Clinical trial NCT03397394
Conditions: Bladder Cancer Urothelial Carcinoma Metastatic Urothelial Carcinoma Renal Pelvis Carcinoma Ureter Carcinoma Urinary Bladder Carcinoma Urethra Carcinoma Muscle Invasive Bladder Cancer
Keywords: PARP inhibitor PARPi HRD ATLAS homologous recombination DNA repair LOH DNA defect DNA anomaly Rucaparib MIBC
Sponsor: pharmaand GmbH
Start date: 2018-06-01; Completion date: 2020-01-15
Enrollment: 97 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the ATLAS study is to determine how patients with locally advanced unresectable or metastatic urothelial carcinoma respond to treatment with rucaparib.

Detailed description:

Arms: arm 1: Oral rucaparib (monotherapy)
Interventions: intervention 1: Rucaparib
Intervention descriptions: intervention 1: Rucaparib will be administered daily.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol: CO-338-085 
Study Title: 
ATLAS: A Phase 2, Open-label Study of Rucaparib in Patients with 
Locally Advanced or Metastatic Urothelial Carcinoma 
Study Number: 
CO-338-085 
Study Phase: 
Phase 2 
Product Name: 
Rucaparib (CO-338) 
IND Number: 
EUDRA CT 
Number: 
Indication: 
Locally advanced unresectable or metastatic transitional cell 
carcinoma of the urothelium (including renal pelvis, ureters, urinary 
bladder, and urethra) 
Investigators: 
Multicenter 
Sponsor Name: 
Clovis Oncology, Inc. 
Sponsor 
Address: 
 
 
 
Responsible 
Medical Officer: 
 
 
Date 
 
Amendment 1: 
24 October 2018 
 
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-338-085 
Title: 
ATLAS: A Phase 2, Open-label Study of Rucaparib in Patients with 
Locally Advanced or Metastatic Urothelial Carcinoma 
Date: 
24 October 2018 
Version: 
Amendment 1 


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PROTOCOL ACCEPTANCE FORM 
Protocol: 
CO-338-085 
Title: 
ATLAS: A Phase 2, Open-label Study of Rucaparib in Patients with 
Locally Advanced or Metastatic Urothelial Carcinoma 
Date: 
24 October 2018 
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 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: 
 
 
 
 
 
 


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SYNOPSIS 
Sponsor 
Clovis Oncology, Inc. 
Name of Finished Product 
Rucaparib tablets  
Name of Active Ingredient 
Rucaparib camsylate (CO-338) 
Study Title 
ATLAS: A Phase 2, Open-label Study of Rucaparib in Patients with Locally Advanced or 
Metastatic Urothelial Carcinoma 
Study Number 
CO-338-085  
Study Phase 
Phase 2 
Rationale 
Bladder cancer is the ninth most common cancer worldwide and amongst the 6 most 
common cancers in the United States (US) and Europe.1,2 In the US, it is estimated that 
there will be over 79,000 new cases of bladder cancer and over 16,000 deaths from bladder 
cancer in 2017.1 Muscle invasive bladder cancer (MIBC) is a platinum-sensitive disease 
with cisplatin-containing chemotherapy being the preferred first-line treatment in the 
adjuvant setting.3 Although the initial response rate for cisplatin-containing chemotherapy 
ranges from 49% to 72%, most patients will have disease relapse within 9 months.4,5 For 
patients ineligible to receive cisplatin, treatment with carboplatin-containing chemotherapy 
or an immune checkpoint inhibitor is typically administered in the first-line setting; 
however, the response rate and time to progression are less than cisplatin-containing 
chemotherapy.3 After disease relapse, the choice of treatment in the second-line setting 
includes immune checkpoint inhibitors, single-agent docetaxel, single-agent paclitaxel, and 
single-agent vinflunine. A majority of patients will have progression of their disease within 
2 to 3 months of starting treatment for relapsed disease.6 Options are limited after 
treatment with platinum-containing chemotherapy and/or an immune checkpoint inhibitor, 
therefore additional therapies are needed.  
Inhibition of deoxyribonucleic acid (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 base excision repair (BER) via poly(adenosine 
diphosphate [ADP]-ribose) polymerase (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 homologous recombination repair (HRR) of DNA, a complex 
process involving multiple proteins. Given the overlap in various DNA repair pathways, 
inhibition of a single pathway is unlikely to have a significant effect on cancer cell death. 
However, 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 that are able to survive, whereas cancer cells with 
pre-existing homologous recombination deficiency (HRD) that are treated with a PARP 


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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.7-9 
Homologous recombination pathway defects, either as an initiating event or a late event in 
the carcinogenetic process, may be responsible for the genetic instability observed in many 
cancers. Targeted next-generation sequencing (NGS) of bladder cancer tumor DNA has 
shown that approximately 11% of tumors have HRD resulting from mutations in DNA 
repair pathway genes.10 HRD has been demonstrated to predict response to cisplatin-based 
chemotherapy in bladder cancer patients.10,11 In addition to deleterious mono- or bi- allelic 
alterations in HRR genes, tumors often have other genomic and/or epigenetic deficits that 
can drive HRD and cause distinct genomic signatures. For example, genome-wide loss of 
heterozygosity (LOH), telomeric allelic imbalance (TAI), and chromosomal breaks are all 
phenotypic markers of HRD.12 Based on an analysis of The Cancer Genome Atlas (TCGA) 
bladder cancer data set (http://cancergenome.nih.gov), approximately 60% of bladder 
cancer tumors may have HRD (Clovis, data on file). In the same data set, platinum-
chemotherapy treated bladder cancer patients with tumors that demonstrated evidence of 
HRD had improved survival as compared to bladder cancer patients with tumors without 
evidence of HRD (Clovis, data on file). 
Rucaparib is a small molecule inhibitor of PARP-1, PARP-2, and PARP-3, that has 
demonstrated preclinical and clinical activity in cancers associated with a deleterious 
mutation in breast cancer gene 1 and 2 (BRCA1/2)1 or other HRR gene, and/or high level 
of genomic LOH. Rucaparib was approved in December 2016 by the US Food and Drug 
Administration (FDA), followed by regular approval in April 2018, for the treatment of 
patients with deleterious BRCA mutation (germline and/or somatic) associated advanced 
epithelial ovarian cancer (EOC), fallopian tube (FTC), or primary peritoneal cancer (PPC) 
who have been treated with 2 or more chemotherapies.13,14 In May 2018, the European 
Commission 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.15 In April 2018, rucaparib was approved in the US by the FDA for 
maintenance treatment for adult patients with recurrent EOC, FTC, or PPC who are in a 
complete or partial response to platinum-based chemotherapy.14 In the study supporting 
this approval, rucaparib demonstrated improved progression-free survival (PFS) as 
maintenance treatment following response to platinum-based chemotherapy. Although 
tumor HRD status was predictive of response to rucaparib, activity was also observed in 
patients with HRD-negative tumors, suggesting an incomplete understanding of the 
biomarkers responsible for PARP inhibitor sensitivity in ovarian cancer.16  
The purpose of this study is to evaluate the efficacy and safety of monotherapy rucaparib 
as treatment for patients with locally advanced unresectable or metastatic urothelial 
bladder cancer. The study will enroll approximately 200 patients, regardless of HRD 
                                                 
1 The typical convention is to use italicized names for genes and plain text names for proteins. However, in this 
document, BRCA mutations which occur at both the gene and protein level are often discussed. Therefore, for 
enhanced readability, BRCA and other genes are written in plain text only throughout this document. 


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status, who have received 1 or 2 prior treatment regimens. Enrollment of patients, 
regardless of HRD status, who have received ≤ 2 prior treatments, is appropriate given that 
available treatment options are limited and both HRD-positive and HRD-negative patients 
may potentially respond to treatment with rucaparib. Primary efficacy will be assessed in a 
prospectively defined HRD-positive population as well as the intent-to-treat (ITT) 
population. Additional secondary and exploratory efficacy and safety endpoints will also 
be evaluated in HRD subgroups and the ITT population.  
Primary Objective: 
• To evaluate objective response rate (ORR) in molecularly-defined homologous 
recombination deficiency (HRD)-positive and intent-to-treat (ITT) populations 
using a prospectively defined molecular signature. 
Secondary Objectives: 
• To evaluate duration of response (DOR) 
• To estimate progression-free survival (PFS) 
• To estimate overall survival (OS) 
• To evaluate the safety and tolerability of rucaparib 
• To evaluate steady-state pharmacokinetics (PK) of rucaparib 
Exploratory Objectives: 
• To assess biomarkers that correlate with response to rucaparib  
• To evaluate circulating cell-free tumor DNA (ctDNA) as a molecular marker of 
response to rucaparib 
• To assess molecular changes over time in plasma and tumor samples 
• To evaluate biomarkers associated with resistance to rucaparib  
Study Design 
This is a Phase 2 multicenter, open-label study evaluating rucaparib for the treatment of 
patients with locally advanced unresectable or metastatic urothelial carcinoma. This study 
will enroll patients with measurable disease per Response Evaluation Criteria in Solid 
Tumors (RECIST) Version 1.1 (v1.1). All patients must have received 1 or 2 prior 
treatment regimens and have radiologic progression during or after the most recent 
regimen. Patients who have received prior PARP inhibitor treatment will be excluded. 
Tumor tissue will be analyzed to determine HRD status (HRD-positive or HRD-negative) 
prior to efficacy analyses. 
This study consists of a Screening Phase, a Treatment Phase, and a Post-treatment Phase. 
Patients will receive rucaparib monotherapy in the Treatment Phase and will undergo 
procedures and assessments including regular safety and efficacy evaluations during the 
entire conduct of the study.  
Screening Phase 
Each patient, with the following exceptions, will undergo a biopsy for collection of tumor 
tissue. Tumor tissue samples should be from primary or metastatic soft tissue tumor (see 
Section 7.6.5.1 for details). Patients who had tumor tissue collected as part of standard of 
care ≤ 6 months prior to the first planned dose of rucaparib and had no intervening anti-
cancer treatments during this period are not required to have a biopsy at screening, 
provided that adequate tumor tissue can be provided for analysis. An archival tumor 


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sample, if available, must also be submitted in addition to the mandatory collection of 
tumor tissue (See Section 7.6.5.2).  
Additional screening assessments will include demographics and medical history, prior 
anti-cancer treatments, prior and current medications and procedures, 12-lead 
electrocardiogram (ECG), Eastern Cooperative Oncology Group (ECOG) performance 
status, local laboratory hematology and serum chemistry measurements, serum pregnancy 
test (for women of childbearing potential only), urinalysis, physical examination, height, 
weight, and vital signs measurements, adverse events (AEs), and tumor assessment by 
computed tomography (CT) scan. 
Patients must meet all inclusion and exclusion criteria as specified in the protocol. 
Treatment Phase 
Patients will be administered rucaparib at a starting dose of 600 mg orally twice daily 
(BID) for continuous 28-day cycles and will undergo procedures and assessments 
including regular safety, PK, and efficacy evaluations during the entire conduct of the 
study. Biomarker blood samples will be collected for ctDNA and genomic DNA analysis 
(see Section 7.6.6 and 7.6.7, respectively). Tumor assessments by CT scan will be 
performed every 8 calendar weeks (±7 days) from Cycle 1 Day 1 up to 18 months and then 
every 12 calendar weeks (±7 days) thereafter and at the End of Treatment Visit, if 
applicable. Copies of tumor scans (and other imaging, as appropriate) will be collected 
from all patients in the study. Patients will continue on rucaparib until radiologic 
progression per RECIST v1.1 as assessed by the investigator, unequivocal clinical disease 
progression, unacceptable toxicity or inability to tolerate further treatment, withdrawal of 
consent, or patient is lost to follow-up. If a patient has radiologic progression per RECIST 
v1.1, but is deriving clinical benefit in the opinion of the investigator, then continuation of 
treatment beyond progression is permitted. In such cases, the decision to continue must be 
documented in source documents and the patient must provide additional consent prior to 
continuing treatment with rucaparib. 
Safety and efficacy data will be periodically reviewed by the Data Monitoring Committee 
(DMC).  
Post-treatment Phase 
Upon treatment discontinuation, patients will have an End of Treatment Visit, a 28-day 
Follow-up Visit, and then will proceed with long-term follow-up. An optional tumor 
biopsy may be collected prior to the start of subsequent anti-cancer therapy from patients 
who experience radiographic or unequivocal clinical disease progression and provide 
appropriate consent.  
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 by 
RECIST v1.1 per investigator, death, loss to follow-up, withdrawal from the study, study 
closure, or initiation of subsequent treatment. Ongoing serious adverse events (SAEs), 
adverse events of special interest (AESIs), and treatment-related Grade 3/4 AEs will be 
followed until either resolution or stabilization has been determined or until patient is lost 
to follow-up. After the 28-day Follow-up Visit, only related SAEs and all AESIs, 
irrespective of causality, need to be reported.  


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All patients will be followed for survival and subsequent treatments every 12 weeks 
(±14 days) relative to the last dose of rucaparib until death, loss to follow-up, withdrawal 
of consent, or study closure. 
Number of Patients   
Approximately 200 patients will be enrolled. 
Number of Sites 
Patients will be enrolled at approximately 65 sites worldwide. 
Inclusion Criteria 
Eligible patients must meet the following 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. Be ≥ 18 years of age at the time the Informed Consent Form (ICF) is signed. 
3. Have histologically or cytologically confirmed locally advanced unresectable 
(tumor, node, metastasis [TNM] staging of T4b and any N; or any T and N2-3) or 
metastatic transitional cell carcinoma of the urothelium (including renal pelvis, 
ureter, urinary bladder, or urethra). Mixed transitional/non-transitional cell 
histologies are allowed. 
4. Received 1 or 2 prior treatment regimens (eg, cisplatin- or carboplatin-containing 
chemotherapy, immune checkpoint inhibitor, and/or clinical trial) for locally 
advanced unresectable or metastatic disease and had confirmed radiologic disease 
progression during or following the most recent treatment. The principal 
investigator is responsible for ensuring the patient has received anti-cancer 
treatment as appropriate in the country of enrollment, taking into account the 
patient’s current health status as well as how the patient responded to/tolerated 
prior treatment(s). 
a. Neoadjuvant and/or adjuvant treatment for muscle invasive disease will be 
considered a treatment regimen if radiologic disease progression occurred 
≤ 12 months from the completion of treatment.  
b. No more than 1 prior platinum-containing chemotherapy regimen for 
advanced disease is permitted. A change of platinum chemotherapy within 
the same treatment regimen will be considered 1 prior platinum-containing 
chemotherapy. Platinum-containing chemotherapy given as radio-
sensitization combined with radiation therapy to control locally advanced 
disease will not be considered as a prior regimen of systemic therapy. 
c. For patients who have never received platinum, the patient must currently 
be ineligible for or refuse cisplatin treatment.  
d. A treatment regimen that is held for reasons other than progression which is 
subsequently resumed at a later date with no other intervening systemic 
anti-cancer treatment is considered 1 treatment regimen. 
5. Mandatory tumor tissue must be collected ≤ 28 days prior to the first dose of 
rucaparib treatment. A biopsy or surgical resection of tumor tissue is required, 
unless archival tumor tissue collected ≤ 6 months prior to the first dose of 
rucaparib is available and no intervening anti-cancer treatments were administered 


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during this period. Tumor tissue should be of adequate quality for molecular 
profiling. (See Section 7.6.5.1) 
6. Have measurable disease as defined by Response Evaluation Criteria in Solid 
Tumors (RECIST) Version 1.1 (v1.1). A measurable tumor lesion in a previously 
irradiated site is acceptable if subsequent progression has been demonstrated in 
that lesion. 
7. Have adequate organ function confirmed by the following laboratory values 
obtained ≤ 14 days prior to first dose of rucaparib: 
a. Bone Marrow Function 
i. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
ii. Platelets > 100 × 109/L  
iii. Hemoglobin ≥ 9 g/dL independent of transfusion ≤ 14 days prior to 
screening hemoglobin assessment. Transfusions are not permitted 
between the screening hemoglobin assessment and the first dose of 
rucaparib. 
b. Hepatic Function 
i. Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) ≤ 3 × upper limit of normal (ULN); if liver metastases, then 
≤ 5 × ULN  
ii. Bilirubin ≤ 1.5 × ULN; < 2 × ULN if hyperbilirubinemia is due to 
Gilbert’s syndrome 
c. Renal Function 
i. Measured or calculated creatinine clearance (CrCL) ≥ 30 mL/min or 
estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2. 
For calculated CrCL or eGFR, the Cockcroft Gault formula or 
institutional standard formula can be used.  
8. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 
or 1 assessed within 14 days prior to first dose of rucaparib. 
9. Have life expectancy ≥ 12 weeks. 
Exclusion Criteria 
Patients will be excluded from participation if any of the following criteria apply: 
1. Active second malignancy for which patient has received treatment within 2 years 
prior to the first dose of rucaparib with exception for the following circumstances:  
a. Curatively treated non-melanoma skin cancer. 
b. Non-invasive diseases such as low risk cervical cancer or any cancer in situ. 
c. Localized (early stage) cancer treated with curative intent (without evidence 
of recurrence and intent for further therapy) and in which no systemic 
therapy was indicated. 
2. Prior treatment with a PARP inhibitor. 
3. Symptomatic and/or untreated central nervous system (CNS) metastases. Patients 
with asymptomatic previously treated CNS metastases are eligible provided they 
have been clinically stable for at least 4 weeks prior to the first dose of rucaparib. 


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4. Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that 
would, in the opinion of the investigator, interfere with absorption of rucaparib. 
5. Known human immunodeficiency virus (HIV) or acquired immunodeficiency 
syndrome (AIDS)-related illness, or history of chronic hepatitis B or C, with the 
exception of patients with sustained virologic response after completion of 
treatment for hepatitis C. 
6. For female patients of childbearing potential and all male patients, 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 
(See Section 4.4). 
b. Pregnant or breast feeding. Women of childbearing potential must have a 
negative serum pregnancy test ≤ 3 days prior to the first dose of rucaparib. 
Women of childbearing potential must not be considering getting pregnant 
during the study and for 6 months following the last dose of rucaparib. 
c. Male patients who refuse to use condoms during sex. Male patients must 
not make semen donations during treatment and for 6 months following the 
last dose of rucaparib. 
7. Received anti-cancer treatment with chemotherapy, radiation, antibody therapy or 
other immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or 
experimental drugs ≤ 14 days prior to first dose of rucaparib and/or ongoing 
treatment-related adverse events National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) > Grade 1 except for 
neuropathy, ototoxicity, alopecia, and electrolyte abnormalities. 
8. Non-study related minor surgical procedure ≤ 5 days, or major surgical procedure 
≤ 21 days, prior to first dose of rucaparib; in all cases, the patient must be 
sufficiently recovered and stable before treatment administration. 
9. 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. 
No waivers of these inclusion or exclusion criteria will be granted by the investigator and 
the sponsor or its designee for any patient enrolled into the study. 
Study Treatment 
Patients will take 600 mg rucaparib orally BID, as close to 12 hours apart as possible and 
preferably at the same times every day, with water starting on Day 1. Rucaparib tablets 
must be swallowed whole and may be taken with or without food. Rucaparib may be 
provided as 200 mg, 250 mg, and/or 300 mg dose strength tablets. 
Patients will take rucaparib BID for continuous 28-day cycles until disease progression as 
assessed by the investigator, or other reason for discontinuation. 
Dose reductions and dose holds are permitted in the event of unacceptable toxicity. 
Concomitant Medications  
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.  


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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. 
Palliative radiotherapy for the treatment of lesions not considered target lesions for tumor 
assessments is permitted during the study.  
No other anti-cancer therapies (including chemotherapy, radiation, antibody, 
immunotherapy, gene therapy, angiogenesis inhibitors, or other experimental drugs) of any 
kind will be permitted while the patient is receiving rucaparib. 
Caution should be used for concomitant medications that are sensitive clinical substrates of 
cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, and/or CYP3A.  
Patients taking digoxin should have their digoxin levels monitored after starting rucaparib 
and then regularly per standard clinical practice.  
Caution is advised when metformin or a medicine that is a breast cancer resistance protein 
(BCRP) substrate (eg, rosuvastatin) is co-administered with rucaparib.  
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.  
Treatment Discontinuation Criteria 
A patient must be discontinued from protocol-prescribed therapy if any of the following 
apply: 
a. Consent withdrawal at the patient’s own request or at the request of their legally 
authorized representative (where acceptable according to national law and/or local 
regulations); 
b. Progression per RECIST v1.1 of patient’s underlying cancer (unless, in the opinion 
of the investigator, the patient continues to derive clinical benefit); 
c. Any event, adverse or otherwise, that, in the opinion of the investigator, would 
pose an unacceptable safety risk to the patient; 
d. 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; 
e. Noncompliance by the patient with protocol mandated procedures; and/or 
f. A positive pregnancy test at any time during the study. 
Efficacy Assessments 
Efficacy measures will include tumor assessments using CT scans of the chest, abdomen, 
and pelvis with appropriate slice thickness per RECIST v1.1 and clinical examination; 
other studies (magnetic resonance imaging [MRI], X-ray, positron emission tomography 
[PET]/CT, bone scan, and ultrasound) may be performed as clinically indicated. MRI may 
be used in place of CT scans for assessment of target lesions if required by local 
authorities. 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 intravenous [IV] and oral contrast) 
then the CT portion of the PET/CT can be used for RECIST measurements. Disease 
assessments will be performed during screening, at the end of every 8 calendar weeks 
(±7 days) during the treatment and post-treatment (if patient discontinued treatment for any 


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reason other than radiologically confirmed disease progression or death) phases until 
radiologically confirmed disease progression, withdrawal of consent, loss to follow-up, 
death, initiation of subsequent treatment, or study closure. Disease assessments should also 
be done at the end of treatment if it has been ≥ 8 calendar weeks since the last assessment. 
Patients who have been on study at least 18 months may decrease the frequency of tumor 
assessments to every 12 calendar weeks (±7 days). If a complete response (CR) or partial 
response (PR) is noted, confirmatory scans should be performed at least 4 weeks after 
response was first documented.  
Copies of tumor scans (and other imaging, as appropriate) will be collected from all 
patients in the study. Independent radiology review (IRR) may be conducted on all or a 
subset of tumor scans collected. 
Safety Assessments 
Safety and tolerability will be assessed based on the following: 
• Incidence, type, seriousness, and severity of AEs reported; 
• Clinical laboratory investigations (hematology, serum chemistry, urinalysis, 
pregnancy); 
• Vital signs (blood pressure, heart rate, and body temperature); 
• 12-lead ECGs; 
• Physical examinations; and 
• ECOG performance status. 
Statistical Methods 
Sample Size  
The overall sample size was determined by considering the number of patients needed for 
adequate safety and activity assessment of HRD-positive patients. Based on the estimated 
prevalence of 60% HRD-positive patients in this population, approximately 200 patients 
will be enrolled into the study. This would result in enrollment of approximately 120 
HRD-positive patients.  
Efficacy Analysis  
Response will be determined using RECIST v1.1. The ORR will be summarized with 
frequencies and percentages. The DOR will be summarized with descriptive statistics (N, 
mean, standard deviation [StD], median, minimum, and maximum) as well as 
categorically. Kaplan-Meier methodology will be used to summarize time to event 
variables. The efficacy analyses will be evaluated for the HRD-positive subgroup, the ITT 
population, and other HRD subgroups.  
Safety Analyses 
Adverse events, clinical laboratory results, vital signs, ECOG performance status, body 
weight, and concomitant medications/procedures will be tabulated and summarized. 
Adverse events will be summarized overall and separately for SAEs, AEs leading to 
discontinuation, AEs leading to death, and NCI CTCAE (Version 4.03 or later) Grade 3 or 
higher AEs. Body weight and vital signs will be summarized descriptively (N, mean, StD, 
median, minimum, and maximum). ECOG performance status will be summarized 
categorically. 


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Data Monitoring Committee 
The study will have a formal Data Monitoring Committee (DMC) that will include 
coordinating investigators and sponsor personnel. The DMC will review both safety and 
efficacy data. 
Interim Safety Monitoring 
A formal safety data review will occur after the first 20 patients have been enrolled and 
completed the first cycle of treatment, and then approximately every 6 months thereafter. 
The protocol will be amended as appropriate to incorporate additional patient safety 
monitoring if new safety signals are noted at any review. 
Interim Efficacy Analysis  
A group sequential interim monitoring plan will be implemented in order to help guide the 
DMC in monitoring the study. The null hypothesis is p=0.10 based on historical data in 
similar patient populations. The study has greater than 90% power to reject the null 
hypothesis at a 5% significance level if the true response rate for rucaparib is 20%.  
Interim analyses will be performed when approximately 60 patients and 120 patients have 
complete data, defined as a documented response (PR or CR), disease progression, or at 
least 4 months of disease assessment data available.  
Additional details regarding this interim monitoring plan are provided in Appendix 4. 


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TABLE OF CONTENTS 
SPONSOR’S MEDICAL EXPERT FOR THE STUDY ...........................................................4 
SYNOPSIS .................................................................................................................................5 
TABLE OF CONTENTS .........................................................................................................15 
LIST OF IN-TEXT TABLES ..................................................................................................19 
LIST OF IN-TEXT FIGURES.................................................................................................19 
LIST OF APPENDICES ..........................................................................................................19 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................20 
1 
INTRODUCTION ...........................................................................................................24 
1.1 
Urothelial Carcinoma .............................................................................................24 
1.1.1 
General Overview ........................................................................................24 
1.1.2 
Treatment of Muscle-invasive Urothelial Carcinoma ..................................24 
1.2 
Mechanism of PARP Inhibition and Homologous Recombination Deficiency ....25 
1.3 
Rucaparib ...............................................................................................................27 
1.3.1 
Background ..................................................................................................27 
1.3.2 
Prior Experience with Rucaparib .................................................................28 
1.4 
Rationale for this Study of Rucaparib ....................................................................33 
2 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................35 
3 
INVESTIGATIONAL PLAN ..........................................................................................36 
3.1 
Overall Study Design and Plan ..............................................................................36 
3.1.1 
Screening Phase ...........................................................................................36 
3.1.2 
Treatment Phase ...........................................................................................37 
3.1.3 
Post-treatment Phase ....................................................................................38 
3.2 
Study Schema.........................................................................................................38 
3.3 
End of Study ..........................................................................................................40 
4 
STUDY POPULATION SELECTION ...........................................................................41 
4.1 
Number of Patients and Sites .................................................................................41 
4.2 
Inclusion Criteria ...................................................................................................41 
4.3 
Exclusion Criteria ..................................................................................................42 
4.4 
Patients or Partners of Patients with Reproductive Potential .................................43 
4.5 
Compliance with Inclusion/Exclusion Criteria ......................................................45 
5 
STUDY TREATMENT(S) ..............................................................................................46 
5.1 
Description of Treatment(s) and Storage ...............................................................46 
5.2 
Packaging and Labeling .........................................................................................46 
5.2.1 
Rucaparib .....................................................................................................46 
5.3 
Method of Assigning Patients to Treatment Groups ..............................................46 
5.4 
Preparation and Administration of Protocol-specified Treatment .........................46 
5.4.1 
Rucaparib Dose Modification Criteria .........................................................47 


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5.4.2 
General Restrictions .....................................................................................49 
5.4.3 
Treatment with Rucaparib beyond Disease Progression .............................50 
5.5 
Blinding/Masking of Treatment .............................................................................50 
5.6 
Treatment Compliance ...........................................................................................50 
5.7 
Accountability of Protocol-specified Treatment ....................................................50 
6 
PRIOR AND CONCOMITANT THERAPY ..................................................................52 
6.1 
Supportive Care .....................................................................................................52 
6.2 
Radiotherapy ..........................................................................................................52 
6.3 
Anti-cancer or Experimental Therapy ...................................................................52 
6.4 
Cytochrome P450 Isoenzyme Inhibitors, Inducers, and Substrates .......................52 
6.5 
Anticoagulants .......................................................................................................53 
6.6 
Other Concomitant Medications ............................................................................53 
7 
STUDY PROCEDURES AND ACTIVITIES .................................................................54 
7.1 
Schedule of Assessments .......................................................................................54 
7.2 
Informed Consent...................................................................................................58 
7.3 
Screening Phase .....................................................................................................58 
7.3.1 
Up to 28 days Prior to Start of Treatment ....................................................58 
7.3.2 
Up to 14 days Prior to Start of Treatment ....................................................59 
7.4 
Treatment Phase .....................................................................................................59 
7.4.1 
Cycle 1 Day 1...............................................................................................59 
7.4.2 
Cycle 1 Day 15.............................................................................................60 
7.4.3 
Cycle 2 Day 1...............................................................................................61 
7.4.4 
Cycle 2 Day 15.............................................................................................62 
7.4.5 
Cycle 3 Day 1 and Every Cycle Thereafter .................................................62 
7.5 
Post-treatment Phase ..............................................................................................63 
7.5.1 
End of Treatment Visit.................................................................................63 
7.5.2 
28-day Follow-up Visit ................................................................................64 
7.5.3 
Long-term Follow-up ...................................................................................65 
7.6 
Methods of Data Collection ...................................................................................65 
7.6.1 
Medical History and Demographic/ Baseline Characteristics .....................65 
7.6.2 
Prior and Concomitant Medication Assessments ........................................66 
7.6.3 
Efficacy Evaluations ....................................................................................66 
7.6.4 
Safety Evaluations .......................................................................................67 
7.6.5 
Biomarker Analysis – Tumor Tissue ...........................................................69 
7.6.6 
Biomarker Analysis – ctDNA from Blood ..................................................70 
7.6.7 
Biomarker Analysis - Genomic DNA from Blood ......................................70 
7.6.8 
Pharmacokinetics Evaluation .......................................................................70 
8 
ADVERSE EVENT MANAGEMENT ...........................................................................71 


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8.1 
Definition of an Adverse Event .............................................................................71 
8.2 
Definition of a Serious Adverse Event ..................................................................71 
8.3 
Definition of an Adverse Event of Special Interest ...............................................72 
8.4 
Events or Outcomes Not Qualifying as Serious Adverse Events ..........................72 
8.5 
Clinical Laboratory Assessments as Adverse Events and Serious Adverse 
Events .....................................................................................................................72 
8.6 
Pregnancy or Drug Exposure during Pregnancy ....................................................73 
8.7 
Recording of Adverse Events, Serious Adverse Events, and Adverse Events of 
Special Interest .......................................................................................................73 
8.7.1 
Onset Date of Adverse Events .....................................................................73 
8.7.2 
Resolution Date of Adverse Events .............................................................74 
8.7.3 
Intensity of Adverse Events .........................................................................74 
8.7.4 
Causal Relationship of Adverse Events to Rucaparib .................................74 
8.7.5 
Outcome and Action Taken .........................................................................75 
8.8 
Follow-up of Adverse Events, Serious Adverse Events, and Adverse Events of 
Special Interest .......................................................................................................75 
8.9 
Regulatory Aspects of Serious Adverse Event and Adverse Events of Special 
Interest Reporting...................................................................................................76 
9 
PLANNED STATISTICAL METHODS ........................................................................77 
9.1 
General Considerations ..........................................................................................77 
9.2 
Analysis Populations ..............................................................................................77 
9.3 
Patient Disposition .................................................................................................77 
9.4 
Demographics and Baseline Characteristics ..........................................................77 
9.5 
Efficacy Analyses ..................................................................................................78 
9.5.1 
Primary Efficacy Analyses ..........................................................................78 
9.5.2 
Secondary Efficacy Analyses ......................................................................78 
9.5.3 
Exploratory Efficacy Analyses ....................................................................78 
9.6 
Pharmacokinetic Analyses .....................................................................................79 
9.6.1 
Exploratory Population Pharmacokinetics and Exposure-Response 
Analyses .......................................................................................................79 
9.7 
Safety Analyses ......................................................................................................79 
9.7.1 
Adverse Events ............................................................................................79 
9.7.2 
Clinical Laboratory Evaluations ..................................................................80 
9.7.3 
Vital Sign Measurements .............................................................................80 
9.8 
Exploratory Biomarker Analysis ...........................................................................81 
9.8.1 
Evaluation of Changes in Tumor Samples and Changes in Circulating 
Cell-free Tumor DNA ..................................................................................81 
9.8.2 
Evaluation of Biomarkers of Resistance to Rucaparib ................................81 
9.9 
Sample Size Considerations ...................................................................................81 


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9.10 
Interim Analysis .....................................................................................................81 
10 PATIENT DISPOSITION ...............................................................................................83 
10.1 
Removal of Patients from the Study or Study Drug ..............................................83 
11 STUDY ADMINISTRATION ........................................................................................84 
11.1 
Regulatory and Ethical Considerations ..................................................................84 
11.1.1 
Regulatory Authority Approvals..................................................................84 
11.1.2 
Institutional Review Board or Independent Ethics Committee Approval ...84 
11.2 
Patient Information and Consent ...........................................................................85 
11.3 
Patient Confidentiality ...........................................................................................85 
11.4 
Study Monitoring ...................................................................................................86 
11.5 
Case Report Forms and Study Data .......................................................................86 
11.6 
Data Monitoring Committee ..................................................................................87 
11.7 
Study Termination and Site Closure ......................................................................87 
11.8 
Modification of the Study Protocol........................................................................88 
11.9 
Retention of Data ...................................................................................................88 
11.10 Quality Control and Assurance ..............................................................................89 
11.10.1 Changes to the Protocol and Deviations ......................................................89 
11.10.2 Study Site Training and Ongoing Monitoring .............................................89 
11.10.3 Direct Access to Source Data/ Documents for Audits and Inspections .......89 
11.11 Clinical Study Report .............................................................................................90 
11.12 Publication and Disclosure Policy .........................................................................90 
11.13 Investigator Oversight ............................................................................................90 
12 REFERENCES ................................................................................................................91 
13 APPENDICES .................................................................................................................95 
 
 
 


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LIST OF IN-TEXT TABLES 
Table 1. Progression-free Survival per Investigator and per IRR in Primary Analysis 
Populations in Study CO-338-014 .....................................................................32 
Table 2. Primary, Secondary, and Exploratory Objectives and Endpoints ...........................35 
Table 3.  Description of Investigational Product....................................................................46 
Table 4. Rucaparib Dose Reduction Steps ............................................................................49 
Table 5. Schedule of Assessments ........................................................................................55 
Table 6. Causal Relationship of Adverse Events to Rucaparib.............................................74 
 
LIST OF IN-TEXT FIGURES 
Figure 1. Study Schema ..........................................................................................................39 
 
LIST OF APPENDICES 
Appendix 1 Response Evaluation Criteria in Solid Tumors Criteria .....................................96 
Appendix 2 Eastern Cooperative Oncology Group (ECOG) Performance Status Scale .....101 
Appendix 3 Examples of Sensitive Clinical Cytochrome P450 (CYP) Substrates ..............102 
Appendix 4 Group Sequential Interim Monitoring Plan ......................................................103 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADP 
adenosine diphosphate 
AE(s) 
adverse event(s) 
AESI(s) 
adverse event(s) of special interest 
AIDS 
acquired immunodeficiency syndrome 
AJCC 
American Joint Committee on Cancer 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-24 
area under the plasma concentration-time curve from 0 to 24 hours 
BCRP 
breast cancer resistance protein 
BER 
base excision repair 
BID 
twice daily 
BRCA 
breast cancer gene 
BRCA1/2 breast cancer gene 1 or breast cancer gene 2 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL 
clearance 
CLIA 
Clinical Laboratory Improvement Amendment 
Cmax 
maximum plasma concentration 
Cmin 
trough plasma concentration 
CNS 
central nervous system 
CO2 
carbon dioxide 
CR 
complete response 
CrCL 
creatinine clearance 
CRF 
Case Report Form 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating cell-free tumor DNA 
CV 
coefficient of variation 
CYP 
cytochrome P450 
ddMVAC dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin 
DDI 
drug-drug interaction(s) 


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DILI 
drug-induced liver injury 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DSB(s) 
double-strand break(s) 
ECG(s) 
electrocardiogram(s) 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form  
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EOC 
epithelial ovarian cancer 
EOT 
End of Treatment 
F 
bioavailability 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FSH 
follicle-stimulating hormone 
FTC 
fallopian tube cancer 
gBRCA 
germline mutation in BRCA 
GC 
gemcitabine and cisplatin 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
HDPE 
high-density polyethylene 
HIPAA 
Health Information Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRD 
homologous recombination deficient or homologous recombination deficiency 
HRR 
homologous recombination repair 
IB 
Investigator’s Brochure 
IC50 
50% inhibitory concentration 
ICF(s) 
Informed Consent Form(s) 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
Inc. 
Incorporated 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRR 
independent radiology review 
ITT 
intent-to-treat 
IUD 
intrauterine device 


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IUS 
intrauterine system 
IV 
intravenous 
IWRS 
Interactive Web Response System 
LD 
longest diameter 
LDH 
lactate dehydrogenase 
LOH 
loss of heterozygosity 
LST 
large-scale state transitions 
MATE 
multidrug and toxin extrusion transporter 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
mCRPC 
metastatic castration-resistant prostate cancer 
MCV 
mean corpuscular volume 
MDS 
myelodysplastic syndrome 
MIBC 
muscle-invasive bladder cancer 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NGS 
next-generation sequencing 
NMIBC 
non-muscle-invasive bladder cancer 
NYHA 
New York Heart Association 
OCT 
organic cation transporter 
ORR(s) 
objective response rate(s) 
OS 
overall survival 
PALB2 
partner and localizer of BRCA2 
PARP 
poly(ADP-ribose) polymerase 
PPC 
primary peritoneal cancer 
PD 
progressive disease (in context of disease monitoring) 
PD-L1 
programmed death ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PPI(s) 
proton pump inhibitor(s) 
PR 
partial response or PR interval 
PT 
Preferred Term 
QD 
once daily 
QRS 
QRS complex/interval 
QT 
QT interval 
RAD51C 
RAD51 paralog C 


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RAD51D 
RAD51 paralog D 
RBC(s) 
red blood cell(s) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SD 
stable disease (in context of disease monitoring) 
SI 
International System of Units 
SOC 
System Organ Class 
SOP(s) 
standard operating procedure(s) 
SSB(s) 
single-strand break(s) 
StD 
standard deviation 
SUSAR(s) suspected unexpected serious adverse reaction(s) 
T1/2 
terminal half-life 
TA1 
telomeric-allelic imbalance 
tBRCA 
tumor tissue mutation in BRCA1/2, includes germline BRCA and somatic BRCA 
TCGA 
The Cancer Genome Atlas 
TEAE 
treatment-emergent adverse event 
Tmax  
time of occurrence of Cmax 
TNM 
tumor, node, metastasis 
UDP 
uridine diphosphate 
UGT 
uridine diphosphate-glucuronosyl transferase 
ULN 
upper limit of normal 
US 
United States 
WBC(s) 
white blood cell(s) 
WHO 
World Health Organization 


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1 
INTRODUCTION 
1.1 
Urothelial Carcinoma 
1.1.1 
General Overview 
Bladder cancer is the ninth most common cancer worldwide and amongst the 6 most 
common cancers in United States (US) and Europe.1,2 In the US, it is estimated there will be 
over 79,000 new cases of bladder cancer and over 16,000 deaths from bladder cancer in 
2017.1 Bladder cancer is more common in men than women (ratio 3:1), and the median age at 
diagnosis is approximately 70 years.17 Urothelial (transitional cell) carcinoma, which 
develops in the renal pelvis, ureter, urinary bladder, and/or proximal two-thirds of the 
urethra, accounts for approximately 90% of bladder cancers. Tumors are staged using the 
tumor, node, metastasis (TNM) staging system by the American Joint Committee on Cancer 
(AJCC) and classified as non-muscle-invasive bladder cancer (NMIBC)(tumors < stage T1) 
or muscle-invasive bladder cancer (MIBC)(tumors > stage T2).18 Treatment 
recommendations are divided according to NMIBC and MIBC. 
NMIBC, low grade tumors (< stage T1) that have not invaded the muscle, accounts for 
approximately 70% of newly diagnosed bladder cancer. With current treatments, the 5-year 
relative survival is over 95% for in situ disease and 70% for stage T1.1 Despite these survival 
rates, 50% to 70% of NMIBC will recur with 10% to 15% of patients progressing to MIBC.17 
MIBC, tumors > stage T2 that have invaded the muscle, accounts for approximately 30% of 
newly diagnosed bladder cancer. Unlike NMIBC, prognosis for MIBC is poor with a 5-year 
survival rate of 35% for stage T2 and 5% for patients with distant metastases.1 Overall 
survival (OS) after initial therapy is 15 months or shorter in this population.4,5 
1.1.2 
Treatment of Muscle-invasive Urothelial Carcinoma 
The initial treatment course for MIBC includes neoadjuvant cisplatin-containing 
chemotherapy, surgery (ie, radical cystectomy, partial cystectomy, or bladder preserving 
procedures), radiation, and/or adjuvant chemotherapy. MIBC is a platinum-sensitive disease 
with cisplatin-containing chemotherapy being the preferred first-line treatment in the 
adjuvant setting.3 The 2 commonly used regimens are a combination of gemcitabine and 
cisplatin (GC) and a combination of dose-dense methotrexate, vinblastine, doxorubicin, and 
cisplatin (ddMVAC). The median OS in patients with metastatic disease for GC and 
ddMVAC is 13 to 15 months.4,5 Although the initial response rate for cisplatin-containing 
chemotherapy ranges from 49% to 72%, most patients will have disease relapse within 
9 months.4,5 For patients who are cisplatin ineligible (patients meeting at least 1 of the 
following: World Health Organization [WHO] or Eastern Cooperative Oncology Group 
[ECOG] performance status > 2, or Karnofsky performance status of 60% to 70%, creatinine 
clearance [CrCL; calculated or measured] < 1 mL/s, > National Cancer Institute [NCI] 
Common Terminology Criteria for Adverse Events [CTCAE] Grade 2 audiometric hearing 
loss, > CTCAE Grade 2 peripheral neuropathy, or New York Heart Association [NYHA] 
class III heart failure),19 a combination of carboplatin and gemcitabine can be administered. 
Until recently, the standard of care for patients who progressed after first-line treatment 


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included single-agent docetaxel, single-agent paclitaxel, single-agent vinflunine, and 
treatment in clinical studies The median OS for these second-line therapies is approximately 
6 to 9 months with objective response rates (ORRs) of 10% to 20%.6 
Recently, immune checkpoint inhibitors have rapidly changed the standard of care for 
treatment of urothelial carcinoma in the second-line setting, as well as in the first-line setting 
for patients ineligible for cisplatin-containing chemotherapy. Several immune checkpoint 
inhibitors, including atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab, 
have received either full or accelerated approval by the US Food and Drug Administration 
(FDA) or European Medicines Agency (EMA) in the second-line setting following 
progression on a platinum-based treatment. The median OS observed with these therapies 
ranges from 7 to 18 months, with ORRs ranging from 15% to 21% regardless of programmed 
death ligand 1 (PD-L1) expression.20-24 Based on these data, immune checkpoint inhibitors 
are now included in guidelines for second-line treatment of metastatic bladder cancer 
following first-line platinum-based therapy and are rapidly becoming standard of care 
treatment in the US.18 
For patients who are not eligible to receive cisplatin in the first-line setting, atezolizumab and 
pembrolizumab are FDA approved agents in this setting. The ORR for atezolizumab and 
pembrolizumab is 23% and 29%, respectively.25,26 Use of these immune checkpoint 
inhibitors in this treatment setting is increasing and they are rapidly becoming standard of 
care treatment.18 
Despite recent advancements in treatment, many patients do not respond to treatment and 
subsequently have rapid disease progression. Therefore, additional therapy options are 
warranted in this patient population.  
1.2 
Mechanism of PARP Inhibition and Homologous Recombination 
Deficiency 
Deoxyribonucleic acid (DNA) is constantly damaged by both endogenous and exogenous 
(environmental) assaults which can result in the formation of single-strand breaks (SSBs). 
Normal cells repair SSBs in DNA through a process known as base excision repair (BER).27 
While there are several pathways for BER, all pathways rely on the activity of 
poly(adenosine diphosphate [ADP] ribose) polymerase (PARP) enzymes. In humans, the 
PARP family encompasses 17 enzymes, of which PARP-1 is the best characterized.28 SSBs 
that are not repaired result in stalled replication forks and the development of double-strand 
breaks (DSBs), which are, in turn, repaired by homologous recombination repair (HRR), a 
complex process involving multiple proteins, including the breast cancer genes 1 and 2 
(BRCA12 and BRCA2).27 
                                                 
2 The typical convention is to use italicized names for genes and plain text names for proteins. However, in this 
document, BRCA mutations which occur at both the gene and protein level are often discussed. Therefore, for 
enhanced readability, BRCA and other genes are written in plain text only throughout this document. 


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PARP inhibitors have shown activity in BRCA1 and BRCA2 (BRCA1/2) mutant and 
homologous recombination deficient (HRD) cancers through a mechanism known as 
synthetic lethality, in which the loss of 2 DNA repair pathways is required for cell death. For 
example, the inhibition of BER from PARP inhibition in a tumor cell with an underlying 
defect in HRR (eg, BRCA1/2 mutation) results in tumor cell death through the accumulation 
of unrepaired DNA damage. Alternatively, homologous recombination proficient cells are 
able to repair SSBs resulting from PARP inhibition.7,8,27 
Multiple genomic and epigenetic alterations can render tumor cells HRD and sensitive to 
PARP inhibition. For example, PARP inhibitors have demonstrated activity in tumor cells 
with deleterious mutations in genes of the HRR pathway such as BRCA1/2, RAD51 
paralog C (RAD51C), RAD51 paralog D (RAD51D), and partner and localizer of BRCA2 
(PALB2). Epigenetic modifications such as BRCA1 and RAD51C promoter 
hypermethylation have also been shown to result in HRD and confer sensitivity to PARP 
inhibitors. Given that multiple genetic and epigenetic mechanisms can render a tumor cell 
HRD, phenotypic genomic biomarkers have been explored to identify these cells. For 
example, genomic loss of heterozygosity (LOH) results from the accumulation of DNA 
damage in HRD tumors through the use of error-prone DNA repair pathways.29,30 Tumors 
with extensive genome-wide LOH, or loss of large chromosomal regions, have been shown 
to be sensitive to PARP inhibition.16,31 Another genomic signature that has been shown to 
identify patients who are more sensitive to PARP inhibition is a biomarker HRD score which 
combines 3 independent measures of HRD (LOH, telomeric-allelic imbalance [TAI], and 
large-scale state transitions [LST]). This combination signature has been shown to confer 
increased sensitivity to PARP inhibition in tumors with a high HRD score when compared to 
tumors with a low HRD score.32 Notably, these genomic signatures can readily be assessed in 
tumors by next-generation sequencing (NGS).29,30 One of the main advantages of assessing 
HRD using genomic signatures is their ability to identify HRD tumors regardless of the 
underlying mechanisms due to the phenotypic nature of the signature.33,34  
In ovarian cancer, it is estimated that half of all high-grade serous tumors have HRD, with 
approximately 15% of carcinomas harboring a germline BRCA mutation, 6% a somatic 
BRCA mutation, and 20% a mutation in, or epigenetic silencing of, another HRR gene. Even 
without an identifiable BRCA or other known HRR gene mutation, many high-grade serous 
ovarian carcinomas display BRCA-like genomic signatures. Rucaparib has been evaluated as 
both a treatment and maintenance therapy for women with ovarian cancer. The results from 
the randomized Phase 3 Study CO-338-014 (ARIEL3; NCT01968213), which assessed 
progression-free survival (PFS) with rucaparib as a maintenance therapy following platinum-
based chemotherapy for patients with platinum-sensitive, recurrent ovarian carcinoma, have 
been published.16 The PFS was significantly longer in the BRCA-mutant and BRCA 
wild-type/LOH high groups compared to the BRCA wild-type/LOH low group; however, 
platinum-sensitive patients treated with rucaparib demonstrated a significant benefit 
compared to placebo in PFS regardless of mutation status (BRCA-mutant, LOH high, and 
intent-to-treat [ITT] populations). Although HRD was predictive of response to rucaparib, 
activity was also observed in the ITT population, suggesting an incomplete understanding of 
the biomarkers responsible for PARP inhibitor sensitivity in ovarian cancer.16 


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While BRCA1/2 mutations are less prevalent in bladder cancer, targeted NGS of bladder 
cancer tumors has shown that approximately 11% of tumors have HRD resulting from 
mutations in DNA repair pathway genes.10 HRD has been demonstrated to predict response 
to cisplatin-based chemotherapy: patients with tumors that demonstrated evidence of HRD 
have been shown to benefit more from platinum chemotherapy than patients with tumors 
without evidence of HRD.10,11 In addition to deleterious mono- or bi- allelic alterations in 
HRR genes, tumors often have other genomic and/or epigenetic deficits that can drive HRD 
and cause distinct genomic signatures. For example, genome-wide LOH, telomeric allelic 
imbalance (TAI), and chromosomal breaks are all phenotypic markers of HRD that are 
prevalent in bladder cancer tumors. Analysis of The Cancer Genome Atlas (TCGA) bladder 
cancer data set (http://cancergenome.nih.gov) indicates that approximately 10% of bladder 
cancer tumors harbor a deleterious alteration in an HRR gene (Clovis, data on file). 
Additionally, genomic scars were detected in tumor samples without any HRR gene 
alterations, suggesting that, overall, approximately 60% of bladder cancer tumors may have 
HRD without having an alteration in a gene of the HRR pathway (Clovis, data on file). In the 
same data set, platinum-chemotherapy treated patients with above-median levels of HRD had 
improved survival when compared to patients with below-median levels of HRD: for these 
HRD subgroups the OS hazard ratio was 0.45 and statistically significant (Wald-
p=0.03)(Clovis, data on file). 
Given the prevalence of alterations in genes of the HRR pathway and the high incidence of 
non-mutation mediated HRD, it is reasonable to estimate that approximately 60% of all 
bladder cancer patients may exhibit HRD. 
1.3 
Rucaparib 
1.3.1 
Background 
Rucaparib is a small molecule inhibitor of PARP-1, PARP-2, and PARP-3 that has 
demonstrated preclinical and clinical activity in cancers associated with a deleterious 
mutation in BRCA1/2 or other HRR gene and/or high level of genomic LOH. Rucaparib was 
approved by the US FDA in December 2016 for the treatment of patients with deleterious 
BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have 
been treated with 2 or more chemotherapies.13,14 In May 2018, the European Commission 
authorized rucaparib (Rubraca) as monotherapy treatment of adult patients with platinum-
sensitive, relapsed or progressive, BRCA-mutated (germline and/or somatic), high-grade 
epithelial ovarian (EOC), fallopian tube (FTC), or primary peritoneal (PPC) cancer, who 
have been treated with 2 or more prior lines of platinum-based chemotherapy, and who are 
unable to tolerate further platinum-based chemotherapy.15 More recently, rucaparib 
demonstrated improved PFS in the maintenance treatment of patients with recurrent 
platinum-sensitive ovarian cancer. Although HRD was predictive of response to rucaparib, 
activity was also observed in HRD-negative patients, suggesting an incomplete 
understanding of the biomarkers responsible for PARP inhibitor sensitivity.16  
Clovis Oncology, Inc. (Clovis; sponsor) is developing rucaparib for oral administration in 
patients with evidence of HRD, including locally advanced unresectable or metastatic 


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transitional cell carcinoma of the urothelium including renal pelvis, ureter, urinary bladder, 
and urethra.  
1.3.2 
Prior Experience with Rucaparib 
An overview of data from nonclinical and clinical studies of rucaparib are provided below 
and described in detail in the rucaparib Investigator’s Brochure (IB). A summary of the 
benefit: risk is also provided in the rucaparib IB. 
1.3.2.1 
Nonclinical Experience with Rucaparib 
The results from nonclinical studies are consistent with the anticipated 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 resistance 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 after oral dosing. 
In vitro, rucaparib reversibly inhibited CYP1A2, CYP2C9, CYP2C19, and CYP3A, and to a 
lesser extent CYP2C8, CYP2D6, and uridine diphosphate (UDP)-glucuronosyltransferase 
(UGT) 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 embryotoxic. 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.35-38 


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1.3.2.2 
Clinical Experience with Rucaparib 
Rucaparib is being evaluated in Phase 1, 2, and 3 clinical studies in patients with advanced 
cancer who have evidence of HRD. There are 4 clinical studies in patients with relapsed, 
high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer: a Phase 2 study in 
patients whose cancer is associated with a germline BRCA (gBRCA) mutation (Study 
CO-338-010 [Study 10]); a Phase 2 biomarker study (Study CO-338-017 [ARIEL2]) 
designed to refine the molecular signature based on HRD associated with a response to 
rucaparib; a randomized, placebo-controlled Phase 3 study (Study CO-338-014 [ARIEL3]) 
evaluating rucaparib as switch maintenance treatment; and Phase 3 Study CO-338-043 
(ARIEL4), which is evaluating rucaparib versus chemotherapy in BRCA1/2-mutant ovarian 
cancer patients with relapsed disease. 
Phase 2 Study CO-338-052 (TRITON2) and Phase 3 Study CO-338-063 (TRITON3) are 
evaluating rucaparib as treatment for patients with metastatic castration-resistant prostate 
cancer (mCRPC) associated with HRD. An additional Phase 2 study in mCRPC patients is 
evaluating rucaparib in combination with nivolumab. 
Additional studies of rucaparib as monotherapy and in combination with other anti-cancer 
therapies in ovarian, prostate, and urothelial cancer, as well as other tumor types, are ongoing 
or planned. 
The rucaparib clinical studies and results are described in more detail in the rucaparib IB. 
1.3.2.2.1 
OVERVIEW OF CLINICAL PHARMACOLOGY 
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 
plasma concentration (Cmax) achieved within 1.5 to 6 hours. The oral bioavailability was 36% 
and terminal half-life (T1/2) was approximately 24 hours. Rucaparib was moderately bound to 
human plasma proteins in vitro (70%). 
At a dose of 600 mg BID rucaparib, steady-state was achieved after approximately 1 week 
with approximately 4-fold accumulation. At the target clinical dose of 600 mg, a high-fat 
meal increased the Cmax and area under the plasma concentration-time curve from 0 to 24 
hours (AUC0-24h) of rucaparib by 20% and 38%, respectively, and delayed the median time to 
occurrence of Cmax (Tmax) by approximately 2.5 hours as compared with these parameters 
under fasted conditions. The effect of food on rucaparib PK is not considered to be clinically 
significant, thus rucaparib can be taken with or without food. 
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. In cancer patients, M324, a carboxylic acid, was a major inactive 
metabolite of rucaparib. 
Drug interactions with rucaparib as a substrate were assessed in a population PK analysis. 
CYP2D6 phenotypes (poor metabolizers, intermediate metabolizers, normal metabolizers, 
and ultra-rapid metabolizers) and CYP1A2 phenotypes (normal metabolizers and 


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hyperinducers) did not significantly impact the steady-state exposure of rucaparib at 600 mg 
BID. Current smokers had overlapping rucaparib exposures as compared to nonsmokers and 
former smokers. Collectively, the results suggest that CYP1A2 and CYP2D6 play a limited 
role in rucaparib metabolism in vivo. Although in vitro rucaparib metabolism mediated by 
CYP3A4 was slow, a significant contribution of CYP3A4 in vivo cannot be excluded. No 
rucaparib dose adjustment is recommended when concomitantly administered with CYP 
inhibitors or inducers. 
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. 
Results from Study CO-338-044 evaluating potential drug-drug interactions (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 
the PK of oral digoxin (a P-gp substrate). Caution should be exercised in the concomitant use 
of drugs that are sensitive clinical substrates of the above CYP enzymes.  
1.3.2.2.2 
OVERVIEW OF EFFICACY 
1.3.2.2.2.1 
Ovarian Cancer Treatment Indication 
On 19 December 2016, the FDA granted accelerated approval, followed by regular approval 
in April 2018, for the marketing of rucaparib (Rubraca®) for monotherapy treatment of 
patients with deleterious BRCA mutation (germline and/or somatic) associated  EOC, FTC, 
or PPC who have been treated with ≥ 2 chemotherapies.14 In May 2018 , the European 
Commission 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.15 
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 data sets and analyses for patients with advanced ovarian cancer 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 Part 2A and Study CO-338-017 Parts 1 and 2, with 
BRCA-mutant ovarian cancer, 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.14  
The primary endpoint on which approval was based is investigator-assessed ORR per 
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1), with ORR by 
central independent radiology review (IRR) conducted as a supportive analysis. ORR by 
investigator was 53.8%, while ORR by IRR was 41.5%, confirming the results of 
investigator assessment for this endpoint.13 Responses were durable, indicated by a duration 
of response (DOR) by investigator assessment of approximately 9.2 months.13  


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1.3.2.2.2.2 
Ovarian Cancer Maintenance Indication 
In April 2018, rucaparib (Rubraca) was approved in the US by the FDA for maintenance 
treatment for adult patients with recurrent EOC, FTC, or PPC who are in a complete or 
partial response to platinum-based chemotherapy.14 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.16 In this study, investigator-assessed 
PFS was the primary efficacy endpoint, with PFS by blinded central 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 (Table 1). 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 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 (tumor tissue mutation in BRCA) 
subpopulations (Table 1). Nearly half (44.6%) of the patients in the rucaparib group showed 
benefit at 1 year compared to 8.8% in the placebo group.16 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.16 These investigator-assessed results were confirmed 
by results of central IRR assessment (Table 1).16  


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Table 1. 
Progression-free Survival per Investigator and per IRR in Primary 
Analysis Populations in Study CO-338-014 
Analysis 
Population 
PFS by Investigator Review 
(Primary Endpoint) 
PFS by Blinded, Central IRR 
(Key Secondary Endpoint) 
Median PFS 
(months) 
Rucaparib vs 
Placeboa 
Hazard Ratiob 
Median PFS 
(months) 
Rucaparib vs 
Placeboa 
Hazard Ratiob 
Primary Analysis Groups 
tBRCA  
(rucaparib n = 130; 
placebo n = 66) 
16.6 vs. 5.4 
(p < 0.0001) 
0.231 
(p < 0.0001) 
26.8 vs. 5.4 
(p < 0.0001) 
0.201 
(p < 0.0001) 
HRD  
(rucaparib n = 236; 
placebo n = 118) 
13.6 vs. 5.4 
(p < 0.0001) 
0.317 
(p < 0.0001) 
22.9 vs. 5.5 
(p < 0.0001) 
0.336 
(p < 0.0001) 
ITT 
(rucaparib n = 375; 
placebo n = 189) 
10.8 vs. 5.4 
(p < 0.0001) 
0.365 
(p < 0.0001) 
13.7 vs. 5.4 
(p < 0.0001) 
0.354 
(p < 0.0001) 
Exploratory Analysis of Non-nested Subgroups 
Non-tBRCA 
LOH+ 
(rucaparib n = 106; 
placebo n = 52) 
9.7 vs. 5.4 
(p < 0.0001) 
0.440 
(p < 0.0001) 
11.1 vs. 5.6 
(p = 0.0114) 
0.554 
(p = 0.0135) 
Non-tBRCA LOH- 
(rucaparib n = 107; 
placebo n = 54) 
6.7 vs. 5.4 
(p = 0.0040) 
0.583 
(p = 0.0049) 
8.2 vs. 5.3 
(p = 0.0002) 
0.470 
(p = 0.0003) 
Abbreviations: HRD = homologous recombination deficiency; IRR = independent radiology review; 
ITT = intent-to-treat; LOH = loss of heterozygosity; non-tBRCA LOH+ = patients without a deleterious 
tBRCA mutation and with percent of tumor genome LOH ≥ 16%; non-tBRCA LOH- = patients without a 
deleterious tBRCA mutation and with percent of tumor genome LOH < 16%; PFS = progression-free 
survival; tBRCA- = tumor tissue mutation in BRCA1 or BRCA2, includes germline BRCA and somatic 
BRCA mutations. 
a 
Stratified log-rank analysis. 
b 
Cox proportional hazard model. 
 
1.3.2.2.3 
OVERVIEW OF SAFETY 
Results of an integrated safety analysis for rucaparib treatment in over 1,000 patients with 
ovarian or prostate cancer who received 600 mg BID rucaparib showed that the most 
common treatment-emergent adverse events (TEAEs) reported were primarily mild to 
moderate (Grade 1-2) in severity and included gastrointestinal disorders (nausea, vomiting, 
diarrhea, and constipation), asthenia/fatigue, anemia/decreased hemoglobin, alanine 
aminotransferase (ALT)/aspartate aminotransferase (AST) increased, decreased appetite, and 
dysgeusia. The most common TEAEs ≥ Grade 3 included anemia/decreased hemoglobin, 
ALT/AST increased, neutropenia/decreased absolute neutrophil count (ANC), and 
asthenia/fatigue.  


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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) and few patients discontinued rucaparib due to ALT/AST elevations.13,16 
Similarly, elevations in creatinine were self-limiting and stabilized over time. 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.13,16 Increased creatinine with rucaparib treatment is likely due to the 
potent inhibition by rucaparib of MATE1 and MATE2-K renal transporters (Section 1.3.2.1). 
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 (AESIs), 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.39,40 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 for rucaparib is 
provided in the rucaparib IB. 
1.4 
Rationale for this Study of Rucaparib 
Patients with MIBC represent a population with advanced disease, poor prognosis, and unmet 
need. The median OS in this patient population is 15 months. Response rates to initial 
treatment with cisplatin-based chemotherapy range from 49% to 72%; however, most 
patients will have disease relapse within 9 months following initial treatment.4,5 Furthermore, 
the majority of patients will progress within 2 to 3 months following failure on first- and/or 
second-line therapy.6 There are limited treatment options beyond first- or second- line 
treatment with platinum-containing chemotherapy and/or an immune checkpoint inhibitor, 
therefore additional therapies for the treatment of patients with MIBC beyond first- or 
second-line are needed. Treatment within clinical studies is considered an appropriate 
treatment option for these patients.18  
Homologous recombination pathway defects may be responsible for the genetic instability 
observed in many cancers including ovarian cancer and urothelial cancer. For ovarian cancer, 
it is estimated approximately 50% of high-grade serous ovarian cancer patients have 
alterations in HRR genes.41 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.16,31 While patients with a BRCA 


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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 a PARP inhibitor.16 Similar to ovarian cancer, an analysis of TCGA bladder 
cancer data set (http://cancergemone.nih.gov) indicates that approximately 60% of bladder 
cancer tumors may have alterations in HRR genes and/or other genomic/epigenetic deficits 
that can drive HRD (Clovis, data on file). The presence of HRD in tumors has been 
demonstrated to predict response to cisplatin-based chemotherapy in bladder cancer.10,11 
Based on these analyses and data, bladder cancer patients have the potential to benefit from 
treatment with a PARP inhibitor.  
The purpose of this study is to assess the efficacy and safety of rucaparib in patients with 
locally advanced unresectable or metastatic urothelial bladder cancer. The study will enroll 
approximately 200 patients, regardless of HRD status, who have received 1 or 2 prior 
treatment regimens. Enrollment of patients, regardless of HRD status, who have received 
≤ 2 prior treatments, is appropriate given that available treatment options are limited and both 
HRD-positive and HRD-negative patients may potentially respond to treatment with 
rucaparib. Primary efficacy will be assessed in a prospectively defined HRD-positive 
population as well as the intent-to-treat (ITT) population. Additional secondary and 
exploratory efficacy and safety endpoints will also be evaluated in HRD subgroups and the 
ITT population. 
 
 


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2 
STUDY OBJECTIVES AND ENDPOINTS 
Primary, secondary, and exploratory objectives and endpoints are shown in Table 2. 
Table 2. 
Primary, Secondary, and Exploratory Objectives and Endpoints 
Primary Objectives 
Primary Endpoints 
To evaluate objective response rate (ORR) in 
molecularly-defined homologous 
recombination deficiency (HRD)-positive and 
intent-to-treat (ITT) populations using a 
prospectively defined molecular signature. 
ORR per Response Evaluation Criteria 
in Solid Tumor (RECIST) Version 1.1 
(v1.1), as assessed by investigator, in 
HRD-positive and ITT populations 
Secondary Objectives 
Secondary Endpoints 
To evaluate duration of response (DOR) 
DOR per RECIST v1.1, as assessed by 
investigator 
To estimate progression-free survival (PFS) 
Disease progression according to 
RECIST v1.1, as assessed by the 
investigator, or death due to any cause 
To estimate overall survival (OS) 
OS 
To evaluate safety and tolerability of 
rucaparib 
Incidence of adverse events (AEs), 
clinical laboratory abnormalities, changes 
in ECGs and vital signs, and dose 
modifications 
To evaluate steady-state pharmacokinetics 
(PK) of rucaparib 
Trough (Cmin) level rucaparib 
concentrations 
Exploratory Objectives 
Exploratory Endpoints 
To assess biomarkers that correlate with 
response to rucaparib 
Biomarkers correlated with response to 
rucaparib 
To evaluate circulating cell-free tumor DNA 
(ctDNA) as a molecular marker of response to 
rucaparib 
Association of cancer-related mutations 
detected in baseline ctDNA samples with 
response to rucaparib  
To assess molecular changes over time in 
plasma and tumor samples 
Association of changes in cancer-related 
mutations detected in plasma and tissue 
samples over time with response to 
rucaparib 
To evaluate biomarkers associated with 
resistance to rucaparib 
Biomarkers associated with resistance to 
rucaparib  
 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a Phase 2 multicenter, open-label study evaluating rucaparib for treatment of patients 
with locally advanced unresectable or metastatic urothelial carcinoma. This study will enroll 
patients with measurable disease per RECIST v1.1. All patients must have received 1 or 2 
prior treatment regimens and have radiologic progression during or after the most recent 
regimen. Patients who have received prior PARP inhibitor treatment will be excluded. Tumor 
tissue will be analyzed to determine the percentage of genomic LOH31 and patients will be 
classified as HRD-positive or HRD-negative for efficacy analyses based on a prespecified 
LOH cut-off defined in the statistical analysis plan (SAP).  
This study consists of a Screening Phase (Section 3.1.1), a Treatment Phase (Section 3.1.2) 
and a Post-treatment Phase (Section 3.1.3). Patients will receive rucaparib monotherapy in 
the Treatment Phase, and will undergo procedures and assessments including regular safety 
and efficacy evaluations during the entire conduct of the study. 
3.1.1 
Screening Phase 
After providing consent to participate, patients will undergo procedures and assessments as 
described in Section 7.3 within 28 days prior to the first dose of rucaparib. During this 
period, unless otherwise required by local regulations, only adverse events (AEs) which are 
related to protocol-mandated assessments will be reported.  
During the Screening Phase, each patient, with the following exceptions, will undergo a 
biopsy for collection of tumor tissue. Tumor tissue samples should be from primary or 
metastatic soft tissue tumor (see Section 7.6.5.1 for details). Patients who had tumor tissue 
collected as part of standard of care ≤ 6 months prior to the first planned dose of rucaparib 
and had no intervening anti-cancer treatments during this period are not required to have a 
biopsy provided that adequate tumor tissue can be provided for analysis. Whenever possible, 
submission of additional archival tumor tissue (with no limit on date of collection) is strongly 
encouraged. If tissue is unable to be submitted prior to the first dose, it must be submitted to 
the sponsor’s central laboratory by Cycle 2 Day 1. Tumor tissue will be analyzed for HRD 
signature status. If an actionable mutation, as defined by the American College of Medical 
Genetics and Genomics (https://www.ncbi.nlm.nih.gov/clinvar/docs/acmg/), is detected from 
this testing, the finding will be made available to the investigator provided the results are 
generated from a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory 
and the patient has consented to receive the results. 
Additional screening assessments will include collection of the patient’s medical information 
and demographics, prior anti-cancer treatments, prior and current medications and 
procedures, physical exam, vital signs, 12-lead ECG, ECOG performance status, laboratory 
safety assessments, urinalysis, serum pregnancy tests (for women of child-bearing potential 
only), and tumor assessments by computed tomography (CT) scans or magnetic resonance 
imaging (MRI) scans (if required by local authorities) and a baseline biomarker blood sample 
for circulating cell-free tumor DNA (ctDNA) analysis as described in Section 7.3.  


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Enrollment will require prospective sponsor (or designee) review and confirmation of 
eligibility, including, but not limited to:  
• details of prior therapy for locally advanced unresectable or metastatic urothelial 
carcinoma 
• screening laboratory assessments 
3.1.2 
Treatment Phase 
Rucaparib will be administered at a starting dose of 600 mg BID. During the Treatment 
Phase, patients will undergo procedures and assessments including regular evaluations for 
safety and efficacy as described in Section 7.4. A blood sample will be collected on Cycle 1 
Day 1 and stored for subsequent genomic DNA testing and exploratory analysis. Blood for 
ctDNA analysis will be collected before dosing on Day 1 of Cycles 1, 2, 3, and at every 
8 weeks thereafter coinciding with radiographic scans. 
Tumor assessments by CT will be performed at the end of every 8 calendar weeks (±7 days) 
from Cycle 1 Day 1 up to 18 months and every 12 calendar weeks (±7 days) thereafter, and 
at the End of Treatment Visit, if applicable. RECIST v1.1 criteria will be used to document 
radiologic response. MRI scans may be performed in place of CT scans if required by local 
authorities. Any drug modifications (interruption, dose reduction, or discontinuation) should 
be documented in the electronic Case Report Form (eCRF) and source documents. If study 
treatment is interrupted, tumor assessments will not be delayed and will be performed on the 
regular study schedule. Copies of all radiologic scans (and other imaging, as appropriate) will 
be collected. 
Patients will receive rucaparib until confirmed radiologic disease progression assessed by 
investigator based on RECIST v1.1, unequivocal clinical disease progression, unacceptable 
toxicity or inability to tolerate further treatment, loss to follow-up, death, or withdrawal of 
consent. Palliative radiation therapy on lesions not considered target lesions for RECIST v1.1 
assessments is allowed and should not result in discontinuation of rucaparib therapy. Patients 
who discontinue study treatment for reasons other than radiologic disease progression or 
death, should continue radiologic tumor assessment performed as described in Section 3.1.3. 
If a patient has radiologic progression per RECIST v1.1, but is deriving clinical benefit in the 
opinion of the investigator, then continuation of treatment beyond progression is allowed per 
Section 5.4.3. In such cases, the decision to continue treatment should be documented in the 
source documents and the patient must provide additional consent prior to continuing 
treatment with rucaparib. These patients will continue to undergo all protocol required 
assessments specified in Table 5. 
Patient safety will be monitored on a regular basis using procedures and assessments 
described in Section 7 and Section 11.4. Safety data will be periodically reviewed by the 
Data Monitoring Committee (DMC) as described in Section 11.6. The DMC will comprise 
coordinating investigators and sponsor representatives. The DMC will meet after the first 
20 patients received rucaparib for at least 1 cycle or discontinued study treatment and 
approximately every 6 months thereafter until completion of the study. 


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3.1.3 
Post-treatment Phase 
The sponsor or designee should be notified of all treatment terminations as soon as possible. 
The date and reason for cessation of rucaparib must be documented in the eCRF and source 
documents. Patients will undergo procedures and assessments during the Post-treatment 
Phase as described in Section 7.5. Upon treatment discontinuation, patients will have an End 
of Treatment Visit (Section 7.5.1), a 28-day Follow-up Visit (Section 7.5.2), and then will 
proceed to long-term follow-up (Section 7.5.3).  
All patients enrolled into the study will provide an End of Treatment Visit blood sample for 
ctDNA analysis. An optional tumor biopsy will be collected prior to the start of subsequent 
anti-cancer therapy from patients who experience radiographic or unequivocal clinical 
disease progression and who provide additional consent. 
For patients who had their last tumor assessment ≥ 8 weeks prior to End of Treatment Visit, a 
tumor assessment must be performed.  
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 [eg, CT scan]) will continue until confirmed radiographic disease progression by 
RECIST v1.1 criteria as assessed by the investigator, loss to follow-up, withdrawal of 
consent, death, initiation of subsequent treatment, or study closure. For these patients, tumor 
assessments should continue to be performed at the end of every 8 calendar weeks (±7 days) 
relative to Cycle 1 Day 1 up to 18 months and then every 12 calendar weeks (±7 days) 
thereafter, until confirmed radiologic disease progression by RECIST v1.1 criteria as 
assessed by the investigator, loss to follow-up, withdrawal of consent, death, or study 
closure.  
Ongoing serious adverse events (SAEs), AESIs, and treatment-related Grade 3/4 AEs will be 
followed until either resolution or stabilization has been determined or until loss to follow-
up. After the 28-day Follow-up Visit, related SAEs and all AESIs (irrespective of causality) 
need to be reported. 
All patients will be followed for survival and subsequent treatments every 12 weeks 
(±14 days) relative to the last dose of rucaparib until death, loss to follow-up, withdrawal of 
consent, or study closure. 
3.2 
Study Schema 
The study schema is provided in Figure 1. 


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Figure 1. Study Schema  
 
 
Screening Phase
(Day -28 to Day -1)
Treatment Phase
Post-treatment Phase
Screening 
Assessments
Within 28 days of 
first dose of 
rucaparib
Cycles 1 and 2
(28-day cycles)
Cycle 3 and subsequent cycles
(28-day cycles)
Day
1
Day
15
Day
1
Tumor Scans*
Disease progression, unacceptable toxicity, or other 
reason for discontinuation of rucaparib
EOT Visit 
After last 
dose of 
rucaparib
28-Day 
Follow-up 
 28 ± 3 
days after 
last dose 
of 
rucaparib
Long-
term 
Follow-up
Disease assessments will continue for 
patients who discontinued treatment 
for reason other than PD*
All patients will be followed for 
survival and subsequent therapies 
every 12 weeks.
EOT – End of Treatment; PD – progressive disease
* Tumor scans every 8 calendar weeks (± 7 days) from Cycle 1 Day 1 up to 18 months 
then every 12 calendar weeks (± 7 days) thereafter


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3.3 
End of Study 
The study will close when all enrolled patients have discontinued treatment and completed 
the 28-day Follow-up Visit, and the long-term follow-up, as applicable. If the study is closed 
for any other reason, individual patients who are continuing to benefit from treatment with 
rucaparib at the time of study closure, and who do not meet any of the criteria for 
withdrawal, will have the option of entering an extension protocol in which they can continue 
to receive rucaparib.  
The sponsor may discontinue the study early for any reason as noted in Section 11.7. 
 


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4 
STUDY POPULATION SELECTION 
4.1 
Number of Patients and Sites 
The total enrollment planned for this study is approximately 200 patients.  
Patients will be enrolled at approximately 65 sites worldwide. 
4.2 
Inclusion Criteria 
Eligible patients must meet the following inclusion criteria. Unless otherwise specified, the 
criteria below apply to 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. Be ≥ 18 years of age at the time the Informed Consent Form (ICF) is signed. 
3. Have histologically or cytologically confirmed locally advanced unresectable (tumor, 
node, metastasis [TNM] staging of T4b and any N; or any T and N2-3) or metastatic 
transitional cell carcinoma of the urothelium (including renal pelvis, ureter, urinary 
bladder, or urethra). Mixed transitional/non-transitional cell histologies are allowed. 
4. Received 1 or 2 prior treatment regimens (eg, cisplatin- or carboplatin-containing 
chemotherapy, immune checkpoint inhibitor, and/or clinical trial) for locally 
advanced unresectable or metastatic disease and had confirmed radiologic disease 
progression during or following the most recent treatment. The principal investigator 
is responsible for ensuring the patient has received anti-cancer treatment as 
appropriate in the country of enrollment, taking into account the patient’s current 
health status as well as how the patient responded to/tolerated prior treatment(s). 
a. Neoadjuvant and/or adjuvant treatment for muscle invasive disease will be 
considered a treatment regimen if radiologic disease progression occurred 
≤ 12 months from the completion of treatment.  
b. No more than 1 prior platinum-containing systemic chemotherapy regimen 
for advanced disease is permitted. A change of platinum chemotherapy 
within the same treatment regimen will be considered 1 prior platinum-
containing chemotherapy. Platinum-containing chemotherapy given as 
radio-sensitization combined with radiation therapy to control locally 
advanced disease will not be considered as a prior regimen of systemic 
therapy. 
c. For patients who have never received platinum, the patient must currently 
be ineligible for or refuse cisplatin treatment.  
d. A treatment regimen that is held for reasons other than progression which 
is subsequently resumed at a later date with no other intervening systemic 
anti-cancer treatment is considered 1 treatment regimen. 
5. Mandatory tumor tissue must be collected ≤ 28 days prior to the first dose of 
rucaparib treatment. A biopsy or surgical resection of tumor tissue is required, unless 
archival tumor tissue collected ≤ 6 months prior to the first dose of rucaparib is 


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available and no intervening anti-cancer treatments were administered during this 
period. Tumor tissue should be of adequate quality for molecular profiling.(See 
Section 7.6.5.1) 
6. Have measurable disease as defined by Response Evaluation Criteria in Solid Tumors 
(RECIST) Version 1.1 (v1.1). A measurable tumor lesion in a previously irradiated 
site is acceptable if subsequent progression has been demonstrated in that lesion. 
7. Have adequate organ function confirmed by the following laboratory values obtained 
≤ 14 days prior to first dose of rucaparib: 
a. Bone Marrow Function 
i. 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
ii. 
Platelets > 100 × 109/L  
iii. 
Hemoglobin ≥ 9 g/dL independent of transfusion ≤ 14 days prior 
to screening hemoglobin assessment. Transfusions are not 
permitted between the screening hemoglobin assessment and the 
first dose of rucaparib. 
b. Hepatic Function 
i. 
Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) ≤ 3 × upper limit of normal (ULN); if liver metastases, 
then ≤ 5 × ULN  
ii. 
Bilirubin ≤ 1.5 × ULN; < 2 × ULN if hyperbilirubinemia is due 
to Gilbert’s syndrome 
c. Renal Function 
i. 
Measured or calculated creatinine clearance (CrCL) 
≥ 30 mL/min or estimated glomerular filtration rate (eGFR) 
≥ 30 mL/min/1.73 m2. For calculated CrCL or eGFR, the 
Cockcroft Gault formula or institutional standard formula can be 
used.  
8. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
assessed within 14 days prior to first dose of rucaparib. 
9. Have life expectancy ≥ 12 weeks. 
4.3 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study. 
1. Active second malignancy for which patient has received treatment within 2 years 
prior to the first dose of rucaparib with exception for the following circumstances:  
a. Curatively treated non-melanoma skin cancer. 
b. Non-invasive diseases such as low risk cervical cancer or any cancer in situ. 
c. Localized (early stage) cancer treated with curative intent (without evidence 
of recurrence and intent for further therapy) and in which no systemic 
therapy was indicated. 
2. Prior treatment with a PARP inhibitor. 


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3. Symptomatic and/or untreated central nervous system (CNS) metastases. Patients 
with asymptomatic previously treated CNS metastases are eligible provided they 
have been clinically stable for at least 4 weeks prior to the first dose of rucaparib. 
4. Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that would, 
in the opinion of the investigator, interfere with absorption of rucaparib. 
5. Known human immunodeficiency virus (HIV) or acquired immunodeficiency 
syndrome (AIDS)-related illness, or history of chronic hepatitis B or C, with the 
exception of patients with sustained virologic response after completion of treatment 
for hepatitis C. 
6. For female patients of childbearing potential and all male patients, 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. 
b. Pregnant or breast feeding. Women of childbearing potential must have a 
negative serum pregnancy test ≤ 3 days prior to the first dose of rucaparib. 
Women of childbearing potential must not be considering getting pregnant 
during the study and for 6 months following the last dose of rucaparib. 
c. Male patients who refuse to use condoms during sex. Male patients must not 
make semen donations during treatment and for 6 months following the last 
dose of rucaparib. 
7. Received anti-cancer treatment with chemotherapy, radiation, antibody therapy or 
other immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or 
experimental drugs ≤ 14 days prior to first dose of rucaparib and/or ongoing 
treatment-related adverse events National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) > Grade 1 except for 
neuropathy, ototoxicity, alopecia, and electrolyte abnormalities. 
8. Non-study related minor surgical procedure ≤ 5 days, or major surgical procedure 
≤ 21 days, prior to first dose of rucaparib; in all cases, the patient must be 
sufficiently recovered and stable before treatment administration. 
9. 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. 
4.4 
Patients or Partners of Patients with Reproductive Potential 
Pregnancy is an exclusion criterion. Women of childbearing potential or male patients of 
reproductive potential with female partners 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 rucaparib 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. 


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Treatment should be discontinued immediately in any woman found to have a positive 
pregnancy test while taking rucaparib. 
Male patients are required to use a condom during sex with a partner to avoid the possibility 
of exposure of the partner to rucaparib, regardless of whether the partner is a woman of 
childbearing potential or not. Male patients must not make semen donations during treatment 
and for 6 months following the last dose of rucaparib. 
Male patients are considered to be of reproductive potential unless permanently sterile by 
bilateral orchiectomy or vasectomized with appropriate post-vasectomy documentation of 
absence of sperm in ejaculate. 
Female patients or partners of male 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 and male 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 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 
• 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 rucaparib.  


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4.5 
Compliance with 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 
This study will assess the investigational drug rucaparib.  
Rucaparib camsylate (also known as CO-338; formerly known as PF-01367338-BW and 
AG-014447) is an oral formulation with a molecular weight of 555.67 Daltons. Rucaparib 
tablets for oral administration will be supplied to the study sites by the sponsor. A brief 
description of the investigational product is provided below with details in the Pharmacy 
Manual. 
Table 3.  
Description of Investigational Product 
Drug Name: 
Rucaparib 
INN: 
Rucaparib 
Formulation:  
(strengths expressed as 
free base) 
Tablet; film-coated; 200 mg (blue, round, debossed with C2), 250 mg 
(white, rounded diamond shape, debossed with C25), 300 mg (yellow, 
oval, debossed with C3)  
How Supplied: 
200 mg, 250 mg, and 300 mg (as free base) strength tablets in high-
density polyethylene bottles or equivalent with child-resistant caps. 
Patients may receive one or more strengths.  
Storage Conditions: 
As directed on the product label  
Abbreviation: INN = International Nonproprietary Name 
 
5.2 
Packaging and Labeling 
5.2.1 
Rucaparib 
All tablets are provided in high-density polyethylene (HDPE) bottles (or equivalent) with 
child-resistant caps and should be stored in the provided containers and as directed on the 
product label. Patients may be dispensed 1 or more strengths depending on their current dose 
of rucaparib. The number of bottles of each strength dispensed will be sufficient to supply 
28 days of treatment (plus a 2-day overage) until the next rucaparib dispensation visit. 
Bottles containing rucaparib tablets will be labeled according to national regulations for 
investigational products. 
5.3 
Method of Assigning Patients to Treatment Groups 
All patients enrolled in the study will receive rucaparib at an initial dose of 600 mg BID. 
5.4 
Preparation and Administration of Protocol-specified Treatment 
The starting dose of rucaparib is 600 mg ingested BID. Patients may take rucaparib with or 
without food. Each dose should be taken with water. Tablets should be swallowed whole 


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without crushing or chewing. Tablet strength combinations shall be determined by the 
Interactive Web Response System (IWRS). 
Patients should take rucaparib doses as close as possible to 12 hours apart, preferably at the 
same times every day. If a patient misses a dose (ie, does not take it within 4 hours of the 
scheduled time), the patient should skip the missed dose and resume taking rucaparib with 
the next scheduled dose. Missed or vomited doses should not be made up. 
Dosing with rucaparib may be held or reduced as described in Section 5.4.1. 
Patients will be provided a sufficient quantity of rucaparib for 28 days, with a small overage, 
until the next rucaparib dispensation visit. Patients will be instructed to bring their rucaparib 
tablets and all containers (empty, partially used, and/or unopened) to the next scheduled visit 
for reconciliation by site personnel. 
5.4.1 
Rucaparib Dose Modification Criteria 
5.4.1.1 
Treatment Interruption Guidelines 
Treatment with rucaparib should be held if any of the following are observed and a dose 
reduction should be considered or implemented. 
• Grade 3 or 4 hematologic toxicity. Anemia should be managed as described below 
(Section 5.4.1.2) 
• Grade 3 or 4 non-hematologic toxicity (except for alopecia, nausea, vomiting, or 
diarrhea adequately controlled with systemic antiemetic/antidiarrheal medication 
administered in standard doses according to the study center routines). Grade 3 or 
Grade 4 ALT/AST elevations should be managed as described below 
(Section 5.4.1.3)  
• In addition, and at the discretion of the investigator, the dose of rucaparib may be 
held and/or reduced for Grade 2 toxicity not adequately controlled by concomitant 
medications and/or supportive care. 
For patients who meet treatment interruption guidelines above, treatment with rucaparib 
should be held until the toxicity improves to ≤ CTCAE Grade 2. Twice daily dosing may 
then be resumed at either the same dose or a lower dose, per investigator discretion. If 
treatment is resumed at the same dose, and the patient experiences the same toxicity, 
treatment should be interrupted, then resumed at a reduced dose following resolution 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. If a patient continues to experience toxicity 
despite dose reduction steps to 300 mg BID, or if dosing with rucaparib is interrupted for 
> 14 consecutive days due to toxicity, treatment should be discontinued, unless otherwise 
agreed and documented between the investigator and the sponsor. 


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5.4.1.2 
Management of Anemia including Evaluation for MDS/AML and Follow-up of 
Patients who Discontinue Treatment with Ongoing Anemia: 
• If the patient develops anemia CTCAE Grade ≥ 3, rucaparib treatment should be held 
until the anemia improves to CTCAE Grade ≤ 2 whereupon daily dosing may then be 
resumed at either the same dose or a lower dose, per investigator discretion.  
• If the duration of dosing is interrupted for > 14 consecutive days due to anemia 
CTCAE Grade ≥ 3, treatment should be permanently discontinued, unless otherwise 
agreed and documented between the investigator and the sponsor or designee.  
• In addition, if anemia CTCAE Grade ≥ 3 persists for > 14 consecutive days, or a 
dependence upon blood transfusion occurs, then weekly complete blood counts 
should be performed until resolution of the event.  
• If, after 42 days of interruption of rucaparib, the anemia has not improved to CTCAE 
Grade ≤ 1 then the patient should be referred to a hematologist and analysis of the 
bone marrow with cytogenetic studies are recommended according to standard 
hematologic practice.  
• The bone marrow analysis should include a bone marrow aspirate (for cellular 
morphology, cytogenetic analysis, and flow cytometry) and a core biopsy (for bone 
marrow cellularity). 
5.4.1.3 
Management of Rucaparib Treatment-Emergent ALT/AST Elevations: 
• Grade 4 ALT/AST elevations: hold rucaparib until values have improved to Grade 2 
or better, then resume rucaparib with a dose reduction. Monitor liver function tests 
weekly for 3 weeks after rucaparib has been restarted. 
• Grade 3 ALT/AST elevations, in the absence of other signs of liver dysfunction, 
should be managed as follows:  
- 
Monitor liver function tests weekly until improvement to ≤ Grade 2. 
- 
Continuation of rucaparib with elevation of ALT/AST up to Grade 3 is permitted 
provided bilirubin is < ULN and alkaline phosphatase is < 3 x ULN.  
- 
If patient has Grade 3 ALT/AST and continues on rucaparib, and levels do not 
decline within 2 weeks or they continue to rise, treatment interruption and 
resolution to ≤ Grade 2 will be required before rucaparib can be resumed, either at 
the current dose or at a reduced dose. 
Drug-induced liver injury (DILI) is described in the US FDA Guidance for Industry, Drug-
Induced Liver Injury: Premarketing Clinical Evaluation42 and should be referenced when 
managing treatment-emergent ALT/AST elevations. 


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Rucaparib treatment must be interrupted if biochemical criteria for suspected DILI are met, 
according to presence of the following laboratory abnormalities: 
ALT or AST > 3 x ULN 
and 
Bilirubin > 2 x ULN 
While treatment is interrupted, the patient should be evaluated for the presence of 
confounding factors including malignant disease in the liver, co-administration of other 
suspect drugs, cholestasis, and viral or autoimmune hepatitis that could have caused the 
laboratory abnormalities. Other laboratory investigations of liver function such as 
international normalized ratio (INR) should be implemented as indicated. If no alternative 
cause is identified, rucaparib must be permanently discontinued. 
All cases of possible DILI will be followed until all abnormalities have returned to normal, 
returned to baseline levels, or an alternative cause is found to explain the combination of the 
increased transaminases and total bilirubin. 
5.4.1.4 
Rucaparib Dose Reduction Steps 
Dose reduction steps are presented in Table 4. 
Dose re-escalation upon improvement of toxicity to ≤ CTCAE Grade 1 is permitted at the 
discretion of the investigator. 
Dose modifications (interruption, reduction, and re-escalation) must be recorded for each 
patient in the appropriate section of the eCRF. 
Table 4. 
Rucaparib Dose Reduction Steps 
Starting Dose 
600 mg BID 
Dose Level – 1 
500 mg BID 
Dose Level – 2 
400 mg BID 
Dose Level – 3* 
300 mg BID 
*Consult with the 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. 
5.4.2 
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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5.4.3 
Treatment with Rucaparib beyond Disease Progression 
Patients will receive rucaparib until confirmed radiologic disease progression as assessed by 
investigator using RECIST v1.1 criteria, unequivocal clinical disease progression, 
unacceptable toxicity or inability to tolerate further treatment, loss to follow-up, death, or 
withdrawal of consent. If a patient receiving rucaparib has met criteria for confirmed 
radiologic disease progression by RECIST v1.1 criteria, but the patient continues to derive 
clinical benefit in the opinion of 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 patient must provide additional consent prior to 
continuing treatment with rucaparib. Clinical scenarios where continuation of rucaparib 
treatment 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 rucaparib will 
continue to have all protocol-required assessments as described in Section 7. 
5.5 
Blinding/Masking of Treatment 
This is an open-label study; the investigational product will not be blinded or masked. All 
patients enrolled will receive rucaparib. 
5.6 
Treatment Compliance 
Study site personnel will review dosing information with the patient (or legally authorized 
representative) on scheduled clinic visit days, providing instructions regarding dose, dose 
frequency, and the number of tablets to be taken for each dose. Patients (or legally authorized 
representative [where acceptable according to national law and/or local regulations]) will be 
instructed to keep all unused tablets and containers (empty, partially used, and/or unopened) 
for accountability and bring them back at the next scheduled clinic visit. A compliance check 
and tablet count will be performed by study personnel. Study site personnel will record 
compliance information on the eCRF. 
Every effort should be made to ensure patients return to the clinic with their rucaparib 
containers/unused rucaparib at each rucaparib dispensation visit. 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. 
5.7 
Accountability of Protocol-specified Treatment 
Study personnel will maintain accurate records of rucaparib receipt, dispensation, use, return, 
destruction, and reconciliation for rucaparib provided by the sponsor. An IWRS will be used 
to manage rucaparib inventory at all sites. In order to function properly, the system will 


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require real-time entry of rucaparib receipt, dispensation, destruction, patient treatment 
discontinuation, etc. by study personnel at the study site. 
The site is responsible for the return or destruction of rucaparib supplied by the sponsor as 
required. Authorization to destroy at the site, rucaparib that has not been dispensed to a 
patient (eg, expired rucaparib), must be requested from the sponsor prior to destruction. Any 
rucaparib supplied by the sponsor that is destroyed, accidentally or deliberately, must be 
accounted for. All rucaparib containers must be accounted for prior to their destruction at the 
study site, according to institutional procedures for disposal of cytotoxic chemotherapeutic 
drugs. Unused rucaparib containers should be destroyed by the site if possible. If destruction 
by the site is not possible, supply should be returned to the drug depot. 
During the course of the study and at completion of the study, the number of rucaparib 
containers received, dispensed, returned, and destroyed must be reconciled. 


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6 
PRIOR AND CONCOMITANT THERAPY 
Patients who have received prior treatment with a PARP inhibitor including intravenous (IV) 
or oral rucaparib are not eligible to participate in this study.  
All procedures performed (eg, thoracentesis, etc.) and medications used during the study 
must be documented in 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 per 
RECIST v1.1 is permitted during the study. Treatment with rucaparib should be held prior to 
initiation of radiation therapy and until the patient has recovered from any radiation related 
toxicity. 
6.3 
Anti-cancer or Experimental Therapy 
No other anti-cancer therapies (including chemotherapy, radiation, antibody or other 
immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or other 
experimental drugs) of any kind, with the exception of palliative radiotherapy, will be 
permitted while the patient is participating in the study. Prior treatment with anti-cancer 
therapies must have been completed > 14 days prior to the first dose of rucaparib. 
6.4 
Cytochrome P450 Isoenzyme Inhibitors, Inducers, and Substrates 
Based on the results from the in vivo CYP interaction study (CO-338-044), rucaparib is a 
moderate inhibitor of CYP1A2, and a weak inhibitor of CYP2C9, CYP2C19, and CYP3A. 
Caution should be used in patients on rucaparib taking concomitant medicines that are 
sensitive clinical substrates of CYP1A2, CYP2C9, CYP2C19, and/or CYP3A (Appendix 3). 
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. Selection of an alternative concomitant 
medication is recommended. 


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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 INR monitored regularly per standard clinical practice. 
6.6 
Other Concomitant Medications 
Therapies considered necessary for the patient’s well-being may be given at the discretion of 
the investigator and should be documented on the eCRF. Other concomitant medications, 
except for analgesics, chronic treatments for concomitant medical conditions, or agents 
required for life-threatening medical problems, should be avoided. Herbal and 
complementary therapies should not be encouraged because of unknown side effects and 
potential drug interactions, but any taken by the patient should be documented appropriately 
on the eCRF.  
Rucaparib marginally increased digoxin area under the plasma concentration-time curve 
(AUC) by 20%. Caution should be exercised for patients receiving rucaparib and requiring 
concomitant medication with digoxin. Patients taking digoxin should have their digoxin 
levels monitored after starting rucaparib and then regularly per standard clinical practice.  
In vitro, rucaparib is a potent inhibitor of MATE1 and MATE2-K, a moderate inhibitor of 
OCT1, and a weak inhibitor of OCT2. As inhibition of these transporters could increase 
metformin renal elimination and decrease liver uptake of metformin, caution is advised when 
metformin is co-administered with rucaparib. In addition, rucaparib is an inhibitor of the 
BCRP with 50% inhibitory concentration (IC50) value suggesting potential BCRP inhibition 
and increased exposures of medicinal products that are BCRP substrate (eg, rosuvastatin). 


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7 
STUDY PROCEDURES AND ACTIVITIES 
7.1 
Schedule of Assessments 
Table 5 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. Tumor assessment visits 
are scheduled relative to Study Day 1.  


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Table 5. 
Schedule of Assessments 
 
Screening 
Phase 
Treatment Phasea 
(±3 days of scheduled timepoint) 
Post-treatment Phase 
Cycles 1 and 2 
Cycle 3+ 
Procedure 
Day -28 to 
Day -1 
Day 1b,c 
Day 15c 
Day 1c 
End of 
Treatment 
Visit 
28-day Follow-up 
Visit 
(28 ±3 days after 
last dose) 
Long-term 
Follow-up 
Informed Consentd 
X 
 
 
 
 
 
 
Medical/Oncology Historye 
X 
 
 
 
 
 
 
Physical Examinationf, Heightf, Weight 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
Xg 
X 
 
X 
X 
X 
 
Vital Signs 
X 
Xh 
Xh 
Xh 
X 
X 
 
Adverse Eventsi 
X 
X 
X 
X 
X 
Xi 
Xi 
Prior/Concomitant Medications and Procedures 
X 
X 
X 
X 
X 
X 
 
12-lead ECGj 
X 
 
 
 
X 
 
 
Hematologyk (local lab) 
Xg 
X 
X 
X 
X 
X 
 
Serum Chemistryl (local lab) 
Xg 
X 
X 
X 
X 
X 
 
Serum Pregnancy Testm (local lab) 
Xg 
X 
 
X 
X 
 
 
Urinalysisn (local lab) 
Xg 
X 
X 
X 
X 
X 
 
Disease Assessment/Tumor Scanso,p 
X 
 
 
Xp 
(X)q 
Xr 
Xr 
Tumor Tissue Biopsy/Resection/Sample 
Xs 
 
 
 
(X)t 
 
 
Archival Tumor Tissue 
(X)u 
 
 
 
 
 
 
ctDNA Blood Samplev (central lab) 
X 
X 
 
Xw 
X 
X 
 
Blood Sample for Genomic Analysis (central lab) 
 
Xx 
 
 
 
 
 
Rucaparib Dispensation/Administration/Accountability 
 
X 
X 
X 
X 
 
 
Plasma PK Sampley (central lab) 
 
Xz 
 
Xz 
 
 
 
Survival and Subsequent Treatments 
 
 
 
 
 
 
Xaa 


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Table 5. 
Schedule of Assessments 
Abbreviations: AE(s) = adverse event(s); AESI(s) = adverse events of special interest; ALP = alkaline phosphatase, ALT = alanine aminotransferase, ANC = absolute neutrophil 
count, AST = aspartate aminotransferase, BRCA = breast cancer gene; BUN = blood urea nitrogen, CO2 = carbon dioxide; CR = complete response, CrCL = creatinine clearance; 
CT = computed tomography, ctDNA = circulating cell-free tumor DNA; ECG(s) = electrocardiogram(s), ECOG = Eastern Cooperative Oncology Group; eGFR = estimated 
glomerular filtration rate; FFPE = formalin-fixed, paraffin-embedded; gBRCA = germline mutation in BRCA; ICF = Informed Consent Form; LDH = lactate dehydrogenase, 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; RBC = red blood cell, RECIST = Response 
Evaluation Criteria in Solid Tumors; SAE(s) = serious adverse event(s), 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 
= 
Any procedures required on Cycle 1 Day 1 may be omitted if completed ≤ 3 days prior to first dose of rucaparib. 
c 
= 
Patients are to refrain from taking their first dose of rucaparib at home on these days. Procedures are to be completed before rucaparib is administered. 
d 
= 
Consent may be completed outside the 28-day screening window as consent does not expire. Reconsent is not required if outside the screening window. 
e 
= 
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. 
f 
= 
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. 
g 
= 
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. 
h 
= 
Vital signs (blood pressure, pulse, and temperature) to be taken on clinic visit days. 
i 
= 
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. 
j 
= 
Heart rate, PR, QRS, QT, 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. 
k 
= 
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 the first dose of rucaparib. Additional and more 
frequent tests may be performed at the investigator’s discretion.  
l 
= 
Includes total protein, albumin, measured or calculated CrCL or eGFR (for CrCL calculation or eGFR, the Cockcroft Gault formula or institutional standard 
formula can also be used), BUN or urea, total bilirubin, ALP, ALT, AST, LDH, glucose, sodium, potassium, chloride, CO2, calcium, phosphorus, and total 
cholesterol. Total cholesterol testing does not require fasting. Blood will be analyzed by a local laboratory and results must be reviewed by the investigator prior 
to the first dose of rucaparib. Additional and more frequent tests may be performed at the investigator’s discretion.   


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Table 5. 
Schedule of Assessments 
m 
= 
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. 
n 
= 
Includes dipstick for protein, glucose, blood, pH, and ketones. If dipstick findings abnormal, perform microscopic evaluation. 
o 
= 
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 studies (MRI, X-ray, PET, and ultrasound) may be performed if required. MRI may be used in place of CT scans if required 
by local authorities. 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 or MRI scans. 
p 
= 
Tumor scans to be performed at the end of every 8 calendar weeks (±7 days) during the Treatment Phase. 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 least 18 months, may decrease the frequency of disease assessments to 
every 12 calendar weeks (±7 days).  
q 
= 
Disease assessments should also be done at the time of treatment discontinuation if it has been ≥ 8 weeks since the last assessment.  
r 
= 
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 by RECIST v1.1 (as assessed by the investigator), loss to follow-
up, withdrawal, death, initiation of subsequent treatment, or study closure.  
s 
= 
A biopsy or resection of tumor tissue must be collected ≤ 28 days prior to first dose of rucaparib. Alternatively, tumor tissue collected ≤ 6 months prior to the 
first dose of rucaparib may be submitted, provided there have been no intervening anti-cancer treatments during this period and the tissue is of adequate quality. 
Tumor tissue must be obtained from a soft tissue tumor lesion; ascites is not acceptable. Refer to the Pathology Charter for detailed sample handling instructions.  
t 
= 
An optional post-treatment tumor biopsy sample may be collected from patients who progress on rucaparib. If the progression is due to new lesions, the 
preference is to obtain the biopsy from the new lesion(s). Additional consent is required. Refer to the Pathology Charter for detailed sample handling 
instructions. 
u 
= 
Archival FFPE tumor tissue must be submitted if available. Refer to the Pathology Charter for detailed sample handling instructions.  
v 
= 
Refer to the Laboratory Manual for detailed sample processing instructions. Cycle 1 ctDNA must be collected even if within 3 days of screening ctDNA. 
w 
= 
To be performed at the time of tumor evaluation for Cycle 3 and in subsequent cycles coinciding with tumor scans through the 28-day Follow-up Visit. 
x 
= 
Cycle 1 Day 1 only 
y 
= 
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 processing instructions.  
z 
= 
Cycles 2, 3, and 4 only.  
aa 
= 
All patients discontinued from treatment, regardless of reason, should be followed for survival and subsequent therapies every 12 weeks 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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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 Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) approved consent form should be 
translated and communicated in the language the patient (or legally authorized representative 
[where acceptable according to national law and/or local regulations]) can understand.  
Additionally, patients participating in the optional tumor tissue biopsy at the time of 
radiologic disease progression/treatment discontinuation must provide additional consent for 
this procedure.  
Patients with radiologic disease progression who are still receiving benefit and are allowed to 
continue rucaparib treatment must also provide additional consent for continued treatment. 
Analyses of blood sample for genomic analysis, plasma ctDNA, and tumor tissue will be 
performed by the sponsor-selected central laboratory.  
The patient will have the option to provide additional consent to allow or not allow the 
sponsor to retain residual samples for future unspecified research.  
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 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. 
7.3.1 
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) 
• Serious adverse event (SAE) monitoring (only report if related to screening procedure) 
• Prior and concomitant medications, any surgical/medical procedures  
• 12-lead ECG 


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• 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). 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 
• Tumor tissue from a primary tumor or a metastatic disease site in the form of a 
formalin-fixed paraffin-embedded (FFPE) block or unstained slides (required). 
(See Section 7.6.5.1) 
• Archival FFPE tumor tissue (if available) (See Section 7.6.5.2) 
• Collect ctDNA blood sample 
7.3.2 
Up to 14 days Prior to Start of Treatment 
• ECOG performance status (Appendix 2) 
• SAE monitoring (only report if related to screening procedure) 
• Hematology 
• Serum chemistry. Note: fasting is not required 
• Urinalysis (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) 
7.4 
Treatment Phase  
During the treatment period, patients will receive oral rucaparib tablets which should be 
taken BID at 600 mg/dose with water and with or without food. In each study visit, the first 
dose of rucaparib will be taken in the clinic, with the remaining doses self-administered by 
the patient at home. Patients should take rucaparib at about the same time every day. Patients 
will inform the clinic staff of any changes to their dose and timing of self-administration of 
oral rucaparib.  
Unless otherwise specified, all patients will undergo the following procedures and 
assessments. 
7.4.1 
Cycle 1 Day 1 
The following procedures will be completed before rucaparib is administered, unless if 
completed ≤ 3 days prior to the first dose of rucaparib in which case they may be omitted: 
• Physical examination 
• Weight 
• ECOG performance status (Appendix 2) 


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• Vital signs 
• Concomitant medications and any surgical/medical procedures 
• Hematology 
• Serum chemistry (fasting is not required) 
• Serum pregnancy test for women of childbearing potential 
• Urinalysis 
• 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) 
• Blood sample for genomic analysis 
• Adverse event (AE) monitoring 
• Patients return all unused tablets and containers (empty, partially used, and/or unopened) 
to the study site for accountability 
• 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. In the event of toxicities, re-treatment or dose modification 
will be according to the criteria described in Section 5.4.1. 
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 before rucaparib is administered: 
• Physical examination 
• Weight 
• Vital signs 
• Concomitant medications and any surgical/medical procedures 
• Hematology 
• Serum chemistry (fasting is not required) 
• Urinalysis 


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• AE monitoring 
• Patients return all unused tablets and containers (empty, partially used, and/or unopened) 
to the study site for accountability 
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. In the event of 
toxicities, re-treatment or dose modification will be according to the criteria described in 
Section 5.4.1. 
7.4.3 
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 rucaparib is administered: 
• Physical examination 
• Weight 
• ECOG performance status (Appendix 2) 
• Vital signs 
• Concomitant medications and any surgical/medical procedures 
• Hematology 
• Serum chemistry (fasting is not required) 
• Serum pregnancy test for women of childbearing potential  
• Urinalysis 
• Collect ctDNA blood sample  
• Collect plasma sample for PK analyses 
• AE monitoring 
• Patients return all unused tablets and containers (empty, partially used, and/or unopened) 
to the study site for accountability 
• Dispensation of rucaparib 


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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. In the event of 
toxicities, re-treatment or dose modification will be according to the criteria described in 
Section 5.4.1. 
7.4.4 
Cycle 2 Day 15 
The following procedures will be completed before rucaparib is administered: 
• Physical examination 
• Weight 
• Vital signs 
• Concomitant medications and any surgical/medical procedures 
• Hematology 
• Serum chemistry (fasting is not required) 
• Urinalysis 
• AE monitoring 
• Patients return all unused tablets and containers (empty, partially used, and/or unopened) 
to the study site for accountability 
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. In the event of 
toxicities, re-treatment or dose modification will be according to the criteria described in 
Section 5.4.1. 
7.4.5 
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. 
Plasma samples for PK analysis should be collected before the morning dose on Cycle 3 
Day 1 and Cycle 4 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 rucaparib is administered: 
• Physical examination 
• Weight 


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• ECOG performance status (Appendix 2)  
• 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 rucaparib for the first 18 months of treatment, and then every 12 calendar weeks 
(±7 days) thereafter  
• Hematology 
• Serum chemistry (fasting is not required) 
• Urinalysis 
• Serum pregnancy test for women of childbearing potential 
• Collect ctDNA blood sample (at time of tumor assessment scans) 
• Collect plasma sample for PK analyses (Cycle 3 Day 1 and Cycle 4 Day 1 only) 
• AE monitoring 
• Patients return all unused tablets and containers (empty, partially used, and/or unopened) 
to the study site for accountability 
• Dispensation 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. 
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. In the event of 
toxicities, re-treatment or dose modification will be according to the criteria described in 
Section 5.4.1. 
7.5 
Post-treatment Phase 
7.5.1 
End of Treatment Visit 
Upon treatment discontinuation, regardless of the reason, patients will have an End of 
Treatment Visit. For patients that have radiologic disease progression by RECIST v1.1, but 
continue to derive benefit in the opinion of the investigator, they will be allowed to continue 
treatment in the Treatment Phase. In such cases, the investigator’s decision to continue 
treatment should be documented in the source documents and the patient must provide 
additional consent prior to continuing treatment with rucaparib as described starting in 
Section 7.4.5 and an End of Treatment Visit will occur at the end of all rucaparib treatment. 
Patients who continue treatment with rucaparib after radiologic disease progression will have 
the option of tumor tissue biopsy collection at time of first disease progression on study 
(requires additional consent). Tumor tissue will be processed locally as FFPE tissue. Refer to 
the Pathology Charter for detailed sample handling instructions. 
The following procedures will be performed at the End of Treatment Visit: 


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• Physical examination 
• Weight 
• ECOG performance status (Appendix 2) 
• Vital signs 
• Concomitant medications and any surgical/medical procedures 
• 12-lead ECG 
• Tumor assessment/ scans if it has been ≥ 8 weeks since the last assessment 
• Hematology 
• Serum chemistry (fasting is not required) 
• Urinalysis 
• Serum pregnancy test for women of childbearing potential 
• Collect ctDNA blood sample  
• AE monitoring 
• Patients return all unused tablets and containers (empty, partially used, and/or unopened) 
to the study site for final accountability. 
• Optional tumor tissue biopsy collection after the time of disease progression (radiologic 
or clinical) and prior to initiation of any subsequent anti-cancer therapy (requires 
additional consent). Tumor tissue will be processed locally as FFPE tissue. Refer to the 
Pathology Charter for detailed sample handling instructions.  
7.5.2 
28-day Follow-up Visit  
The following procedures will be performed for all patients at 28 (±3) days after the last dose 
of rucaparib.  
• Physical examination 
• Weight 
• ECOG performance status (Appendix 2) 
• Vital signs 
• Concomitant medications and any surgical/medical procedures 
• Tumor assessment only for those patients that have not had radiographic progression 
confirmed by investigator assessment 
• Hematology  
• Serum chemistry (fasting is not required) 
• Urinalysis  


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• Collect ctDNA blood sample  
• AE monitoring 
• Information collected for subsequent treatments and adverse event of special interest 
(AESI) will require appropriate documentation (ie, laboratory and/ or pathology reports) 
and should be reported as indicated in Section 8.9. 
Patients who do not withdraw from the study at this visit will continue with long-term 
follow-up as described in Section 7.5.3.  
7.5.3 
Long-term Follow-up 
Patients who complete a 28-day Follow-up Visit after the last dose of rucaparib will continue 
in long-term follow-up as described below. 
• If applicable, tumor assessment (using the same methodology as was used at initial study 
screening [eg, CT scan or MRI scan if required by local authorities]) when the reason for 
treatment discontinuation was other than death or disease progression based on radiologic 
assessment and it has been ≥ 8 weeks since last scan or disease progression was noted on 
the last scan. Tumor assessment should continue to be performed at the end of every 
8 calendar weeks (±7 days) relative to Cycle 1 Day 1 up to 18 months, then every 12 
calendar weeks (±7 days), until confirmed radiologic disease progression by RECIST 
v1.1 criteria as assessed by the investigator, loss to follow-up, withdrawal, death, 
initiation of subsequent treatment, or study closure.  
• All patients discontinued from treatment, regardless of reason, will be followed and 
information collected for subsequent treatments and survival every 12 weeks from last 
dose of rucaparib until death, loss to follow-up, withdrawal of consent from study, or 
closure of the study. Follow-up can be performed via the telephone and can be completed 
to coincide with scheduled tumor assessments.  
• SAEs related to rucaparib and all AESIs, irrespective of causality, are to be reported as 
specified in Section 8.9.  
7.6 
Methods of Data Collection 
7.6.1 
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 rucaparib, unless serious and 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 urothelial carcinoma (and other malignancy, if applicable), prior 
surgeries/treatments received for cancer, dates of treatment administration, best response 


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achieved, date of progression and how assessed, and BRCA or other HRR gene mutation 
status (if known).  
7.6.2 
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 rucaparib through the 
completion of the 28-day Follow-up Visit after treatment discontinuation. Medications 
information will be entered in the appropriate eCRF after it is obtained at each study visit. 
7.6.3 
Efficacy Evaluations 
Target and non-target lesions will be evaluated for evidence of radiographic response based 
on RECIST v1.1 criteria.  
Tumor assessments will be performed during screening (baseline), at the end of every 
8 calendar weeks (±7 days) relative to the first dose of rucaparib (Cycle 1 Day 1) up to 
18 months, then every 12 calendar weeks (±7 days), until confirmed radiologic disease 
progression by RECIST v1.1 criteria as assessed by the investigator, loss to follow-up, 
withdrawal from study, death, or study closure. Tumor assessments should be performed at 
the time of treatment discontinuation if the reason was other than radiologically confirmed 
disease progression and it has been ≥ 8 weeks since the last assessment. 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 by RECIST v1.1 per investigator, death, 
loss to follow-up, withdrawal from the study, study closure, or initiation of subsequent 
treatment. 
Tumor assessments should consist of clinical examination and appropriate imaging 
techniques (ie, CT scans of the chest, abdomen, and pelvis with appropriate slice thickness 
per RECIST v1.1); other studies (magnetic resonance imaging (MRI), X-ray, positron 
emission tomography [PET]/CT, and ultrasound) may also be performed if required. MRI 
may be used in place of CT scans for assessment of target lesions if required by local 
authorities. 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. If a patient has known brain metastases, this disease should be 
evaluated at each required assessment time. 
If a complete response (CR) or partial response (PR) is noted, confirmatory scans should be 
performed at least 4 weeks after response was first documented. 
Copies of CT scans (and other imaging, as appropriate) will be collected from all patients. 
IRR may be conducted on all or a subset of CT scans.  


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7.6.4 
Safety Evaluations 
7.6.4.1 
Adverse Event Assessment 
The investigator has the responsibility for assessing the safety of the patients and for 
compliance with the protocol to ensure study integrity. During the screening period, unless 
otherwise required by local regulations, SAEs which are related to protocol-mandated 
assessments will be reported. Once enrolled and rucaparib is administered, patients will be 
monitored for all AEs/SAEs/AESIs during study participation and until 28 days after the last 
dose of rucaparib. After the 28-day window, only treatment-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 (Version 4.03 or later) and recorded on the eCRF. 
Complete details for monitoring AEs, including the definition of drug-related AEs, are 
provided in Section 8. 
7.6.4.2 
Clinical Laboratory Investigations 
Samples for hematology, serum chemistry, urinalysis, and pregnancy, will be analyzed by a 
local laboratory. The panels of laboratory tests to be performed are shown below: 
Hematology: red blood cell (RBC) count and parameters (hemoglobin, hematocrit, mean 
corpuscular volume [MCV], mean corpuscular hemoglobin [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 at screening, during 
treatment at each study visit, at the End of Treatment Visit, and 28-day Follow-up Visit for 
all patients. Hematology results must be reviewed by the investigator before the start of 
treatment with rucaparib and ongoing at times testing occurs. Additional and more frequent 
tests may be performed at the investigator’s discretion. 
Serum Chemistry: total protein, albumin, CrCL or eGFR using the Cockcroft-Gault formula 
or institutional standard formula, blood urea nitrogen (BUN) or urea, total bilirubin, alkaline 
phosphatase (ALP), ALT, AST, lactate dehydrogenase (LDH), glucose, sodium, potassium, 
chloride, carbon dioxide (CO2), calcium, phosphorus, and total cholesterol, at screening, 
during treatment at each study visit, at the End of Treatment Visit, and 28-day Follow-up 
Visit for all patients. Fasting is not required before blood sampling. Serum chemistry results 
must be reviewed by the investigator before the start of treatment with rucaparib and ongoing 
at times testing occurs. Additional and more frequent tests may be performed at the 
investigator’s discretion. 
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, and 28-day Follow-up Visit for all patients, but may be conducted at other 
times as clinically indicated. 


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Serum Pregnancy: for women of childbearing potential only. A serum pregnancy test must 
be performed ≤ 3 days prior to first dose of rucaparib (a negative result is required before 
dosing can begin) and at the End of Treatment Visit. A serum pregnancy test must be 
performed ≤ 3 days prior to Day 1 of every cycle during the Treatment Phase. A positive 
serum pregnancy test during study participation must be reported to the sponsor. Refer to 
Section 8.6 for details.  
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 will be documented on the eCRF as an AE. Refer 
to Section 8.5 for guidelines on reporting of abnormal laboratory values as AEs. 
7.6.4.3 
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, at the End of Treatment Visit, and the 28-day Follow-up Visit. 
7.6.4.4 
12-Lead Electrocardiogram 
For all patients, 12-lead ECGs will be performed at the following times: 
• Screening (within 28 days prior to enrollment) 
• End of Treatment Visit 
The following will be measured or calculated: heart rate, PR, QRS, QT, 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.  
7.6.4.5 
Body Weight and Height 
Height will be measured during the screening visit only. Weight will be measured per 
institutional guidelines during screening, during treatment at each study visit, at the End of 
Treatment Visit, and at the 28-day Follow-up visit. 
7.6.4.6 
Physical Examinations 
Physical examinations will include an assessment of all the major body systems. Complete 
physical examinations will be performed during screening and at treatment discontinuation. 
Physical examinations at study visits during the Treatment Phase and 28-day Follow-up Visit 
will be limited as appropriate.  
7.6.4.7 
ECOG Performance Status 
ECOG performance status (Appendix 2) will be assessed during screening, at study visits 
during the Treatment Phase, at the End of Treatment Visit, and at the 28-day Follow-up Visit. 


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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. 
7.6.5 
Biomarker Analysis – Tumor Tissue 
7.6.5.1 
Biomarker Analysis – Mandatory Tumor Tissue Collection 
Submission of pre-treatment tumor tissue is mandatory, and defined as a biopsy or surgical 
specimen obtained prior to the first dose of rucaparib from a primary or metastatic soft tissue 
tumor lesion that has not been previously irradiated. Ascites is not an acceptable specimen 
for the tumor tissue requirement. If tumor tissue was collected within 6 months of the first 
dose of rucaparib and no intervening anti-cancer treatments were administered during this 
period, this tissue may be submitted for the pre-treatment tumor tissue requirement. The 
tumor tissue should be of adequate quality for molecular profiling and be provided in the 
form of an FFPE block or unstained slides (see Pathology Charter). The required pre-
treatment tumor tissue should be submitted to the sponsor’s laboratory by Cycle 2 Day 1 of 
study treatment, and an associated pathology report should accompany each tumor sample 
specimen. 
The submitted tumor samples will undergo central HRD testing in order to assess each 
participant’s HRD tumor status by NGS molecular profiling. If an actionable mutation, as 
defined by the American College of Medical Genetics and Genomics 
(https://www.ncbi.nlm.nih.gov/clinvar/docs/acmg/), is detected from this testing, the finding 
will be made available to the investigator provided the results are generated from a CLIA-
certified laboratory and the patient has consented to receive the results. 
Additional genomic, transcriptional, or epigenetics assays may also be performed on 
available specimens to understand the genomics of bladder cancer, as well as molecular 
factors driving the response and resistance to rucaparib.  
7.6.5.2 
Biomarker Analysis –Archival Biopsy 
Archival FFPE tumor tissue must be submitted if available. There is no age limit to these 
samples. If available, a pathology report should be included with the specimen. Sample 
details will be provided in the Pathology Charter. 
These samples will be used for molecular profiling to understand the genomics of bladder 
cancer, as well as the evolution and impact of intervening therapies on molecular drivers of 
rucaparib sensitivity. 
7.6.5.3 
Biomarker Analysis – Optional Biopsy after progression 
End of treatment and/or upon progression tumor biopsies are not mandatory, but their 
collection is strongly encouraged, and will be used for molecular profiling to determine 
potential mechanisms of resistance to rucaparib. Patients must provide additional consent for 
the optional tumor tissue biopsy sample. New lesions or lesions that are growing should be 


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prioritized for the optional biopsy. If possible, collect the lesion responsible for progression. 
Sample collection details will be provided in the Pathology Charter. 
7.6.6 
Biomarker Analysis – ctDNA from Blood 
Blood samples for plasma ctDNA will be collected during screening, before dosing on Day 1 
of Cycles 1, 2, 3, and at every 8 weeks thereafter coinciding with radiographic scans, and at 
the end of treatment discontinuation from all patients entered in the study. 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 rucaparib.  
7.6.7 
Biomarker Analysis - Genomic DNA from Blood 
A blood sample for genomic analysis will be collected at Cycle 1 Day 1 from all patients. 
Sample collection details will be provided in the Laboratory Manual. 
Genomic DNA may be purified and tested to determine whether any mutations identified 
from NGS tissue testing are of germline origin. Because the germline analysis will be done 
near the end of the study, there are no plans to share these results with the investigator and 
the patient. However, if an actionable mutation, as defined by the American College of 
Medical Genetics and Genomics (https://www.ncbi.nlm.nih.gov/clinvar/docs/acmg/), is 
detected, these incidental finding will be made available to the investigator provided the 
results are generated from a CLIA-certified laboratory and the patient has consented to 
receive the results.  
7.6.8 
 Pharmacokinetics Evaluation 
Plasma samples are to be collected for trough level PK analysis of rucaparib 1 hour before 
the morning dose on Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 4 Day 1. If the start of the 
next dose is postponed or suspended, the PK sample should be collected as close as possible 
to 12 hours after the previous dose. Refer to the Laboratory Manual for sample collection 
details for PK samples.  


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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, not on the physical examination eCRF, which is reserved for physical signs or 
findings). 
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 rucaparib through 28 days after last dose) 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 1 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 Event 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 trial 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 8.9 for reporting instructions).  
8.4 
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: 
• Preplanned 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 rucaparib or concomitant medication unless the event meets SAE 
criteria (eg, hospitalization). 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/SAE. 
• Events that meet the SAE criteria (as outlined in Section 8.2) and occur after informed 
consent, but before the first dose of rucaparib, which are considered unrelated to 
screening procedures. 
8.5 
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 lab 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 1 of the following criteria is met: 
• an action on rucaparib treatment 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 


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8.6 
Pregnancy or Drug Exposure during Pregnancy 
If a patient becomes pregnant during the course of the study, rucaparib dosing should be held 
immediately. 
Pregnancy is not considered to be an AE or SAE; however, all pregnancies occurring during 
study participation or within 6 months of last dosing must be reported to the sponsor using 
the Pregnancy Report Form within the same timelines as for an SAE. 
All pregnancies should be followed through to outcome. Once the outcome of a pregnancy is 
known, the Pregnancy Outcome Report Form should be completed and submitted to the 
sponsor. 
AEs, SAEs, or AESIs that occur during pregnancy will be assessed and processed according 
to the AE or SAE/ AESI processes using the appropriate AE or SAE/ AESI forms.  
8.7 
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 rucaparib, unless 
due to a protocol-mandated procedure, will be recorded on the Medical History eCRF. Any 
event related to a protocol-mandated procedure should be reported during the screening 
period. Any AE that occurs after first dose of rucaparib through 28 days after receiving the 
last dose of rucaparib will be recorded on the AE eCRF. After the 28-day reporting window 
after discontinuation of rucaparib treatment, only SAEs assessed as related to rucaparib and 
all AESIs, irrespective of causality, need to be reported. Information on the follow-up of 
AEs, SAEs, and AESIs is provided in Section 8.8.  
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. 
Each AE is to be evaluated for causal relationship, severity, and seriousness to the 
investigational drug. 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 
rucaparib, whether or not related to rucaparib, 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.  
8.7.1 
Onset Date of Adverse Events 
The onset date is the date that the event or the signs or symptoms related to the event started. 


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8.7.2 
Resolution Date of Adverse Events 
The resolution date is the date that the events 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. 
8.7.3 
Intensity of Adverse Events 
The severity of each AE will be graded using the NCI CTCAE, Version 4.03 or later grading 
scale (https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).43  
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 those events that led to the patient’s death  
8.7.4 
Causal Relationship of Adverse Events to Rucaparib 
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, and de-challenge or re-challenge with rucaparib.  
Table 6. 
Causal Relationship of Adverse Events to Rucaparib 
Causality 
Description 
Not Related 
to 
Rucaparib 
• 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 
rucaparib  
• It does not follow a known pattern of response to rucaparib  
• It does not reappear or worsen when rucaparib is restarted 
• An alternative explanation is likely, but not clearly identifiable 


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Table 6. 
Causal Relationship of Adverse Events to Rucaparib 
Causality 
Description 
Related to 
Rucaparib  
• An AE that is difficult to assign to alternative causes 
• It follows a strong or reasonable temporal sequence from administration 
of rucaparib 
• 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 rucaparib 
• It is confirmed with a positive re-challenge or supporting laboratory data 
 
8.7.5 
Outcome and Action Taken 
The investigator will record the action taken and outcome for each AE according to the 
following criteria: 
Action Taken with Study Drug (note all that apply) 
• None 
• Dose reduced/delayed 
• Study drug temporarily interrupted 
• Study drug permanently discontinued 
• Other (specify) 
Outcome 
• Recovered 
• Recovered with sequelae 
• Recovering/ Resolving/ Improving 
• Ongoing 
• Death 
• Lost to follow-up 
8.8 
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 
rucaparib. Any SAEs, AESIs, and treatment-related Grade 3/4 AEs must be followed until 


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resolution or stabilization, death, or until lost to follow-up. After the 28-day window, 
treatment-related SAEs and all AESIs, irrespective of causality, need to be reported.  
8.9 
Regulatory Aspects of Serious Adverse Event and Adverse Events 
of Special Interest Reporting 
All SAEs and AESIs, regardless of relationship to rucaparib, must be reported to the sponsor/ 
SAE designee within 24 hours of knowledge of the event, during the study through 28 days 
after receiving the last dose of study treatment, according to the procedures below. After the 
28‑day specified window, only SAEs considered to be treatment‑related and all AESIs, 
regardless of treatment relationship, should be reported. It is important that the investigator 
provide an assessment of relationship of the SAE or AESI to study treatment at the time of 
the initial report. The Serious Adverse Event (SAE)/ Adverse Events of Special Interest 
(AESI) Report Form must be used for reporting SAEs and AESIs. The contact information 
for reporting of SAEs and AESIs can be found on the SAE/ AESI Reporting Form and 
Pregnancy Report 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 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. 


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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
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, the 25th, 50th (median), and 75th percentiles 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 rucaparib administration.  
All statistical analyses will be conducted with the SAS® System, Version 9.3 or higher. 
Further details regarding the statistical analyses planned in this study will be outlined in the 
SAP.  
9.2 
Analysis Populations  
The following analysis populations are defined for the study: 
Safety Population – The safety population will include all patients who received at least 
1 dose of rucaparib. 
Intent-to-treat Population (ITT) – The ITT population will include all patients who 
received at least 1 dose of rucaparib. 
HRD-positive Population – Tumor tissue will be analyzed to determine the percentage of 
genomic LOH,31 and patients will be classified as HRD-positive or HRD-negative based on a 
prespecified LOH cut-off defined in the SAP. The HRD-positive population will include all 
patients who received at least 1 dose of rucaparib and are classified as HRD-positive.  
9.3 
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 will be summarized. 
9.4 
Demographics and Baseline Characteristics 
Demographic (eg, age, race, and ethnicity as allowed by local regulations) and key baseline 
characteristics will be summarized for the safety and ITT populations. 


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9.5 
Efficacy Analyses 
All efficacy analyses will be conducted using the ITT and HRD-positive populations. 
9.5.1 
Primary Efficacy Analyses 
The primary efficacy endpoint of ORR is defined as a best confirmed response of CR or PR 
by RECIST v1.1 (Appendix 1) as assessed by the investigator. The ORR will be summarized 
with frequencies and percentages for the ITT and HRD-positive populations as well as other 
HRD subgroups. 
9.5.2 
Secondary Efficacy Analyses 
9.5.2.1 
Duration of Response 
Duration of confirmed response is defined as the time from the date that a response is first 
reported to the time that progression is first documented after the confirmed response. 
9.5.2.2 
Progression-free Survival 
Progression-free survival (PFS) will be calculated as 1+ the number of days from the first 
dose of rucaparib to disease progression or death due to any cause, whichever occurs first. 
Patients without a documented event of progression will be censored on the date of their last 
adequate tumor assessment (ie, radiologic assessment) or date of first dose of rucaparib if no 
post-baseline tumor assessments have been performed. 
9.5.2.3 
Overall Survival 
Overall survival (OS) is defined as the date from first dose of rucaparib to the date of death 
due to any cause. Patients who have not died will be censored at the date last known to be 
alive. 
9.5.3 
Exploratory Efficacy Analyses 
9.5.3.1 
Evaluation of Biomarkers of Response to Rucaparib 
Next-generation sequencing (NGS) will be performed to measure defects in HRR genes and 
determine their correlation with response. Genomic alterations that may be assessed include 
deleterious mono- and bi- allelic variants in genes of the HRR pathway, genome-wide LOH, 
telomeric allelic imbalance (TAI), large-scale state transitions (LST), and tumor mutational 
burden. Patients will be classified based on the presence or absence of these markers of 
HRD, and possible associations of these biomarkers with response to rucaparib will be 
explored. 
9.5.3.2 
Evaluation of Circulating Tumor DNA as a Molecular Marker of Response 
Pairwise comparisons will be performed for HRR genotyping results between centrally-
assessed screening biopsy tissue, archival primary tissue (where available), and plasma 
ctDNA in all combinations. In particular, the concordance of genotyping results between 


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archival primary tissue and screening biopsy tissue will be assessed to explore whether the 
HRD status of the archival primary specimen accurately reflects that found in a screening 
tissue biopsy. Additionally, the sensitivity and specificity of plasma HRD assessment relative 
to the tissue results will be explored.   
9.6 
Pharmacokinetic Analyses 
In all patients with at least 1 PK sample collected, the trough plasma rucaparib PK data (Cmin) 
and summary statistics (N, mean, StD, minimum, median, maximum, coefficient of variation 
[CV]%]) will be reported.  
9.6.1 
Exploratory Population Pharmacokinetics and Exposure-Response 
Analyses 
The PK data and selected safety and efficacy endpoints will be included in exploratory 
population PK and exposure-response analyses, and the results will be reported separately. 
9.7 
Safety Analyses 
Safety endpoints include incidence of AEs, clinical laboratory abnormalities, and dose 
modifications. 
Data from all patients in the safety population will be included in the safety analyses. AEs, 
clinical laboratory results, vital signs, ECG results, ECOG performance status, body weight, 
and concomitant medications/ procedures will be tabulated and summarized. 
9.7.1 
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 Version 4.03 or later. Only treatment-emergent adverse events (TEAEs) 
will be collected: TEAEs are defined as AEs with onset date on or after the date of first dose 
of rucaparib until the date of the last rucaparib dose plus 28 days.  
The number and percentage of patients who experienced TEAEs for each System Organ 
Class (SOC) and Preferred Term (PT) will be presented. Multiple instances of the TEAE in 
each SOC and multiple occurrences of the same PT are counted only once per patient. The 
number and percentage of patients with at least 1 TEAE will also be summarized.  
Separate tables will be presented as follows: 
• All TEAEs; 
• TEAEs by CTCAE grade; 
• Grade 3 or higher TEAEs; 
• Treatment-related TEAEs; 
• Serious TEAEs; 


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• TEAEs with an outcome of death; 
• TEAEs leading to discontinuation of study medication; 
• TEAEs resulting in interruption/delay of study medication; and 
• TEAEs resulting in dose reduction of study medication. 
The incidence of TEAEs will be summarized by relationship to rucaparib 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.  
9.7.2 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations include the continuous variables for hematology, serum 
chemistry, and urinalysis. The laboratory values will generally be presented in International 
System of Units (SI) units. The on-treatment period will be defined as the time from the first 
dose of rucaparib to 28 days after the last dose of rucaparib. 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 4 criteria according to CTCAE). 
9.7.3 
Vital Sign Measurements 
The on-treatment period will be defined as the time from the first dose of rucaparib to 
28 days after the last dose of rucaparib. 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. 


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9.8 
Exploratory Biomarker Analysis 
9.8.1 
Evaluation of Changes in Tumor Samples and Changes in Circulating 
Cell-free Tumor DNA 
Molecular profiling of ctDNA will be performed to assess changes over time that may be 
associated with response and resistance to rucaparib. The analysis will include, but not be 
limited to, allele frequencies and emergence of HRR gene mutations and alterations in other 
components of DNA repair and oncogenic signaling pathways.  
Analyses may be performed on a subset of patients if it becomes clear that the analysis will 
have limited scientific value in some patients (eg, because of very low titer of ctDNA from 
plasma or low tumor cellularity in tumor samples), or if there are not enough serially 
collected blood samples from individual patients to allow for adequate biomarker evaluation. 
9.8.2 
Evaluation of Biomarkers of Resistance to Rucaparib 
Changes in the molecular profile over time of matched pairs of archival, pre- and post-
treatment tumor tissue (if available), and plasma will be evaluated and associations with 
resistance to rucaparib will be explored. Analysis of ctDNA from serially collected blood 
will be performed to assess early changes in ctDNA that may associate with the emergence 
of mechanisms of resistance. The analysis will include, but not be limited to, reversion 
mutations in HRR genes that restore wild-type function and alterations in other components 
of DNA repair and oncogenic signaling pathways. 
9.9 
Sample Size Considerations 
The overall sample size was determined by considering the number of patients needed for 
adequate safety and activity assessment of HRD-positive patients. Based on the estimated 
prevalence of 60% HRD-positive patients in this population, approximately 200 patients will 
be enrolled into the study. This would result in enrollment of approximately 120 
HRD-positive patients. The overall sample size will enable robust estimates of response for 
the ITT population as well as allow for an exploration to define the optimal HRD signature 
that correlates with response to rucaparib. The null hypothesis for response rate based on 
historical data in similar patient populations is p=0.10. With a total sample size of 
200 patients, the study has greater than 90% power to reject the null hypothesis at a 5% 
significance level if the true response rate for rucaparib is 20%.   
9.10 Interim Analysis 
A group sequential interim monitoring plan will be implemented in order to help guide the 
DMC in monitoring the study. The null hypothesis is p=0.10 based on historical data in 
similar patient populations. The study has greater than 90% power to reject the null 
hypothesis at a 5% significance level if the true response rate for rucaparib is 20%.  
Interim analyses will be performed when approximately 60 patients and 120 patients have 
complete data, defined as a documented response (PR or CR), disease progression, or at least 
4 months of disease assessment data available.  


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If the response rate does not meet continuance criteria for the ITT population, the DMC will 
further evaluate the benefit: risk for study treatment, both overall and separately for patients 
in different HRD subgroups, and make a recommendation whether further enrollment into 1 
or all groups should be discontinued. 
Additional details regarding this group sequential interim monitoring plan are provided in 
Appendix 4. 


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10 PATIENT DISPOSITION 
10.1 Removal of Patients from the Study or Study Drug 
A patient must be discontinued from protocol prescribed therapy if any of the following 
apply: 
• Consent withdrawal for any reason at the patient’s own request or at the request of their 
legally authorized representative (where acceptable according to national law and/or local 
regulations); 
• Radiographic progression of patient’s underlying cancer per RECIST v1.1 (unless, in the 
opinion of the investigator, the patient continues to derive clinical benefit; treatment 
beyond progression is permitted with additional consent); 
• Unequivocal clinical progression of the patient’s underlying cancer that, in the opinion of 
the investigator, requires immediate change in systemic anti-cancer therapy, or results in 
marked deterioration in ECOG performance status to Grade 3 or higher 
• 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; or 
• Noncompliance by the patient with protocol mandated procedures. 
Discontinuation of treatment does not necessarily indicate study discontinuation for a patient. 
Samples collected for research will continue to be used unless the patient explicitly 
withdraws consent for their use. If the patient withdraws consent to continue in the study or 
discontinues the study for another reason it will be documented on the appropriate eCRF. A 
patient may withdraw consent to participate in an additional part of a study that has an 
additional consent (ie, optional tumor biopsy) yet continue to participate and be 
treated/ followed in the main part of the study.  
The sponsor may discontinue the study early for any of the reasons noted in Section 11.7. 


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11 STUDY ADMINISTRATION 
11.1 Regulatory and Ethical Considerations 
This study will be conducted in compliance with the protocol; Good Clinical Practices 
(GCPs), including International Conference on Harmonisation (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 (21CRF50) 
and applicable local requirements. 
11.1.1 
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. 
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 are processed. The trial will be registered on 
www.clinicaltrials.gov, EudraCT, and other applicable trial registry systems as appropriate. 
11.1.2 
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 
Informed Consent Form (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.  
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.  


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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.  
11.2 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 
Good Clinical Practice (GCP) guidelines and the Declaration of Helsinki. 
It is the responsibility of the investigator to obtain signed ICFs from each patient 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and prior to undertaking any study-related procedures.  
The 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.  
The patient will have the option to provide additional consent to allow or not allow the 
sponsor to retain residual samples for future unspecified research. 
11.3 Patient Confidentiality 
The investigator must assure that patients’ anonymity is strictly maintained and that their 
identities are protected from unauthorized parties. Only patient identifiers such as year of 
birth, and an identification code (ie, not names) should be recorded on any form submitted to 
the sponsor and the IRB/ IEC. The investigator must record all screened and enrolled 
patients. Enrolled patients will be recorded 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 Investigator’s Brochure (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 study and thereafter. This information is not 
to be disclosed to any third party (except employees or agents directly involved in the 


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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. 
11.4 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 may be waived) and at appropriate intervals during the study until after the last patient is 
completed. The monitor will also perform a study closure visit. Visits may also be conducted 
by sponsor personnel.  
In accordance with ICH GCP guidelines, the investigator must ensure provision of sufficient 
time, reasonable space, and adequate qualified personnel for the monitoring visits. The visits 
are for the purpose of verifying adherence to the study protocol and the completeness, 
consistency, and accuracy of data entered on the eCRF and other documents.  
The investigator will make all source data (ie, the various study records, 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 and review). 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.  
11.5 Case Report Forms and Study Data 
Data collection is the responsibility of the clinical trial staff at the site under the supervision 
of the site investigator. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.   
Data recorded in the eCRF derived from source documents should be consistent with the data 
recorded on the source documents.  
Clinical data (including adverse events [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 


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appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
source documents. 
11.6 Data Monitoring Committee 
A DMC will be established to review safety data in compliance with a prospective charter. 
The DMC will comprise coordinating investigators and sponsor representatives. The DMC 
responsibilities, authorities, 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 also ensure the study is beneficial to patients 
(see Section 9.10). 
The DMC will meet after the first 20 patients received rucaparib for at least 28 days or 
discontinued study treatment, and then approximately every 6 months after sufficient data 
have been collected. Safety and efficacy will be assessed by the DMC at the interim analyses 
at 60 and 120 patients. The DMC chairperson or sponsor may convene an unscheduled DMC 
meeting if there are newly identified significant safety concerns. Following data review, the 
DMC will recommend continuation, revision, or termination of the study and/or continuing 
or halting enrollment into a particular subgroup. Details regarding the DMC will be in the 
committee charter.  
11.7 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. 
If the trial 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). 
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 discontinues the development of rucaparib. 


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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.  
11.8 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. 
11.9 Retention of Data 
The study site will maintain a study file, which should contain, at minimum, the IB, the 
protocol and any amendments, drug accountability records, correspondence with the 
IEC/IRB and the sponsor, and other study-related documents. The investigator should have 
control of all essential documents generated by the site. Source documents must be 
maintained, ALCOAC (attributable, legible, contemporaneous/complete, original, accurate) 
used. Any changes to source data should be traceable. 
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 trial-related records are no longer needed.  
Patients’ medical records and other original data will be archived in accordance with the 
archiving regulations or facilities of the investigational site. 


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11.10 Quality Control and Assurance 
The sponsor will implement and maintain quality control and quality assurance procedures 
with written standard operating procedures (SOPs) that take a risk-based approach to ensure 
that the study is conducted and data are generated, documented, and reported in compliance 
with the protocol, GCP, and applicable regulatory requirements.  
11.10.1 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 subject 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 
having been approved by an appropriate IRB/IEC.  
11.10.2 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, onsite 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 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. 
11.10.3 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 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 SOPs and 
applicable laws, rules, and regulations. 
Representatives of the FDA or other regulatory agencies, including IRB/IEC representatives 
may also conduct an audit of the study. If informed of such an inspection, the investigator 
should notify the sponsor immediately. The investigator will ensure that the auditors have 


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access to the clinical supplies, study site facilities, and laboratory, and that all data (including 
original source documentation) and all study files are available, if requested. 
11.11 Clinical Study Report 
A clinical study report will be prepared under the responsibility and supervision of the 
sponsor and signed by the sponsor’s chief medical officer, thereby indicating their agreement 
with the analyses, results, and conclusions of the clinical study report.  
11.12 Publication and Disclosure Policy 
All data generated from this study are the property of the sponsor and shall be held in strict 
confidence along with all information furnished by the sponsor. 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. Written permission to the investigator will 
be contingent on the review by the sponsor of the statistical analysis and manuscript, and will 
provide for nondisclosure of the sponsor’s 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.  
11.13 Investigator Oversight 
The investigator has a responsibility for supervising all delegated staff. 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 and data generated.   


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40. Friedenson B. The BRCA1/2 pathway prevents hematologic cancers in addition to breast 
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13 APPENDICES 
Appendix 1 
Response Evaluation Criteria in Solid Tumors Criteria 
Appendix 2 
Eastern Cooperative Oncology Group (ECOG) Performance Status Scale 
Appendix 3 
Examples of Sensitive Clinical Cytochrome P450 (CYP) Substrates  
Appendix 4 
Group Sequential Interim Monitoring Plan 


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Appendix 1 
Response Evaluation Criteria in Solid Tumors Criteria 
The RECIST guidelines (Version 1.1) are described in Eisenhauer (2009)44 and at 
http://www.eortc.be/Recist/Default.htm. A short summary is given below. 
Measurable Disease: 
Tumor lesions: measurable lesions are defined as those that can be accurately measured in at 
least 1 dimension (longest diameter to be recorded) with the following: 
• A minimum size of 10 mm by CT scan (CT scan thickness no greater than 5 mm). 
• A minimum size of 10 mm caliper measurement by clinical exam (lesions that cannot be 
accurately measured with calipers should be recorded as nonmeasurable). 
• A minimum size of 20 mm by chest X-ray. 
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
Malignant lymph nodes: to be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be not greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.  
Nonmeasurable Disease: 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis), as well as truly nonmeasurable 
lesions, are considered nonmeasurable disease. Lesions considered truly nonmeasurable 
include leptomeningeal disease, ascites, pleural/pericardial effusions, inflammatory breast 
disease, lymphangitic involvement of skin and lung, and abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible imaging 
techniques.  
Bone Lesions 
Bone lesions, cystic lesion, and lesions previously treated with local therapy require 
particular comment. Bone scan, PET scan, or plain films are not considered adequate 
imaging techniques to measure bone lesions. However, these techniques can be used to 
confirm the presence or disappearance of bone lesions. 
Lytic bone lesions or mixed lytic–blastic lesions with identifiable soft tissue components that 
can be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above. 
Blastic bone lesions are nonmeasurable. 


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Cystic Lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) because they are, by 
definition, simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered as measurable lesions 
if they meet the definition of measurability described above. However, if noncystic lesions 
are present in the same patient, these are preferred as target lesions. 
Lesions with Prior Local Treatment 
Tumor lesions situated in a previous irradiated area or in an area subjected to other 
locoregional therapy are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
Target Lesions 
All measurable lesions up to a maximum of 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 criteria require unequivocal quantification of the changes in tumor size for adequate 
interpretation of the sum of target lesions. Consequently, when the boundaries of the primary 
are difficult to delineate, this tumor should not be considered a target lesion. 
Guidelines for Evaluation of Measurable Disease 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the antitumor effect of a treatment. 


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Evaluation of Target Lesions 
Complete Response 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or nontarget) must have reduction in 
short axis to < 10 mm. 
Partial Response 
At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD. 
Stable Disease 
Neither sufficient shrinkage to qualify for partial response nor 
sufficient increase to qualify for PD, taking as reference the 
smallest sum LD since the treatment started. 
Progressive Disease 
At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum on study (this includes 
the baseline sum if that is the smallest on study). In addition to 
the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. The appearance of one 
or more new lesions is also considered progression. 
Abbreviations: LD = longest diameter; PD = progressive disease. 
 
Evaluation of Nontarget Lesions 
Complete Response 
Disappearance of all nontarget lesions and normalization of 
tumor marker level. 
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 
Appearance of 1 or more new lesions and/or unequivocal 
progression of existing nontarget lesions. 
If tumor markers are initially above the institutional ULN, they must normalize for a patient 
to be considered a complete responder.  
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). The patient’s best response assignment will depend on 
the achievement of both measurement and confirmation criteria.  


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Evaluation of Best Overall Response 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not 
evaluated 
No 
PR 
SD 
Non-PD or not 
evaluated 
No 
SD 
Not Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = 
complete response 
NE = 
not evaluable. 
PD = 
progressive disease 
PR 
= 
partial response 
SD = 
stable disease 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
symptomatic deterioration. Every effort should be made to document the objective 
progression, even after discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends on this determination, it is recommended that the 
residual lesion be investigated (fine needle aspiration/biopsy) prior to confirming the 
complete response status. 
Confirmatory Measurement/Duration of Response 
Confirmation 
If a complete response (CR) or partial response (PR) is noted, confirmatory scans should be 
performed at least 4 weeks after response was first documented. 
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). 


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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 
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 
Eastern Cooperative Oncology Group (ECOG) 
Performance Status Scale 
ECOG Performance Status 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature (eg, light house work or office work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
5 
Dead. 
In the event performance status is assessed by the Karnofsky Performance Status scale, the 
following conversion chart applies. 
Karnofsky Performance Status 
ECOG 
Performance 
Status 
General 
Description 
Score 
Specific Description 
Score 
Able to carry on 
normal activity and 
to work; no special 
care needed 
100 
Normal; no complaints; no evidence of 
disease 
0 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease 
1 
80 
Normal activity with effort; some signs 
or symptoms of disease 
Unable to work; 
able to live at home 
and care for most 
personal needs; 
varying amount of 
assistance needed 
70 
Cares for self, unable to carry on 
normal activity or to do active work 
2 
60 
Requires occasional assistance, but is 
able to care for most of personal needs 
50 
Requires considerable assistance and 
frequent medical care 
3 
Unable to care for 
self; requires 
equivalent of 
institutional or 
hospital care; 
disease may be 
progressing rapidly 
40 
Disabled; requires special care and 
assistance 
30 
Severely disabled; hospital admission is 
indicated although death not imminent 
4 
20 
Very sick; hospital admission 
necessary; active supportive treatment 
necessary 
10 
Moribund; fatal processes progressing 
rapidly 
0 
Dead 
5 


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Appendix 3 
Examples of Sensitive Clinical Cytochrome P450 (CYP) 
Substrates  
CYP Enzyme 
Sensitive Substratesa 
CYP1A2 
alosetron, caffeine, duloxetine, melatonin, ramelteon, tasimelteon, 
theophylline, tizanidine 
CYP2C9 
celecoxib 
CYP2C19 
S-mephenytoin, omeprazole 
CYP3A 
alfentanil, avanafil, buspirone, conivaptan, darifenacin, darunavir, 
ebastine, everolimus, ibrutinib, lomitapide, lovastatin, midazolam, 
naloxegol, nisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, 
tipranavir, triazolam, vardenafil, budesonide, dasatinib, dronedarone, 
eletriptan, eplerenone, felodipine, indinavir, lurasidone, maraviroc, 
quetiapine, sildenafil, ticagrelor, tolvaptan 
a Sensitive substrates are drugs that demonstrate an increase in AUC of ≥5-fold with strong index inhibitors 
of a given metabolic pathway in clinical DDI studies. 
Source: Draft FDA Guidance on Clinical Drug Interaction Studies - Study Design, Data Analysis, and 
Clinical Implications, 2017.45 More example drugs can be found at the FDA’s website: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin
g/ucm093664.htm#table3-1 
 
 
 


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Appendix 4 
Group Sequential Interim Monitoring Plan 
Introduction 
This plan describes an adaptive study design for the evaluation of rucaparib in patients with 
locally advanced or metastatic urothelial carcinoma. The adaptive design utilizes interim 
analyses that allow for early stopping for futility after DMC review of futility analysis of the 
ITT population, the efficacy for HRD subgroups and all safety analyses. 
The trial will enroll 60-200 subjects in a single experimental arm. 
Objective response rate by RECIST v1.1 as assessed by the investigator will be summarized 
for the ITT and HRD-positive populations as well as for the exploratory HRD groups. 
Primary Analysis 
Let p be the true response rate. The primary analysis compares p to a performance goal of 
0.10, and is thus a hypothesis test of 
H0 : p ≤ 0.10        H1 : p>0.10 
Starting with a noninformative Beta(0.1,0.9) prior on p, the posterior distribution is  
p|data~Beta(0.1+Y, 0.9+N-Y) 
where Y is the observed number of responses and N is the number of complete subjects in 
the trial. The trial is a success if 
Pr(p > 0.10 | data) > 0.95 
This threshold maintains type I error at 5%. We consider an alternative threshold (0.935) that 
increases type I error slightly but obtains greater power for comparison. 
Design 
The trial sequentially enrolls patients and interim analyses are conducted. At the time of each 
interim analysis, there will be N patients with a 4-month endpoint and M patients that are 
incomplete. Let Y be the number of responders among the complete patients. 
The model computes pmax, the predictive probability of trial success if the trial is followed to 
the maximum (targeted) sample size and all patients are followed to completion. Let Wmax be 
the number of eventual responders among the unknown patients (incomplete and currently 
unenrolled). The distribution of Wmax is a BetaBinomial(MAXN-N,0.1+Y,0.9+N-Y). The 
predictive probability pmax is the probability Wmax results in trial success when N=200 
subjects are complete. 
The model indicates trial futility at any interim analysis if pmax<threshold, indicating that 
there is limited probability that the trial will reach success even at the maximum sample size.  


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For this study design with N=60 minimum, N=200 maximum, a 5% futility threshold, and 
interims at N=60 and N=120, the required number of successes to continue is summarized in 
the table below. For example, in the first row we require 5/60, indicating we must have at 
least 5 successes out of the first 60 patients (so 5 would continue). 
Interim 
Minimum to Continue  
(5% predictive probability) 
1 (N=60) 
5/60 (8.3%) 
2 (N=120) 
13/120 (10.8%) 
 
Example Trials 
Example trial 1 
The trial enrolls until the first interim analysis at N=60 ITT patients complete. At this 
interim, we have 13/60 (21.7%) responses with 40 patients awaiting follow-up. This result is 
clearly encouraging compared to a 10% baseline rate. With 140 patients still requiring data, 
the predictive probability of success on the ITT population is 97.5%, well above the 
threshold for futility. Response among HRD subgroups is evaluated and the trial continues. 
The second interim analysis occurs with N=120 ITT patients complete, obtaining 22/120 
(18.3%) with 27 incomplete. Response among HRD subgroups is evaluated. With 80 patients 
remaining needing follow-up, the predictive probability of success is 99.0%, clearly high and 
the trial continues. 
At N=200, we obtain 37/163 responses (22.7%). This results in a posterior probability greater 
than 99.99% and a successful trial. 
Example Trial 2 
The trial enrolls until the first interim analysis at N=60 ITT patients complete. At this 
interim, we have 3/60 (5%) responses with 40 patients awaiting follow-up. The predictive 
probability of success at this point is only 0.4%. This is below the threshold for futility for 
the ITT population. The DMC would examine response among HRD subgroups as well as 
safety data and make a recommendation to stop the trial or continue. If the trial was stopped 
at this point, it is assumed that all enrolled patients will continue to be followed. 
In that follow-up, the trial ended with 12/100 responses (12%). While greater than 10%, this 
is insufficient for a successful trial (Pr(trmt beats ctrl)=56.7%) and the trial would have been 
very unlikely to meet its primary objective even had N=200 subjects been enrolled. 
Example Trial 3 
The trial enrolls until the first interim analysis at N=60 ITT patients complete. At this 
interim, we have 5/60 (8.3%) responses with 40 patients awaiting follow-up. With 140 
patients still requiring data, the predictive probability of success on ITT is 5.1%, barely 


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above the threshold for futility. Response among HRD subgroups is evaluated and the trial 
continues. 
The second interim analysis occurs with N=120 complete, obtaining 14/120 (11.7%) with 31 
incomplete. With 80 patients remaining needing follow-up, the predictive probability of 
success is 13.1%, also high enough to continue. Response among HRD subgroups is 
evaluated and the DMC recommends that the trial continue. 
At N=200, we obtain 20/200 responses (10.0%). This results in a posterior probability of 
47.5% and a nonsuccessful trial. 
Simulations and Operating Characteristics 
The operating characteristics of this trial were determined through trial simulation and 
compared to a potential Simon 2-stage design. We computed the operating characteristics 
under the assumptions that p=0.10 (null hypothesis) and p=0.11, 0.12, …, 0.25.  
A total of 10,000 trials were simulated per scenario. In each, subjects were accrued according 
to a Poisson process with an average of 1.5 subjects per week. In each simulated trial, 
interims analyses were conducted according to prespecified rules and the results were 
recorded. 
The detailed results are shown in the following tables for Expected Sample size and for 
Power, respectively. 
Expected 
Sample Size 
p=0.10 (null) 
p=0.15 
p=0.20 
p=0.25 
Fixed 
200.00 
200.00 
200.00 
200.00 
Simon 
141.52 
188.83 
204.28 
205.92 
Adjusted 
150.85 
192.38 
199.60 
199.98 
Unadjusted 
151.60 
192.67 
199.40 
199.99 
 
Pr(trial success) 
p=0.10 (null) 
p=0.15 
p=0.20 
p=0.25 
Fixed 
0.043 
0.683 
0.989 
0.999 
Simon 
0.049 
0.673 
0.977 
0.999 
Adjusted 
0.062 
0.736 
0.991 
1.000 
Unadjusted 
0.039 
0.675 
0.985 
0.999 
 
The next table shows the details of if and where each of the adjusted adaptive trial 
simulations stopped for futility. For each simulated trial, the trial could stop at N=60 
complete, N=120, or run to the maximum sample size. Note that trials that stop at N=60 or 
N=120 complete actually we enroll more than 60 or 120 subjects due to the “overrun,” 
patients enrolled while waiting for the required patient to complete. In addition, we 
summarize the probability of a “futility to success flip flop” (FSFF). In actual 


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implementation, when a trial is stopped for futility, you will not get to see what would have 
happened had you enrolled until N=200. However, in simulation we can simulate those 
remaining subjects and determine how many futility stops occurred for trials that would 
ultimately have been successful. 
Pr(trial success) 
p=0.10 (null) 
p=0.15 
p=0.20 
p=0.25 
Futility N=60 
0.270 
0.042 
0.004 
0.000 
Futility N=120 
0.331 
0.054 
0.000 
0.000 
Pr(FSFF) 
0.004 
0.022 
0.004 
0.000 
 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
ATLAS: A Phase 2, Open-label Study of Rucaparib in Patients with 
Locally Advanced or Metastatic Urothelial Carcinoma 
 
 
 
 
PROTOCOL NUMBER: 
 CO-338-085 
VERSION: 
 1 
DATE FINAL: 
 31 January 2018  
SPONSOR: 
 Clovis Oncology, Inc. 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or 
regulations. Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them. 




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TABLE OF CONTENTS 
TABLE OF CONTENTS ...........................................................................................................3 
LIST OF IN-TEXT TABLES ....................................................................................................5 
LIST OF IN-TEXT FIGURES...................................................................................................5 
LIST OF APPENDICES ............................................................................................................5 
ABBREVIATIONS AND SPECIALIST TERMS ....................................................................6 
1 
INTRODUCTION ...........................................................................................................8 
2 
OVERALL STUDY DESIGN, OBJECTIVES, AND ENDPOINTS .............................8 
2.1 
Study Design ............................................................................................................8 
2.2 
Study Objectives and Endpoints ............................................................................10 
2.3 
Sample Size Justification .......................................................................................10 
3 
GENERAL ANALYSIS CONVENTIONS ..................................................................11 
3.1 
Analysis Populations ..............................................................................................11 
3.2 
Definition of HRD Signature .................................................................................11 
4 
PATIENT DISPOSITION .............................................................................................12 
5 
PROTOCOL DEVIATIONS .........................................................................................12 
6 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ....................................12 
6.1 
Demographics ........................................................................................................12 
6.2 
Baseline Clinical Characteristics ...........................................................................12 
6.3 
Medical History .....................................................................................................13 
7 
STUDY DRUG EXPOSURE AND COMPLIANCE ...................................................13 
8 
PRIOR AND CONCOMITANT MEDICATIONS ......................................................14 
9 
EFFICACY ANALYSIS ...............................................................................................14 
9.1 
Primary Efficacy Analysis .....................................................................................14 
9.2 
Secondary Efficacy Analyses ................................................................................14 
9.2.1 
Duration of Confirmed Response ................................................................14 
9.2.2 
Progression-free Survival.............................................................................14 
9.2.3 
Overall Survival ...........................................................................................15 
9.3 
Exploratory Efficacy Analyses ..............................................................................15 
9.3.1 
Correlation of Biomarkers with Response to Rucaparib .............................15 
9.3.2 
Evaluation of Circulating Cell-free Tumor DNA as a Molecular Marker 
of Response to Rucaparib ............................................................................15 
9.3.3 
Assessment of Molecular Changes Over Time in Plasma and Tumor 
Samples ........................................................................................................16 
9.3.4 
Evaluation of Biomarkers Associated with Resistance to Rucaparib ..........16 
9.4 
Exploratory Pharmacokinetic Analyses .................................................................16 
10 
STATISTICAL / ANALYTICAL ISSUES ..................................................................16 
10.1 
Handling of Dropouts or Missing Data ..................................................................16 


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10.2 
Pooling of Centers in Multi-Center Studies ...........................................................16 
10.3 
Multiple Comparison / Multiplicity .......................................................................16 
10.4 
Examination of Subgroups .....................................................................................17 
10.5 
Interim Analyses and Data Monitoring ..................................................................17 
11 
SAFETY ANALYSIS ...................................................................................................17 
11.1 
Adverse Events ......................................................................................................17 
11.2 
Clinical Laboratory Evaluations ............................................................................18 
11.3 
Vital Signs ..............................................................................................................19 
12 
REFERENCES ..............................................................................................................20 
13 
APPENDICES ...............................................................................................................21 
 


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LIST OF IN-TEXT TABLES 
Table 1. Primary, Secondary, and Exploratory Objectives and Endpoints ...........................10 
 
 
LIST OF IN-TEXT FIGURES 
Figure 1. Study Schema ............................................................................................................9 
  
 
LIST OF APPENDICES 
Appendix 1 
Response Evaluation Criteria in Solid Tumors ............................................21 
Appendix 2 
Group Sequential Interim Monitoring Plan .................................................26 
 
 
 
 
 
 


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ABBREVIATIONS AND SPECIALIST TERMS 
AE(s) 
adverse event(s) 
ACT 
anti-cancer therapy 
ADP 
adenosine diphosphate 
ATC 
Anatomical Therapeutical Chemical (coding) 
BID 
twice daily 
BRCA 
breast cancer gene 
BRCA1 
breast cancer gene 1 
BRCA2 
breast cancer gene 2 
CI 
confidence interval  
Cmin 
trough plasma concentration 
CR 
complete response 
CrCL 
creatinine clearance 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
ct DNA 
circulating cell-free tumor DNA 
CV 
coefficient of variation 
DMC 
data monitoring committee 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of Treatment 
FMI 
Foundation Medicine, Inc. 
HRD 
homologous recombination deficiency 
HRR 
homologous recombination repair 
ICH 
International Council on Harmonisation 
invPFS 
progression-free survival, investigator-assessed 
ITT 
intent-to-treat 
LOH 
loss of heterozygosity 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NGS 
next-generation sequencing 
ORR 
objective response rate 


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OS 
overall survival 
PALB2 
partner and localizer of BRCA2 
PARP 
poly(ADP-ribose) polymerase 
PD 
progressive disease 
PFS 
progression-free survival  
PK 
pharmacokinetic(s) 
PR 
partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP  
statistical analysis plan 
SI 
International System of Units 
SNP(s) 
single-nucleotide polymorphism(s) 
StD 
standard deviation 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 


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1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical analyses and data summaries to 
be performed to assess the efficacy, safety, and pharmacokinetics (PK) of rucaparib 
(CO-338) for Clovis Oncology, Inc sponsored clinical study CO-338-085, entitled “ATLAS: 
A Phase 2, Open-label Study of Rucaparib in Patients with Locally Advanced or Metastatic 
Urothelial Carcinoma.”  
2 
OVERALL STUDY DESIGN, OBJECTIVES, AND ENDPOINTS 
2.1 
Study Design 
This clinical trial is a Phase 2 multicenter, open-label study evaluating rucaparib 600 mg 
twice daily (BID) for treatment of patients with recurrent locally advanced or metastatic 
urothelial carcinoma. This study will enroll patients with measurable disease per Response 
Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1). All patients must have 
received 1 or 2 prior standard of care treatment regimens and have radiologic progression 
during or after the most recent regimen. Patients who have received prior poly(adenosine 
diphosphate [ADP]-ribose) polymerase (PARP) inhibitor treatment will be excluded. Tumor 
tissue collected prior to rucaparib treatment will be analyzed to determine homologous 
recombination deficiency (HRD) status.  This HRD status will be utilized to classify patients 
into molecularly-defined subgroups for efficacy analyses. The criteria used to determine if a 
patient is HRD-positive has been prospectively defined in this SAP (see Section 3.2).  
The study schema is shown in Figure 1. This study consists of a Screening Phase, a 
Treatment Phase, and a Post-treatment Phase. Patients will receive rucaparib monotherapy in 
the Treatment Phase, and will undergo procedures and assessments including regular safety 
and efficacy evaluations during the entire conduct of the study. 
 
 


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Figure 1. 
Study Schema  
 
 
Screening Phase
(Day -28 to Day -1)
Treatment Phase
Post-treatment Phase
Screening 
Assessments
Within 28 days of 
first dose of 
rucaparib
Cycles 1 and 2
(28-day cycles)
Cycle 3 and subsequent cycles
(28-day cycles)
Day
1
Day
15
Day
1
Tumor Scans*
Disease progression, unacceptable toxicity, or other 
reason for discontinuation of rucaparib
EOT Visit 
After last 
dose of 
rucaparib
28-day 
Follow-up 
 28 ± 3 
days after 
last dose 
of 
rucaparib
Long-
term 
Follow-up
Disease assessments will continue for 
patients who discontinued treatment 
for reason other than PD*
All patients will be followed for 
survival and subsequent therapies 
every 12 weeks.
EOT = End of Treatment; PD = progressive disease
* Tumor scans every 8 calendar weeks (±7 days) from Cycle 1 Day 1 up to 18 months
then every 12 calendar weeks (±7 days) thereafter


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2.2 
Study Objectives and Endpoints 
Table 1. 
Primary, Secondary, and Exploratory Objectives and Endpoints 
Primary Objectives 
Primary Endpoints 
To evaluate objective response rate (ORR) in 
molecularly-defined homologous 
recombination deficiency (HRD)-positive and 
intent-to-treat (ITT) populations using a 
prospectively defined molecular signature. 
ORR per Response Evaluation Criteria 
in Solid Tumor (RECIST) Version 1.1 
(v1.1), as assessed by investigator, in 
HRD-positive and ITT populations 
Secondary Objectives 
Secondary Endpoints 
To evaluate duration of response (DOR) 
DOR per RECIST v1.1, as assessed by 
investigator 
To estimate progression-free survival (PFS) 
Disease progression according to 
RECIST v1.1, as assessed by the 
investigator, or death due to any cause 
To estimate overall survival (OS) 
OS 
To evaluate safety and tolerability of 
rucaparib 
Incidence of adverse events (AEs), 
clinical laboratory abnormalities, changes 
in ECGs and vital signs, and dose 
modifications 
To evaluate steady-state pharmacokinetics 
(PK) of rucaparib 
Trough (Cmin) level rucaparib 
concentrations 
Exploratory Objectives 
Exploratory Endpoints 
To assess biomarkers that correlate with 
response to rucaparib 
Clinical efficacy of rucaparib in 
biomarker defined cohorts  
To evaluate circulating cell-free tumor DNA 
(ctDNA) as a molecular marker of response to 
rucaparib 
Association of cancer-related mutations 
detected in baseline ctDNA samples with 
response to rucaparib  
To assess molecular changes over time in 
plasma and tumor samples 
Association of changes in cancer-related 
mutations detected in plasma and tissue 
samples over time with response to 
rucaparib 
To evaluate biomarkers associated with 
resistance to rucaparib 
Biomarkers associated with resistance to 
rucaparib  
 
2.3 
Sample Size Justification 
The overall sample size was determined by considering the number of patients needed for 
adequate safety and activity assessment of HRD-positive patients. Based on the estimated 


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prevalence of 60% HRD-positive patients in this population, approximately 200 patients will 
be enrolled into the study. This would result in enrollment of approximately 120 HRD-
positive patients. The overall sample size will enable robust estimates of clinical activity in 
the HRD-positive and ITT populations. 
3 
GENERAL ANALYSIS CONVENTIONS 
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.1,2 
Estimates of the proportion surviving across time will be plotted, and if estimable, the 50th 
(median) percentile with the corresponding 95% confidence interval (CI) will be presented. 
The number of patients with events and the number of censored patients over time will also 
be displayed.  
Baseline is defined as the last measurement on or prior to the first dose of rucaparib 
administration, unless otherwise specified.  
All statistical analyses will be conducted with the SAS® System, Version 9.3 or higher.  
3.1 Analysis Populations 
The following analysis populations are defined for the study: 
Safety Population – The safety population will include all patients who received at least 
1 dose of rucaparib. 
Intent-to-treat Population (ITT) – The ITT population will include all patients who 
received at least 1 dose of rucaparib. 
HRD-positive Population – The HRD-positive population will include all patients who 
received at least 1 dose of rucaparib and are classified as HRD-positive by the prospectively-
defined HRD signature (See Section 3.2). 
3.2 
Definition of HRD Signature 
The HRD signature for this study is defined as the percentage of genome with loss of 
heterozygosity (LOH).3 Patients whose tumors have genome-wide LOH ≥ 10% will be 
considered HRD-positive.  
A mandatory tumor specimen is required for all patients; these tissue samples will be 
analyzed by Foundation Medicine, Inc. (FMI) using a next-generation sequencing (NGS) 
assay. This assay interrogates approximately 3,500 single-nucleotide polymorphisms (SNPs) 
across the genome and detects alterations in 310 genes.4 The SNPs on this panel will be used 


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to quantify the percentage of the genome with LOH, a marker of HRD shown to be 
associated with PARP inhibitor sensitivity in patients with relapsed ovarian cancer. This 
study will assess if LOH is correlated with PARP inhibitor sensitivity in patients with 
recurrent bladder cancer. 
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 treatment discontinuation will be summarized. 
5 
PROTOCOL DEVIATIONS 
The number of patients with major protocol deviations (eg, inclusion or exclusion criteria) 
will be determined prior to data base lock and will be summarized with frequencies and 
percentages or provided in a patient listing. 
Protocol deviations will not be used to exclude any patients from the efficacy analyses. 
6 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
All demographic and baseline characteristics will be summarized for the safety, ITT, and 
HRD-positive populations. 
6.1 
Demographics 
The demographic variables will be summarized with frequency tabulations and descriptive 
statistics. The demographic variables presented will include age, height, weight, gender, race, 
and region using the following categorizations: 
• Age (years): ≤ 50, 51-60, 61-70, 71-80, 81-90, > 90; 
• Height (cm): ≤ 75, > 75-100, > 100-125, > 125-150, > 150-175, > 175; 
• Weight (kg): ≤ 50, > 50-75, > 75-100, > 100-125, > 125-150, > 150; 
• Race: American Indian or Alaska Native, Asian, Black, Native Hawaiian or Pacific 
Islander, White, Other, Not Reported 
• Region: North America, Europe/Other 
6.2 
Baseline Clinical Characteristics 
The following variables will be summarized with frequency tabulations: 
• Histology (pure urothelial and mixed) 
• De novo metastases (Y/N) 
• Eastern Cooperative Oncology Group (ECOG) performance status (0, 1) 
• Time since diagnosis of primary tumor (months) (0 to 12, > 12 to 24, > 24) 


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• Hemoglobin concentration (< 10 g/dL and ≥ 10 g/dL) 
• Creatinine Clearance (CrCL) (< 60 mL/min and ≥ 60 mL/min) 
• Metastatic sites (visceral, liver, lymph node only) 
• Number of prior anti-cancer regimens (1, 2, >2) 
• Prior platinum chemotherapy (Y/N) 
• Type of prior platinum chemotherapy (cisplatin-based, carboplatin-based) 
• Prior immune checkpoint inhibitor therapy (Y/N) 
• Prior intravesical BCG (Y/N) 
• Prior intravesical chemotherapy (Y/N) 
• Prior neoadjuvant chemotherapy (Y/N) 
• Prior adjuvant chemotherapy (Y/N) 
• Prior radiotherapy (Y/N) 
• Smoking status (current, former, never) 
• Previous cystectomy/nephrouretectomy: (Y/N) 
• Number of Bellmunt risk factors (0, 1, 2, 3) 
Descriptive statistics may also be used to summarize the continuous variables. Other baseline 
characteristic variables of interest may also be summarized if deemed appropriate. 
6.3 
Medical History 
Medical history events will be classified using the Medical Dictionary for Regulatory 
Activities (MedDRA) classification system version 20.1 or more recent. Medical history data 
will be summarized using frequency tabulations by system organ class and preferred term. 
7 
STUDY DRUG EXPOSURE AND COMPLIANCE 
The following variables will be summarized: 
• Number of cycles initiated 
• Duration of treatment (days, months) 
• Dose intensity  
• Number of dose reductions 
Duration of treatment will be calculated as 1+ the number of days from study drug start date 
to date of study drug discontinuation. Dose intensity will be calculated as the actual dose 
received divided by the assigned dose amount. Descriptive statistics and 
frequencies/percentages for appropriate categorizations will be used to summarize study drug 
exposure variables. 


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8 
PRIOR AND CONCOMITANT MEDICATIONS 
All concomitant treatments documented during the study period will be summarized in 
frequency tabulations. Prior/concomitant medication coding will utilize World Health 
Organization (WHO) Drug version 2017MAR01DDE (Enhanced). 
Separate data summaries of prior medications will be provided. Prior medications will be 
defined as those medications with both a start and a stop date that is before the day of the 
first dose of study drug administration. If either the start date and/or the stop date of the 
medication is missing so that it is unclear whether the medication was stopped prior to first 
dose of study drug administration then the medication will be included in the summary of the 
concomitant medications. 
9 
EFFICACY ANALYSIS 
Efficacy analyses will be performed using the ITT and HRD-positive populations. 
9.1 
Primary Efficacy Analysis 
The primary efficacy endpoint of ORR is defined as the proportion of patients with a 
confirmed response of complete response (CR) or partial response (PR) by RECIST v1.1 
(Appendix 1) as assessed by the investigator. The ORR will be summarized with frequencies 
and percentages. 
9.2 
Secondary Efficacy Analyses 
9.2.1 
Duration of Confirmed Response  
The duration of confirmed response is defined as the time from the date that a response is 
first documented per RECIST v1.1 by the investigator to the time that progression is first 
documented per RECIST v1.1 by the investigator, plus 1 day. 
The duration of confirmed response will be analyzed and summarized in a Kaplan-Meier 
plot. Any patient with an ongoing response at the time of data cut-off for analysis will be 
censored at the date of the last post-baseline scan. In the case of a low censoring rate, the 
duration of response may be summarized with descriptive statistics.   
9.2.2 
Progression-free Survival 
Progression-free survival (PFS) is defined as the time from first dose of rucaparib to the date 
of first objective evidence of progression documented by the investigator per RECIST v1.1 
or death due to any cause, whichever occurs first, plus 1 day. Patients without a documented 
event of progression will be censored on the date of their last adequate post-baseline tumor 
scan or date of first dose of study drug if no tumor scans have been performed. If a patient 
discontinues study drug due to something other than PD and subsequently begins another 
anti-cancer therapy (ACT) prior to a PFS, that patient will be censored at the last tumor scan 
prior to the start of ACT. However, PFS events occurring more than 90 days after 
discontinuation of study drug, but prior to start of subsequent ACT, will not be included in 


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the analysis and such patients will be censored at their last scan prior to the end of the 90-day 
window. 
PFS will be summarized in a Kaplan-Meier plot; however in the case of a low censoring rate, 
it may be summarized with descriptive statistics. 
9.2.3 
Overall Survival 
OS is defined as the date from first dose of rucaparib to the date of death due to any cause, 
plus 1 day. For patients who have not died as of the time of data cut-off for analysis, data will 
be censored at the date the patient was last known to be alive.  
OS will be summarized in a Kaplan-Meier plot; however in the case of a low censoring rate, 
it may be summarized with descriptive statistics. 
9.3 
Exploratory Efficacy Analyses 
The activity of rucaparib will be evaluated in molecularly-defined HRD subgroups as 
described below. For all exploratory efficacy analyses, ORR, PFS, and OS (as defined in 
Section 9) may be used as endpoints. However, not all endpoints and analyses may be 
performed if the subgroups become small and limit the interpretation of the results. In 
addition, not all samples may be tested if it becomes clear that the analysis will have limited 
scientific value. 
9.3.1 
Correlation of Biomarkers with Response to Rucaparib  
In addition to the pre-specified cutpoint of 10% genome-wide LOH defining the HRD-
positive population, the clinical activity of rucaparib will be evaluated in HRD-positive and 
HRD-negative groups defined by cutpoints across the range of all observed percent LOH 
values. Tumors will be analyzed by NGS to quantify the percentage of the genome with LOH 
and classified as HRD-positive and HRD-negative groups according to the LOH cutpoint. 
Outcome benefit in both groups will be evaluated. 
Tumors with a deleterious alteration in a gene involved in homologous recombination repair 
(HRR), such as BRCA1 and BRCA2, have been associated with rucaparib activity. The 
clinical activity of rucaparib in patients with a deleterious monoallelic or biallelic alteration 
in BRCA1, BRCA2, PALB2, RAD51C, and/or RAD51D, as well as other genes involved in 
homologous recombination DNA repair, will be evaluated. The activity of rucaparib in other 
biomarker-defined subgroups (e.g., microsatellite instability, tumor mutational burden, 
PD-L1 expression, gene expression profiling) may also be assessed.  
9.3.2 
Evaluation of Circulating Cell-free Tumor DNA as a Molecular Marker of 
Response to Rucaparib 
Deleterious alterations in genes of the HRR pathway will also be interrogated using ctDNA 
extracted from baseline plasma samples. The clinical activity of rucaparib will be evaluated 
in subgroups of patients with a HRR gene alteration, as well as in subgroups of patients with 
other alterations detected in the ctDNA assay.  


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9.3.3 
Assessment of Molecular Changes Over Time in Plasma and Tumor 
Samples 
Deleterious alterations in genes of the HRR pathway, and other biomarkers (eg, 
microsatellite instability, tumor mutational burden, gene expression profiling), will be 
interrogated in tumor tissue samples (when available) and ctDNA extracted from serially 
collected samples. Changes in the profiles observed in these samples will be evaluated for 
biomarkers of response to rucaparib.  
9.3.4 
Evaluation of Biomarkers Associated with Resistance to Rucaparib 
Tumor tissue (when available) and plasma collected at the time of disease progression will be 
profiled to identify potential alterations associated with resistance to rucaparib. Samples may 
be tested using genomic, transcriptional, and proteomic assays. Analysis of ctDNA from 
serially collected blood samples may be performed to identify and characterize the 
emergence of mechanisms of resistance. The analysis will include, but not be limited to, 
reversions of HRR gene alterations that restore wild-type function and alterations in other 
components of DNA repair and oncogenic signaling pathways.   
9.4 
Exploratory Pharmacokinetic Analyses 
In all patients with at least one PK sample collected, the trough plasma rucaparib PK data 
(Cmin) and summary statistics of Cmin (N, mean, StD, minimum, median, maximum, 
coefficient of variation [CV] %), and the mean (±StD) concentration versus time plot will be 
reported. The PK data and selected safety and efficacy endpoints will be included in 
exploratory population PK and exposure-response analyses, and the results will be reported 
separately. 
10 STATISTICAL / ANALYTICAL ISSUES 
10.1 Handling of Dropouts or Missing Data 
All data will be used to their maximum possible extent, but without any imputations for 
missing data. All time-to-event analyses will include censoring and the rules for deriving the 
censored values are described in more detail under each of the time-to-event endpoint 
descriptions.   
10.2 Pooling of Centers in Multi-Center Studies 
All centers will be pooled for analysis. 
10.3 Multiple Comparison / Multiplicity 
No adjustments for multiple comparisons will be made. 


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10.4 Examination of Subgroups 
Analyses of efficacy, safety, and exploratory endpoints may be analyzed by baseline 
demographics and clinical characteristics listed in Sections 6.1and 6.2 or for other subgroups 
of interest as appropriate. 
10.5 Interim Analyses and Data Monitoring 
A group sequential interim monitoring plan will be implemented in order to help guide the 
data monitoring committee (DMC) in monitoring the study. The null hypothesis is p=0.10 
based on historical data in similar patient populations. The study has greater than 90% power 
to reject the null hypothesis at a 5% significance level if the true response rate for rucaparib 
is 20%.  
Interim analyses will be performed when approximately 60 patients and 120 patients have 
complete data, defined as a documented response (PR or CR), disease progression, or at least 
4 months of disease assessment data available.  
If the response rate does not meet continuance criteria for the ITT population, the DMC will 
further evaluate the benefit: risk for study treatment, both overall and separately for patients 
in different HRD subgroups, and make a recommendation whether further enrollment into 1 
or all groups should be discontinued. 
Additional details regarding this group sequential interim monitoring plan are provided in 
Appendix 2. 
11 SAFETY ANALYSIS 
The safety analyses will be performed using the safety population. 
11.1 Adverse Events 
Adverse events will be classified using the MedDRA classification system. The severity of 
the toxicities will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) whenever possible. Treatment-emergent 
adverse events (TEAEs) are defined as AEs with onset date on or after the date of first dose 
of study medication until the date of the last study medication dose plus 28 days. Adverse 
events will be considered treatment-emergent if all or part of the date of onset of the AE is 
missing and it cannot be determined if the AE meets the definition for treatment-emergent. 
The number and percentage of patients who experienced TEAEs for each system organ class 
and preferred term will be presented. Multiple instances of the TEAE in each system organ 
class and multiple occurrences of the same preferred term are counted only once per patient. 
The number and percentage of patients with at least one TEAE will also be summarized.   
The incidence of TEAEs will also be summarized by relationship to study drug according to 
the following categories: “treatment-related,” or “not treatment-related”. If a patient 


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experiences multiple occurrences of the same AE with different relationship categories, the 
patient will be counted once, as a relationship category of treatment-related.   
If a patient experiences multiple occurrences of the same AE with different toxicity grades, 
the patient will be counted once for the maximum (most severe) toxicity grade. AEs with a 
missing toxicity grade will be presented in the summary table with a toxicity grade of 
“Missing.” For each toxicity grade, the number and percentage of patients with at least one 
TEAE of the given grade will be summarized.    
The time to the first TEAE and first treatment-related TEAE that results in a dose reduction, 
delay, interruption, or discontinuation of study drug is defined as 1+ the number of days from 
the first dose of study drug to the start of the first TEAE.  
Separate tables will be presented including but not limited to: 
• All TEAEs; 
• TEAEs by CTCAE grade; 
• Grade 3 or greater TEAEs; 
• Treatment-related TEAEs, overall and by categories: CTCAE grade, grade 3 or greater, 
resulting in dose reduction, resulting in dose interruption, resulting in dose 
discontinuation, outcome of death; 
• Serious TEAEs, overall and by categories: age, sex, and treatment-relatedness; 
• TEAEs with an outcome of death; 
• TEAEs leading to discontinuation of study medication; 
• TEAEs resulting in interruption of study medication; and 
• TEAEs resulting in reduction, delay, or interruption of study medication. 
• Time to the first TEAE that results in a reduction, delay, interruption, or discontinuation 
of study drug. 
• Time to the first treatment-related TEAE that results in a reduction, delay, interruption, or 
discontinuation of study drug. 
Non-TEAEs (pre-treatment and post-treatment) will be presented in the by-patient data 
listings for the safety population.  
11.2 Clinical Laboratory Evaluations 
Clinical laboratory evaluations include the continuous variables for hematology, serum 
chemistry, and urinalysis. The laboratory values will generally be presented in International 
System (SI) units. The on-treatment period will be defined as the time from first dose to 28 
days after the last dose of study drug. Laboratory values collected during the on-treatment 
period will be included in the summary tables. The laboratory values collected after the on-
treatment period will only be presented in the data listings.   
The summary of laboratory data will include shift tables based on CTCAE for shifts in grade 
from baseline to maximum, minimum, and last value during the on-treatment period.  


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The summary of laboratory data will include descriptive statistics (N, mean, StD, minimum, 
median, and maximum) of the maximum, minimum, and last value during the on-treatment 
period. Summaries using descriptive statistics of the change from baseline to the maximum, 
minimum, and last value during the on-treatment period will also be given.     
Supporting laboratory data including normal ranges and abnormal laboratory flags will be 
provided using by-patient listings. Separate listings will be produced for clinically significant 
laboratory abnormalities (ie, those that meet Grade 3 or 4 criteria according to CTCAE). 
11.3 Vital Signs 
The on-treatment period will be defined as the time from first dose to 28 days after the last 
dose of study drug. Vital sign measurements collected during the on-treatment period will be 
included in the summary tables. The vital sign measurements collected after the on-treatment 
period will only be presented in the data listings.   
The summary of vital sign data will include descriptive statistics (N, mean, StD, minimum, 
median, 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. The data will be presented separately for each 
randomized treatment group and overall.   
 


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12 REFERENCES 
1. 
Kaplan EL, Meier P. Nonparametric Estimation from Incomplete Observations. J Am 
Stat Assoc. June 1958;53(282):457-81. 
2. 
Rich JT, Neely JG, Paniello RC, Voelker CC, Nussenbaum B, Wang EW. A practical 
guide to understanding Kaplan-Meier curves. Otolaryngol Head Neck Surg. 
2010;143(3):331-6. 
3. 
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. 
4. 
Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J, et al. 
Development and validation of a clinical cancer genomic profiling test based on 
massively parallel DNA sequencing. Nat Biotechnol. 2013;31(11):1023-31. 
5. 
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. 
 


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13 APPENDICES 
Appendix 1 
Response Evaluation Criteria in Solid Tumors 
The RECIST guidelines (Version 1.1) are described in Eisenhauer (2009)5 and at 
http://www.eortc.be/Recist/Default.htm. A short summary is given below. 
Measurable Disease: 
Tumor lesions: measurable lesions are defined as those that can be accurately measured in at 
least 1 dimension (longest diameter to be recorded) with the following: 
• A minimum size of 10 mm by CT scan (CT scan thickness no greater than 5 mm). 
• A minimum size of 10 mm caliper measurement by clinical exam (lesions that cannot be 
accurately measured with calipers should be recorded as nonmeasurable). 
• A minimum size of 20 mm by chest X-ray. 
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
Malignant lymph nodes: to be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be not greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.  
Nonmeasurable Disease: 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis), as well as truly nonmeasurable 
lesions, are considered nonmeasurable disease. Lesions considered truly nonmeasurable 
include leptomeningeal disease, ascites, pleural/pericardial effusions, inflammatory breast 
disease, lymphangitic involvement of skin and lung, and abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible imaging 
techniques.  
Bone Lesions 
Bone lesions, cystic lesion, and lesions previously treated with local therapy require 
particular comment. Bone scan, PET scan, or plain films are not considered adequate 
imaging techniques to measure bone lesions. However, these techniques can be used to 
confirm the presence or disappearance of bone lesions. 
Lytic bone lesions or mixed lytic–blastic lesions with identifiable soft tissue components that 
can be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above. 


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Blastic bone lesions are nonmeasurable. 
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 criteria require unequivocal quantification of the changes in tumor size for adequate 
interpretation of the sum of target lesions. Consequently, when the boundaries of the primary 
are difficult to delineate, this tumor should not be considered a target lesion. 
Guidelines for Evaluation of Measurable Disease 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the antitumor effect of a treatment. 


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Evaluation of Target Lesions 
Complete Response 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or nontarget) must have reduction in short axis to 
< 10 mm. 
Partial Response 
At least a 30% decrease in the sum of the LD of target lesions, taking 
as reference the baseline sum LD. 
Stable Disease 
Neither sufficient shrinkage to qualify for partial response nor 
sufficient increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started. 
Progressive Disease 
At least a 20% increase in the sum of the LD of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study). In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 
mm. The appearance of one or more new lesions is also considered 
progression. 
Abbreviations: LD = longest diameter; PD = progressive disease. 
 
Evaluation of Nontarget Lesions 
Complete Response 
Disappearance of all nontarget lesions and normalization of tumor 
marker level. 
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 
Appearance of 1 or more new lesions and/or unequivocal 
progression of existing nontarget lesions. 
If tumor markers are initially above the institutional ULN, they must normalize for a patient 
to be considered a complete responder.  
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). The patient’s best response assignment will depend on 
the achievement of both measurement and confirmation criteria.  
Evaluation of Best Overall Response 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 


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Evaluation of Best Overall Response 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
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 
CR 
= 
complete response 
NE 
= 
not evaluable. 
PD 
= 
progressive disease 
PR 
= 
partial response 
SD 
= 
stable disease 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
symptomatic deterioration. Every effort should be made to document the objective 
progression, even after discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends on this determination, it is recommended that the 
residual lesion be investigated (fine needle aspiration/biopsy) prior to confirming the 
complete response status. 
Confirmatory Measurement/Duration of Response 
Confirmation 
If a complete response (CR) or partial response (PR) is noted, confirmatory scans should be 
performed at least 4 weeks after response was first documented. 
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. 


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Duration of Stable Disease 
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 
Group Sequential Interim Monitoring Plan 
Introduction 
This plan describes an adaptive study design for the evaluation of rucaparib in patients with 
locally advanced or metastatic urothelial carcinoma. The adaptive design utilizes interim 
analyses that allow for early stopping for futility after DMC review of futility analysis of the 
ITT population, the efficacy for HRD subgroups and all safety analyses. 
The trial will enroll 60-200 subjects in a single experimental arm. 
Objective response rate by RECIST v1.1 as assessed by the investigator will be summarized 
for the ITT and HRD-positive populations as well as for the exploratory HRD groups. 
Primary Analysis 
Let p be the true response rate. The primary analysis compares p to a performance goal of 
0.10, and is thus a hypothesis test of 
H0 : p ≤ 0.10        H1 : p>0.10 
Starting with a noninformative Beta(0.1,0.9) prior on p, the posterior distribution is  
p|data~Beta(0.1+Y, 0.9+N-Y) 
where Y is the observed number of responses and N is the number of complete subjects in 
the trial. The trial is a success if 
Pr(p > 0.10 | data) > 0.95 
This threshold maintains type I error at 5%. We consider an alternative threshold (0.935) that 
increases type I error slightly but obtains greater power for comparison. 
Design 
The trial sequentially enrolls patients and interim analyses are conducted. At the time of each 
interim analysis, there will be N patients with a 4-month endpoint and M patients that are 
incomplete. Let Y be the number of responders among the complete patients. 
The model computes pmax, the predictive probability of trial success if the trial is followed to 
the maximum (targeted) sample size and all patients are followed to completion. Let Wmax be 
the number of eventual responders among the unknown patients (incomplete and currently 
unenrolled). The distribution of Wmax is a BetaBinomial(MAXN-N,0.1+Y,0.9+N-Y). The 
predictive probability pmax is the probability Wmax results in trial success when N=200 
subjects are complete. 
The model indicates trial futility at any interim analysis if pmax<threshold, indicating that 
there is limited probability that the trial will reach success even at the maximum sample size.  


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For this study design with N=60 minimum, N=200 maximum, a 5% futility threshold, and 
interims at N=60 and N=120, the required number of successes to continue is summarized in 
the table below. For example, in the first row we require 5/60, indicating we must have at 
least 5 successes out of the first 60 patients (so 5 would continue). 
Interim 
Minimum to Continue  
(5% predictive probability) 
1 (N=60) 
5/60 (8.3%) 
2 (N=120) 
13/120 (10.8%) 
 
Example Trials 
Example trial 1 
The trial enrolls until the first interim analysis at N=60 ITT patients complete. At this 
interim, we have 13/60 (21.7%) responses with 40 patients awaiting follow-up. This result is 
clearly encouraging compared to a 10% baseline rate. With 140 patients still requiring data, 
the predictive probability of success on the ITT population is 97.5%, well above the 
threshold for futility. Response among HRD subgroups is evaluated and the trial continues. 
The second interim analysis occurs with N=120 ITT patients complete, obtaining 22/120 
(18.3%) with 27 incomplete. Response among HRD subgroups is evaluated. With 80 patients 
remaining needing follow-up, the predictive probability of success is 99.0%, clearly high and 
the trial continues. 
At N=200, we obtain 37/163 responses (22.7%). This results in a posterior probability greater 
than 99.99% and a successful trial. 
Example Trial 2 
The trial enrolls until the first interim analysis at N=60 ITT patients complete. At this 
interim, we have 3/60 (5%) responses with 40 patients awaiting follow-up. The predictive 
probability of success at this point is only 0.4%. This is below the threshold for futility for 
the ITT population. The DMC would examine response among HRD subgroups as well as 
safety data and make a recommendation to stop the trial or continue. If the trial was stopped 
at this point, it is assumed that all enrolled patients will continue to be followed. 
In that follow-up, the trial ended with 12/100 responses (12%). While greater than 10%, this 
is insufficient for a successful trial (Pr(trmt beats ctrl)=56.7%) and the trial would have been 
very unlikely to meet its primary objective even had N=200 subjects been enrolled. 
Example Trial 3 
The trial enrolls until the first interim analysis at N=60 ITT patients complete. At this 
interim, we have 5/60 (8.3%) responses with 40 patients awaiting follow-up. With 140 
patients still requiring data, the predictive probability of success on ITT is 5.1%, barely 
above the threshold for futility. Response among HRD subgroups is evaluated and the trial 
continues. 


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The second interim analysis occurs with N=120 complete, obtaining 14/120 (11.7%) with 31 
incomplete. With 80 patients remaining needing follow-up, the predictive probability of 
success is 13.1%, also high enough to continue. Response among HRD subgroups is 
evaluated and the DMC recommends that the trial continue. 
At N=200, we obtain 20/200 responses (10.0%). This results in a posterior probability of 
47.5% and a nonsuccessful trial. 
Simulations and Operating Characteristics 
The operating characteristics of this trial were determined through trial simulation and 
compared to a potential Simon 2-stage design. We computed the operating characteristics 
under the assumptions that p=0.10 (null hypothesis) and p=0.11, 0.12, …, 0.25.  
A total of 10,000 trials were simulated per scenario. In each, subjects were accrued according 
to a Poisson process with an average of 1.5 subjects per week. In each simulated trial, 
interims analyses were conducted according to prespecified rules and the results were 
recorded. 
The detailed results are shown in the following tables for Expected Sample size and for 
Power, respectively. 
Expected 
Sample Size 
p=0.10 (null) 
p=0.15 
p=0.20 
p=0.25 
Fixed 
200.00 
200.00 
200.00 
200.00 
Simon 
141.52 
188.83 
204.28 
205.92 
Adjusted 
150.85 
192.38 
199.60 
199.98 
Unadjusted 
151.60 
192.67 
199.40 
199.99 
 
Pr(trial success) 
p=0.10 (null) 
p=0.15 
p=0.20 
p=0.25 
Fixed 
0.043 
0.683 
0.989 
0.999 
Simon 
0.049 
0.673 
0.977 
0.999 
Adjusted 
0.062 
0.736 
0.991 
1.000 
Unadjusted 
0.039 
0.675 
0.985 
0.999 
 
The next table shows the details of if and where each of the adjusted adaptive trial 
simulations stopped for futility. For each simulated trial, the trial could stop at N=60 
complete, N=120, or run to the maximum sample size. Note that trials that stop at N=60 or 
N=120 complete actually we enroll more than 60 or 120 subjects due to the “overrun”, 
patients enrolled while waiting for the required patient to complete. In addition, we 
summarize the probability of a “futility to success flip flop” (FSFF). In actual 
implementation, when a trial is stopped for futility, you will not get to see what would have 
happened had you enrolled until N=200. However, in simulation we can simulate those 
remaining subjects and determine how many futility stops occurred for trials that would 
ultimately have been successful. 


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Pr(trial success) 
p=0.10 (null) 
p=0.15 
p=0.20 
p=0.25 
Futility N=60 
0.270 
0.042 
0.004 
0.000 
Futility N=120 
0.331 
0.054 
0.000 
0.000 
Pr(FSFF) 
0.004 
0.022 
0.004 
0.000