 
confirmed objective radiological disease progression, as assessed by the investigator. Tumor 
assessments are to be performed prior to the next scheduled IV nivolumab treatment. 
Patients experiencing confirmed disease progression by RECIST v1.1 will be discontinued from 
treatment and enter follow-up. If the patient has met criteria for confirmed radiologic progression 
by RECIST, but the patient is still receiving benefit from the study drug(s) according to the 
investigator (eg, patient has mixed radiologic response or is continuing to have symptomatic 
benefit), then continuation of treatment will be considered for a maximum cumulative duration 
of 24 months following initiation of combination treatment. In such cases, the decision to 
continue receiving treatment with study drug(s) must be documented in source documents, and 
the patient must provide additional consent at their next routine study visit. Patients will continue 
to have all protocol-required assessments specified in the Schedule of Assessments (Table 6) and 
Pharmacokinetic and Immunogenicity Sample Collections (Table 7). 
Safety and efficacy data will be periodically reviewed by the study Data Monitoring Committee 
(DMC) (Section 8.12).  
3.1.3 
End of Treatment 
Upon treatment discontinuation, regardless of reason, patients will have an End of Treatment 
Visit. Assessments will include AEs, physical examination, vital signs and weight 
measurements, hematology, clinical chemistry, and CA-125 measurement , 12-lead ECG, ctDNA 
analysis, concomitant medications, therapies and procedures, ECOG performance status, disease 
status assessment, and study drug accountability.  
An optional tumor biopsy will be collected from patients who experience disease progression 
and provide appropriate consent. This sample should be collected prior to any subsequent 
therapy. 
3.1.4 
Post-treatment Follow-up Phase 
All patients will be followed for at least 100 days (+7 days) after the last IV dose of study 
treatment. The 28-day Follow-up Visit (FU-28) should occur 28 days (±3 days) after last dose of 
study drug (oral or IV, whichever is later) or can be performed on the date of discontinuation if 
that date is at least 28 days from the last dose. Assessments will include AEs, physical 
examination, vital signs and weight measurements, local laboratory hematology, clinical 


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chemistry, and CA-125 measurement, ECG, ctDNA analysis, concomitant medications, therapies 
and procedures, and study drug accountability. Follow-up Visit for IV study drug (FU-100) 
should occur at least 100 days (+7 days) from the last IV dose of study drug. The same 
assessments performed at FU-28 will be performed at FU-100; however, clinical chemistry and 
hematology are only necessary if toxicities are present. If a patient remains on oral study drug 
after discontinuation of IV study drug, FU-100 can be performed at the next cycle visit, provided 
it has been at least 100 days (+7 days) since the last IV dose.  
Patients who discontinue treatment for reason other than disease progression or death should 
continue to have tumor scans performed at 12-week intervals from Cycle 2 Day 1 (flexibility 
with scheduling within 1 week prior to planned imaging date is permitted) until objective 
radiological disease progression by RECIST v1.1 is documented, as assessed by the investigator. 
Patients will also be followed long-term for survival, subsequent treatments, disease progression 
(if treatment discontinuation was for reason other than disease progression or death), and 
monitoring for secondary malignancy every 12 weeks (±14 days) until death, loss to follow-up, 
withdrawal of consent, or study closure.  
3.2 
Removal of Patients From Therapy or Assessment 
A patient must be discontinued from treatment with study drug if any of the following apply: 
• 
Consent withdrawal at the patient’s own request or at the request of their legally 
authorized representative. 
• 
Progression of patient’s underlying disease by RECIST v1.1 as assessed by the 
investigator, unless the patient is still receiving benefit from the study drug(s) according 
to the investigator, the investigator has consulted with the sponsor’s medical officer or 
designee, and the patient has provided additional consent at the next study visit.  
• 
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. 
• 
Noncompliance by the patient with protocol mandated procedures; and/or 
• 
A positive pregnancy test at any time during the study. 
• 
Study-specific treatment withdrawal rules for rucaparib and nivolumab (defined in 
Section 5.5.1.2).   
 
The sponsor may discontinue the study early for any of the reasons noted in Section 10.6. 
3.3 
Study Schema 
The study schema is provided in Figure 2. 


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Figure 2. 
Study Schema 
 
Screening Phase
(Day -28 to Day -1)a
Treatment Phase
Post-treatment Phase
Screening 
Assessments
Within 28 days of 
first dose of study 
medication 
(rucaparib/
nivolumab)b
Cycles 1 and 2
(28-day cycles)
Cycle 3 and beyond
 (28-day cycles)
Day
1
Day
15
Day
1
Tumor Scansc
Disease progression, unacceptable toxicity, or 
other reason for discontinuation of study 
medication
EOT Visit
 
After last 
dose of 
study 
medication
Follow-up 
(FU-28)
 28 ± 3 
days after 
last dosed 
of study 
medication
Follow-up
Long-
term 
Disease assessments will continue for 
patients who discontinued treatment 
for reason other than PDc
All patients will be followed for 
survival and subsequent therapies 
every 12 weeks.
Abbreviations: EOT = End of Treatment; FU-100 = 100-day Follow-up Visit after last dose of IV study drug; FU-28 = 28-day Follow-up Visit after last dose of 
study drug (oral or IV, whichever is later); PD = progressive disease
a  Mandatory tumor tissue collection for Cohorts A1 and A2 will be collected ≤ 42 days prior to the first dose of rucaparib (> 42d if no intervening therapy).   
b  For Cohort A1 and A2, within 28 days of first dose of oral rucaparib. 
c  Post-baseline tumor scans every 8 calendar weeks (±7 days) from the start of oral/IV combination treatment on Cycle 2 Day 1 for Cohorts A1 and A2, up to 18 
months, then every 12 calendar weeks (±7 days) thereafter.
d  Follow-up (FU-28) to occur 28 ±3 days after last dose of rucaparib and/or nivolumab, whichever occurs later.
Follow-up 
(FU-100) 
 100 + 7 
days after 
last dose 
of 
nivolumab
 


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3.4 
End of Study 
The study will close when all enrolled patients have discontinued treatment and completed the 
100-day Follow-up Visit (Section 7.4.7.3), and the LTFU, as applicable (Section 7.4.8). If the 
study is closed for any other reason, individual patients who are continuing to benefit from 
treatment with study drugs at the time of study closure, and who do not meet any of the criteria 
for withdrawal, may have the option of entering an extension protocol in which they can 
continue to receive study drugs. The sponsor may discontinue the study early for any reason as 
noted in Section 10.6. 
3.5 
Discussion of Study Design 
This is a multicenter, open-label, 2-stage, 2-cohort study to evaluate rucaparib in combination 
with nivolumab in patients with either high-grade serous or endometrioid ovarian cancer 
(Cohort A1 gBRCAwt; Cohort A2 gBRCAmut). 
In Cohort A1, rucaparib monotherapy oral study drug will be administered in Cycle 1 prior to the 
initiation of the combination oral and IV study drug administration in Cycle 2 within this study 
to explore the hypothesis that immune priming of the tumor microenvironment will enhance 
activity of the combination. This regimen will also be followed for the exploratory Cohort A2. 
Unless contraindicated, a tumor sample will be collected from patients in Cohorts A1 and A2 
after initiation of rucaparib treatment, but before initiation of nivolumab treatment, and analyzed 
by the central laboratory to assess molecular markers of efficacy or resistance, as well as the 
effect of rucaparib on the immune microenvironment (Section 7.5.6.1). 


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4 
STUDY POPULATION SELECTION 
4.1 
Number of Patients and Sites 
A total of 28 to 53 patients are planned for enrollment at approximately 15 study sites in the US: 
18 to 43 patients are planned for Cohort A1 (ovarian, gBRCAwt), 10 patients are planned for 
Cohort A2 (ovarian, gBRCAmut).  
4.2 
Inclusion Criteria 
Eligible patients must meet the following applicable inclusion criteria: 
1. Have signed an Institutional Review Board (IRB)/ Independent Ethics Committee (IEC)-
approved Informed Consent Form (ICF) prior to any study-specific evaluation. 
2.  ≥ 18 years of age at the time the ICF is signed 
3. Have adequate organ function confirmed by the following laboratory values obtained at 
screening (within 14 days prior to the first dose of study drug): 
a. Bone Marrow Function 
- 
ANC ≥ 1.5 × 109/L 
- 
Platelets ≥ 100 × 109/L  
- 
Hemoglobin ≥ 9 g/dL  
b. Hepatic Function 
- 
AST and ALT ≤ 1.5 × upper limit of normal (ULN) 
- 
Bilirubin ≤ 1.5 × ULN; < 2 × ULN if hyperbilirubinemia is due to Gilbert's 
syndrome 
- 
Serum albumin ≥ 30 g/L (3.0 g/dL) 
c. Renal Function 
- 
Serum creatinine ≤ 1.5 × ULN unless estimated glomerular filtration rate (GFR) 
≥ 30 mL/min using the Cockcroft Gault formula 
4. Have life expectancy ≥ 16 weeks, in the opinion of the investigator. 
5. Women of childbearing potential must have a negative serum pregnancy test ≤ 3 days 
prior to administration of the first dose of study drug 
6. Have a histologically confirmed diagnosis of high-grade serous or 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 
7. Have measurable disease as defined by RECIST v1.1 (Cohort A1 only) 
8. A mandatory biopsy or resection of tumor tissue must be collected ≤ 42 days prior to first 
dose of rucaparib. Alternatively, tumor tissue collected > 42 days prior to the first dose of 


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rucaparib may be submitted, provided there have been no intervening anticancer 
treatments during this period and the tissue is of adequate quality. See Section 7.5.6.1. 
Patients may be enrolled prior to tumor tissue being analyzed by the central laboratory, 
provided there is confirmation that the tumor tissue has been received by the central 
laboratory. 
9. (Cohort A1) Have gBRCAwt ovarian cancer (ie, patients with a deleterious germline 
mutation in BRCA1 or BRCA2, as determined by a local laboratory that has received an 
international or country-specific quality standards certification, are excluded). 
OR 
(Cohort A2) Have gBRCAmut ovarian cancer (ie, deleterious germline BRCA1/2 
mutation, as determined by a local laboratory that has received an international or country 
specific quality standards certification). 
10. Be willing to have a mandatory biopsy of tumor tissue collected at Cycle 1 Day 28 of 
treatment.  
11. Have relapsed/progressive disease as confirmed by radiologic assessment 
12. Received 1 or 2 prior regimens, including ≥ 1 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); 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. 
13. Have an ECOG performance status of 0 to 1 < 14 days prior to first dose of rucaparib. 
 
4.3 
 Exclusion Criteria 
Patients will be excluded from participation if any of the following applicable criteria apply: 
1. Active second malignancy, ie, patient known to have potentially fatal cancer present for 
which she may be (but not necessarily) currently receiving treatment. 
- 
Patients with a history of malignancy that has been completely treated, with no 
evidence of active cancer for 3 years prior to enrollment, or patients with 
surgically-cured low-risk tumors, such as early-stage cervical or endometrial cancer 
or non-melanoma skin cancers, are allowed to enroll. 
2. Known central nervous system brain metastases. 
3. Has evidence of interstitial lung disease, active pneumonitis, myocarditis, or a history of 
myocarditis. 


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4. Patients with an active, known or suspected autoimmune disease (eg, autoimmune 
hepatitis). Patients with type I diabetes mellitus, hypothyroidism only requiring hormone 
replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring 
systemic treatment, or conditions not expected to recur in the absence of an external 
trigger are permitted to enroll. 
5. Patients with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days of enrollment. Inhaled or topical steroids, and adrenal replacement steroid doses 
> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune 
disease. 
6. Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that would, in 
the opinion of the investigator, interfere with absorption of study treatment. 
7. Known history of positive test for HIV or AIDS. Note: Testing for HIV must be 
performed at all sites where mandated locally. 
8. Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, 
eg, hepatitis B surface antigen (HBsAg, Australia antigen) positive, or hepatitis C antibody 
(anti-HCV) positive (except if HCV-RNA negative). 
9. For female patients of childbearing potential, the following are exclusion criteria, as 
applicable: 
a. Refusal to use highly effective method of contraception or to practice true abstinence 
during treatment and for 6 months after the last dose of rucaparib study treatment. 
b. Pregnant or breast feeding.  
c. Women of childbearing potential must not be considering getting pregnant during the 
study and for 6 months following the last dose of rucaparib. 
10. Non-study related minor surgical procedure (eg, placement of a central venous access 
port) ≤ 5 days, or major surgical procedure ≤ 21 days, prior to first dose of study drug; in 
all cases, the patient must be sufficiently recovered and stable before treatment 
administration. 
11. Presence of any other condition that may increase the risk associated with study 
participation or may interfere with the interpretation of study results, and, in the opinion 
of the investigator, would make the patient inappropriate for entry into the study. 
12. Hospitalization for bowel obstruction within 12 weeks prior to enrollment. 
13. Prior treatment with a PARP inhibitor (PARPi) or immune checkpoint inhibitor. 
(Exception: patient is eligible if they received a prior PARPi as front-line maintenance 
therapy and patient did not have disease progression whilst on the PARPi, providing 
inclusion criterion 11 is also met at time of screening). 
14. Received treatment with chemotherapy, radiation, antibody therapy or other 
immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or experimental 
drugs ≤ 14 days prior to first dose of study drug and/or ongoing adverse effects from such 
treatment > NCI CTCAE v5.0 Grade 1, with the exception of Grade 2 non-hematologic 


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toxicity such as alopecia, peripheral neuropathy, and related effects of prior 
chemotherapy that are unlikely to be exacerbated by treatment with study drug.   
15. Non-epithelial tumors (pure sarcomas) or ovarian tumors with low malignant potential 
(ie, borderline tumors) or mucinous tumors. Mixed Mullerian tumors/carcinosarcomas 
are allowed. 
 
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. 
4.4 
Patients or Partners of Patients of Reproductive Potential 
Pregnancy is an exclusion criterion. Women of childbearing potential must not be considering 
getting pregnant and must avoid pregnancy during the study and for at least 6 months after the 
last dose of study drug (oral or IV, whichever is later), or longer if requested by local authorities.  
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 during the Treatment Phase and at the 
time of treatment discontinuation. Pregnancy testing will be conducted locally. Treatment should 
be discontinued immediately in any woman found to have a positive pregnancy test while taking 
rucaparib and/or nivolumab. 
Female patients are considered to be of childbearing potential unless 1 of the following applies: 
• Considered to be permanently sterile. Permanent sterilization includes hysterectomy, 
bilateral salpingectomy, and/or bilateral oophorectomy; or 
• 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.  
Female patients of reproductive potential must practice highly effective methods (failure rate 
< 1% per year) of contraception with their partners, if of reproductive potential, during treatment 
and for 6 months following the last dose of rucaparib and/or nivolumab, or longer if requested by 
local authorities. Highly effective contraception includes: 
• Ongoing use of progesterone only injectable or implantable contraceptives; 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS);  
• Bilateral tubal occlusion;  
• Sexual abstinence as defined as complete or true abstinence, acceptable only when it is the 
usual and preferred lifestyle of the patient; periodic abstinence (eg, calendar, 
symptothermal, post-ovulation methods) is not acceptable; or 


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• Male sterilization, with appropriate post vasectomy documentation of absence of sperm in 
ejaculate. 
Patients will be instructed to notify the investigator if pregnancy is discovered either during or 
within 6 months of completing treatment with study drug. 
4.5 
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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5 
STUDY TREATMENT(S) 
5.1 
Description of Treatment(s) and Storage 
Patients will receive open-label oral rucaparib + IV nivolumab combination treatment. 
5.1.1 
Investigational Drug Product – Rucaparib 
Rucaparib camsylate (also known as CO-338; formerly known as PF-01367338 and AG-014447) 
is an oral formulation. Rucaparib tablets for oral administration will be supplied to the study sites 
by the sponsor. A brief description of rucaparib is provided in Table 2 with details in the 
Pharmacy Manual. 
Table 2. 
Description of Rucaparib Tablets 
Drug Name: 
Rucaparib 
INN: 
Rucaparib 
Formulation:  
(strengths expressed as 
free base) 
Tablet; film coated; 200 mg (blue, round, debossed with C2), 250 mg 
(white, diamond shape, debossed with C25), 300 mg (yellow, oval, 
debossed with C3)  
How Supplied: 
200 mg, 250 mg, and 300 mg (as free base) strength tablets in 60 count 
bottles. Patients may receive one or more strengths.  
Storage Conditions: 
15–30°C (59–86°F). 
 
5.1.2 
Investigational Drug Product – Nivolumab 
Nivolumab, also referred to as BMS-936558-01 or BMS-936558, is a soluble protein consisting 
of 4 polypeptide chains, which include 2 identical heavy chains and 2 identical light chains 
(molecular weight: 146 kDa). A brief description of nivolumab is provided in Table 3 with 
details in the Pharmacy Manual. 
Table 3. 
Description of Nivolumab for Injection 
BMS Number: 
BMS-936558-01 
INN 
Nivolumab 
Other names: 
Opdivo, BMS-936558, MDX1106, ONO-4538, anti-PD-1 
How Supplied 
10 mg/mL concentrate for solution for infusion as 100 mg/10 mL single 
dose glass vials 
Storage Conditions: 
As directed on the product label 
 
5.2 
Packaging and Labeling 
5.2.1 
Rucaparib Tablets 
Rucaparib tablets are provided in 60-count high-density polyethylene (HDPE) bottles with child 
resistant caps and should be stored in the provided containers and as directed on the product 
label. Patients will be dispensed one or more strengths depending on their current dose of 


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rucaparib. The number of bottles of each strength dispensed will be sufficient to supply 28-days 
treatment per cycle, including a small overage. 
Details with respect to packaging and labeling of rucaparib tablets are described in the pharmacy 
manual. 
5.2.2 
Nivolumab 
Nivolumab will be supplied by the sponsor as a 10 mg/mL solution in glass vials.  
The vials and outer carton will be labeled according to national regulations for investigational 
products. 
The solution will be diluted for administration as an infusion in sodium chloride 9 mg/mL (0.9%) 
solution or glucose 50 mg/mL (5%). 
Details with respect to packaging and labeling of nivolumab for injection are described in the 
pharmacy manual. 
5.3 
Method of Assigning Patients to Treatment Groups 
All patients enrolled in the study will receive oral rucaparib at an initial dose of 600 mg BID 
continuously commencing C1D1, and IV nivolumab at an initial dose of 480 mg Q4W 
commencing C2D1. 
5.4 
Preparation and Administration of Protocol-specified Treatment 
The investigator or designee will be responsible for distributing oral study drug to all patients, 
and the pharmacist or authorized designee will be responsible for preparing the IV study drug for 
all patients.  
Rucaparib and nivolumab will be assigned by an interactive response technology (IRT) system.  
5.4.1 
Rucaparib 
Rucaparib 600 mg is administered orally BID (as close as possible to 12 hours apart, preferably 
at the same times every day) with water starting on Day 1. Study drug (tablets) may be taken 
with or without food. Tablets should be swallowed whole without crushing or chewing. Oral 
study drug will be provided as 200 mg, 250 mg, and 300 mg [as free base] dose strength tablets. 
If a patient vomits after dosing, the dose will not be made up; the patient will take their next dose 
at the regularly scheduled interval. 
Each treatment cycle of oral study drug is 28 days, and treatment will begin on Day 1 of Cycle 1. 
Patients will be provided a sufficient quantity of study drug to last until Day 1 of the next 
treatment cycle. Patients will be instructed to bring their study drug tablets and all containers 
(empty, partially used, and/or unopened) to the next scheduled visit for reconciliation by site 
personnel.  


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5.4.2 
Nivolumab 
Nivolumab is administered as 480 mg via a 30-minute IV infusion on Day 1 of every 28-day 
cycle, starting on Cycle 2 Day 1. IV study drug infusion should be prepared as specified in the 
Pharmacy Manual. Refer to the current version of the IB and/or Pharmacy Manual for complete 
storage, handling, dispensing, and infusion information. 
5.5 
Dose Modification Criteria 
Doses of oral study drug (rucaparib), and/or IV study drug (nivolumab), may be interrupted or 
delayed for toxicity and other protocol-specified criteria. Dose reductions are permitted for oral 
study drug but not for IV study drug (see Section 5.5.1). The assessment for delay or 
discontinuation should be made separately for the oral study drug (rucaparib) and the IV study 
drug (nivolumab); however, if toxicity is considered related to all study drugs or if the 
investigator is unable to determine which study drug is the cause of the AE, then all study drugs 
in the combination should be delayed and/or discontinued. Treatment may be prematurely 
discontinued due to withdrawal of consent, unacceptable toxicity, disease progression, 
completion of treatment cycles, or termination of the study, whichever occurs first. 
Dose modification and re-treatment of oral and/or IV study drug are to be based on the criteria 
presented in Table 4. 


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Table 4. 
Dose Modification and Re-treatment Criteria for Oral and IV Study Drugs 
Adverse Event 
Severity 
(CTCAE 
Grade) 
Oral Study Drug  
(rucaparib) 
IV Study Drug  
(nivolumab) 
Dose 
Modification1  
Re-
treatment 
Dose 
Modification2 
Re-
treatment 
Non-hematological Non-skin AEs 
Adverse event, except fatigue 
2 
None 
N/A 
Hold 
Grade ≤ 1 or 
baseline3 
Any adverse event (related events lasting > 7 days for nivolumab, 
exceptions below)  
3 or 4 
Hold 
≤ Grade 24 
Discontinue 
 
Exceptions with rucaparib 
Alopecia, nausea, vomiting, or diarrhea adequately controlled 
with systemic antiemetic/antidiarrheal medication administered 
in standard doses according to the study center routines 
3 or 4 
None 
 
 
ALT/AST provided no signs of liver dysfunction (see laboratory 
section below) 
3 
None 
 
 
Exceptions with nivolumab 
Uveitis, pneumonitis, bronchospasm, neurological toxicity, 
myocarditis, hypersensitivity reason or infusion reaction of any 
duration 
3 
 
Discontinue 
 
Endocrinopathies, adequately controlled with only physiologic 
hormone replacement 
3 
Hold 
Grade ≤ 1 or 
baseline3 
Drug-related adrenal insufficiency or hypophysitis 
2 
Hold 
Grade ≤ 1 or 
baseline3 
Adrenal insufficiency regardless of control with hormone 
replacement 
3 
Discontinue 
 
Laboratory abnormalities except as specified below 
3 
Hold 
Grade ≤ 1 or 
baseline3 
Drug-related ALT, AST, or bilirubin 
3 
Discontinue5 
 
Adverse event or laboratory abnormality except for those below 
that do not require delay 
4 
Discontinue 
 
Asymptomatic amylase or lipase 
4 
Hold 
Grade ≤ 1 or 
baseline3 


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Table 4. 
Dose Modification and Re-treatment Criteria for Oral and IV Study Drugs 
Adverse Event 
Severity 
(CTCAE 
Grade) 
Oral Study Drug  
(rucaparib) 
IV Study Drug  
(nivolumab) 
Dose 
Modification1  
Re-
treatment 
Dose 
Modification2 
Re-
treatment 
Isolated electrolyte imbalances/abnormalities not associated 
with clinical sequelae/corrected w/supplementation /appropriate 
management w/in 72 hours of onset 
4 
Hold 
Grade ≤ 1 or 
baseline3 
Endocrinopathy AEs6 
3 
Hold 
Grade ≤ 1 or 
baseline3 
Non-hematological Toxicity (Skin) 
Adverse event 
3 
Hold 
Grade 24 
Hold 
 
Hematological Toxicity 
Hematological toxicity (related events lasting >7 days for 
nivolumab, exceptions below) 
3-4 
Hold7 
Grade 24 
Discontinue 
 
Confirmed MDS or AML (all new secondary malignancies are 
Grade 4 per CTCAE 5.0)  
4 
Discontinue 
 
Discontinue 
 
Exceptions with nivolumab 
Laboratory abnormalities except as specified below 
3 
 
Hold 
Grade ≤ 1 or 
baseline3 
Thrombocytopenia > 7 days or associated with bleeding 
3 
Discontinue 
 
Laboratory abnormality except for those below that do not require 
delay 
4 
Discontinue 
 
Neutropenia ≤ 7 days 
4 
Hold 
Grade ≤ 1 or 
baseline3 
Lymphopenia or leukopenia 
4 
Hold 
Grade ≤ 1 or 
baseline3 
Laboratory Abnormalities 
Laboratory abnormality 
3 
Hold 
Grade 24 
Hold 
 
ALT, AST, and/or bilirubin abnormalities 
2 
None 
N/A 
Hold8 
Grade ≤ 1 or 
baseline3 
ALT/AST elevations 
3 
None, 
provided no 
N/A  
Discontinue7 
 


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Table 4. 
Dose Modification and Re-treatment Criteria for Oral and IV Study Drugs 
Adverse Event 
Severity 
(CTCAE 
Grade) 
Oral Study Drug  
(rucaparib) 
IV Study Drug  
(nivolumab) 
Dose 
Modification1  
Re-
treatment 
Dose 
Modification2 
Re-
treatment 
signs of liver 
dysfunction9 
ALT/AST elevations 
4 
Hold 
≤Grade 2 
Reduce 
dose10 
Discontinue 
 
ALT or AST > 3 × ULN AND bilirubin > 2 × ULN (suspected 
DILI) 
 
Hold9 
Follow guidelines in 
Section 8.10 
Discontinue 
 
Creatinine elevations 
2 
(≥ 1.5 x 
baseline11) 
None 
N/A 
Hold 
Grade ≤ 1 or 
baseline3 
Creatinine elevations 
3 
Hold 
Grade 24 
Hold 
Grade ≤ 1 or 
baseline3 
Exception with nivolumab 
Grade 3 lymphopenia or asymptomatic amylase or lipase 
3 
 
None 
 
Dosing-related 
Any event that leads to delay in dosing lasting > 8 weeks from the 
previous dose requires discontinuation, with the exception of 
dosing delays to allow for prolonged steroid tapers to manage 
AEs.  
• Dosing delays lasting > 8 weeks from the previous dose that 
occur for non-drug-related reasons may be allowed if 
approved by the study medical monitor/designee 
 
 
Discontinue 
 
Toxicity despite dose reduction steps to 200 mg BID or 
interruption of oral drug for > 14 consecutive days except if 
allowed if approved by the study medical monitor/designee.  
 
Discontinue 
 
 


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Table 4. 
Dose Modification and Re-treatment Criteria for Oral and IV Study Drugs 
Adverse Event 
Severity 
(CTCAE 
Grade) 
Oral Study Drug  
(rucaparib) 
IV Study Drug  
(nivolumab) 
Dose 
Modification1  
Re-
treatment 
Dose 
Modification2 
Re-
treatment 
• Prior to re-initiating treatment in a patient with a dosing 
delay > 14 days, the study medical monitor/designee must 
be consulted.  
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AML = acute myeloid leukemia; AST = aspartate aminotransferase; BID -= twice daily; 
CTCAE = Common Terminology Criteria for Adverse Events; DILI = drug-induced liver injury; IV = intravenous; MDS = myelodysplastic syndrome; N/A = not 
applicable; ULN = upper limit of normal 
1Oral drug may be discontinued for any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the investigator, presents a substantial 
clinical risk to the patient with continued oral study treatment dosing. In addition, and at the discretion of the investigator, the dose of oral study drug may be 
held and/or reduced for Grade 2 toxicity not adequately controlled by concomitant medications and/or supportive care. 
2In addition to the criteria below, nivolumab should be held if there is any AE, laboratory abnormality, or intercurrent illness that, in the judgment of the 
investigator, warrants delaying the dose of study medication or discontinued if there is any AE, laboratory abnormality, or intercurrent illness that, in the 
judgment of the investigator, presents a substantial risk to the patient with continued IV study drug dosing. Patients who require dose hold should be re-evaluated 
weekly or more frequently if clinically indicated and resume dosing during the next scheduled dosing window (Cycle X, Day 1 ±3 days) after re-treatment 
criteria are met.  
3Patients may resume treatment with IV study drug when the drug-related AE(s) improve to Grade ≤ 1 or resolve to baseline value, with the following exceptions 
which are allowed: Grade 2 fatigue, Grade 2 skin toxicity (if no Grade 3 drug related skin AE). For patients with Grade 2 AST, ALT, or total bilirubin elevations, 
dosing may resume when laboratory values return to baseline and management with corticosteroids, if needed, is complete. Drug-related pulmonary toxicity, 
diarrhea or colitis must have resolved to baseline before treatment is resumed. Patients with persistent Grade 1 pneumonitis after completion of a steroid taper 
over at least 1 month may be eligible for retreatment if discussed with and approved by the study medical monitor. Patients with drug-related endocrinopathies 
adequately controlled with only physiologic hormone replacement may resume treatment after consultation with the study medical monitor. Adrenal 
insufficiency requires discontinuation regardless of control with hormone replacement.  
4The patient may continue at same or reduced dose at the discretion of the investigator. If treatment is resumed at the same dose, and the patient experiences the 
same toxicity, treatment should be interrupted, then resumed at a reduced dose following improvement of the event to ≤ CTCAE Grade 2. If the patient continues 
to experience toxicity, additional dose reduction steps are permitted; however, the investigator should consult with the sponsor’s medical monitor before 
reducing to 300 mg BID.  
5In most cases of Grade 3 ALT or AST elevation, IV study drug will be permanently discontinued. For patients with Grade 3 ALT or AST elevations after the 
start of IV dosing, but on a background of previous elevations on the first cycle of oral study drug, IV study drug hold is required, but discontinuation is not 
required, if ALT/AST elevations begin to resolve before the next scheduled infusion, and toxicity is considered to be mainly related to oral study treatment, after 
the investigator discusses the case with the study medical monitor. Levels will be monitored every 3 days; if they continue to rise more than 20%, the Hepatic 


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Table 4. 
Dose Modification and Re-treatment Criteria for Oral and IV Study Drugs 
Adverse Event 
Severity 
(CTCAE 
Grade) 
Oral Study Drug  
(rucaparib) 
IV Study Drug  
(nivolumab) 
Dose 
Modification1  
Re-
treatment 
Dose 
Modification2 
Re-
treatment 
Adverse Event Management Algorithm for a Grade 3 event will be followed (see Appendix 6). Treatment with IV drug may be resumed if levels return to Grade 
2. If total bilirubin elevations > 2 × ULN accompany any of the ALT/AST elevations, IV drug should be discontinued.  
6Such as, hyper- or hypothyroidism, or glucose intolerance, that resolve or are adequately controlled with physiologic hormone replacement (corticosteroids, 
thyroid hormones) or glucose-controlling agents, respectively, may not require discontinuation after discussion with and approval from the study medical 
monitor/designee. Grade 4 drug-related adrenal insufficiency or hypophysitis requires discontinuation regardless of control with hormone replacement.  
7If any blood parameters remain clinically abnormal > 4 weeks of dose interruption, the patient should be referred to hematologist for further investigations. Bone 
marrow analysis and/or blood cytogenetic analysis should be considered at this stage according to standard hematological practice.  
8For patients with Grade 2 ALT or AST elevations with onset after dosing of oral study drug, IV study treatment hold is not required if ALT/AST elevations 
begin to resolve before the next scheduled infusion and toxicity is considered to be mainly related to oral study treatment. If a subsequent ALT/AST increase of 
more than 20% is observed following infusion of IV study drug, the next IV study drug administration will be held and, if further increase is observed, the 
Hepatic Adverse Event Management Algorithm will be followed (see Appendix 6). In this case, IV study drug should be discontinued if Grade 2 elevations 
return post re-challenge. If total bilirubin elevations > 2 × ULN accompany any of the ALT/AST elevations, IV drug should be discontinued.  
9Bilirubin must be within normal limits and alkaline phosphatase must be < 3 x ULN. Monitor liver function tests weekly. If the patient has Grade 3 ALT/AST 
and continues on oral study drug, and levels do not decline within 2 weeks or they continue to rise, treatment interruption and improvement to ≤ Grade 2 will be 
required before oral study drug can be resumed, either at the current dose or at a reduced dose.  
10Monitor liver function tests weekly for 3 weeks after oral study drug has been restarted.  
11Grade 2 for nivolumab is described as ≥ 1.5 x baseline and baseline is the day the combination treatment starts (ie, Cycle 2 Day 1 in Cohort A1 and A2). 


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5.5.1 
Dose Reduction 
5.5.1.1 
Rucaparib 
The dose reduction steps for oral study drug are presented in Table 5. 
Dose escalation upon improvement of toxicity to ≤ CTCAE Grade 1 is permitted at the discretion 
of the investigator. 
Dose modifications must be recorded for each patient in the appropriate section of the electronic 
case report form (eCRF). 
Table 5. 
Oral Study Drug Dose Reduction Steps 
Starting Dose 
600 mg BID 
Dose Level: – 1 
500 mg BID 
Dose Level: – 2 
400 mg BID 
Dose Level: – 3a 
300 mg BID 
a Consult with sponsor’s medical monitor before reducing to dose level −3. Further dose reduction may be 
possible, but requires consultation with the sponsor’s medical monitor. 
5.5.1.2 
Nivolumab 
There will be no dose reductions  permitted for IV study drug. 
5.6 
Management Algorithms for Immuno-oncology Agents 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab is considered an I-O agent in this 
protocol. Early recognition and management of AEs associated with I-O agents may mitigate 
severe toxicity. Management Algorithms have been developed to assist investigators in assessing 
and managing the following groups of AEs: 
• Gastrointestinal 
• Renal 
• Pulmonary 
• Hepatic 
• Endocrinopathy 
• Skin 
• Neurological 
The above algorithms are found in Appendix 6 of this protocol. 


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5.7 
Treatment of Infusion-related Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, they are unlikely to 
be immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction 
were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, 
hypotension, hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 4 
infusion reactions should be reported within 24 hours to the study medical monitor and reported 
as an SAE if it meets the criteria. Infusion reactions should be graded according to NCI CTCAE 
(v5.0) guidelines.66 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate: 
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated): 
• Remain at bedside and monitor patient until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 
50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 
30 minutes before additional IV study drug administrations. 
For Grade 2 symptoms: (moderate reaction required therapy or infusion interruption but 
responds promptly to symptomatic treatment (eg, antihistamines, non-steroidal 
anti-inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids); prophylactic 
medications indicated for ≥ 24 hours): 
• Stop the study treatment infusion, begin an IV infusion of normal saline, and treat the 
patient with diphenhydramine 50 mg IV (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000 mg; remain at bedside and monitor patient until 
resolution of symptoms. Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% 
of the original infusion rate when symptoms resolve; if no further complications ensue 
after 30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor 
patient closely. If symptoms recur, then no further study treatment will be administered at 
that visit. 
• For future infusions, the following prophylactic pre-medications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg should be administered at least 30 minutes before IV study drug infusion. If 
necessary, corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used 
 
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalization indicated for other clinical sequelae (eg, renal 
impairment, pulmonary infiltrates). Grade 4: Life--threatening; pressor or ventilatory support 
indicated): 


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• Immediately discontinue infusion of study drug. Begin an IV infusion of normal saline 
and treat the patient as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Patient should be monitored 
until the investigator is comfortable that the symptoms will not recur. Study drug will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor patient until recovery of the 
symptoms. 
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids). 
5.8 
Treatment Compliance 
5.8.1 
Rucaparib Treatment Compliance 
Documentation of dosing will be recorded in a study specific dosing diary provided by the 
sponsor (or designee). Dosing noncompliance is defined as a patient missing > 14 days of 
medication in a 28-day window for 2 consecutive visits for a nonprotocol-specified reason. The 
sponsor may require patients meeting noncompliance criteria to discontinue study treatment. 
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 keep all unused tablets and containers (empty, partially used, 
and/or unopened) for accountability at the next scheduled clinic visits. A compliance check and 
tablet count will be performed by study personnel during clinic visits. Additional details 
regarding study drug dispensation and return can be found in the pharmacy manual. 
Every effort should be made to ensure patients return to the clinic with their study drug 
containers/unused study drug 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. This may serve as source documentation for the purpose of entering dosing data 
on the appropriate eCRF. 
5.8.2 
Nivolumab Treatment Compliance 
Each dose of IV study drug will be prepared by a pharmacist or authorized designee and 
transferred to an infusion set, in accordance with the protocol and applicable local safe handling 
procedures. The IV infusion will be monitored by the investigator or designee. Treatment 
compliance will be monitored by drug accountability, and any preparation of infusion deviations 
(eg, infusion less/greater than 30 min) will be recorded on the patient’s eCRF.  


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5.9 
Accountability of Protocol-specified Treatment 
Study personnel will maintain accurate records of study drug receipt, dispensation, use, return, 
destruction, and reconciliation for study drugs provided by the sponsor. The IRT 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 site. 
The site is responsible for the return or destruction of study drug supplied by the sponsor. 
Authorization to destroy study drug at the site that has not been dispensed to a patient (eg, 
expired study drug), must be requested from the sponsor prior to destruction. All study drug 
containers must be accounted for prior to their destruction at the study center, according to 
institutional procedures for disposal of hazardous materials. Unused and returned study drug 
product and containers should be destroyed on-site if possible. If destruction on site is not 
possible, supply should be returned to the drug depot, following the sponsor’s instructions. 
During the course of the study and at completion of the study, the number of study drug units 
and containers received, dispensed, returned, and destroyed must be recorded and reconciled. 
Additional details regarding study drug accountability can be found in the Pharmacy Manual.  
5.10 Treatment of Study Drug beyond Disease Progression 
Patients will receive study drug until confirmed radiologic disease progression as assessed by 
investigator using RECIST v1.1 criteria, unacceptable toxicity or inability to tolerate further 
treatment, loss to follow-up, death, or withdrawal of consent.  
If a patient receiving study drug has met criteria for confirmed radiologic disease progression by 
RECIST v1.1 criteria, but the patient continues to derive clinical benefit per the investigator, 
then continuation of treatment will be permitted. In such cases, the investigator’s decision to 
continue treatment should be documented in the source documents and the sponsor’s medical 
officer or designee should be informed. The patient must provide additional consent at their next 
scheduled study visit to continue treatment with study drug. Clinical scenarios where 
continuation of study drug after radiographic progression may be considered include 1) a patient 
for whom radiographic progression develops slowly while disease-related symptoms remain well 
controlled, 2) a patient who experiences progression in a site of disease that is unlikely to 
adversely affect prognosis (eg, enlargement of a solitary lymph node), or 3) a patient with 
general disease control but limited progression in sites of disease that can be managed with local 
therapies such as surgery or radiation. Patients continuing to receive study drug will continue to 
have all protocol-required assessments as described in Section 7. 
Continuation of treatment will be considered for a maximum cumulative duration of 24 months 
after initiation of oral/IV combination study treatment, or until confirmation of further 
progression as assessed by the investigator, whichever is sooner. 


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6 
PRIOR AND CONCOMITANT THERAPY 
Drug-drug interactions between nivolumab and rucaparib are unlikely (see Section 1.1.3.2). 
Cohorts A1 and A2 Ovarian:  
Patients who have received prior treatment with a PARP inhibitor (PARPi), including IV or oral 
rucaparib or an immune checkpoint inhibitor for any previous malignancy are not eligible to 
participate in this study. Exception: patients who received a prior PARPi as front-line 
maintenance therapy and did not have disease progression on the PARPi, are eligible to 
participate in the study, providing inclusion criterion 11 is met at the time of screening. 
All procedures performed (eg, thoracentesis, etc.) during the study must be documented on the 
eCRF. 
6.1 
Supportive Care 
During the study, supportive care (eg, antiemetics; analgesics for pain control) may be used at 
the investigator’s discretion and in accordance with institutional procedures. Supportive care 
must be recorded for each patient in the appropriate section of the eCRF.  
Erythropoietin, darbepoetin alfa, and/or hematopoietic colony-stimulating factors for treatment 
of cytopenias should be administered per standard of care and according to institutional 
guidelines. Transfusion thresholds for blood product support will be in accordance with 
institutional guidelines. 
6.2 
Radiotherapy 
Palliative radiotherapy on lesions not considered target lesions for tumor evaluation is permitted 
during the study. Treatment with study drug should be held prior to initiation of radiation therapy 
and until the patient has recovered from any radiation related toxicity. 
6.3 
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 palliative radiotherapy and hormonal treatment. Prior treatment with such excluded 
anticancer therapies must have been completed > 14 days prior to the first dose of study drug. 
Any botanical preparations (eg, herbal supplements or traditional Chinese medicines) intended to 
treat the disease under study, or provide supportive care are prohibited (except those prescribed 
as supportive care by a health care professional as per Section 6.1). 
6.4 
CYP450 Isoenzyme Inhibitors, Inducers, and Substrates 
Based on the results from the in vivo CYP interaction study (Study CO-338-044), rucaparib is a 
moderate inhibitor of CYP1A2, and a weak inhibitor of CYP2C9, CYP2C19, and CYP3A. 


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Caution should be used in patients on rucaparib taking concomitant medicines that are substrates 
of CYP1A2, CYP2C9, CYP2C19, and/or CYP3A with narrow therapeutic windows 
(Appendix 4). Selection of an alternative concomitant medication is recommended. 
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 (Appendix 5). 
6.5 
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. 
6.6 
Immunosuppressive Agents 
Immunosuppressive agents are prohibited, with the exception of inhaled or topical steroids, and 
adrenal replacement steroid doses > 10 mg daily prednisone equivalent, in the absence of active 
autoimmune disease. Patients are permitted the use of topical, ocular, intra-articular, intranasal, 
and inhalational corticosteroids (with minimal systemic absorption). Adrenal replacement steroid 
doses > 10 mg daily prednisone are permitted. A brief (less than 3 weeks) course of 
corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune 
conditions (eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted. 
Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 14 days of treatment 
assignment are excluded.  
6.7 
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. Any botanical preparations (eg, herbal 
supplements or traditional Chinese medicines) intended to treat the disease under study, or 
provide supportive care are prohibited (except those prescribed as supportive care by a health 
care professional). Any botanical preparations taken by the patient should be documented 
appropriately on the eCRF.  
Rucaparib marginally increased digoxin 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 MATE-1 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 


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with IC50 value suggesting potential BCRP inhibition and increased exposures of medicinal 
products that are BCRP substrate (eg, rosuvastatin). 
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. 
6.8 
Imaging Restrictions and Precautions 
It is the local imaging facility’s responsibility to determine, based on patient attributes (eg, 
allergy history, diabetic history, and renal status), the appropriate imaging modality and contrast 
regimen for each patient. Oral and/or IV contrast should be used whenever possible and 
appropriate, and rectal contrast should only be considered in patients with peritoneal disease. 
Imaging contraindications and contrast risks should be considered in this assessment. Patients 
with renal insufficiency should be assessed as to whether or not they should receive contrast and 
if so, what type and dose of contrast is appropriate. Specific to MRI, patients with severe renal 
insufficiency (ie, estimated GFR < 30 mL/min/1.73 m2) are at increased risk of nephrogenic 
systemic fibrosis. MRI contrast should not be given to this patient population. In addition, 
patients are excluded from MRI if they have tattoos, metallic implants, pacemakers, etc. 
The ultimate decision to perform MRI in an individual patient in this study rests with the site 
radiologist, the investigator and the standard set by the local IEC. 
6.9 
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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7 
STUDY PROCEDURES AND METHODS 
7.1 
Schedule of Assessments 
Table 6 summarizes the procedures and assessments to be performed for all patients. Study 
procedures and assessments should be performed as close to the scheduled time as possible, but 
within ±3 days of the scheduled time unless otherwise stated. 
Table 7 summarize the timing of collection of PK and immunogenicity samples.  
Table 8 and Table 9 summarize the timing of peripheral blood biomarker sample collection. 
Applicable imaging guidelines should be followed for the collection of images and the 
radiological assessment of disease.  
Tumor tissues (screening and optional sample at the time of disease progression), PK samples, 
and ctDNA, biomarker samples will need to be sent to central laboratories for processing. 
Clinical chemistry, hematology, urinalysis, pregnancy testing, serology testing, CA-125, and 
ECG will be conducted at a local laboratory. Please refer to study laboratory manuals for detailed 
collection, processing, and shipment requirement.   


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Table 6. 
Study CO-338-097 Schedule of Assessments 
 
Screening Phase 
Treatment Phasea 
(±3 days of scheduled timepoint) 
Post-treatment Phase 
Cycle 1 
Cycle 2 
Cycle 3+ 
Procedure 
D-28 to D-1b 
D1c,d 
D15e 
D28 
D1d 
D15d 
D1d 
EOT 
FU-28 
28 ±3 d 
after last 
oral/IV dose 
FU-100 
100 +7 d 
after last IV 
dose 
LTFU 
Informed Consente 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Oncology 
Historyf 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examinationg, 
Heightg, Weight 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
ECOG Performance 
Status 
Xh 
X 
 
 
X 
 
X 
X 
X 
X 
 
Vital Signs 
X 
Xi 
Xi 
 
Xi 
Xi 
Xi 
X 
X 
X 
 
Adverse Eventsj 
X 
X 
X 
 
X 
X 
X 
X 
Xi 
Xj 
Xj 
Prior/Concomitant 
Medications and 
Procedures 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
12-lead ECGk (local lab) 
X 
 
 
 
 
 
 
X 
 
 
 
Hematologyl (local lab) 
Xh 
X 
X 
 
X 
X 
X 
X 
X 
Xm 
 
Clinical Chemistryn (local 
lab) 
Xh 
X 
X 
 
X 
X 
X 
X 
X 
Xm 
 
Serum Pregnancy Testo 
(local lab) 
Xh 
X 
 
 
X 
 
X 
X 
 
 
 
Urinalysisp (local lab) 
Xh 
X 
X 
 
X 
X 
X 
X 
X 
X 
 


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Table 6. 
Study CO-338-097 Schedule of Assessments 
 
Screening Phase 
Treatment Phasea 
(±3 days of scheduled timepoint) 
Post-treatment Phase 
Cycle 1 
Cycle 2 
Cycle 3+ 
Procedure 
D-28 to D-1b 
D1c,d 
D15e 
D28 
D1d 
D15d 
D1d 
EOT 
FU-28 
28 ±3 d 
after last 
oral/IV dose 
FU-100 
100 +7 d 
after last IV 
dose 
LTFU 
Disease 
Assessment/Tumor 
Scansq,r 
X 
 
 
 
 
 
Xr 
(Start on 
C4D1) 
(X)s 
Xt 
Xt 
Xt 
Mandatory Tumor Tissue 
Biopsy/Resection/Sample 
Xu 
 
 
Xv  
 
 
 
(X)w 
 
 
 
Peripheral Blood Samples 
for Biomarker Analysesx 
(central lab) 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
Rucaparib Dispensation/ 
Administration 
 
X 
 
 
X 
 
X 
 
 
 
 
Nivolumab IV 
Administrationy 
 
 
 
 
X 
 
X 
 
 
 
 
Plasma PK Samplez 
(central lab) 
 
Xaa 
 
 
Xaa 
 
Xaa 
 
Xaa 
Xaa 
 
Survival and Subsequent 
Treatments 
 
 
 
 
 
 
 
 
 
 
Xab 
CA-125 Measurement 
(local lab) 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
Abbreviations: AE(s) = adverse event(s); AESI(s) = adverse event(s )of special interest; ALP = alkaline phosphatase, ALT = alanine aminotransferase, ANC = 
absolute neutrophil count, AST = aspartate aminotransferase, BUN = blood urea nitrogen, CLcr= creatinine clearance; CO2 = carbon dioxide; CR = complete response, 
CT = computed tomography, ctDNA = circulating cell-free tumor DNA; D = day of cycle; ECG(s) = electrocardiogram(s), ECOG = Eastern Cooperative Oncology 
Group; EOT = End of Treatment Visit; FFPE = formalin-fixed, paraffin-embedded; FU-100 = 100-day Follow-up Visit after last dose of IV study drug; FU-28 = 28-
day Follow-up Visit after last dose of study drug (oral or IV, whichever is later); fT3 = free triiodothyronine; fT4 = free thyroxine; FU = follow-up; HCO3- = 


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Table 6. 
Study CO-338-097 Schedule of Assessments 
 
Screening Phase 
Treatment Phasea 
(±3 days of scheduled timepoint) 
Post-treatment Phase 
Cycle 1 
Cycle 2 
Cycle 3+ 
Procedure 
D-28 to D-1b 
D1c,d 
D15e 
D28 
D1d 
D15d 
D1d 
EOT 
FU-28 
28 ±3 d 
after last 
oral/IV dose 
FU-100 
100 +7 d 
after last IV 
dose 
LTFU 
bicarbonate; HIV = human immunodeficiency virus; ICF = Informed Consent Form; LDH = lactate dehydrogenase, LTFU = long-term follow-up; MCH = mean 
corpuscular hemoglobin, MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume, MRI = magnetic resonance imaging, PET = 
positron emission tomography, PK = pharmacokinetic, PR = partial response or PR interval, QRS = QRS complex/interval; QT = QT interval; QTcF = corrected QT 
interval Fridericia’s formula; RBC = red blood cell, RECIST = Response Evaluation Criteria in Solid Tumors; SAE(s) = serious adverse event(s); T3 = 
triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone; WBC = white blood cell. 
a 
= Treatment cycles are 28 days. Unless otherwise specified, all assessments are to be completed within ±3 days of scheduled time point. 
b 
= Exceptions to this screening window include the mandatory tumor tissue collection for Cohorts A1 and A2 as described under footnote ‘u’.  
c 
= Any procedures required on Cycle 1 Day 1 may be omitted if completed ≤ 3 days prior to first dose of study drug. 
d 
= Patients are to refrain from taking their first dose of rucaparib at home on these days. Procedures are to be completed before any study drug is administered. 
e 
= Consent may be completed outside the 28-day screening window as consent does not expire. Reconsent is not required if outside the screening window. The 
screening period begins with the first study-specific procedure, performed outside standard of care, and only after consent for study participation has been 
provided. 
f 
= Patient’s medical record must include prior treatments received, dates of administration, date of progression, and radiology report(s) to support assessment of 
disease progression. gBRCA test results, if known, will also be captured. 
g 
= A complete physical exam should be performed at Screening and End of Treatment Visits; a limited physical exam may be performed at all other visits. Height 
at screening only. 
h 
= To be performed ≤ 14 days prior to the first dose of rucaparib. Serum pregnancy test to be performed ≤ 3 days prior to the first dose of rucaparib, if applicable. 
i 
= Vital signs (blood pressure, pulse, and temperature) to be taken on clinic visit days, after the patient has been resting for at least 5 minutes. 
j 
= AEs (inclusive of SAEs and AESIs) occurring after first dose of rucaparib through 28 days after last dose of rucaparib will be recorded. In addition, SAEs 
occurring after signing of the ICF and that were related to a screening procedure will also be reported. Ongoing SAEs, AESIs, and treatment-related Grade 3/4 
AEs will be followed to resolution or stabilization, death, or until lost to follow-up. Only related SAEs and AESIs (regardless of causality) will be reported 
after the 28-day Follow-up Visit. 


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Table 6. 
Study CO-338-097 Schedule of Assessments 
 
Screening Phase 
Treatment Phasea 
(±3 days of scheduled timepoint) 
Post-treatment Phase 
Cycle 1 
Cycle 2 
Cycle 3+ 
Procedure 
D-28 to D-1b 
D1c,d 
D15e 
D28 
D1d 
D15d 
D1d 
EOT 
FU-28 
28 ±3 d 
after last 
oral/IV dose 
FU-100 
100 +7 d 
after last IV 
dose 
LTFU 
k 
= Heart rate, PR, QRS, QT, QTcF and rhythm. Investigator to review results and assess as normal or abnormal (clinically significant or not clinically 
significant). ECGs to be repeated as clinically indicated. 
l 
= Includes RBC count and parameters (hemoglobin, hematocrit, MCV, MCH, MCHC), reticulocyte count, WBC count, and differential (with ANC), and platelet 
count. Blood will be analyzed by a local laboratory and results must be reviewed by the investigator prior to dosing with rucaparib. Additional and more 
frequent tests may be performed at the investigator’s discretion.  
m 
= Only required if toxicities are present. 
n 
= Includes total protein, albumin, measured or calculated CLcr (for CLcr calculation, the Cockcroft Gault formula or institutional standard formula can be used), 
BUN or urea, total bilirubin, ALP, ALT, AST, LDH, glucose, sodium, potassium, magnesium, chloride, CO2/HCO3-, calcium, phosphorus, TSH, fT3, fT4, 
TSH, with reflexive fT3 and fT4 if TSH is abnormal on treatment, and total cholesterol. Total cholesterol testing does not require fasting. If pancreatitis is 
suspected clinically, serum lipase and amylase should be analyzed. Blood will be analyzed by a local laboratory and results must be reviewed by the 
investigator prior to dosing with rucaparib. Tests for hepatitis C antibody and hepatitis B surface antigen are required at screening. Testing for HIV must also 
be performed at screening if mandated locally by a given site. Additional and more frequent tests may be performed at the investigator’s discretion.   
o 
= 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. 
p 
= Includes dipstick for protein, glucose, blood, pH, and ketones. If dipstick findings abnormal, perform microscopic evaluation. To be conducted at screening 
only, but may be conducted at other times as clinically indicated. 
q 
= Disease assessment to include clinical examination and appropriate imaging techniques, including CT scans of the chest, abdomen, and pelvis, with 
appropriate slice thickness per RECIST; other assessments (MRI, X-ray, PET, and ultrasound) may be performed if required. The same methods used to detect 
lesions at baseline are to be used to follow the same lesions throughout the clinical study. If a patient has known brain metastases, this disease should be 
evaluated at each required assessment. Copies of CT scans will be collected from all patients. Independent radiology review may be conducted on all or a 
subset of CT scans. 
r 
= Tumor scans to be performed at the end of every 8 calendar weeks (±7 days) during the Treatment Phase, from the start of the oral/IV combination treatment 
on Cycle 2 Day 1.A confirmatory scan should be performed ≥ 4 weeks after an initial response of PR or CR is observed. Patients who have been on study at 


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Table 6. 
Study CO-338-097 Schedule of Assessments 
 
Screening Phase 
Treatment Phasea 
(±3 days of scheduled timepoint) 
Post-treatment Phase 
Cycle 1 
Cycle 2 
Cycle 3+ 
Procedure 
D-28 to D-1b 
D1c,d 
D15e 
D28 
D1d 
D15d 
D1d 
EOT 
FU-28 
28 ±3 d 
after last 
oral/IV dose 
FU-100 
100 +7 d 
after last IV 
dose 
LTFU 
least 18 months, may decrease the frequency of disease assessments to every 12 calendar weeks (±7 days). Tumor assessments should continue as per protocol 
even if dosing is delayed. 
s 
= Disease assessments should also be done at the time of treatment discontinuation if it has been ≥ 8 weeks since the last assessment.  
t 
= If treatment was discontinued for reasons other than radiologic disease progression or death, radiologic tumor assessment (using the same methodology as was 
used at initial study screening) will continue until confirmed radiographic disease progression, death, or initiation of subsequent treatment. Assessment at 12-
week (±7days) intervals from Cycle 4 Day 1  for the first 18 months after initiation of study treatment, and every 24 weeks (±14 days) thereafter, until 
objective radiological disease progression by RECIST v1.1, as assessed by the investigator, is documented. 
u 
= A mandatory biopsy or resection of tumor tissue must be collected ≤ 42 days prior to first dose of rucaparib. Alternatively, tumor tissue collected > 42 days 
prior to the first dose of rucaparib may be submitted, provided there have been no intervening anticancer treatments during this period and the tissue is of 
adequate quality. Tumor tissue samples should be from primary or metastatic tissue. Patients may be enrolled prior to tumor tissue being analyzed by the 
central laboratory, provided there is confirmation that the tumor tissue has been received by the central laboratory 
 
Tumor tissue must be obtained from a soft tissue tumor lesion; ascites is not acceptable. Refer to the Laboratory Manual for detailed sample handling 
instructions. 
v 
=  An additional mandatory biopsy will be collected at Cycle 1 Day 28 (−5 days), unless tumor biopsy procedure is contraindicated (eg, unacceptable risk in the 
opinion of the investigator). This additional biopsy will be collected prior to commencement of nivolumab on Cycle 2 Day 1 (= Cycle 1 Day 28 
[window:-5 days]). Tumor tissue must be obtained from a soft tissue tumor lesion; ascites is not acceptable. Refer to the Laboratory Manual for detailed 
sample handling instructions.  
w 
= An optional post-treatment tumor biopsy sample may be collected from patients who progress on study treatment. 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 Laboratory Manual for detailed sample handling 
instructions. 
x 
= Refer to Table 8 and Table 9, and the Laboratory Manual for detailed sample collection and processing instructions. Cycle 1 ctDNA must be collected even if 
within 3 days of screening ctDNA. 
y 
= Nivolumab administration will commence on Cycle 2 Day 1. 


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Table 6. 
Study CO-338-097 Schedule of Assessments 
 
Screening Phase 
Treatment Phasea 
(±3 days of scheduled timepoint) 
Post-treatment Phase 
Cycle 1 
Cycle 2 
Cycle 3+ 
Procedure 
D-28 to D-1b 
D1c,d 
D15e 
D28 
D1d 
D15d 
D1d 
EOT 
FU-28 
28 ±3 d 
after last 
oral/IV dose 
FU-100 
100 +7 d 
after last IV 
dose 
LTFU 
z 
= A single sample should be collected as close as possible to 12 hours after the last dose has been taken and prior to the next dose. Refer to the Laboratory 
Manual for sample collection and processing instructions.  
aa 
= Refer to PK sampling Table 7.  
ab 
= All patients discontinued from treatment, regardless of reason, should be followed for survival and subsequent therapies every 12 weeks (±14 days) until death, 
loss to follow-up, withdrawal of consent from study, or study closure, whichever happens first. Follow-up can be performed via the telephone.  
 


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Table 7. 
Pharmacokinetic and Immunogenicity Sample Collections 
Study Day (Cycle, Day)a 
(1 Cycle = 28 days) 
Time 
(Event) 
Time 
(Relative to 
Start of 
Infusion) 
Pharmacokinetic 
Blood Sample for 
Nivolumab 
Immunogenicity 
Blood Sample for 
Nivolumab 
Pharmacokinetic 
Blood Sample for 
Rucaparibb 
C2D1 
(Predose)c 
00:00 
X 
X 
X 
(EOI)d 
00:30 
X 
 
 
C3D1 
(Predose)c 
00:00 
X 
 
X 
C4D1 
(Predose)c 
00:00 
 
 
X 
C6D1 
(Predose)c 
00:00 
X 
X 
X 
CXD1: Every 4 cycles after C6 D1 (ie, C10D1, 
C14D1, etc.) 
(Predose)c 
00:00 
X 
X 
 
Safety Follow-up Visits, FU-28 and FU-100 
(28 days and 100 days, respectively, from the 
treatment discontinuation during the Treatment 
Phase or at 24 months) 
NA 
NA 
X 
X 
 
Abbreviations: EOI = end of infusion; FU-100 = 100-day Follow-up Visit after last dose of IV study drug; FU-28 = 28-day Follow-up Visit after last dose of study 
drug (oral or IV, whichever is later); NA = not applicable; PK = pharmacokinetic. 
a 
= If a patient discontinues study drug treatment during the sampling period (ie, prior to 24 months), all subsequent CXD1 samples will be inapplicable, 
but samples will be collected on FU-28 and FU-100 for nivolumab PK and immunogenicity analysis. 
b 
= PK samples for rucaparib are to be collected approximately 12 hours after the last dose, but prior to the next dose (ie, within 1 hour). If dosing is held 
for toxicity or any other reason, PK sample should still be collected at the end of treatment Cycles 1, 2, 3, and 5. 
c 
= All predose samples for nivolumab should be taken (preferably within 30 minutes) prior to the start of nivolumab infusion. If it is known that a dose is 
going to be delayed, then the predose sample should be collected just prior to the delayed dose. However, if a predose sample is collected but the dose 
is subsequently delayed, an additional predose sample should not be collected. 
d 
= EOI-nivo: EOI samples should be collected immediately (preferably within 5 minutes) prior to stopping nivolumab infusion. If the end of 
infusion is delayed, the collection of the EOI samples should be delayed accordingly. Please ensure accurate collection of time/date of sample 
collection. EOI samples may not be collected from the same IV access as drug was administered. 
 
 


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Table 8. 
Peripheral Blood Biomarker Sample Collection 
Study Day (Cycle, Day) 
(1 Cycle = 28 days) 
Time 
Genomic DNA from 
blood 
Immunophenotyping 
(PBMC)  
Neo-epitope DNAseq 
Serum cytokine/ 
chemokine profiling 
C1D1 
Predose 
X 
X 
X 
X 
C2D1 
Predose 
 
X 
X 
X 
C5D1 
Predose 
 
X 
X 
X 
C7D1 
Predose 
 
 
X 
X 
C9D1 
Predose 
 
 
X 
X 
Upon Disease Progression 
N/A 
 
X 
X 
X 
Abbreviations: DNAseq = deoxyribonucleic acid sequencing; N/A = not applicable; PBMC = peripheral blood mononuclear cells. 
 
Table 9. 
Blood Sample Collection for ctDNA 
Blood for ctDNA 
Plasma 
Screening 
Predose 
Upon Disease 
Progression 
Safety Follow-up Visits,  
FU-28 and FU-100b 
C1D1 
C2D1 
C3D1 
CXD1a 
Cohort A 
X 
X 
X 
X 
X (starting with C4) 
X 
X 
 
 
 
 
 
 
 
 
Abbreviations: ctDNA = circulating tumor DNA; FU-100 = 100-day Follow-up Visit after last dose of IV study drug; FU-28 = 28-day Follow-up Visit after 
last dose of study drug (oral or IV, whichever is later). 
a 
= After cycle 3, collect blood for ctDNA at every other cycle from the start of the oral/IV combination treatment on Cycle 2 Day 1 for Cohorts A1/A2.  
b 
= FU-28 and FU-100, 28 days and 100 days, respectively, from the treatment discontinuation during the Treatment Phase or at 24 months 


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7.2 
Informed Consent 
The investigator or their designee shall discuss with each patient the nature of the study and its 
requirements. To participate in the study, informed consent must be obtained from each potential 
patient prior to any study activities. The information on the IRB/IEC-approved consent form 
should be translated and communicated in the language the patient (or legally-authorized 
representative) can understand. A separate consent form may be used for tissue testing. 
Analysis of tumor tissue for a deleterious BRCA1/2 mutation (germline or somatic) will be 
performed using the Foundation Medicine’s NGS test (germline/somatic status will not be 
differentiated in the test report). These results will be provided to patients who consent to receive 
this information. In the event a BRCA1/2 alteration is identified in tumor tissue, the patient may 
be referred by the investigator for genetic counseling and potential germline testing per 
institutional guidelines. If mutations other than BRCA1/2 are identified by the NGS test, they 
will also be provided to patients who consent to receive this information when they discontinue 
from treatment. 
Additionally, patients participating in the optional tumor tissue biopsy at the time of radiographic 
disease progression/ treatment discontinuation must provide additional consent for this 
procedure.  
All procedures and assessments are to be completed within ±3 days of the scheduled time unless 
otherwise stated. 
7.3 
Screening Phase 
Following written informed consent, and unless otherwise specified, the following assessments 
will be performed prior to enrollment within the allowable windows of time as indicated below. 
Assessments performed within the specified windows, but prior to patient signing informed 
consent, are acceptable to be used as a study procedure only if confirmed to have been standard 
of care. Screening procedures may be repeated if the findings/results are considered invalid or 
not representative of the patient’s baseline medical status. When screening procedures are 
repeated, the rationale should be documented in the source file. 
Consent may be completed outside the 28-day screening window as consent does not expire. 
Reconsent is not required if outside the screening window. The screening period begins with the 
first study-specific procedure, performed outside standard of care, and only after consent for 
study participation has been provided. 
7.3.1 
Up to 42 Days Prior to Start of Treatment 
A mandatory biopsy or resection of tumor tissue must be collected ≤ 42 days prior to first dose of 
rucaparib. Alternatively, tumor tissue collected > 42 days prior to the first dose of rucaparib may 
be submitted, provided there have been no intervening anticancer treatments during this period 
and the tissue is of adequate quality. Tumor tissue samples should be from primary or metastatic 
tissue. Patients may be enrolled prior to tumor tissue being analyzed by the central laboratory, 
provided there is confirmation that tumor tissue is available to be sent to the central laboratory. 


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Tumor tissue must be obtained from a soft tissue tumor lesion; ascites is not acceptable. Refer to 
the Laboratory Manual for detailed sample handling instructions. See Section 7.5.6.1 for central 
laboratory analysis. 
7.3.2 
Up to 28 Days Prior to Start of Treatment 
• Medical/oncology history, including demographic information  
• Physical examination by body system, including height and weight 
• Vital signs (blood pressure, pulse, and body temperature) 
• SAE monitoring (only report if related to screening procedure) 
• Prior and concomitant medications, any surgical/medical procedures  
• 12-lead ECG (Local) 
• Tumor assessment: assessments should consist of clinical examination and appropriate 
imaging techniques (preferably CT scans of the chest, abdomen, and pelvis with appropriate 
slice thickness per RECIST v1.1). Other assessments (MRI, X-ray, positron emission 
tomography [PET], and ultrasound) may be performed if required. The same methods used to 
detect lesions at baseline are to be used to follow lesions throughout the clinical study.  
• If a patient has known brain metastases, this disease should be evaluated at each required 
assessment time 
• Collect ctDNA blood sample (Central) 
 
7.3.3 
Up to 14 Days Prior to Start of Treatment 
• ECOG performance status (Appendix 3) 
• SAE monitoring (only report if related to screening procedure) 
• Hematology (Local) 
• Clinical chemistry (Local). Note: fasting is not required 
• Urinalysis (Local) (performed on freshly voided clean sample) 
• Serum pregnancy test for women of childbearing potential (must be completed ≤ 3 days prior 
to the first dose of rucaparib) 
• CA-125 Measurement (Local) 
 
7.4 
Treatment Phase 
7.4.1 
Cycle 1 Day 1 
The following procedures will be completed before the first dose of rucaparib is administered, 
unless if completed ≤ 3 days prior to the first dose of rucaparib in which case they may be 
omitted, IV nivolumab will be administered after the first dose of rucaparib: 


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• Physical examination 
• Weight 
• ECOG performance status (Appendix 3) 
• Vital signs 
• Concomitant medications and any surgical/medical procedures 
• Hematology (Local) 
• Clinical chemistry (Local) (fasting is not required) 
• Serum pregnancy test for women of childbearing potential (Local) 
• Urinalysis (Local) 
• Collect ctDNA blood sample (this sample must be collected even if a sample was collected 
within 3 days prior to the first dose of rucaparib) 
• CA-125 Measurement (Local) 
• Blood sample for genomic analysis (Central) (If sample is not collected on Day 1 of Cycle 1, 
it should be collected as soon as possible thereafter) 
• Blood sample for immunophenotyping (peripheral blood mononuclear cells [PBMC])  
• Blood sample for neo-epitope DNA sequencing (DNAseq) 
• Blood sample for cytokine/chemokine profiling 
• AE monitoring 
• Dispensation of rucaparib 
 
Rucaparib tablets will be dispensed to the patient in sufficient quantity to last until the next 
rucaparib dispensation visit, with a small overage. Patients will ingest rucaparib twice daily at 
about the same times every day as close as possible to 12 hours apart. Rucaparib should be taken 
with water and with or without food. Patients will keep all unused tablets and containers (empty, 
partially used, and/or unopened) and return with them to the study site for accountability at the 
next visit. Nivolumab IV will be administered as described in the Pharmacy Manual. In the event 
of toxicities, re-treatment or dose modification will be according to the criteria described in 
Table 4. 
Site personnel will account for all rucaparib that is administered or dispensed to the patient 
during the study visit and document appropriately. 
7.4.2 
Cycle 1 Day 15 
Patients will be instructed to refrain from taking their first dose of rucaparib at home on the day 
of their visit. The following procedures will be completed prior to rucaparib dosing and ±3 days 
of this visit. IV nivolumab will be administered after rucaparib. 


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• Physical examination 
• Weight 
• Vital signs 
• Concomitant medications and any surgical/medical procedures 
• Hematology (Local) 
• Clinical chemistry (Local) (fasting is not required) 
• Urinalysis (Local) 
• AE monitoring 
 
7.4.3 
Cycle 1 Day 28 
A mandatory tumor tissue biopsy will occur on C1D28 (window: −5 days) prior to 
commencement of IV study medication (See Section 7.5.6.1). 
7.4.4 
Cycle 2 Day 1 
Patients will be instructed to refrain from taking their first dose of rucaparib at home on the day 
of their visit to collect plasma samples for PK and the ctDNA blood sample. 
Plasma samples for PK analysis should be collected before the morning dose as close as possible 
to 12 hours after the previous dose. If the start of the next dose is delayed, the PK sample should 
still be collected during this visit instead of the delayed start of the next study visit. 
The following procedures will be completed before the morning dose of rucaparib is 
administered and may be performed ±3 days of this visit. IV nivolumab will be administered 
after rucaparib.  
• Physical examination 
• Weight 
• ECOG performance status (Appendix 3) 
• Vital signs 
• Concomitant medications and any surgical/medical procedures 
• Hematology (Local) 
• Clinical chemistry (Local) (fasting is not required) 
• Serum pregnancy test for women of childbearing potential (Local)  
• Urinalysis (Local) 
• Collect ctDNA blood sample (Central) – Reduced volume collected at this visit. Please see 
Laboratory Manual for details. 


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• CA-125 Measurement (Local) 
• PK sample collection (Central) - according to Table 7  
• Blood sample for immunophenotyping (PBMC)  
• Blood sample for neo-epitope DNAseq 
• Blood sample for cytokine/chemokine profiling 
• AE monitoring 
• Patients return all unused tablets and containers (empty, partially used, and/or unopened) to 
the study site for accountability 
• Dispensation of rucaparib 
• Administration of IV nivolumab (after the morning dose of rucaparib) 
 
Patients will ingest rucaparib twice daily at about the same times every day as close as possible 
to 12 hours apart. Rucaparib should be taken with water and with or without food. Nivolumab IV 
will be administered as described in the Pharmacy Manual. In the event of toxicities, re-treatment 
or dose modification will be according to the criteria described in Section 5.5. 
7.4.5 
Cycle 2 Day 15 
Patients will be instructed to refrain from taking their first dose of rucaparib at home on the day 
of their visit. The following procedures will be completed before the morning dose of rucaparib 
is administered and may be performed ±3 days of this visit. IV nivolumab will be administered 
after rucaparib. 
• Physical examination 
• Weight 
• Vital signs 
• Concomitant medications and any surgical/medical procedures 
• Hematology (Local) 
• Clinical chemistry (Local) (fasting is not required) 
• Urinalysis (Local) 
• AE monitoring 
 
7.4.6 
Cycle 3 Day 1 and Every Cycle Thereafter 
Patients will be instructed to refrain from taking their first dose of rucaparib at home on study 
visits when plasma samples for PK and/or ctDNA blood samples are collected. 


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Plasma samples for PK analysis should be collected before the morning dose on Cycle 3 Day 1, 
Cycle 4 Day 1, and Cycle 6 Day 1, as close as possible to 12 hours after the previous dose. If the 
start of the next dose is delayed, the PK sample should still be collected during this visit instead 
of the delayed start of the next study visit; 
The following procedures will be completed before the morning dose of rucaparib is 
administered and may be performed ±3 days of these visits. IV nivolumab will be administered 
after rucaparib. 
• Physical examination 
• Weight 
• ECOG performance status (Appendix 3)  
• Vital signs 
• Concomitant medications and any surgical/medical procedures 
• Tumor assessment scans at the end of every 8 calendar weeks (±7 days) from the first dose of 
nivolumab (ie, Cohorts A1/A2: commencing C4D1) for the first 18 months of treatment, and 
then every 12 calendar weeks (±7 days) thereafter  
• Hematology (Local) 
• Clinical chemistry (Local) (fasting is not required) 
• Urinalysis (Local) 
• Serum pregnancy test for women of childbearing potential (Local) 
• Collect ctDNA blood sample (Central) (after Cycle 3, collect according schedule in Table 9) 
• PK and immunogenicity sample collection (Central) - according to Table 7  
• Blood sample for immunophenotyping (PBMC) (Table 9) 
• Blood sample for neo-epitope DNAseq (Table 8) 
• Blood sample for cytokine/chemokine profiling (Table 8) 
• CA-125 Measurement (Local) 
• AE monitoring 
• Patients return all unused tablets and containers (empty, partially used, and/or unopened) to 
the study site for accountability 
• Dispensation of rucaparib 
• Administration of IV nivolumab (after the morning dose of rucaparib) 
 
Patients will ingest rucaparib twice daily at about the same times every day as close as possible 
to 12 hours apart. Rucaparib should be taken with water and with or without food. Nivolumab IV 
will be administered as described in the Pharmacy Manual. In the event of toxicities, re-treatment 
or dose modification will be according to the criteria described in Section 5.5. 


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7.4.7 
Post-treatment Follow-up Phase 
7.4.7.1 
End of Treatment 
Upon treatment discontinuation, regardless of the reason, patients will have an End of Treatment 
Visit. The following procedures will be performed: 
• Physical examination 
• Weight 
• Vital signs 
• 12-lead ECG (Local) 
• Concomitant medications and procedures 
• Tumor scans (using the same methodology as was used at screening) if reason for treatment 
discontinuation was other than disease progression based on radiologic assessment 
• ECOG performance status (Appendix 3) 
• Hematology (Local) 
• Clinical chemistry (Local) (fasting is not required) 
• Urinalysis (Local) 
• Serum pregnancy test for women of childbearing potential (Local) 
• CA-125 measurement (Local) 
• Blood sample for ctDNA analysis (Central) 
• Blood sample for immunophenotyping (PBMC)  
• Blood sample for neo-epitope DNAseq 
• Blood sample for cytokine/chemokine profiling 
• AE monitoring 
• Optional tumor tissue biopsy collection at time of disease progression/treatment 
discontinuation (requires additional consent). Tumor tissue will be processed locally as FFPE 
tissue. Refer to the Laboratory Manual for detailed sample handling instructions. 
• Patients return all unused tablets and containers (empty, partially used, and/or unopened) to 
the study site for accountability 
 
7.4.7.2 
28-day Safety Follow-up (FU-28) 
The procedures to be performed for all patients 28 (±3) days after the last dose of study drug 
(oral or IV, whichever is later) are listed below.   
• Physical examination 


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• Weight 
• Vital signs 
• ECOG performance status (Appendix 3) 
• Disease assessment for patients who discontinued treatment for reason other than disease 
progression or death. Tumor scans should continue to be performed at 12-week intervals (up 
to 7 days prior permitted) for the first 3 years after initiation of oral/IV combination study 
treatment and every 24 weeks thereafter until radiologic disease progression by 
RECIST v1.1, as assessed by the investigator, is documented 
• Blood sample for ctDNA analysis should be collected at the same time as radiological 
imaging 
• CA-125 measurement (Local) should be performed at the same time as radiological imaging 
• Hematology (Local) 
• Clinical chemistry (Local) (fasting is not required) 
• Urinalysis (Local) 
• PK and immunogenicity sample collection (Central) - according to Table 7  
• AE monitoring 
• Concomitant medications and procedures 
 
7.4.7.3 
100-day Safety Follow-up (FU-100) 
The procedures to be performed for all patients at least 100 days (+7 days) after the last dose of 
IV study drug are listed below. If a patient remains on oral study drug after discontinuation of IV 
study drug, the 100-day Safety Follow-up Visit can be performed at a cycle visit, provided it has 
been at least 100 days since the last IV dose.   
• Physical examination 
• Weight 
• Vital signs 
• ECOG performance status (Appendix 3) 
• Disease assessment for patients who discontinued treatment for reason other than disease 
progression or death. Tumor scans should continue to be performed at 12-week (±7 days) 
intervals for the first 18 months  years after initiation of study treatment and every 24 weeks 
thereafter until radiologic disease progression by RECIST v1.1, as assessed by the 
investigator, is documented 
• Blood sample for ctDNA analysis should be collected at the same time as radiological 
imaging (Central) 
• CA-125 measurement (Local) should be performed at the same time as radiological imaging. 


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• Hematology (Local) (only required if toxicities are present) 
• Clinical chemistry (Local) (fasting is not required) (only required if toxicities are present) 
• Urinalysis (Local) 
• PK and immunogenicity sample collection (Central) - according to Table 7  
• AE monitoring 
• Concomitant medications and procedures 
 
7.4.8 
Long-term Follow-up 
Patients who complete the Safety Follow-up Visit(s) after the last dose of study treatment will 
continue in long-term follow-up as described below. 
• Disease assessment for patients who discontinued treatment for reason other than disease 
progression or death. Tumor scans should continue to be performed at 12-week (±7 days) 
intervals for the first 18 months after initiation of study treatment, and every 24 weeks 
(±14 days) thereafter, until radiologic disease progression by RECIST v1.1, as assessed by 
the investigator, is documented. 
• CA-125 measurement (Local) may be performed at the same time as radiological imaging, at 
the discretion of the investigator. 
• Subsequent treatments, secondary malignancy monitoring, and overall survival information 
will be collected for all patients every 12 weeks (±14 days) until death, loss to follow-up, 
withdrawal of consent from study, or closure of the study. Follow-up can be performed via 
the telephone. Diagnosis of any secondary malignancy requires appropriate documentation 
(ie, laboratory and/or pathology reports) and should be reported as indicated in Section 8.10. 
• SAEs related to study drug and all AESIs, irrespective of causality, are to be reported as 
specified in Section 8.10.  
 
7.5 
Methods of data collection 
7.5.1 
Medical History and Demographic/ Baseline Characteristics 
Basic demographic and baseline characteristics will be collected during screening. In addition to 
the evaluation of a patient’s medical history in terms of study eligibility, all relevant medical 
conditions will be documented on the appropriate eCRF. Events that occur after signing of 
informed consent but prior to initiation of study drug, unless due to a protocol-mandated 
procedure, should be recorded on the Medical History eCRF.  
The patient’s entire oncology history will be collected on the appropriate eCRF including date of 
diagnosis for epithelial ovarian, primary peritoneal, or fallopian tube cancer (and other 
malignancy, if applicable), prior surgeries/ treatments received for cancer, dates of treatment 
administration, best response achieved, date of progression and how assessed, radiology reports, 
and BRCA1/2 mutation status and if gBRCA or sBRCA (if known).  


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7.5.2 
Prior and Concomitant Medication Assessments 
Medications being used by the patient will be recorded as prior medications during screening and 
as concomitant medications following receipt of the first dose of study drug through the 
completion of the 100-day Safety Follow-up Visit after IV treatment discontinuation. 
Medications information will be entered in the appropriate eCRF after it is obtained at each study 
visit. 
Following treatment discontinuation, subsequent anticancer treatments will be collected for all 
patients every 12 (±7 days) or 24 weeks (±14 days), to coincide with the appropriate frequency 
of follow-up tumor assessments, until death, loss to follow-up, withdrawal of consent from 
study, or closure of the study. With the exception of the 28-day and 100-day Safety Follow-up 
Visits, follow up can be performed via the telephone.  
7.5.3 
Efficacy Evaluations 
7.5.3.1 
Disease/ Tumor Assessments 
Tumor assessment measurements will be performed at screening, at the end of every 8 weeks of 
treatment (±7 days is permitted) relative to Cycle 2 Day 1 until objective radiological disease 
progression. Tumor assessments should be performed at the time of treatment discontinuation if 
the reason for discontinuation was other than radiologically confirmed disease progression and it 
has been ≥ 8 weeks since the last assessment. In addition, tumor assessments should be made as 
clinically indicated. 
Disease assessment will comprise clinical examination and appropriate imaging techniques per 
RECIST v1.1 (ie, CT scans of the chest, abdomen, and pelvis with appropriate slice thickness per 
RECIST); other complementary assessments (MRI, X-ray, PET, and ultrasound) may be 
performed if required. If a site can document that the CT performed as part of a PET/CT is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast) then the CT portion of 
the PET/CT can be used for RECIST measurements. All sites of disease should be followed, and 
the same methods used to detect lesions at baseline are to be used to follow the same lesions 
throughout the clinical study. The same methods used to detect lesions at baseline are to be used 
to follow the same lesions throughout the clinical study. Scans of the chest, abdomen, and pelvis 
performed to determine the extent of disease at baseline should also be performed at each time of 
disease assessment, even if the scans were negative at baseline. Investigators should perform 
scans of other anatomical sites that, in their judgment, are appropriate to assess based on each 
patient’s tumor status. The sponsor may provide scans for IRR.  
Tumor response will be interpreted using RECIST v1.1. Disease progression will only be 
determined by RECIST v1.1. Patients who meet GCIG CA-125 criteria for disease progression 
should have a radiologic assessment and be assessed by RECIST. If the radiologic assessment 
does not confirm disease progression, patients should continue on treatment and continue to be 
assessed by RECIST v1.1 per the protocol schedule of assessments. 
Patients who discontinued treatment for reason other than disease progression or death should 
continue to have tumor scans performed at 12-week intervals (±7 days is permitted) until 


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objective radiologic disease progression by RECIST v1.1, as assessed by the investigator, is 
documented, or initiating subsequent anticancer treatment. 
Copies of CT scans (and other imaging, as appropriate) may be provided for IRR. 
7.5.3.2 
Tumor Markers 
Blood samples to assess CA-125 will be collected at screening, on Day 1 of Cycle 1, at the start 
of every cycle thereafter, at treatment discontinuation, and as clinically indicated. All CA-125 
tests will be performed by a local laboratory. 
7.5.4 
Safety Evaluations 
7.5.4.1 
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. During the screening period, unless otherwise 
required by local regulations, SAEs which are related to protocol-mandated assessments will be 
reported. Once enrolled and study drug is administered, patients will be monitored for all 
AEs/SAEs/AESIs during study participation and until 28 days after the last dose of study drug 
and 100 days after the last dose of IV study drug, whichever occurs later. After the 28-day (oral 
and/or IV, whichever occurs later) or 100-day (IV) window, only study drug-related SAEs and 
all AESIs, irrespective of causality, need to be reported. Any ongoing SAEs, AESIs, or 
treatment-related Grade 3/4 AEs will be followed until resolution or stabilization or until loss to 
follow-up. AEs and laboratory abnormalities will be graded according to the NCI CTCAE 
grading system (v5.0) and recorded on the eCRF. 
Complete details for monitoring AEs, including the definition of drug-related AEs, are provided 
in Section 8. 
7.5.4.2 
Clinical Laboratory Investigations 
All clinical laboratory samples for safety will be collected and analyzed by the site’s local 
laboratory. The panels of laboratory tests to be performed are shown below: 
Hematology: Red blood cell (RBC) count and parameters (hemoglobin, hematocrit, MCV, 
MCH, and mean corpuscular hemoglobin concentration [MCHC]) and reticulocyte count, white 
blood cell (WBC) count and differential (with ANC), and platelet count will be assessed for all 
patients at screening, during treatment at each study visit, and at the End of Treatment Visit, 
28-day Safety Follow-up Visit (FU-28), and at the 100-day Safety Follow-up Visit (FU-100), if 
toxicities are present. Hematology results must be reviewed by the investigator before the start of 
study drug and ongoing at times testing occurs. Additional and more frequent tests may be 
performed at the investigator’s discretion. 
Clinical Chemistry: total protein, albumin,  measured clearance (CLcr), BUN or urea, total 
bilirubin, alkaline phosphatase (ALP), ALT, AST, lactate dehydrogenase (LDH), glucose, 
sodium, potassium, magnesium, chloride, bicarbonate (CO2,/HCO3-), calcium, phosphorus, 
thyroid stimulating hormone (TSH), free triiodothyronine (T3; fT3), free thyroxine (T4, fT4), 


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TSH with reflexive fT3 and fT4 if TSH is abnormal on treatment, folic acid, and total cholesterol 
will be assessed for all patients at screening, during treatment at each study visit, and at the End 
of Treatment Visit, 28-day Safety Follow-up Visit (FU-28), and at the 100-day Safety Follow-up 
Visit (FU-100), if toxicities are present. Fasting is not required before blood sampling. If 
pancreatitis is suspected clinically, serum lipase and amylase should be analyzed. Clinical 
chemistry results must be reviewed by the investigator before the start of treatment with study 
drug and ongoing at times testing occurs. 
In addition to the clinical chemistry assessments above, serology serum for hepatitis C antibody 
and hepatitis B surface antigen should be performed at screening. Testing for HIV must also be 
performed at screening if mandated locally by a given site. 
Urinalysis: performed locally on a freshly voided clean sample by dipstick for protein, glucose, 
blood, pH, and ketones. If dipstick findings are abnormal based on the investigator’s judgment, 
then a microscopic evaluation will be performed to assess the abnormal findings. Urinalysis will 
be performed at screening, during treatment at each study visit, at the End of Treatment Visit, at 
the 28-day Follow-up Visit, and at the 100-day Follow-up Visit for all patients, but may be 
conducted at other times as clinically indicated.  
Local laboratory reports will be reviewed by the investigator or delegated physician who will 
then comment on out of range parameters and assess clinical significance. Clinically significant 
abnormalities and associated panel results, as well as results of any additional tests performed as 
follow-up to the abnormalities, will be documented on the eCRF- as an AE. Refer to Section 8.6 
for guidelines on reporting of abnormal laboratory values as AEs. 
7.5.4.3 
Vital Signs 
Vital signs will include blood pressure, pulse, and body temperature and will be taken after the 
patient has been resting for at least 5 minutes during screening, at study visits during the 
Treatment Phase, and at the End of Treatment Visit. 
7.5.4.4 
12-Lead Electrocardiogram 
For all patients, local 12-lead ECGs will be taken at screening (within 28 days prior to first dose 
of study drug) and at the end of treatment. 
The following will be measured or calculated: heart rate, PR, QRS, QT, QTcF, and rhythm. The 
investigator or qualified designee will review the ECGs locally and assess the results as normal 
or abnormal (clinically significant or not clinically significant). 
If it is clinically indicated, ECGs can be performed at other times during the study.  
7.5.4.5 
Body Weight and Height 
Height will be measured during the screening visit only. Weight will be measured per 
institutional guidelines during screening, on Day 1 of each cycle, and at the End of Treatment 
and Follow-up Visits. 


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7.5.4.6 
Physical Examinations 
Physical examinations will include an assessment of all the major body systems. Complete 
physical examinations will be performed during screening and at the End of Treatment Visit. 
Physical examinations at study visits during the Treatment Phase will be limited as appropriate.  
7.5.4.7 
ECOG Performance Status 
ECOG performance status (Appendix 3) will be assessed during screening, at study visits during 
the Treatment Phase, End of Treatment Visit, and Follow-up Visits. The ECOG performance 
status should be assessed by the same study personnel at each visit, if possible. For eligibility 
purposes, patients with borderline ECOG performance status should be considered carefully to 
avoid enrolling patients who may have significant impairment. 
7.5.5 
Pharmacokinetic and Immunogenicity Evaluations 
Samples for nivolumab and rucaparib PK and immunogenicity assessments will be collected for 
all patients, as described in Table 7. For nivolumab, corresponding serum samples designated for 
either PK or immunogenicity assessments may also be used for either of those analyses, if 
required (eg, insufficient sample volume to complete testing). 
7.5.5.1 
Rucaparib Pharmacokinetic Sample Collection 
For all patients, plasma samples are to be collected for trough level PK analysis of oral study 
drug within 1 hour before the morning dose on Day 1 of Cycle 2, 3, 4, and 6. Plasma samples are 
to be collected approximately 12 hours after the last oral dose, but prior to the next oral dose (ie, 
typically within 1 hour prior to dosing). If oral dosing is held for toxicity or any other reason, 
plasma samples for PK should still be collected at the end of treatment Cycles 1, 2, 3, and 5. 
A central laboratory will be used for bioanalysis of plasma rucaparib concentration 
measurement. Please refer to the laboratory manual for details on collection and processing of 
blood PK samples. 
7.5.5.2 
Nivolumab Pharmacokinetic Sample Collection 
All time points are relative to the start of IV treatment administration. All on-treatment time 
points are intended to align with days on which IV treatment is administered. If it is known that a 
dose is going to be delayed, then the pre-dose sample should be collected just prior to the 
delayed dose. However, if a pre-dose sample is collected but the IV dose is subsequently 
delayed, then an additional pre-dose sample should not be collected. 
Blood samples should be drawn from a site other than the nivolumab infusion site (ie, 
contralateral arm) on days of infusion. All samples collected predose should be collected just 
prior to the administration from the contralateral arm (ie, the arm not used for the infusion). If 
the nivolumab infusion was interrupted, the interruption details will also be documented on the 
eCRF. Further details of PK sample collection and processing will be provided to the site in the 
Laboratory Manual. Serum concentration analyses for nivolumab will be performed by validated 
bioanalytical method(s). 


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7.5.5.3 
Nivolumab Immunogenicity Assessments 
Samples for nivolumab immunogenicity assessment will be collected from all patients receiving 
nivolumab/rucaparib as described in Table 7. 
The serum samples will be analyzed for anti-nivolumab drug antibody (ADA) by validated 
immunoassays. Samples with a positive ADA response may also be analyzed for neutralizing 
ADA response to nivolumab. The immunogenicity (and corresponding drug exposure) data from 
these samples will be reported as part of a patient’s overall immunogenicity assessment. Selected 
serum samples may be analyzed by an exploratory method that measure nivolumab or detect 
ADA for technology exploration purposes; exploratory results will not be reported. Further 
details of immunogenicity sample collection and processing will be provided to the site in the 
Laboratory Manual.  
7.5.6 
Biomarker Analysis 
7.5.6.1 
Biomarker Analysis – Mandatory Tumor Tissue Collection 
A sufficient quantity of tumor tissue collected at screening must be provided during the 
screening process and submitted to the central laboratory directly for determination of HRD 
status. Patients may be enrolled prior to central tissue analysis, provided there is confirmation 
that the tumor tissue has been received by the central laboratory. Within 5 days and prior to 
commencement of IV nivolumab treatment on Cycle 2 Day 1 (= Cycle 1 Day 28 [window: 
−5 days]), collection of a primary or metastatic tumor sample is mandatory for patients, unless 
tumor biopsy procedure is contraindicated (eg, unacceptable risk in the opinion of the 
investigator). 
All tumor specimens submitted need to contain enough tumor tissue for 1 × 4 µm section for 
hematoxylin and eosin (H&E) and approximately 5 × 10 µm sections [unstained], or equivalent, 
for determination of HRD status, and 4 × 4 µm sections and 2 × 10 µm sections, or equivalent 
for other planned analyses. The tumor tissue sample must be of adequate quality (at least 20% 
tumor content [≥ 30% is strongly preferred] with a minimum of 80% nucleated cellular content), 
or a new sample must be acquired. Check with sponsor if tumor tissue sample is inadequate for 
all testing. 
Gene expression signatures associated with inflammation/immune activation will also be 
assessed.67 Refer to the Laboratory Manual for details.  
A tumor tissue biopsy sample at or following disease progression until the start of the next 
treatment 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), the lesion(s) 
should be prioritized for the optional biopsy. Detailed sample handling instructions are located in 
the Laboratory Manual. 
The tumor specimens will be sequenced using Foundation Medicine’s NGS-based test, which 
examines a panel of cancer-related genes, including BRCA1/2 and other homologous 
recombination pathway genes, and assesses the percentage of genomic LOH. The goal is to 
assess mutations in these genes as molecular markers for predicting response or resistance to the 


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combination of rucaparib and nivolumab. In addition to determining HRD status, gene 
expression profiling on extracted RNA will be analyzed to classify tumors into gene expression 
molecular subtypes, which have been shown to be associated with patient survival in HGSOC.68 
The NGS-based test will also enable assessment of TMB as a molecular marker for efficacy.  
In addition, immunohistochemistry staining of the tumor specimen will be performed to assess 
protein expression of immune-related markers, such as PD-L1, as a molecular marker for 
efficacy. Immunohistochemistry staining of immune lineage and immunogenic cell death 
markers on pre-rucaparib treatment tumor specimen (collected during screening) and 
post-rucaparib treatment tumor specimen (collected at Cycle 1 Day 28) will be performed to 
study the effect of rucaparib on the immune microenvironment. NGS results will be provided to 
the investigator. 
7.5.6.2 
Biomarker Analysis – ctDNA 
Blood samples will be collected during screening, before dosing beginning on Day 1 of Cycles 1, 
2, 3, and at specified subsequent cycles, at treatment discontinuation, and though the 100-day 
Follow-up Visit, as scheduled in Table 9. Sample collection details will be provided in the 
Laboratory Manual. 
These samples will be used for ctDNA profiling to assess alterations in genes that may be 
associated with response and resistance to the combination of rucaparib and nivolumab. 
7.5.6.3 
Biomarker Analysis - Genomic DNA from Blood 
A blood sample for genomics analysis will be collected at Cycle 1 Day 1 (or next visit if not 
collected at Cycle 1 Day 1) from all patients for determination of germline status of mutations 
identified using NGS testing. Results of actionable alterations may be made available to the 
investigator, subject to patients consent. Sample collection details will be provided in the 
Laboratory Manual. 
7.5.6.4 
Other Peripheral Blood Biomarker Analyses 
Peripheral blood samples will also be collected at selected time points on-treatment (C1D1, 
C2D1, C5D1, C7D1, C9D1), at the time of progression, and safety follow-ups for biomarker 
analyses that may predict sensitivity to nivolumab, including flow cytometry 
immunophenotyping, neo-epitope DNA sequencing, and serum cytokine/chemokine profiling. 
A schedule of blood biomarker analysis is provided in Table 8. Sample collection and processing 
details will be provided in the Laboratory Manual. 
7.5.6.5 
Additional Research  
The patient will have the option to provide additional consent to allow the sponsor to retain 
residual samples for future unspecified research.  


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8 
ADVERSE EVENT MANAGEMENT 
8.1 Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a patient administered a medicinal 
product that does not necessarily have a causal relationship with this treatment. 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. 
It is the responsibility of the investigator to document all AEs that occur during the study. AEs 
should be elicited by asking the patient a non-leading question (eg, “Have you experienced any 
new or changed symptoms since we last asked/since your last visit?”). The existence of an AE 
may be concluded from a spontaneous report of the patient; from the physical examination; or 
from special tests such as the ECG, laboratory assessments, or other study-specified procedure 
(source of AE). Symptoms reported spontaneously by the patient during the physical 
examination would also qualify as an AE (and hence documented on the AE eCRF). 
8.2 Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that occurs at any dose (or, occurs after informed 
consent is given and prior to dosing if the SAE is related to a study 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 of oral drug and 100 days after the last 
dose of IV study drug, whichever occurs later) must be treated as an SAE and reported as 
such. An event related to a study procedure that occurs after informed consent, but prior to 
dosing that results in death must also be reported as an SAE.  
• Is life-threatening (patient is at immediate risk of death from the event as it occurred) 
• Requires in-patient hospitalization (formal admission to a hospital for medical reasons) or 
prolongation of existing hospitalization 
• Results in persistent or significant disability/ incapacity 
• Results in a congenital anomaly or birth defect 
• Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home or the 
development of drug dependency or drug abuse. 
 


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8.3 
Definition of an Adverse Events of Special Interest 
AESIs (serious or nonserious) are defined as AEs 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 study sponsor to other parties (eg, regulators) might also be 
warranted. 
Details on the sponsor’s currently agreed list of AESIs for rucaparib can be found in the current 
rucaparib IB. These AESIs are to be reported to the sponsor within 24 hours (see Section 8.10 
for reporting instructions).  
8.4 
Immune-mediated Adverse Events 
Immune-mediated AEs (IMAEs) are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which 
were exacerbated by the induction of autoimmunity. Information supporting the assessment will 
be collected on the patient’s eCRF. 
Details on IMAEs can be found in the current nivolumab IB.  
8.5 
Events or Outcomes Not Qualifying as Serious Adverse Events 
The following are not considered SAEs and therefore do not need to be reported as such: 
• Pre-planned or elective hospitalization including social and/ or convenience situations (eg, 
respite care) 
• Hospital visits of less than 24 hours duration (eg, patient presents to the emergency room, but 
is not admitted to a ward)  
• Overdose of either study drug or concomitant medication unless associated with an SAE. 
However, the event should still be captured as a nonserious AE on the appropriate eCRF 
page 
• 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 or a serious adverse event.  
• Events that meet the SAE criteria (as outlined in Section 8.2) and occur after informed 
consent but before the first dose of study drug, which are considered unrelated to screening 
procedures. 


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8.6 Clinical Laboratory Assessments as Adverse Events and Serious 
Adverse Events 
It is the responsibility of the investigator to assess the clinical significance of all abnormal values 
as defined by the list of reference ranges from the local laboratory. In some cases, significant 
changes in laboratory values within the normal range will require similar judgment. 
An abnormal laboratory value that is not already associated with an AE is to be recorded as an 
AE only if any one of the following criteria is met: 
• an action on the study drug is made as a result of the abnormality 
• intervention for management of the abnormality is required 
• at the discretion of the investigator should the abnormality be deemed clinically significant 
 
8.7 Pregnancy or Drug Exposure during Pregnancy 
If a patient becomes pregnant during the course of the study, study drug(s) should be held 
immediately. 
Pregnancy is not considered to be an AE or SAE; however, all pregnancies occurring during 
study participation or within 6  months of last dosing must be reported to the sponsor using the 
Pregnancy Report Form within the same timelines as for an SAE. 
All pregnancies will be followed through to outcome. Once the outcome of a pregnancy is 
known, the Pregnancy Outcome Report Form will be completed and reported to the sponsor. 
AEs, SAEs, or AESIs that occur during pregnancy will be assessed and processed according to 
the AE or SAE/ AESI processes using the appropriate AE or SAE/ AESI forms.   
8.8 Recording of Adverse Events, Serious Adverse Events, and Adverse 
Events of Special Interest 
Events that occur after signing of informed consent but prior to initiation of study drug, unless 
due to a protocol-mandated procedure, will be recorded on the Medical History eCRF. Any AE 
that occurs after first dose of study drug through 28 days after receiving the last dose of oral 
study drug or 100 days after receiving the last dose of IV study drug, whichever occurs later, will 
be recorded on the AE eCRF. After the 28-day or 100-day reporting window after 
discontinuation of treatment, only SAEs assessed as related to study drug and all AESIs, 
irrespective of causality, need to be reported. Information on the follow-up of AEs, SAEs, and 
AESIs is provided in Section 8.9. 
In order to avoid vague, ambiguous, or colloquial expressions, the AE should be recorded in 
standard medical terminology rather than the patient’s own words. Whenever possible, the 
investigator should combine signs and symptoms that 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. 


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Each AE is to be evaluated for causal relationship to the investigational drug, severity, and, 
seriousness. The action taken, and the outcome must also be recorded. 
SAEs and AESIs that occur during the study or within 28 days after receiving the last dose of 
oral study drug or 100 days after receiving the last dose of IV study drug, whichever is later, 
whether or not related to study drug, must be reported immediately (ie, within 24 hours of 
knowledge of the event or additional information for a previously reported event) to the 
sponsor/SAE designee. The contact information for reporting of SAEs/AESIs can be found on 
the SAE/ AESI Reporting Form.  
8.8.1 Onset date of Adverse Events 
The onset date is the date that the event or the signs or symptoms related to the event started. 
8.8.2 Resolution date of Adverse Events 
The resolution date is the date that the event or the signs / symptoms related to the event resolved 
or resolved with sequelae or enter the resolution date as the date when the patient has reached a 
new baseline if event is not expected to resolve. 
8.8.3 Intensity of Adverse Events 
The severity of each AE will be graded using the NCI CTCAE, v5 or later grading scale.66  
Severity is not the same as Serious. 
For AEs not covered by NCI CTCAE, the severity will be characterized as mild, moderate, 
severe, life-threatening, or fatal according to the following definitions: 
• Mild events are usually transient and do not interfere with the patient’s daily activities 
• Moderate events introduce a low level of inconvenience or concern to the patient and may 
interfere with daily activities 
• Severe events interrupt the patient’s usual daily activities and hospitalization (or prolongation 
of hospitalization) may be required 
• Life-threatening events require urgent intervention to prevent death 
• Fatal events are events that lead to the patient’s death 
 
8.8.4 Causal Relationship of Adverse Events to Study Drug 
Medical judgment should be used to determine the cause of the AE considering all relevant 
factors such as, but not limited to, the underlying study indication, coexisting disease, 
concomitant medication, relevant history, pattern of the AE, temporal relationship to the study 
medication, dechallenge or rechallenge with the study drug (Table 10).  


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Table 10. 
Causal Relationship of Adverse Events to Study Drug 
Not Related to 
Study Drug 
• An AE that is clearly due to extraneous causes (eg, concurrent disease, 
concomitant medications, disease under study, etc.) 
• It does not follow a reasonable temporal sequence from administration of 
the study drug. 
• It does not follow a known pattern of response to study drug 
• It does not reappear or worsen when study drug is restarted. 
• An alternative explanation is likely, but not clearly identifiable. 
Related to 
Study Drug 
• An AE that is difficult to assign to alternative causes. 
• It follows a strong or reasonable temporal sequence from administration of 
study drug. 
• It could not be reasonably explained by the patient’s clinical state, 
concurrent disease, or other concomitant therapy administered to the 
patient.  
• It follows a known response pattern to study drug 
• It is confirmed with a positive rechallenge or supporting laboratory data. 
 
8.9 
Follow-Up of Adverse Events, Serious Adverse Events, and Adverse 
Events of Special Interest 
All AEs (including SAEs and AESIs) occurring during the study are to be followed up in 
accordance with good medical practice until resolved; judged no longer clinically significant; or, 
if a chronic condition, until fully characterized through 28 days after the last dose of oral study 
drug or 100 days after the last dose of IV study drug, whichever occurs later. Any SAEs, AESIs, 
and treatment-related Grade 3/4 AEs must be followed until resolution or stabilization, or until 
lost to follow-up. After the 28- or 100-day window, treatment-related SAEs and all AESIs, 
irrespective of causality, need to be reported.  
8.10 Potential Drug-Induced Liver Injury 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria,41 must be reported as SAEs (see Section 8.11 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), 


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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. 
 
8.11 Regulatory Aspects of Serious Adverse Event and Adverse 
Events of Special Interest Reporting 
It is important that the investigator provide an assessment of relationship of the SAE or AESI to 
study treatment at the time of the initial report. For reporting SAEs/AESIs or pregnancies, use 
the applicable report forms. The contact information for reporting of SAEs and AESIs can be 
found on each of the forms. 
The sponsor or its designee is responsible for submitting reports of AEs associated with the use 
of the drug that are both serious and unexpected to the US FDA, according to 21 Code of Federal 
Regulations (CFR) 312.32; to the Japanese Pharmaceuticals and Medical Devices Agency 
(PMDA); to the European regulatory authorities according to the European Commission Clinical 
Trials Directive (2001/20/EC); and to other applicable 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), 
the sponsor 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. 
The sponsor or its designee will submit all safety updates and periodic reports to the regulatory 
authorities as required by applicable regulatory requirements. 
8.12 Data Monitoring Committee 
A study DMC will be established and be comprised of the coordinating investigator and sponsor 
representatives. The DMC composition, responsibilities, and procedures for this study will be 
documented in the DMC Charter, which will be endorsed by the DMC members and signed by 
the DMC chair prior to the first data review meeting.  
The DMC will review on an ongoing basis the study progress and clinical data to ensure the 
study remains beneficial to patients. The DMC will review the overall safety and efficacy data of 
rucaparib in combination with nivolumab, and by study cohort, to determine whether the study 
benefit/risk remains positive during the study. 
The DMC will meet after the first 10 patients (Cohort A1) have either (a) received at least one 
Cycle of study treatment with Rucaparib and Nivolumab, (b) discontinued study treatment or 
(c) died of any cause. The DMC will perform continuous safety review at least every 6 months. 
The DMC chairperson or sponsor may convene an unscheduled DMC meeting if there are any 
emergent significant safety concerns. Following data review, the DMC will recommend 


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continuation, revision, or termination of the study and/or continuing or suspending enrollment 
into the study or a particular study cohort. 
9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
All safety analyses will be summarized for all patients who received at least 1 full or partial dose 
of protocol-specified treatment. Efficacy will be summarized for all treated patients according to 
the intent-to-treat principle. Cohorts A1 and A2 will be summarized separately for all safety and 
efficacy analyses.  
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 (StD), 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, 
median (50th percentile) with the 95% confidence interval (CI) will be summarized. 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. Unless otherwise specified, baseline is defined as the last measurement on or prior to the 
first day of study drug administration.  
All statistical analyses will be conducted with the statistical analysis software (SAS®) System, 
Version 9.3 or higher. Further details around the statistical analyses planned in this study will be 
outlined in the Statistical Analysis Plan (SAP).  
9.2 
Determination of Sample Size 
Between 28 to 53 patients will be enrolled in this non-randomized 2-cohort study, which 
includes a 2-stage study design for Cohort A1. 
• Cohorts A1 and A2 (Ovarian): Oral rucaparib + IV nivolumab 
◦ 
Cohort A1 (n = 18-43) 
◦ 
Cohort A2 (n = approximately 10) 
 
9.2.1 
Cohort A1 
For Cohort A1, a Simon 2-stage design to evaluate ORR by RECIST v1.1 criteria per 
investigator will be used. With an optimal design, a minimum of 18 patients will be enrolled and 
a maximum of 43 patients. After the first 18 patients have either a) completed 16 weeks of 
treatment, or b) discontinued treatment prior to completing, an interim analysis will be 
performed (ie, Stage 1). If ≤ 2/18 patients in Stage 1 have a confirmed objective response (CR or 


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PR per investigator), a DMC will evaluate the overall benefit: risk for study treatment and make 
a recommendation whether further enrollment should be discontinued. If ≥ 3/18 patients have a 
confirmed objective response, then enrollment will continue with additional patients in Stage 2. 
With 43 total patients, characteristics of the Simon 2-stage design include: 
• 5% probability of accepting a minimally effective drug (ie, ORR of 10%) 
• 80% probability of accepting an effective drug (ie, ORR of 25%) 
 
9.2.2 
Cohort A2 
Cohort A2 is an exploratory cohort which will enroll approximately 10 patients classified as 
gBRCAmut. 
9.3 
Analysis Populations  
Safety Population: The Safety Population will consist of all patients who received at least 1 full 
or partial dose of any protocol-specified treatment. 
9.4 
Patient Disposition 
Patient disposition will be summarized using frequency counts and the corresponding 
percentages. The number of patients in each analysis population, number of patients 
discontinued, and the primary reason for discontinuation from treatment will be summarized. 
9.5 
Demographics and Baseline Characteristics 
All demographic (eg, age, race, and ethnicity as allowed by local regulations) and baseline 
characteristics will be summarized for the safety population. 
The following disease and baseline characteristics variables will also be summarized with 
frequency tabulations: 
• Time since diagnosis (months): > 12 to 24, > 24 
• Baseline laboratory parameters: graded based on CTCAE 
Molecularly defined subgroups based on HRD and TMB and other definitions as appropriate. 
• Number of prior anticancer regimens; also split out by 
- 
Number of prior chemotherapy regimens 
- 
Number of prior platinum-based regimens 
• Progression-free interval following the last platinum regimen received (months); 0-6, 
> 6-12, > 12-24, > 24; 
• Partially Sensitive: PD ≥ 6 to < 12 months after last dose of platinum 
• Sensitive: PD ≥ 12 months after last dose of platinum 


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Descriptive statistics may also be used to summarize the continuous variables. 
9.6 
Efficacy Analyses 
All primary and secondary efficacy analyses will be summarized for the Safety Population for 
Cohort A1. Cohort A2 has an exploratory objective for evaluation of rucaparib on the immune 
microenvironment (see Section 9.6.3). 
9.6.1 
Primary Efficacy Analyses  
The primary efficacy endpoint of ORR is defined as a best confirmed response of CR or PR by 
RECIST v1.1 as assessed by the investigator. 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.  
9.6.2 
Secondary Efficacy Analysis 
9.6.2.1 
ORR Assessed by RECIST and GCIG CA-125 Criteria  
The endpoint of ORR assessed by RECIST v1.1 or GCIG CA-125 criteria is defined as a best 
confirmed response of CR or PR using RECIST v 1.1 as assessed by the investigator or a 
confirmed response per GCIG CA-125 criteria. The endpoint of CA-125 response rate defined as 
at least a 50% reduction in CA-125 as assessed by GCIG criteria (Appendix 2). The response 
rate will be summarized with frequencies and percentages in addition to 95% CI of the 
proportion using Clopper-Pearson methodology. The combined ORR will be assessed as 
indicated in Table 11.  
Table 11. 
RECIST and GCIG CA-125 Criteria 
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  
Abbreviations: CA-125 = cancer antigen 125; CR = complete response; GCIG = Gynecologic Cancer InterGroup; 
PD = progressive disease; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors; 
SD = stable disease 


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The response rate will be summarized with frequencies and percentages in addition to 95% CI of 
the proportion using Clopper-Pearson methodology. 
9.6.2.2 
ORR by RECIST v1.1 as Assessed by the Investigator and GCIG CA-125 Response 
According to Molecularly-defined HRD Subgroups 
All patients in Cohort A1 will have a centralized tumor tissue test and the results from the NGS 
test will be utilized to divide the patients into the following molecularly-defined HRD 
subgroups:  
• Non-tBRCA LOH+: Patients who are found to not have the a BRCA mutation in their 
tumor, but where the percent of LOH is ≥ 16% (ie, BRCAwt/LOHhigh); 
• Non-tBRCA LOH-: Patients who are found to not have a BRCA mutation in their tumor, but 
where the percent of LOH is < 16% (ie, BRCAwt/LOHlow); 
• 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) (ie, BRCAwt/LOHunknown); or  
• sBRCA (somatic tBRCA): Patients who are found to have a BRCA mutation in their tumor 
but not in their blood sample. 
 
The analyses of the response rates for each of these HRD subgroups will be performed as 
described in Section 9.6.2.1. In addition, different cut-off of LOH may be explored.  
9.6.2.3 
Progression-free Survival (PFS) 
Progression-free survival as assessed by investigator by RECIST is defined as the time from first 
dose to disease progression, according to RECIST v1.1 criteria as assessed by investigator, or 
death due to any cause, whichever occurs first. PFS will be calculated as 1+ the number of days 
from the first dose of study treatment to first occurrence of disease progression (per 
RECIST v1.1) or death due to any cause, whichever occurs first. For patients who continue 
treatment post-progression, the first date of progression (per RECIST v1.1) will be used for the 
analysis. Patients without a documented event of progression will be censored on the date of 
their last adequate tumor assessment (ie, radiologic assessment) or date of first dose of study 
treatment if no post-baseline tumor assessments have been performed. Only tumor scans prior to 
start of any subsequent anticancer treatment are included. 
The Kaplan-Meier methodology will be used to summarize PFS. If able to be estimated, the 
50th percentile (median) together with a 95% CI, will be presented based on log-log transformation. 
The number of patients with events and the number of censored patients will also be presented. 
9.6.2.4 
Duration of Confirmed Response (DOR) 
Duration of response (DOR) for any confirmed RECIST CR or PR will be measured from the date of 
the first response until the first date that PD is documented. DOR will be summarized as a time to 
event variable. For patients who continue treatment post-progression, the first date of progression 
(per RECIST v1.1) will be used for the analysis. Any patients with an ongoing response will be 


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censored on the date of their last adequate tumor assessment (ie, radiologic assessment) or date of 
first dose of study treatment if no post-baseline tumor assessments have been performed. Only 
tumor scans prior to start of any subsequent anticancer treatment are included.  
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 events and the 
number of censored patients will also be presented  
9.6.3 
Exploratory Efficacy Analysis 
The following exploratory analyses will be further described in the SAP: 
• ORR by RECIST v1.1 as assessed by the investigator in exploratory Cohort A2 
• ORR by RECIST v1.1 and GCIC CA-125 criteria in exploratory Cohort A2 
• PFS in exploratory Cohort A2 
• DOR in exploratory Cohort A2 
• Explore mutations in BRCA1, BRCA2, other HRR genes as molecular markers of 
efficacy 
• Explore PD-L1 expression as a molecular marker of efficacy 
• Explore LOH, TMB, and other genomic and transcriptional signatures as molecular 
markers of efficacy 
 
9.7 
ctDNA and immunogenicity Analyses   
Tumor tissue, plasma, and blood specimens will be used for exploratory biomarker analyses in 
an effort to understand the association of these markers with clinical activity or resistance to 
rucaparib and/or nivolumab, including efficacy and/or adverse events. 
9.8 
Safety Analyses 
All safety analyses will be summarized by cohort.  
Safety endpoints are incidence of AEs, clinical laboratory abnormalities, and dose modifications. 
Data from all patients who receive at least 1 dose of any study drug will be included in the safety 
analyses. AEs, clinical laboratory results, vital signs, ECG results, , and concomitant 
medications/ procedures will be tabulated and summarized. 
9.8.1 
Adverse Events 
Adverse events will be classified using the Medical Dictionary for Regulatory Activities 
(MedDRA) classification system. The severity of the toxicities will be graded according to the 
NCI CTCAE v5 or later. Only TEAEs will be collected: TEAEs are defined as AEs with onset 


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date on or after the date of first dose of study drug until 28 days after the last dose of oral study 
drug or 100 days after the last dose of IV study drug, whichever occurs later.  
The number and percentage of patients who experienced TEAEs for each system organ class 
(SOC) and preferred term will be presented. Multiple instances of the TEAE in each SOC and 
multiple occurrences of the same preferred term are counted for the worst only once per patient. 
The number and percentage of patients with at least one TEAE will also be summarized.  
Tables for TEAEs and treatment-related TEAEs will be presented as follows but are not limited 
to: 
• All; 
• By CTCAE grade; 
• Grade 3 or greater; 
• Serious; 
• TEAEs with an outcome of death; 
• TEAEs leading to discontinuation of study drug; 
• TEAEs resulting in interruption/delay of study drug; and 
• TEAEs resulting in dose reduction 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 1 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% CI. 
Non-TEAEs (pre-treatment and post-treatment) will be presented in the by patient data listings for 
the safety population. MedDRA PTs were combined for the following similar terms  
• Asthenia/Fatigue 
• Alanine Aminotransferase (ALT)/ Aspartate Aminotransferase (AST) Increased  


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• Anaemia and/or Low/Decreased Haemoglobin  
• Thrombocytopenia and/or Low/Decreased Platelets  
• Neutropenia and/or Low/Decreased Absolute Neutrophil Count (ANC)  
 
In addition, the analysis of combined terms for anemia is explored as a time to first event analysis as 
described above. Transfusions (blood or plasma) and concomitant medications/growth factor support 
received for cytopenias are provided in patient listings. 
9.8.2 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations include the continuous variables for hematology, clinical 
chemistry, and urinalysis. The laboratory values will generally be presented in International 
System of Units (SI). The on-treatment period will be defined as the time from the first dose of 
study drug to 100 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 shift tables based on CTCAE for shifts in grade 
from baseline to maximum, minimum and last value during the on-treatment period.  
Supporting laboratory data including normal ranges and abnormal laboratory flags will be 
provided using by-patient listings. Separate listings will be produced for clinically significant 
laboratory abnormalities (ie, those that meet Grade 3 or Grade 4 criteria according to CTCAE). 
9.8.3 
Vital Sign Measurements 
The on-treatment period will be defined as the time from the first dose of study drug to 100 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, StD, minimum, 
median, third quartile, and maximum) of the maximum, minimum and last value during the 
on-treatment period. Summaries using descriptive statistics (N, mean, StD, 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.  
9.9 
Pharmacokinetic Analysis 
9.9.1 
Rucaparib Pharmacokinetic Analysis 
In all patients with at least one PK sample collected, the trough plasma rucaparib PK data (Cmin) 
and summary statistics (N, mean, StD, minimum, median, max, CV%]) will be reported. 


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The PK data may be further analyzed by a PPK approach. The post hoc estimated exposures will 
be used for ER analyses of selected efficacy and safety endpoints if the data permit. The PPK 
and the ER analyses may be presented separately from the main clinical study report. 
9.9.2 
Nivolumab Pharmacokinetic Analysis 
In all patients with at least one PK sample collected, the serum nivolumab PK data, including 
Cmin and concentration at the end of infusion (Ceoi) and summary statistics (N, mean, StD, 
minimum, median, max, CV%]) will be reported. 
The PK data may be further analyzed by a PPK approach. The post hoc estimated exposures will 
be used for ER analyses of selected efficacy and safety endpoints if the data permit. The PPK 
and the ER analyses may be presented separately from the main clinical study report. 
9.9.3 
Anti-Nivolumab Antibodies  
Anti-nivolumab antibodies in serum samples will be determined. Positive samples will be 
analyzed for neutralizing antibodies. The results will be reported. 
9.10 Interim Analysis 
An interim analysis of ORR by RECIST v1.1 criteria per investigator for Cohort A1 will be 
performed at Stage 1 of the Simon 2-stage design for the study. Enrollment in the study will 
continue while the interim analysis (Stage 1 criteria) occurs for Cohort A1. The DMC will 
review data for the interim analysis and provide recommendation if Stage 1 criteria are not met 
for Cohort A1. If Stage 1 criteria are not met, the DMC will evaluate the overall benefit: risk for 
study treatment, and make a recommendation whether further enrollment should be discontinued. 
If Stage 1 criteria in the Simon 2-stage design are met, the enrollment will continue with 
additional patients in Stage 2. 


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10 STUDY ADMINISTRATION 
10.1 Regulatory and Ethical Considerations 
This study will be conducted in compliance with the protocol; Good Clinical Practices (GCPs), 
including International Council on Harmonization (ICH) Technical Requirements for 
Registration of Pharmaceuticals for Human Use Guidelines; ICH E6 (R2); FDA regulatory 
requirements; and in accordance with the ethical principles of the Declaration of Helsinki. The 
ethical principles underlying European Union Directive 2001/20/EC and the United States Code 
of Federal Regulations, Title 21, Part 50 and Part 56 (21CFR50), and applicable local 
requirements.  
10.1.1 
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 www.clinicaltrials.gov, European Clinical Trials Database 
(EudraCT), and other applicable trial registry systems as appropriate. 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). 
10.1.2 
Institutional Review Board or Independent Ethics Committee Approval 
This protocol and any material to be provided to the patient (such as advertisements, patient 
information sheets, 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.  
The sponsor 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 ICF 
will be transmitted to the sponsor. 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 and approval.  


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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 ICF, 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.  
10.2 Patient Information and Consent 
All information about the clinical study, including the patient information and the ICF, is 
prepared and used for the protection of the human rights of the patient according to ICH GCP 
guidelines, applicable regulations, and the Declaration of Helsinki. 
It is the responsibility of the investigator to obtain signed ICFs from all patients 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 ICF, 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 ICF consistent with the study 
protocol version used and approved by the relevant IEC/IRB. The ICF 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 participation in the study with the 
investigator concerned. Both the patient and the person explaining the study and with whom the 
patient can discuss the informed consent will sign and date the ICF. A copy of the signed ICF 
will be retained by the patient and the original ICF will be filed in the investigator file unless 
otherwise agreed.  
10.3 Patient Confidentiality 
The investigator must assure that patients’ anonymity is strictly maintained and that their 
identities are protected from unauthorized parties, in accordance with applicable data protection 
requirements. Only patient identifiers such as initials, year of birth, and an identification code (ie, 
not names) should be recorded on any form submitted to the sponsor and the IRB/ IEC, as far as 
permitted by applicable local requirements. 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 the sponsor or designee including, but 
not limited to, the IB, 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 


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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. 
10.4 Study Monitoring 
On behalf of the sponsor, a contract research organization (CRO) or contract monitor will 
contact and visit the investigator at the study center prior to the entry of the first patient (unless 
the sponsor or the CRO has worked with the center recently, in which case this initial visit 
maybe waived) and at appropriate intervals during the study until after the last patient is 
completed. The monitor will also perform a study closure visit. Sponsor representatives may also 
contact and visit the investigators and monitor data during the study.  
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 (ie, 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 (ie, 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.  
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.  
10.5 Case Report Forms and Study Data 
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 study 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. 
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. 


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Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and 
clinical laboratory data will be entered into Medidata Rave, 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 electronic data capture and completing eCRFs is included in the 
investigator files. All questions or comments related to electronic capture should be directed to 
the assigned monitor. 
Clinical data will be entered directly from the source documents.  
10.6 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, 
the sponsor and the investigator will assure that adequate consideration is given to the protection 
of the patients’ interests. 
The sponsor reserves the right to 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; or 
• The sponsor or collaborator discontinues the development of study medication. 
 
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 
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).  


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10.7 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 the sponsor. 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. 
10.8 Retention of Study Documents 
The study site will maintain a study file, which should contain the Essential Documents for the 
Conduct of a Clinical Trial defined in ICH E6(R2) §8. The investigator should have control of all 
essential documents generated by the site. Source documents must be maintained, ALCOA-C 
(attributable, legible, contemporaneous/complete, original, accurate) 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 the 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 ICFs, copies 
of all eCRFs, query responses, and detailed records of drug disposition to enable evaluations or 
audits from regulatory authorities and the sponsor 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 the sponsor. 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 the sponsor. Copies of original documents 
should fulfill the requirements for certified copies. Should the investigator wish to assign the 
study records to another party or move them to another location, the sponsor must be notified in 
writing of the new responsible person and/or the new location. The sponsor will inform the 
investigator, in writing, when the study-related records are no longer needed. 
All clinical study information should be recorded, handled, and stored in a way that allows 
accurate reporting, interpretation, and verification, irrespective of the media used. 


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The sponsor and the 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. 
Patients’ medical records and other original data will be archived in accordance with the 
archiving regulations or facilities of the investigational site. 
10.9 Quality Control and Assurance 
The sponsor will implement and maintain quality control and quality assurance procedures with 
written standard operating procedures to ensure that the study is conducted, and data are 
generated, documented, and reported in compliance with the protocol, GCP, and applicable 
regulatory requirements.  
Aspects of the study that are essential to ensure human subject protection and reliability of study 
results should be the focus of these procedures. 
10.9.1 
Changes to the Protocol and Deviations 
The investigator may not deviate from the protocol unless necessary to eliminate immediate 
hazards to the patient. A deviation may result in the patient having to be withdrawn from the 
study and rendering that subject nonevaluable. Any deviation must be documented in the source 
documents and reported to the sponsor. 
If changes to the study are required, they must be provided in a formal protocol amendment 
authorized by the sponsor, and having been approved by an appropriate IRB/IEC.  
10.9.2 
Study Site Training and Ongoing Monitoring 
Each investigator and the site personnel for this study will be trained by the sponsor and/ or a 
designee (ie, a CRO) on the design, conduct, procedures, and administrative aspects of this 
study. This may include, but is not limited to, on-site training, Investigator Meeting(s), and/ or 
tele/ videoconferencing. Training may be ongoing as refresher, to address specific items, or to 
introduce changes in the study.  
In accordance with Code of Federal Regulations 21 CFR 312.56, ICH GCP and local regulations, 
the clinical monitor will periodically inspect via direct access to records, all eCRFs, study 
documents, medical records (office, clinic, or hospital) for patients in this study (anonymity is to 
be preserved), research facilities, and clinical laboratory facilities associated with this study at 
mutually convenient times during and after completion of the study. If these requirements are in 
conflict with local regulatory restrictions or institutional requirements, the investigator must 
inform the sponsor of these restrictions before initiation of the study. 
10.9.3 
Direct Access to Source Data/ Documents for Audits and Inspections 
The investigator site is to maintain a record of locations of essential documents and study source 
documents. Members of the sponsor’s GCP Quality Assurance Department or designees may 


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conduct an audit of a clinical site at any time during or after completion of the study. The 
investigator will be informed if an audit is to take place and advised as to the scope of the audit. 
Inspections and audits are typically carried out during the clinical and reporting phases of this 
study to ensure that the study is conducted, and data are generated, documented, and reported in 
compliance with the protocol, GCP, written standard operating procedures (SOPs) and applicable 
laws, rules, and regulations. 
Representatives of the FDA, European Medicines Agency (EMA), or other regulatory agencies, 
or IRB/IEC representatives may also conduct an audit or inspection of the study. If informed of 
such an activity, the investigator should notify the sponsor immediately. The investigator will 
ensure that the auditors and inspectors have access to the clinical supplies, study site facilities, 
and laboratory, and that all data (including original source documentation) and all study files and 
electronic records are available, if requested. 
10.10 Clinical Study Report 
A clinical study report (CSR) will be prepared, regardless of whether the study is completed, 
under the responsibility and supervision of the sponsor and signed by the sponsor’s Chief 
Medical Officer, Head of Biostatistics, and Head of Regulatory Affairs; thereby indicating their 
agreement with the analyses, results, and conclusions of the clinical study report. The CSR will 
be provided to the regulatory agency(ies) as required by the applicable regulatory requirements. 
10.11 Publication and Disclosure Policy 
All data generated from this study will be maintained by the sponsor. All data generated from 
this study, and all information furnished by the sponsor, the investigators, and other participating 
study groups shall be held in strict confidence. Independent analysis and/or publication of these 
data by the investigator(s) or any member of their staff are not permitted without the prior 
written consent of the sponsor. Any collaborative publications will be authored in accordance 
with the applicable guidelines (eg, International Committee of Medical Journal Editors 
[ICJME]).69 Written permission to the investigator will be contingent on the review of the 
statistical analysis and manuscripts/abstract by the sponsor and participating cooperative groups, 
and will provide for nondisclosure of the confidential or proprietary information. In all cases, the 
parties agree to provide all manuscripts or abstracts to all other parties 60 days prior to 
submission. This will enable all parties to protect proprietary information and to provide 
comments based on information that may not yet be available to other parties.  
10.12 Investigator Oversight 
The investigator has a responsibility for supervising any individual or party to whom they 
delegate study-related duties and functions conducted at the study 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). The 
investigator should implement procedures to ensure integrity of the study-related duties, 
functions performed, and any data generated.  


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11 REFERENCE LIST 
1. Ame JC, Spenlehauer C, de Murcia G. The PARP superfamily. Bioessays. 2004;26(8):882-
93. 
2. Ashworth A. A Synthetic Lethal Therapeutic Approach: Poly(ADP) Ribose Polymerase 
Inhibitors for the Treatment of Cancers Deficient in DNA Double-Strand Break Repair. J 
Clin Oncol. 2008;26(22):3785-90. 
3. 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. Br J Cancer. 2012;107(10):1776-82. 
4. Clovis Oncology UK Ltd. RUBRACA (rucaparib) SmPC. March 2019; Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/004272/WC500249806.pdf. 
5. Clovis Oncology Inc. RUBRACA (rucaparib) Prescribing Information. April 2018; Available 
from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf. 
6. Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbé C, et al. Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin 
Cancer Res. 2009;15(23):7412-20. 
7. Hamanishi J, Mandai M, Ikeda T, Minami M, Kawaguchi A, Murayama T, et al. Safety and 
Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant 
Ovarian Cancer. J Clin Oncol. 2015;33(34):4015-22. 
8. Bristol-Myers Squibb Company. OPDIVO (nivolumab) Prescribing Information. April 2018; 
Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125554s058lbl.pdf. 
9. Bristol-Myers Squibb Pharma EEIG. OPDIVO (nivolumab) SmPC. 2017; Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/003985/WC500189765.pdf. 
10. TCGA. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609-15. 
11. Bolton KL, Chenevix-Trench G, Goh C, Sadetzki S, Ramus SJ, Karlan BY, et al. Association 
between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial 
ovarian cancer. JAMA. 2012;307(4):382-90. 
12. Boyd J, Sonoda Y, Federici MG, Bogomolniy F, Rhei E, Maresco DL, et al. 
Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA. 
2000;283(17):2260-5. 
13. Strickland KC, Howitt BE, Shukla SA, Rodig S, Ritterhouse LL, Liu JF, et al. Association 
and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of 
tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian 
cancer. Oncotarget. 2016;7(12):13587-98. 


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14. Lee JM, Cimino-Mathews A, Peer CJ, Zimmer A, Lipkowitz S, Annunziata CM, et al. Safety 
and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in 
Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular 
Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women's Cancers: A Dose-
Escalation, Phase I Study. J Clin Oncol. 2017;35(19):2193-202. 
15. Karzai F, Madan RA, Owens H, et al. Combination of PDL-1 and PARP inhibition in an 
unselected population with metastatic castrate-resistant prostate cancer (mCRPC). J Clin 
Oncol. 2017;35 (suppl; abstr 5026). 
16. Swisher EM, Lin KK, Oza AM, Scott CL, Giordano H, Sun J, et al. Rucaparib in relapsed, 
platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, 
multicentre, open-label, phase 2 trial. Lancet Oncol. 2017;18(1):75-87. 
17. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence 
and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J 
Cancer. 2015;136(5):E359-86. 
18. Morgan RJ, Jr., Alvarez RD, Armstrong DK, Boston B, Burger RA, Chen LM, et al. NCCN 
Clinical Practice Guidelines in Oncology: epithelial ovarian cancer. J Natl Compr Canc 
Netw. 2011;9(1):82-113. 
19. Cannistra SA. Cancer of the ovary. N Engl J Med. 2004;351(24):2519-29. 
20. Salvador S, Rempel A, Soslow RA, Gilks B, Huntsman D, Miller D. Chromosomal 
instability in fallopian tube precursor lesions of serous carcinoma and frequent monoclonality 
of synchronous ovarian and fallopian tube mucosal serous carcinoma. Gynecol Oncol. 
2008;110(3):408-17. 
21. Levanon K, Crum C, Drapkin R. New insights into the pathogenesis of serous ovarian cancer 
and its clinical impact. J Clin Oncol. 2008;26(32):5284-93. 
22. Flesken-Nikitin A, Hwang CI, Cheng CY, Michurina TV, Enikolopov G, Nikitin AY. 
Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche. 
Nature. 2013;495(7440):241-5. 
23. Reed E, Dabholkar M, Chabner BA. Platinum Analogues. In: Chabner BA, Longo DL, 
editors. Cancer Chemotherapy and Biotherapy. Philadelphia: Lippincott-Raven Publishers; 
1996. p. 357-78. 
24. Pfisterer J, Ledermann JA. Management of platinum-sensitive recurrent ovarian cancer. 
Semin Oncol. 2006;33(2 Suppl 6):S12-6. 
25. Naumann RW, Coleman RL. Management strategies for recurrent platinum-resistant ovarian 
cancer. Drugs. 2011;71(11):1397-412. 
26. Parkinson CA, Brenton JD. Predictive Biology of Ovarian Cancer. In: Kehoe S, editor. 
Gynaecological Cancers: Biology and Therapeutics. London: RCOG; 2011. p. 41-54. 
27. Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, et al. 
Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: 
The AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32(13):1302-8. 


Rucaparib 
 
Clovis Oncology 
Clinical Study Protocol: CO-338-097 Amendment 1 
 
30 July 2019 
Confidential 
Page 123 of 145 
 
28. Roche Registration Limited. AVASTIN (bevacizumab) SmPC. 19 July 2016 [accessed 19 
September 2016]; Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000582/WC500029271.pdf. 
29. Kikkawa F, Nawa A, Ino K, Shibata K, Kajiyama H, Nomura S. Advances in treatment of 
epithelial ovarian cancer. Nagoya J Med Sci. 2006;68(1-2):19-26. 
30. Hennessy BT, Coleman RL, Markman M. Ovarian cancer. Lancet. 2009;374(9698):1371-82. 
31. Wang ZC, Birkbak NJ, Culhane AC, Drapkin R, Fatima A, Tian R, et al. Profiles of genomic 
instability in high-grade serous ovarian cancer predict treatment outcome. Clin Cancer Res. 
2012;18(20):5806-15. 
32. Coleman RL, Oza AM, Lorusso D, Aghajanian C, Oaknin A, Dean A, et al. Rucaparib 
maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy 
(ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 
2017;390(10106):1949-61. 
33. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the 
DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 
2005;434(7035):917-21. 
34. Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science. 
2017;355(6330):1152-8. 
35. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of 
BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 
2005;434(7035):913-7. 
36. Ménissier de Murcia J, Ricoul M, Tartier L, Niedergang C, Huber A, Dantzer F, et al. 
Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic 
development in mouse. Embo J. 2003;22(9):2255-63. 
37. Schreiber V, Amé JC, Dollé P, Schultz I, Rinaldi B, Fraulob V, et al. Poly(ADP-ribose) 
polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association 
with PARP-1 and XRCC1. J Biol Chem. 2002;277(25):23028-36. 
38. Dantzer F, Mark M, Quenet D, Scherthan H, Huber A, Liebe B, et al. Poly(ADP-ribose) 
polymerase-2 contributes to the fidelity of male meiosis I and spermiogenesis. Proc Natl 
Acad Sci U S A. 2006;103(40):14854-9. 
39. Oza AM, Tinker AV, Oaknin A, Shapira-Frommer R, McNeish IA, Swisher EM, et al. 
Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade 
ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: Integrated 
analysis of data from Study 10 and ARIEL2. Gynecol Oncol. 2017;147(2):267-75. 
40. Coleman RL, Brady MF, Herzog TJ, Sabbatini P, Armstrong DK, Walker JL, et al. 
Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in 
recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group 
study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 
2017;18(6):779-91. 


Rucaparib 
 
Clovis Oncology 
Clinical Study Protocol: CO-338-097 Amendment 1 
 
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Page 124 of 145 
 
41. US Department of Health and Human Services, Food and Drug Administration, CDER, 
CBER. 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. 
42. Temple R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 
2006;15(4):241-3. 
43. Bristol-Myers Squibb Company. OPDIVO (nivolumab) Prescribing Information. September 
2017; Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125554s041lbl.pdf. 
44. Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol. 
2003;21:807-39. 
45. Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection 
and immunosubversion. Nat Rev Immunol. 2006;6(10):715-27. 
46. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from 
immunosurveillance to tumor escape. Nat Immunol. 2002;3(11):991-8. 
47. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 
2005;23:515-48. 
48. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of 
the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative 
regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-34. 
49. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 
and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8(3):239-45. 
50. Habicht A, Dada S, Jurewicz M, Fife BT, Yagita H, Azuma M, et al. A link between PDL1 
and T regulatory cells in fetomaternal tolerance. J Immunol. 2007;179(8):5211-9. 
51. Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial 
ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus 
topotecan. J Clin Oncol. 2001;19(14):3312-22. 
52. Cannistra SA, Matulonis UA, Penson RT, Hambleton J, Dupont J, Mackey H, et al. Phase II 
study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous 
cancer. J Clin Oncol. 2007;25(33):5180-6. 
53. Crotzer DR, Sun CC, Coleman RL, Wolf JK, Levenback CF, Gershenson DM. Lack of 
effective systemic therapy for recurrent clear cell carcinoma of the ovary. Gynecol Oncol. 
2007;105(2):404-8. 
54. Birkbak NJ, Wang ZC, Kim JY, Eklund AC, Li Q, Tian R, et al. Telomeric allelic imbalance 
indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov. 
2012;2(4):366-75. 


Rucaparib 
 
Clovis Oncology 
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Page 125 of 145 
 
55. Friedlander M, Meniawy T, Markman B, Mileshkin LR, Harnett PR, Milward M, et al. A 
phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 (A317) in combination 
with the PARP inhibitor BGB-290 (290) in advanced solid tumors. J Clin Oncol. 2017;35(15 
(suppl)):3013. 
56. Konstantinopoulos PA, Waggoner SE, Vidal GA, Mita MM, Fleming GF, Holloway RW, et 
al. TOPACIO/Keynote-162 (NCT02657889): A phase 1/2 study of niraparib + 
pembrolizumab in patients (pts) with advanced triple-negative breast cancer or recurrent 
ovarian cancer (ROC)—Results from ROC cohort. J Clin Oncol. 2018;36(15_suppl):106. 
57. Coleman RL, Oza AM, Lorusso D, Aghajanian C, Oaknin A, Dean A, et al. Rucaparib 
maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy 
(ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. 2017. 
58. Clovis Oncology, Inc. RUBRACA (Rucaparib) [prescribing information]. December 2016; 
Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/209115s000lbl.pdf. 
59. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab 
versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 
2015;373(2):123-35. 
60. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus 
Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 
2015;373(17):1627-39. 
61. Hellmann MD, Rizvi NA, Goldman JW, Gettinger SN, Borghaei H, Brahmer JR, et al. 
Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer 
(CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 
2017;18(1):31-41. 
62. Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in 
Untreated Melanoma. N Engl J Med. 2015;373(13):1270-1. 
63. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. 
Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 
2015;373(19):1803-13. 
64. Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, et al. Pooled Analysis 
of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in 
Unresectable or Metastatic Melanoma. J Clin Oncol. 2015;33(17):1889-94. 
65. Popova T, Manie E, Rieunier G, Caux-Moncoutier V, Tirapo C, Dubois T, et al. Ploidy and 
Large-Scale Genomic Instability Consistently Identify Basal-like Breast Carcinomas with 
BRCA1/2 Inactivation. Cancer Res. 2012;72(21):5454-62. 
66. US Department of Health and Human Services, National Institutes of Health, National 
Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. 
27 November 2017; Available from: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quic
k_Reference_8.5x11.pdf. 


Rucaparib 
 
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Page 126 of 145 
 
67. Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, et al. IFN-γ-
related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 
2017;127(8):2930-40. 
68. Leong HS, Galletta L, Etemadmoghadam D, George J, Australian Ovarian Cancer S, Kobel 
M, et al. Efficient molecular subtype classification of high-grade serous ovarian cancer. J 
Pathol. 2015;236(3):272-7. 
69. International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals. December 2017; 
Available from: http://www.icmje.org/recommendations/. 
70. 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). Eur J 
Cancer. 2009;45(2):228-47. 
71. National Cancer Institute. Common Terminology Criteria for Adverse Events, Version 4.03. 
14 June 2010 [accessed 19 November 2014]; Available from: 
http://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. 
72. 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. 
73. US Department of Health andHuman Services, Food and Drug Administration, CDER. Draft 
Guidance for Industry: Drug Interaction Studies - Study Design, Data Analysis, Implications 
for Dosing, and Labeling Recommendations. February 2012; Available from: 
https://www.xenotech.com/regulatory-documents/2012/2012_guidance.aspx. 
74. US Food and Drug Administration. Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers.  [updated 27 Oct 2014]; Available from: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIntera
ctionsLabeling/ucm093664.htm. 
 
 


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12 APPENDICES 
Appendix 1 
Response Evaluation Criteria in Solid Tumors Criteria 
A summary of RECIST guidelines (Version 1.1) is provided below. For full details, please refer 
to RECIST guidelines (Version 1.1) described in Eisenhauer (2009)70 and 
http://www.eortc.be/Recist/Default.htm.  
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 lesions, 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 2 lesions per organ and 5 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 Version 1.1 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 diameters of target lesions, taking as 
reference the baseline sum diameters. 
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 diameters 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. (Note: The appearance 
of one or more new lesions is also considered progression.) 
 
Special Notes on the Assessment of Target Lesions 
Lymph Nodes: Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when lymph 
nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if complete 
response criteria are met, since a normal lymph node is defined as having a short axis of 
< 10 mm. 
Target lesions that become too small to measure: While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (eg, 2 mm). However, sometimes lesions or lymph nodes that 
are recorded as target lesions at baseline become so faint on CT scan that the radiologist may not 
feel comfortable assigning an exact measure and may report them as being ‘too small to 
measure’. When this occurs, it is important that a value be recorded on the eCRF. If it is the 
opinion of the radiologist that the lesion has likely disappeared, the measurement should be 
recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned. 
Evaluation of Nontarget Lesions 
Complete Response 
Disappearance of all nontarget lesions and normalization of tumor marker 
level. All lymph nodes must be non-pathological in size (< 10 mm short axis) 
Stable 
Disease/Incomplete 
Response 
Persistence of 1 or more nontarget lesion(s) or/and maintenance of tumor 
marker level above the normal limits. 
Progressive Disease 
Unequivocal progression (see comments below) of existing non-target lesions. 
(Note: the appearance of one or more new lesions is also considered 
progression.) 
 


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Special Notes on the Assessment of Non-Target Lesions 
The concept of progression of non-target disease requires additional explanation as follows: 
When the patient also has measurable disease: In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy (see examples 
in RECIST1.1).71 A modest ‘increase’ in the size of one or more non-target lesions is usually not 
sufficient to quality for unequivocal progression status. The designation of overall progression 
solely on the basis of change in non-target disease in the face of SD or PR of target disease will 
therefore be extremely rare. 
When the patient has only non-measurable disease: This circumstance arises in some Phase 3 
studies, such as this study, when it is not a criterion of study entry to have measurable disease. 
The same general concepts apply here as noted above, however, in this instance there is no 
measurable disease assessment to factor into the interpretation of an increase in non-measurable 
disease burden. Because worsening in non-target disease cannot be easily quantified (by 
definition: if all lesions are truly non-measurable) a useful test that can be applied when 
assessing patients for unequivocal progression is to consider if the increase in overall disease 
burden based on the change in non-measurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease: ie, an increase in tumor 
burden representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% 
increase diameter in a measurable lesion). While it would be ideal to have objective criteria to 
apply to non-measurable disease, the very nature of that disease makes it impossible to do so, 
therefore the increase must be substantial. See further examples in Appendix II of the 
RECIST1.1 publication.71 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the patient’s baseline lesions show partial or complete response. For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is 
not.  
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the patient who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered that reveals metastases. The patient’s brain metastases are considered to be evidence of 
PD even if he/she did not have brain imaging at baseline.  


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If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
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).  
Evaluation of Best Overall Response: Patients with Target (±Non-Target) Disease 
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 
 
Evaluation of Best Overall Response: Patients with Non-Target Disease Only 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
endpoint for assessment of efﬁcacy in some studies so to assign this category when no lesions can be 
measured is not advised. 
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. 


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Duration of Response 
CT scans are required for this study at screening and every 12 calendar weeks (within 7 days 
before is permitted) after initiation of oral/IV combination therapy. Patients who have been on 
study at least 18 months, may decrease the frequency of disease/ tumor assessments to every 
16 weeks.  
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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Appendix 2 
Modified Gynecological Cancer Intergroup (GCIG) 
Guidelines for Response Using CA-125 
GCIG Guidelines for Response Using CA-12572 (adapted for use in this study). 
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 2 x ULN 
and at least 2 additional samples after the start of treatment.  
A response to CA-125 has occurred if there is at least a 50% decrease as the result of the 
treatment. The pre- and post-treatment samples must satisfy the following criteria: 
1. There must be at least 1 sample that is > 2 x ULN prior to initiation of treatment 
2. The second sample (post-treatment) must be ≤ 50% of the pre-treatment sample; 
3. The confirmatory third sample must be ≥ 21 days after the second sample and ≤ 110% of the 
second sample; 
4. Any intervening samples between samples 2 and 3 must be ≤ 110% of the previous sample 
unless considered to be increasing because of tumor lysis. 
 
Patients are not evaluable by CA-125 if they have received mouse antibodies or if there has been 
medical or surgical interference with their peritoneum or pleura during the previous 28 days. 
 
 


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Appendix 3 
ECOG Performance Status Scale 
Eastern Cooperative Oncology Group (ECOG) Performance Status Scale 
ECOG Performance Status 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature (eg, light house work or office work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours. 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
 
 
 


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Appendix 4 
Examples of CYP Substrates with Narrow Therapeutic 
Range 
CYP Enzyme 
Substrates with Narrow Therapeutic Rangea 
CYP1A2 
Tizanidine, theophylline 
CYP2C9 
Warfarin, phenytoin  
CYP3A 
Alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, tacrolimus, terfenadine 
a CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship indicates 
that small increases in their exposure levels by the concomitant use of CYP inhibitors may lead to serious safety 
concerns (eg, Torsades de Pointes). 
Source: Draft FDA Guidance on Drug Interaction Studies — Study Design, Data Analysis, Implications for 
Dosing, and Labeling Recommendations, 201273 
 
 
 


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Appendix 5 
Example Strong CYP3A Inhibitors or Inducers 
Enzyme and interaction 
Example drugs  
Strong CYP3A inhibitors 
boceprevir, cobicistat, conivaptan, danoprevir and ritonavir, elvitegravir 
and ritonavir, grapefruit juice, indinavir and ritonavir, itraconazole, 
ketoconazole, lopinavir and ritonavir, paritaprevir and ritonavir and 
(ombitasvir and/or dasabuvir), posaconazole, ritonavir, saquinavir and 
ritonavir, telaprevir, tipranavir and ritonavir, troleandomycin, 
voriconazole, clarithromycin, diltiazem, idelalisib, nefazodone, nelfinavir 
Strong CYP3A inducers 
carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s 
wort 
This table is recommended by the Draft FDA Guidance: Clinical Drug Interaction Studies -Study Design, Data 
Analysis, and Clinical Implications, 2017.74 The table is prepared and maintained by the FDA to provide examples 
of clinical strong CYP3A inhibitors or inducers but is not intended to provide an exhaustive list. 
 
 
 


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Appendix 6 
Management Algorithms for Immuno-oncology Agents 
These general guidelines constitute guidance to the investigator and may be supplemented by 
discussions with the medical monitor representing the sponsor. The guidance applies to all 
immuno-oncology agents and regimens. 
A general principle is that differential diagnosis should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated. 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimens being used. 
Adverse events reported in this study, will be assessed according to NCI-CTCAE v5.0 or later. 
Please note, however, that the following AE management algorithms apply criteria from NCI-
CTCAE v4 for the guidance and management decisions concerning the specified toxicities. 
While any difference between the 2 versions of the criteria are likely to be minimal, please 
ensure that there is documentation at the site explaining situations where an AE management 
decision may be based on a different grading to that entered in the database. 
 


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