Conditions: Prostate Cancer Metastatic
Keywords: metastatic hormone sensitive
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 12
Healthy volunteers: no

Brief summary:
The aim of this research is to find out if the study drug rucaparib leads to lowering of PSA levels in men with metastatic prostate cancer that has not yet been treated with androgen deprivation therapy (also referred to as metastatic hormone sensitive prostate cancer) and who have an inherited mutation in a gene involved in repairing DNA damage. The research will also examine if rucaparib is safe in individuals with metastatic prostate cancer.

Prior research studies have shown that drugs like rucaparib can be of benefit to patients with advanced metastatic prostate cancer who are resistant to androgen deprivation therapy AND who carry a mutation in a DNA repair gene. We are studying if rucaparib will be an effective treatment for these patients earlier in their treatment course (for example, prior to the start of medicines that lower testosterone level). It is unknown whether rucaparib will have the same benefit in men with metastatic prostate cancer carrying a mutation in a DNA repair gene, prior to the use of medicines that lower your testosterone level.

Detailed description:
With respect to germline mutations, a recent study found that the incidence of inherited DNA-repair gene alterations in metastatic prostate cancer to be significantly higher (11.8%) than in both men with localized prostate cancer (4.6%) and in the general population at large (2.7%). Specifically, mutations in 7 genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, RAD51D, GEN1) were significantly enriched in patients with metastatic prostate cancer compared to the general population. These findings suggest that a subset of men are more likely to develop metastatic prostate cancer (i.e. those with germline mutations in DNA-repair genes) and may potentially benefit from PARPi therapy.

The clinical activity of PARPi in patients with DNA-repair mutations and metastatic prostate cancer has now been established. Focusing specifically on patients with a germline mutation in a pre-specified group of DNA-repair genes, we hypothesize that targeted therapy with PARPi should be sufficient to induce a clinical response irrespective of hormonal (castration-sensitive or castration-resistant) status. Our hypothesis is based largely on the data from Mateo et al showing a clinical response rate of 88% in a heavily pre-treated population of mCRPC patients with a DNA repair mutation, with the most pronounced responses being in men with germline inactivation.

For men with mHSPC, this trial would also provide an alternative to ADT. Identification of a non-hormonal based therapy is warranted as ADT is associated with a shorter time to castration resistance in men harboring a germline DNA repair mutation versus those with intact DNA repair. However, given that primary ADT (in mHSPC) is a standard first-line therapy, all patients on trial must be ineligible for or decline standard-of-care hormonal treatment. For patients with mHSPC who do not respond to PARPi, we will build safety rules into the trial design to take patients off study at first signs of progression. Primary ADT (mHSPC) would still remain a treatment option upon progression.

Arms:
arm 1: Rucaparib 600mg by mouth twice daily, continuous dosing

Interventions: intervention 1: Rucaparib
Intervention descriptions: intervention 1: Continuous dosing

Protocol document:
Prot_SAP_000.pdf: 
Rucaparib in Hormone Sensitive Prostate Cancer 
IRB00156514 
Johns Hopkins 
NCT03413995
 
 
 
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Protocol Version 7.0 Date: March 4, 2022 
Phase II Trial of Rucaparib in Patients with Metastatic and Non-
Metastatic Hormone-Sensitive Prostate Cancer Harboring DNA Repair 
Gene Mutations (TRIUMPH) 
 
PCCTC LOI #: c18-220 
IND 137691 EXEMPT IND 
Lead Site and Sponsor: Johns Hopkins University 
 
Principal Investigator: 
Statistician 
Mark C. Markowski, M.D., Ph.D. 
Hao Wang, Ph.D. 
Prostate Cancer Program 
201 N. Broadway, Room 9131 
Baltimore, MD 21287 
Tel 410-614-0567 
Fax 410-614-8397 
Division of Biostatistics & Bioinformatics, 
Sidney Kimmel Comprehensive Cancer 
Center at Johns Hopkins, Johns Hopkins 
University School of Medicine, Baltimore, MD, 
USA. 
Tel 410-614-3426 
Tel 410-955-4884 
email: mmarko12@jhmi.edu 
email: hwang76@jhmi.edu; 
 
Project Manager 
 
Serina King 
 
201 N. Broadway, Room 9132 
Baltimore, MD 21287 
Tel 410-614-6139 
email: sking18@jhmi.edu 
 
Lead Study Pathologist 
Tamara Lotan, MD 
Department of Pathology 
Johns Hopkins School of Medicine 
CRB2 Room 343 
1550 Orleans Street 
Baltimore, MD 21231 email: tlotan1@jhmi.edu 
Participating Sites: 
Johns Hopkins University 
Weill Cornell/NYP Hospital 
 
 
 
 
 
 
 
 
 


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Protocol Version 7.0 Date: March 4, 2022 
Protocol Version 1.0 Protocol Date: December 12, 2017 
Amended Version Date: Version 2.0 dated August 1, 2018 
Amended Version Date: Version 3.0 dated November 5, 2018 
Amended Version Date: Version 4.0 dated February 4, 2019Amended Version Date: Version 5.0 
dated June 18, 2020 
Amended Version Date: Version 6.0 April 26, 2021 
Amended Version Date: Version 7.0 March 4, 2022 
 
CONFIDENTIALITY STATEMENT 
The information in this document is provided to you as an investigator, potential investigator, 
consultant, or contractor, for review by you, your staff, and the appropriate Institutional Review 
Board or Ethics Committee. By accepting this document, you agree that the information 
contained herein will not be disclosed to others without written authorization from the lead 
site/sponsor, except to the extent necessary to initiate the study or conduct study-related 
activities. 
Participating Site 
Lead Investigator 
Role 
Weill-Cornell/NYP Hospital 
Cora Sternberg M.D., FACP 
PI 


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INVESTIGATOR’S APPROVAL OF PROTOCOL 
 
Title: Phase II Trial of Rucaparib in Patients with Metastatic and Non-Metastatic Hormone-
Sensitive Prostate Cancer Harboring DNA Repair Gene Mutations (TRIUMPH) 
 
 
 
 
 
Principal Investigator Signature:  
_______________________________________________________ 
Principal Investigator Print:  
_______________________________________________________ 
Date:   
 
 
 
_______________________________________________________ 
 
 
 
 
 
 
 
 


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SYNOPSIS 
Title 
Phase II Trial of Rucaparib in Patients with Metastatic and Non-Metastatic Hormone-
Sensitive Prostate Cancer Harboring DNA Repair Gene Mutations (TRIUMPH) 
Lead site 
Johns Hopkins University 
Sponsor 
IND holder 
Clovis Oncology 
IND 137691(EXEMPT IND) 
Investigational 
agent 
Rucaparib 600mg by mouth twice daily, continuous dosing 
Phase 
2 
Target 
population 
• 
adult male > 18 years of age 
• 
Histologic or cytologic diagnosis of adenocarcinoma of the prostate. 
• 
Either (1) Metastatic disease as defined for one or more bone metastases confirmed 
by bone scintigraphy or radiographic soft tissue metastasis. Pelvic lymph nodes will 
be considered as metastatic disease if they measure >15 mm in short-axis diameter. 
Or (2) biochemically recurrence disease as defined by a PSA >0.2 ng/ml post 
prostatectomy or a PSA rise of 2ng/ml or more from the nadir after radiation 
therapy. 
• 
Germline or somatic mutation in one or more homologous recombination DNA-
repair genes (BRCA1, BRCA2, ATM, CHEK2, NBN, BRIP1, RAD50, RAD51C, RAD51D, 
PALB2, MRE11, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, 
FANCL, FANCM) as documented by a clinical-grade, saliva, tissue, or blood based 
genetic test or molecular sequencing. 
• 
Patients must be informed about and must decline androgen deprivation therapy 
(ADT)-based systemic therapy  
• 
Serum PSA at screening > 2.0 ng/mL 
• 
Serum testosterone level: > 100 ng/dL at time of screening 
• 
patients with biochemical recurrence must have a PSADT < 9 months, based upon 
>3 consecutive measurements collects in the past 12 months, at least 4 weeks 
apart, calculated using MSKCC calculator 
• 
life expectancy >12 months 
• 
ECOG performance status  < 2 
• 
Adequate bone marrow, renal and liver function (ANC >1.5K, Plt >100K, Hgb >10 
g/dL; Cr <1.5 mg/dL; AST/ALT < 3x ULN; Total Bilirubin <1.5x ULN). 
Study centers 
Two sites in the United States 
Start 
date/Duration 
First patients are expected to be enrolled in March 2018. Accrual is estimated to last 2 
years with up to 12 months of follow-up after the last patient has been entered. 


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Expected 
enrollment 
30 patients (Up to a max of 10 patients with non-BRCA1/BRCA2/ATM homologous 
recombination DNA-repair mutations allowed, ensuring at least 20 
BRCA1/BRCA2/ATM-positive patients). 
Rationale 
At the time of metastatic disease, continuous ADT (+/- docetaxel, +/- abiraterone) is 
commonly initiated for the treatment of prostate cancer.  However, many men find it 
difficult to tolerate treatment-related toxicities, including sexual impotency, decreased 
libido, hot flashes, and weight gain. These symptoms can persist with the development 
of castration resistance.  Treatment with non-AR targeted agents, such as PARPi, may 
avoid or delay the toxicities of hormonal therapy. Therefore, there is an unmet 
medical need to develop non-hormonal therapies for men with newly diagnosed 
metastatic prostate cancer who wish to avoid or defer the initiation of chronic ADT.  
There is also a similar need for those patients with biochemically recurrence prostate 
cancer at high risk of developing metastatic disease (i.e. PSADT < 9 months). 
The clinical activity of PARPi in patients with homologous recombination DNA-repair 
mutations and metastatic prostate cancer has now been established.  Focusing 
specifically on patients with an inactivating mutation in a pre-specified group of DNA-
repair genes, we hypothesize that targeted therapy with PARPi should be sufficient to 
induce a clinical response irrespective of hormonal (castration-sensitive or castration-
resistant) status.  Our hypothesis is based largely on the data from Mateo et al (NEJM 
2015) showing a clinical response rate to olaparib of 88% in a heavily pre-treated 
population of mCRPC patients with a DNA repair mutation, with the most pronounced 
responses being in men with germline inactivation.(1) For men with metastatic 
hormone sensitive prostate cancer (mHSPC) and high risk biochemically recurrent 
disease (BCR), this trial would also provide an alternative to ADT. However, given that 
primary ADT (in mHSPC and high risk BCR) is a standard first-line therapy, all patients 
on trial must be ineligible for or decline standard-of-care hormonal treatment.  For 
patients with mHSPC who do not respond to PARPi, we have incorporated safety rules 
into the trial design to take patients off study at first signs of progression.  Primary ADT 
(+/- docetaxel, +/- abiraterone) would still remain a treatment option upon 
progression. 
The primary hypothesis of this study is that outcomes for patients with mHSPC and 
high risk BCR with an inactivating homologous repair mutation will be improved by 
this therapeutic agent (rucaparib) 
Objectives 
Primary 


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To estimate the PSA50 response rate to rucaparib in patients with metastatic and non-
metastatic prostate cancer that harbor an inactivating mutation in a homologous 
recombination DNA repair gene while on treatment with rucaparib, defined as a 
decline in PSA to 50% of baseline level, confirmed with a second measurement at least 
4 weeks apart (PCWG3). 
 
Secondary 
• 
To estimate the median PSA progression-free survival (PCWG3). 
• 
To estimate the median progression-free survival (PCWG3). 
• 
To estimate the objective response rate (ORR) in those patients with 
measurable disease. 
• 
To determine the safety/tolerability of rucaparib in a population of men with 
hormone sensitive prostate cancer. 
 
Correlatives/Tertiary  
• 
To measure the quantitative change in gamma-H2AX, RAD51, 53BP1 formation 
in tumor tissue following treatment with rucaparib (M1 disease only). 
• 
To develop an RNA expression signature associated with response to rucaparib 
(M1 disease only). 
• 
To estimate the percentage of patients with a loss-of-function mutation or total 
allelic loss of second somatic gene allele (i.e. LOH, or biallelic inactivation) (In 
all patients undergoing biopsy or with archived tissue). 
• 
To investigate any association between PARP-1 and PARP-2 protein and mRNA 
expression levels in tumor with response to rucaparib (In all patients 
undergoing biopsy or with archived tissue). 
• 
To examine the incidence of reversion mutations in circulating tumor DNA at 
clinical progression. 
 
 
Study design 
The study is an open-label single arm Phase II trial.  Eligible patients are those with 
metastatic hormone-sensitive prostate cancer (mHSPC) or high-risk biochemically 
recurrent prostate cancer (BCR).  All patients must have a documented germline or 
somatic mutation in a homologous recombination DNA-repair gene (BRCA1, BRCA2, 
ATM, CHEK2, NBN, BRIP1, RAD50, RAD51C, RAD51D, PALB2, MRE11, FANCA, FANCB, 
FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM).  Germline genetic 
testing and molecular sequencing as a screening for eligibility will not be offered. A 
mandatory tumor biopsy will be performed prior to the start of therapy in all patients 
with metastatic disease (if tumor material is not successfully obtained at the time of 
biopsy, then archival material will be sought).  A second, OPTIONAL tumor biopsy will 
take place after three months of therapy.  
After enrollment, patients will be treated with rucaparib at the established dose of 
600mg by mouth twice daily.  Patients will be followed monthly with clinic visits, 
safety labs (including CBC w/diff, Comp), PSA, and toxicity assessments.  Treatment 
[with a minimum drug exposure of 12 weeks] will be continued until PSA progression 
(PCGW3 criteria) or clinical/radiographic progression (whichever comes first), or until 
unmanageable toxicity requiring drug cessation.   Patients who remain on treatment 


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for >12 months can begin to have their clinic visits, safety labs (including CBC w/diff, 
Comp), PSA, and toxicity assessments  every 3 months. 
A trial schema for study treatment appears below: 
 
 
 
 
 
 
 
 
 
 
 
Criteria for 
evaluation 
Primary Endpoint 
• 
PSA50 response rate, defined as a decline in PSA to ≥50% of baseline level, 
confirmed with a second measurement at least 4 weeks later (PCWG3).  
Secondary Endpoints 
• 
Safety/Tolerability, defined as incidence of CTCAE v5.0 grade ≥3 toxicities 
experienced by patients on the trial. 
• 
PSA progression-free survival, defined as a time from initiation on rucaparib 
therapy until PSA increase of 25%, confirmed with another measurement at 
least 4 weeks later (PCWG3). 
• 
Radiographic progression–free survival (PCWG3): time to radiographic or 
clinical progression or death, whichever comes first. Based on RECIST version 
N=30 pts
mHSPC / BCR
HRD mutated
Rucaparib
600mg po BID
Cycle Length: 28 days
Continuous dosing
C1D1
C2D1
C3D1
Day -7
Biopsy (M1 only)
Visit
Labs
PSA
Visit
Labs
PSA
Biopsy (M1 only)
C4D1
Visit
Labs
PSA
Visit
Labs
PSA
CT C/A/P 
Bone Scan


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1.1 and PCWG3 definitions including: Progression of soft tissue lesions according 
to RECIST 1.1; Progression of bone lesions detected with bone scan according to 
PCWG3 criteria; Radiologically‐confirmed spinal cord compression or 
pathological fracture due to malignant progression, or other clinical event 
deemed to be cancer‐related 
• 
Objective response rate, defined as the proportion of patients with measureable 
disease achieving a complete/partial response in target lesions (RECIST 1.1). 
 
Exploratory Endpoints 
• 
PSA50 response, defined as decline in PSA to ≥50% of baseline level, confirmed 
with a second measurement at least 4 weeks later, in patients with and without a 
loss-of-function mutation or total allelic loss of second (somatic) gene allele (i.e. 
biallelic inactivation) (In patients who undergo biopsy or with archival tissue 
available). 
• 
To associate PSA response to rucaparib with changes in gamma-H2AX, RAD51, 
53BP1 formation in tumor tissue compared to baseline (In M1 patients who 
undergo biopsy). 
• 
To associate mRNA expression array signature with PSA response (In M1 
patients only who undergo biopsy). 
• 
To associate PSA response to rucaparib with baseline PARP-1 and PARP-2 
protein and mRNA expression levels in baseline tumor biopsy specimens or 
archived tissue. 
• 
To associate the incidence of reversion mutations with clinical progression. 
Exploratory Analyses 
Estimate the percentage of patients with a loss-of-function mutation or total allelic loss of 
second (somatic) gene allele (i.e. biallelic inactivation): 
The DNA mutations present in the tumor will be identified through Foundation 
Medicine sequencing.  Patients with biallelic inactivation in an HRD gene(BRCA1, 
BRCA2, ATM, CHEK2, NBN, BRIP1, RAD50, RAD51C, RAD51D, PALB2, MRE11, FANCA, 
FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM) will be 
considered biomarker positive.  For biomarker positive and biomarker negative 
subjects, we will calculate PSA50 response rates with confidence intervals for hypothesis 
generation.   
 
mRNA expression profile signature (positive and negative) and PSA50 response rates:  
Subjects will have pretreatment tumor (or archived tissue) tested with mRNA 
expression profiling and scored for likelihood for response to rucaparib per the 
Decipher GRID platform (GenomeDx).  For subjects considered to have a positive mRNA 
expression signature based upon a binary score assigned via the GenomeDx proprietary 
algorithm, a PSA50 response rate will be calculated.  Similarly, a calculation will be 
performed for subjects considered to have a negative sRNA expression signature.  
PARP-1, PARP-2, γH2AX, RAD51, 53BP1 mRNA/protein levels:  
In patients that have biopsy-able disease, subjects will have pretreatment and on-
treatment tumor biopsy specimens analyzed.  IHC and RNA in situ hybridization staining 


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PARP-1 and PARP-2 will be performed on the pretreatment samples and scored on scale 
of 0 (none) to 3 (intense staining), and the results will be associated with responses for 
both proteins, separately, using descriptive statistics and Fisher’s Exact Tests.   
Immunofluorescence will be used to quantify the median intensity of each gH2AX, 
RAD51m and 53BP1 foci per cell as well determine the median number of foci per cell 
on the pretreatment biopsies.   Using analytical microscopy, Drs. Meeker and Heaphy 
have developed imaging software, which can isolate single nuclei and quantify both the 
intensity and number of immunofluorescent foci per nucleus (i.e. per cell). Using FFPE 
tissue obtained at biopsy, we will examine the change in DNA damage foci number and 
intensity (reported as median percent change) induced by PARPi in PSA50 responders 
versus non-responders using a T-test.   
Reversion Mutations: 
Subjects will have circulating tumor DNA (ctDNA) examined by FoundationACT testing 
before starting treatment and at clinical progression while on rucaparib.  We will report 
the incidence and describe the observed reversion mutation, a known mechanism of 
resistance to PARP inhibition. 
Statistical 
method 
Primary Analysis 
The primary endpoint of this study is PSA50 response, defined as a decrease in the PSA to 
≥50% less than the baseline PSA upon enrollment in the trial.  The decrease must be 
confirmed by a second measurement at least 4 weeks apart.  For purposes of meeting 
the primary endpoint, patients will be considered to have done so if they have a PSA50 
response only while on therapy with rucaparib.  PSA values will be measured monthly 
during the trial.  All patients who take at least one dose of rucaparib will be considered 
evaluable for the primary endpoint.  If patients do not have follow-up PSAs after 
initiation rucaparib therapy due to stopping therapy for toxicity or withdrawing 
consent, then they will be replaced.   
Secondary Analysis 
Safety: 
Patients will be assessed for toxicities at each clinical evaluation.  Toxicities will graded 
according to CTCAE v5.0 standardized grading scales.  The incidence of grade 3-5 
toxicities will be reported.  Patients will be assessed for toxicity as long as they are 
taking rucaparib, and patients will continue to be followed if rucaparib is discontinued 
for toxicity until the toxicities improve to grade 1 or resolve. Toxicities will be reported 
as a tabulated table by type and grade. 
PSA progression-free survival (PSA-PFS): 
A standard definition of PSA progression per PCWG3 will be used.  PSA-PFS will be 
defined as an increase in 25% over a nadir value, confirmed by a follow-up PSA at least 4 
weeks later.  If patients are removed from study prior to PSA progression, then they will 
be censored at that time.  We will use the Kaplan-Meier method to estimate the median 
PSA-PFS. 
Radiographic progression-free survival (PFS): 
Progression-free survival will be measured from the time of first dose to objective 
clinical or radiographic tumor progression as defined by PCWG3 for progressive disease 


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or death, and summarized using a Kaplan-Meier curve. Progression will be assigned to 
the earliest observed time. Patients whose disease has not progressed at follow-up will 
be censored at the date when the last tumor assessment determined a lack of 
progression.  We will use the Kaplan-Meier method to estimate the median PFS. 
Objective response rate: 
The objective response rate is defined as the percentage of patients with measurable 
disease at baseline who achieve an objective response by RECIST1.1 criteria (i.e. 
Complete response or Partial Response) to rucaparib.   We will estimate the objective 
response rate, along with the exact 95% confidence interval, for the population of 
patients.   
Sample size/Power calculation: 
The sample size is calculated to detect an improved PSA50 response rate from 50% to 
75%. An optimal Simon two stage design is planned. A total of 12 patients will be 
entered in the first stage and the data analyzed for futility 12 weeks after the last patient 
begins rucaparib treatment. If 6 or fewer subjects have a PSA response, the study will be 
terminated and we will conclude the regimen is ineffective. If ≥7 subjects respond, then 
an additional 16 patients will be studied, for a total of 28 patients.  If a total of 17 or 
fewer subjects respond in stage one and two combined, we consider this regimen 
ineffective. If a total of 18 or more respond, we conclude the regimen is promising and 
warrants further study. The maximum sample size will be increased to 30 patients to 
account for possible dropouts.  The total number of patients allowed with a non-BRCA1 
or -BRCA2 mutations will be capped at 10. This will ensure that at least 20 men will be 
enrolled with BRCA1/BRCA2 mutations.    
 
This design provides 90% power to detect an absolute 25% increase in PSA response 
rate with a one-sided type I error of 0.1. The probability of early stopping is 0.61 under 
the null hypothesis that the PSA response rate is 50%.  
Safety analysis Standard safety summaries will be provided for treatment exposure, patient disposition, 
adverse events leading to discontinuation, serious adverse events, and all events 
resulting in death, including those up to 30 days after treatment discontinuation. The 
incidence of adverse events will be tabulated and reviewed for potential significance 
and clinical importance. 


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TABLE OF CONTENTS 
1. INTRODUCTION .................................................................................................................................................................. 13 
1.1 
Disease Background .......................................................................................................................................................... 13 
1.2 
Treatment Background .................................................................................................................................................... 14 
1.3 
Rationale ................................................................................................................................................................................. 20 
2.1 
Primary Objective ............................................................................................................................................................... 22 
2.2 
Secondary Objectives ........................................................................................................................................................ 22 
2.3 
Correlative/Exploratory/Tertiary Objectives ....................................................................................................... 22 
3. 
PATIENT SELECTION ................................................................................................................................................. 22 
3.1 
Target Population ............................................................................................................................................................... 22 
3.2 
Expected Enrollment ......................................................................................................................................................... 23 
3.3 
Inclusion Criteria ................................................................................................................................................................ 23 
3.4 
Exclusion Criteria................................................................................................................................................................ 24 
4. 
PATIENT REGISTRATION AND ENROLLMENT PLAN ...................................................................................... 25 
4.1 
Registration Procedure .................................................................................................................................................... 25 
5. 
TREATMENT/INTERVENTION PLAN .................................................................................................................... 27 
5.1 
Screening/Pretreatment Assessment (Day -7 ± 7 days) ................................................................................... 29 
5.2 
Treatment/Intervention Period (Day 1 of each 28 day cycle +/- 3 days, ongoing) .............................. 31 
5.3 
Treatment-Limiting Adverse Event ............................................................................................................................ 32 
5.4 
Dosing and Dose Modifications .................................................................................................................................... 32 
5.5 
End of Treatment/Treatment Discontinuation Visit 28 days after last dose +/- 3 days) .................. 38 
5.7 
Correlative/Special Studies ............................................................................................................................................ 39 
5.8 
Concomitant Medications ............................................................................................................................................... 39 
5.9 
Contraception ....................................................................................................................................................................... 40 
6. 
THERAPEUTIC/DIAGNOSTIC AGENT(S)/MODALITY(-IES) .......................................................................... 41 
6.1 
Description of Treatments .............................................................................................................................................. 41 
6.2 
Pharmacokinetics ............................................................................................................................................................... 41 
6.3 
Dosage Selected, Preparation, and Schedule of Administration .................................................................... 41 
6.4 
Removing Patients from the Protocol........................................................................................................................ 42 
7. 
ADVERSE EVENTS ....................................................................................................................................................... 42 
7.1 
Definitions .............................................................................................................................................................................. 43 
7.2 
Expectedness ........................................................................................................................................................................ 46 
7.3 
Recording and Grading ..................................................................................................................................................... 47 
7.4 
Reporting Adverse Events .............................................................................................................................................. 48 
8. 
CRITERIA FOR OUTCOME ASSESSMENT/THERAPEUTIC RESPONSE........................................................ 49 
8.1 
Outcome Assessment ........................................................................................................................................................ 49 
8.2 
Therapeutic Response ...................................................................................................................................................... 50 
8.3 
Response Criteria for Primary and Secondary Endpoints ................................................................................ 51 
8.4 
Criteria for Progressive Disease. .................................................................................................................................. 53 
9. 
DATA REPORTING AND REGULATORY REQUIREMENTS .............................................................................. 54 
9.1 
Data Entry .............................................................................................................................................................................. 55 
9.2 
Data Management ............................................................................................................................................................... 56 
9.3 
Clinical Trial Agreement .................................................................................................................................................. 56 
10. 
STATISTICAL CONSIDERATIONS ........................................................................................................................... 56 
10.1 Study Endpoints .................................................................................................................................................................. 57 
10.2 Analysis Populations ......................................................................................................................................................... 59 
10.3 Safety Analysis ..................................................................................................................................................................... 60 
11. 
PROTECTION OF HUMAN SUBJECTS..................................................................................................................... 60 
11.1 Ethical Considerations ...................................................................................................................................................... 60 
11.2 Protocol Amendments ...................................................................................................................................................... 60 
11.3 Written Informed Consent .............................................................................................................................................. 61 


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11.4 Protection of Privacy ......................................................................................................................................................... 61 
11.5 Terminating or Modifying the Study .......................................................................................................................... 61 
12. 
REFERENCES ................................................................................................................................................................. 63 
APPENDIX A: PERFORMANCE STATUS CRITERIA ....................................................................................................... 65 
APPENDIX B: MEDICATIONS WITH THE POTENTIAL FOR DRUG-DRUG INTERACTIONS ............................. 66 
APPENDIX C: LABORATORY MANUAL ............................................................................................................................. 67 
APPENDIX D: GLOSSARY OF ABBREVIATIONS AND ACRONYMS ........................................................................... 68 
APPENDIX E. ACCEPTABLE BIRTH CONTROL METHODS ......................................................................................... 74 
APPENDIX F. ACTIONS REQUIRED IN CASES OF COMBINED INCREASE OF AMINOTRANSFERASE AND 
TOTAL BILIRUBIN – HY’S LAW ........................................................................................................................................... 75 
List of Tables: 
Table 1         Study Calendar 
 
 
 
 
 
 
 
 
           26 
Table 2         Management of Anemia 
 
 
 
 
 
 
                           32 
Table 3         Management of Neutropenia, Leukopenia, Thrombocytopenia  
 
 
           32 
Table 4          Relationship of Adverse Event to Study Drug  
 
 
 
 
           44 
Table 5         RECIST1.1 Response Criteria for Target Lesions 
   
 
 
 
           48 
Table 6          RECIST1.1 Response Criteria for Nontarget Lesions 
 
 
 
 
           49 
Table 7          Categories for Response to Treatment 
 
 
 
 
 
           56 
 
 
 
List of Figures: 
Trial Schema 
 
 
 
 
 
 
 
 
 
 
             6 
Figure 1        Clinical States of Prostate Cancer 
 
 
 
 
 
 
           12 
Figure 2        Efficacy of Single Agent Rucaparib in the MDA-MB-436 (BRCA1 Mutant) Orthotopic Xenograft  
  
 
        Model 
 
 
 
 
 
 
 
 
 
           16 
 


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1. INTRODUCTION 
1.1 
Disease Background 
 
Prostate cancer is the most commonly diagnosed non-cutaneous malignancy in men, with 
an estimated 180,000 cases annually in the United States (2).  It is the second most common 
cause of cancer mortality in the United States as well, with over 26,000 deaths in 2016 (2).  
The discrepancy between the incidence and mortality numbers demonstrate its potential 
curability if treated while disease is local, as well as the non-lethal nature of some cancers, 
even if not treated definitively.   While many men are cured of their disease, many others 
will unfortunately progress to incurable and lethal metastatic disease. 
 
1.1.1 Clinical States of Prostate Cancer 
 
The course of prostate cancer from diagnosis to death is best categorized as a series of 
clinical states (Fig. 1). These states are defined by the extent of disease and status of 
responsiveness to hormonal therapy.  Therapies have been developed for specific states, as 
each state presents unique risks to the patient and different responsiveness of the disease 
to therapy. 
 
 
Figure 1 
Clinical states of prostate cancer (3) 
 
1.1.2  Metastatic Non-Castrate Disease State 
Patients may develop metastatic prostate cancer following a recurrence after local therapy 
or present with M1 disease as the first diagnoses of prostate cancer. Continuous androgen 
deprivation therapy (ADT) is initiated for the treatment of metastatic hormone sensitive 
prostate cancer (mHSPC).  In recent years, the addition of docetaxel to ADT in mHSPC 
patients with high volume disease has been shown to improve overall survival.(4,5) In 
addition, suppressing adrenal androgen synthesis via abiraterone acetate also improved 
survival when combined with ADT.  However, many men find it difficult to tolerate 
treatment-related toxicities, including sexual impotency, decreased libido, hot flashes, and 
weight gain.  For instance, in the STAMPEDE trial, 99% of patients on the ADT only arm 
experienced any Grade 1-5 adverse event (32% of patients experienced a Grade 3-5 adverse 
event).(4)  These symptoms can persist with the development of castration resistance.  


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Treatment with non-AR targeted agents, such as PARPi, may avoid or delay the toxicities of 
hormonal therapy. 
1.2 
Treatment Background 
1.2.1 
Description and mechanism of action 
Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) functions in the DNA repair 
pathway, specifically by serving in base excision repair of DNA single strand breaks.  
Inhibition of PARP results in inability for cells to repair single strand breaks.  Cells normally 
would employ the error-free homologous recombination pathway to repair such defects.  
However, in tumors that harbor defects in these DNA repair genes (such as BRCA1/2), the 
strand breaks lead to chromosomal instability and eventually cell death (6).   
 
Rucaparib (CO-338) is a small molecule inhibitor of PARP being developed for the 
treatment of ovarian cancer and other solid tumor malignancies associated with 
homologous recombination deficiency (HRD). Rucaparib has been shown to potently inhibit 
PARP-1, PARP-2, and PARP-3 and has demonstrated activity in a background of breast 
cancer gene 1 and 2 (BRCA1 and BRCA2) mutations in both clinical and nonclinical studies. 
 
1.2.2     Nonclinical activity 
Investigators should be familiar with the current rucaparib (CO-338) Investigator Brochure 
(IB). 
 
Pharmacology 
Rucaparib is a potent, oral small molecule inhibitor of PARP enzymes, including PARP-1, 
PARP-2, and PARP-3, which play critical roles in DNA repair. Rucaparib has shown to have 
in vitro and in vivo anti-tumor activity in BRCA1 and BRCA2 homozygous mutant cell lines. 
These findings provide a rationale for the clinical assessment of rucaparib as monotherapy 
in patients with hereditary (germline) and acquired (somatic) deficiencies of BRCA1 and/or 
BRCA2.  
 
Safety pharmacology studies showed that any adverse effects of rucaparib on 
cardiovascular or central nervous systems occurred at doses that were either 5-fold (motor 
activity in rats) or 10-fold (in vitro hERG assay) higher than the clinical dose of 600 mg 
twice daily (BID). There were no adverse cardiovascular effects observed in dogs. Effects on 
the respiratory system were evaluated within repeat-dose toxicity studies in dogs and 
showed no effects on vital signs or respiration rate.  
Pharmacokinetics, Metabolism, and Drug-Drug Interaction Potential 
Rucaparib pharmacokinetics (PK) and metabolism, and potential factors affecting these 
parameters were evaluated in vitro and in animals. A single oral dose of rucaparib in mice, 
rats, and dogs demonstrated a time to maximum plasma concentration (Tmax) of 2 to 8 hours 
and an absolute oral bioavailability (F) of 17% to 75%. Toxicokinetic evaluations from 1- 
and 3-month repeat-dose toxicity studies in rats and dogs, and a dose-range-finding 
embryo-fetal development study in pregnant rats, showed dose-dependent increases in 
exposure and no marked sex-related differences or significant accumulation after repeat 
oral administration.  
 


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In vitro plasma protein binding studies in mouse, rat, and dog plasma showed moderate 
binding and ranged from 49.5% to 66.8%. Plasma protein binding in humans was 70.2% at 
clinically observed plasma rucaparib concentrations.  
Following a single oral dose of [14C] rucaparib in male and female Sprague-Dawley rats, 
rucaparib-derived radioactivity was well distributed into tissues with concentrations higher 
than that in blood at all monitored time points. The tissues with the highest radioactive 
concentrations were cecum, kidney medulla, adrenal gland medulla, stomach, liver, and 
small intestine. Concentrations in most tissues were below or near the lower limit of 
quantification by 7 days postdose, except for liver, kidney (cortex and medulla in male, 
medulla in female), testis, uterus, ovary, and adrenal gland (cortex in male and cortex and 
medulla in female). 
Following a single oral dose of [14C] rucaparib in male pigmented Long-Evans rats, the 
rucaparib-derived radioactivity was well distributed into tissues. The radioactivity 
distribution pattern in pigmented and albino rats was qualitatively similar, with the 
exception of the uveal pigment of the eyes and the pigmented skin where a higher 
concentration of radioactivity was observed, suggesting an association of radioactive drug-
related material with melanin. At 7 days and 50 days after dosing, radioactivity was still 
detectable in the pigmented skin and uveal pigment of the eyes, respectively.  
Rucaparib is not extensively metabolized in vitro. In vitro recombinant CYP phenotyping 
results indicated that CYP2D6, and to a lesser extent, CYP1A2 and CYP3A4, have the ability 
to metabolize rucaparib.  
Following oral administration of [14C] rucaparib camsylate to male and female intact 
Sprague-Dawley rats, 93.0% to 94.7% of the dose was recovered in feces and 5.7% to 7.3% 
of the dose was recovered in urine. Following oral administration of [14C] rucaparib 
camsylate to beagle dogs, approximately 89% of the dose was recovered by 168 hr 
postdose. Fecal excretion was the major elimination route, with the mean dose recovery of 
81% and 77% in males and females, respectively, and approximately 6% in urine in both 
males and females. 
In vitro, rucaparib reversibly inhibited CYP1A2, CYP2C19, CYP2C9, and CYP3A, and to a 
lesser extent CYP2C8, CYP2D6, and UGT1A1. Rucaparib induced CYP1A2, and down 
regulated CYP2B6 and CYP3A4 in human hepatocytes at clinically relevant exposures.  
Two in vitro studies using human liver microsomes and specific P450 probe substrates 
were conducted to evaluate the ability of rucaparib to inhibit 8 CYP isoforms (CYP1A2, 
CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). Based on the more 
conservative potency observed in the two studies, and in order of decreasing potency, 
rucaparib reversibly inhibited CYP1A2 (IC50 = 3.55 M), CYP2C19 (IC50 = 5.42 M), CYP2C9 
(IC50 = 12.9 M), CYP3A (IC50 = 17.2 to 22.9 M), CYP2C8 (Ki = 16.7 M), and CYP2D6 (IC50 = 
41.6 M).  
The direct inhibition potential of rucaparib on recombinantly expressed 
uridinediphosphoate-glucuronosyletransferase (UGT) 1A1 and UGT2B7 was evaluated. 
Rucaparib inhibited UGT1A1 with an IC50 of 31.9 M; no inhibition of UGT2B7 was observed 
(IC50>100 M). 


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Rucaparib is a substrate for both P-glycoprotein (P-gp) and the breast cancer resistance 
protein (BCRP) and has the potential to inhibit P-gp and BCRP in the gut.  
Rucaparib is a potent inhibitor of multidrug and toxin extrusion transporter (MATE) 1 and 
MATE2-K, and a moderate inhibitor of organic cation transporter (OCT) 1. Inhibition of 
MATE1, MATE2-K, and OCT2 has been reported to mediate renal excretion of creatinine in 
humans.(7,8) Given that the steady-state total Cmax of rucaparib at 600 mg BID was 13- and 
43-fold above IC50 value of MATE1 and MATE2-K, respectively, MATE1 and MATE2-K 
inhibition is considered a plausible mechanistic explanation for the mild to moderate 
creatinine elevations observed with rucaparib treatment.  
The effect of rucaparib co-administration on the PK of sensitive substrates of CYP1A2, 
CYP2C9, CYP2C19, CYP3A, and P-gp is currently being assessed in a cocktail-based drug-
drug interaction study in patients. The specific probe substrates being assessed are caffeine 
(CYP1A2), S-warfarin (CYP2C9), omeprazole (CYP2C19), midazolam (CYP3A4), and digoxin 
(P-gp). 
Toxicology 
Rucaparib was evaluated in single- and repeat-dose studies (up to 13 weeks) in both rats 
and dogs. Target organs included the hematopoietic system and gastrointestinal tract. No 
cardiovascular findings were noted in any of the oral toxicity studies. 
 
In vitro genetic toxicology assays demonstrated rucaparib to be clastogenic. Bacterial 
mutagenicity data for rucaparib were clearly negative in 4 microbial tester strains both with 
and without metabolic activation and equivocal in a fifth tester strain (TA98) in the absence 
of metabolic activation. 
In the non-GLP dose range finding, embryo-fetal development study in rat, rucaparib caused 
maternal toxicity at doses ≥ 500 mg/kg/day. Rucaparib was also found to be a selective 
developmental toxicant in that it was embryotoxic at all doses. 
Rucaparib was not phototoxic when administered to Long Evans pigmented rats orally at 
doses up to 750 mg/kg/dose, followed by a single exposure to solar-simulated ultraviolet 
radiation. 
1.2.3     Preclinical studies 
The anti-tumor activity of rucaparib at doses of 2, 5, 15, 50, and 150 mg/kg BID was 
evaluated in the orthotopic BRCA1 mutant MDA-MB-436 TNBC xenograft model (Figure 2). 
Rucaparib was generally well-tolerated; however, in the 150 mg/kg BID group, treatment-
related mortality was observed in 1 animal, and 3 animals had a dosing interruption of 2 to 
6 days due to body weight loss. Based on these observations, additional nutrient 
supplement was provided to all groups, and rucaparib was generally well-tolerated at all 
dose levels for the remainder of the study. Rucaparib administration resulted in dose-
dependent and statistically significant reduction in mean tumor volumes on the last day of 
dosing (Day 28) in all rucaparib treated groups, with > 100% tumor growth inhibition (TGI) 
observed in animals treated with 50 and 150 mg/kg BID. The tumors were monitored for 11 
days after dosing was terminated (Day 39), and dose- dependent and statistically significant 
TGI was also observed in all rucaparib treated groups.  


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Figure 2 – Efficacy of Single Agent Rucaparib in the MDA-MB-436 (BRCA1 Mutant) Orthotopic 
Xenograft Model 
In vivo studies were conducted to evaluate the anti-tumor effects of rucaparib as a single 
agent in the BRCA2 mutant HBCx-17 and BRCA wild-type HBCx-6 TNBC PDX models. Both 
models have mutated TP53. Rucaparib was administered at doses of 50 mg/kg QD, 150 
mg/kg QD, and 150 mg/kg BID for 24 and 28 days in the HBCx-17 and HBCx-6 models, 
respectively. Minimal body weight loss was observed in all rucaparib-treated groups. 
Rucaparib treatment at all doses evaluated resulted in significant reduction in tumor 
growth, with mean tumor/control (T/C) volumes ranging from 7.0% to 15.2% and 0.6% to 
14.7% in the HBCx-17 and HBCx-6 models, respectively. In both studies, tumors were 
monitored for 13 to 15 days after rucaparib dosing was discontinued. In the HBCx-17 
model, 50% of the mice treated with 150 mg/kg BID rucaparib had a PR or CR, whereas in 
the HBCx-6 model 100% of the mice treated with 150 mg/kg QD or 300 mg/kg BID 
rucaparib had a PR or CR.  
The efficacy of 150 mg/kg BID rucaparib was evaluated in the PAXF 1876, PAXF 2005, and 
PAXF 2094 pancreatic PDX models that have deleterious BRCA2 frame shift mutations. The 
median body weight loss in rucaparib treated groups in the 3 studies ranged from 2.5% to 
9% as compared to 0% to 5.8% in the groups receiving the vehicle control. On Day 28 of 
dosing, rucaparib showed differential sensitivity in the 3 models, with a T/C of 4.5%, 26.1%, 
and 55.6% for the PAXF 2005, PAXF 2094, and PAXF 1876 models, respectively.  
1.2.4    Clinical studies 
Rucaparib has been evaluated in Phase 1 and 2 clinical studies and is being evaluated in 
ongoing Phase 2 and Phase 3 clinical studies. The early clinical program assessed safety and 
efficacy of rucaparib in patients with malignancies commonly treated with 
chemotherapeutic agents.  
 
Initially, an intravenous [IV] formulation of rucaparib was administered in combination 
with a variety of chemotherapies; later, the oral formulation of rucaparib was administered 
in combination with chemotherapy and as a monotherapy. The oral formulation as 
monotherapy is the focus of current development efforts. The IV formulation is no longer in 
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Four studies (A4991002, A4991005, A4991014, CO-338-023 [RUCAPANC]) have been 
completed and 8 studies (CO-338-010, CO-338-014 [ARIEL3], CO-338-017 [ARIEL2], CO-
338-044 [DDI], CO-338-043 [ARIEL4], CO-338-045 [ADME], CO-338-052 [TRITON2], and 
CO-338-063 [TRITON3]) are ongoing.  
 
Details of all completed, ongoing, and planned studies are described briefly below. 
Additional information is provided in the rucaparib IB.  
 
Completed Studies  
• 
A4991002: a Phase 1 open-label, dose-escalation study of IV rucaparib in combination with 
temozolomide (TMZ) in patients with advanced solid tumors (Part 1) or malignant 
melanoma (Part 2).  
• 
A4991005: a Phase 2, open-label study of IV rucaparib in combination with TMZ in patients 
with metastatic melanoma.  
• 
A4991014: a Phase 1, open-label, dose-escalation study of IV and oral rucaparib 
administered with different chemotherapeutic agents in patients with an advanced solid 
tumor.  
• 
CO-338-023 (RUCAPANC): a Phase 2, single-arm, open-label study of monotherapy oral 
rucaparib as treatment for patients with previously treated locally advanced or metastatic 
pancreatic ductal adenocarcinoma and a known deleterious BRCA mutation. 
Ongoing Studies 
• 
CO-338-010: 3-part, open-label, Phase 1/2 study of monotherapy oral rucaparib. 
o Part 1: a Phase 1 portion evaluating PK and safety of escalating doses of rucaparib in 
patients with solid tumors; this portion identified 600 mg twice daily (BID) as the 
recommended starting dose for future studies (n = 56; completed). 
o Part 2: a Phase 2 portion evaluating the efficacy and safety of rucaparib in patients 
with relapsed, high-grade ovarian cancer associated with a BRCA mutation.  
▪ 
Part 2A enrolled patients with a gBRCA mutation who had received 2 to 4 
prior treatment regimens (n = 42; enrollment complete).  
▪ 
Part 2B enrolled patients with a gBRCA or sBRCA mutation who received at 
least 3 prior chemotherapy regimens (n = 9 as of the 27 June 2016 cut-off 
date [closed to enrollment on 1 July 2016]).  
o Part 3: a Phase 2 portion in patients with a relapsed solid tumor associated with a 
BRCA mutation in order to characterize the PK, food effect, and safety profile of a 
higher dose strength tablet (n = 26; enrollment complete). 
• 
CO-338-017 (ARIEL2): a 2-part open-label Phase 2 study of monotherapy oral rucaparib for 
treatment of relapsed, high-grade ovarian cancer patients. It is designed to identify tumor 
characteristics that may predict sensitivity to rucaparib. Patients will be classified into 
molecularly-defined subgroups, including tumor BRCA (tBRCA, inclusive of both germline 
and somatic BRCA) and BRCA-like, by a prospectively defined genomic signature.  
o Part 1 enrolled patients with platinum-sensitive, relapsed disease who received ≥ 1 
prior platinum regimen (n = 204; enrollment complete).  
o Part 2 is enrolling patients with relapsed disease who received at least 3 prior 
chemotherapy regimens (n = 262 as of the 27 June 2016 cut-off date [closed to 
enrollment on 29 July 2016]).  
• 
CO-338-014 (ARIEL3): a Phase 3, randomized, double-blind study of monotherapy oral 
rucaparib versus placebo as switch maintenance treatment in patients with platinum-
sensitive-, relapsed, high-grade ovarian cancer who achieved a response to platinum-based 


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chemotherapy (n = 560 as of the 27 June 2016 cut-off date [closed to enrollment on 19 July 
2016]).  
• 
CO-338-044 (DDI study): a 2-part, Phase 1, open-label, multiple-probe drug-drug 
interaction (DDI) study to determine the effect of rucaparib on PK of caffeine, S-warfarin-, 
omeprazole, midazolam, and digoxin in patients with advanced solid tumors in Part 1, 
followed by optional continued treatment with rucaparib in Part 2 (n = 5; enrollment 
ongoing). 
• 
CO-338-043 (ARIEL4): a phase 3 study evaluating rucaparib versus chemotherapy as 
treatment for patients with relapsed high-grade ovarian cancer associated with a 
deleterious BRCA1/2 mutation 
• 
CO-338-045 (ADME): a 2-part open-label Phase 1, single-dose study of the disposition of 
[14C]-radiolabel rucaparib in patients with advanced solid tumors, with the option to 
continue rucaparib therapy. 
• 
CO-338-052 (TRITON2): a Phase 2 study evaluating rucaparib efficacy in mCRPC whose 
tumors are associated with HRD by enrolling mCRPC patients with mutations in BRCA1/2, 
ATM, or other HR genes. All patients will be required to have progressed on prior AR-
targeted therapy (abiraterone acetate, enzalutamide, or investigational AR-targeted agent) 
and also have progressed after one prior taxane-based chemotherapy for mCRPC. 
CO-338-063 (TRITON3): a Phase 3, randomized, 2-arm study evaluating rucaparib vs. 
physician’s choice (abiraterone acetate, enzalutamide or docetaxel) in patients with mCRPC 
associated with a deleterious BRCA1/2 or ATM mutation (n = ~300). 
1.2.5     Clinical safety summary 
Treatment-related adverse events (AEs; all grades) reported in ≥15% of patients treated 
with 600 mg BID rucaparib include gastrointestinal and related symptoms (nausea, 
vomiting, dysgeusia, and abdominal pain), anemia, asthenia/fatigue, neutropenia, 
thrombocytopenia, and headache. Elevated alanine aminotransferase (ALT) and/or 
aspartate aminotransferase (AST) levels were also reported. Elevations of ALT/AST 
occurred early (within first 2-4 weeks of treatment), were generally mild to moderate 
(Grades 1-2), not accompanied by any significant changes in bilirubin levels, often transient, 
and resolved to within normal ranges or stabilized. As has been observed with rucaparib 
and other PARP inhibitors, myelosuppression may be delayed and observed after a period 
of continuous dosing. All treatment-related AEs were successfully managed with 
concomitant medication and treatment interruption and/or dose reduction, or supportive 
care (in the case of myelosuppression AEs). 
 
Extensive centrally reviewed electrocardiogram (ECG) monitoring was conducted in the 
Phase 1 portion of Study CO-338-010 and results are available for 55 of 56 treated patients. 
No patient had a QTcF measurement ≥ 500 msec and only 1 patient had a QTcF 
measurement ≥ 480 msec. This measurement occurred in a patient receiving 480 mg BID 
rucaparib and concomitant administration of citalopram, a medication with known 
potential to cause QT prolongation. This patient continued to receive rucaparib 
monotherapy at a dose of 480 mg BID with no further QTcF measurement ≥ 480 msec. Only 
1 patient had a QTc increase from baseline > 60 msec. This patient had a history of QT 
prolongation prior to study entry and received 1 dose of rucaparib before discontinuing 
from the study due to eligibility violation. Overall, rucaparib in doses up to 840 mg BID 
exhibited a mean change of QTcF from baseline of 11.3 msec at the maximum concentration 
(5565 ng/mL) observed in the study. At a dose of 600 mg BID, the mean values for change of 


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QTcF in Cycle 1 ranged from 5.0 to 14.0 msec. Overall, the alteration of the mechanism of 
repolarization was minimal. There were no AEs suggestive of cardiac arrhythmia (eg, 
presyncope, syncope, sudden death) in any patient.  
1.3 
Rationale 
1.3.1 
Rationale for conducting the study 
Much of the early work studying mechanism of action and efficacy of PARPi has been done 
in ovarian and breast cancer due to the well-characterized incidence of BRCA1/2 mutations 
in these cancers.  However, somatic mutations in DNA-repair genes have been identified in 
both primary(9) and metastatic castration-resistant prostate cancer (mCRPC)(10), with 
prevalence rates of approximately 5-10% in localized prostate cancer and 20-25% in 
metastatic castration-resistant prostate cancer (mCRPC).   
These findings served as the rationale to test PARPi (olaparib) in heavily pre-treated 
mCRPC (TOPARP-A trial, Mateo et al., NEJM 2015).(1) Although the presence of a DNA-
repair defect in the tumor was not an eligibility requirement, the response rate to olaparib 
was 33% in the unselected population (16 of 49; 95% CI 20-48%), including a PSA decline 
of over 50% (PSA50) in 10/49 patients.  The trial did identify somatic and germline 
mutations in DNA-repair genes, and the presence of a DNA-repair defect correlated with 
improved response rates (88% vs. 6%) as well as improved progression-free (9.8 vs. 2.7 
months) and overall (13.8 vs. 7.5 months) survival compared to DNA-repair proficient 
cancers.  Notably, all 7 patients with a BRCA2 mutation achieved a PSA50 response and 4/5 
patients with an ATM mutation had a clinical response to olaparib.  The most pronounced 
responses were observed in those patients with germline, inactivating mutations in BRCA2, 
most of which also had somatic loss-of-heterozygosity of the second allele in the tumor.  
Several studies are now ongoing to confirm PARPi as a potential treatment strategy for 
mCRPC either as a single agent (NCT01682772) or in combination with next-generation 
hormonal therapies (NCT01576172, NCT02500901). The FDA recently announced 
breakthrough designation for olaparib in patients with mCRPC refractory to novel hormonal 
therapy, with germline or somatic mutations in BRCA1/2 or ATM.  
With respect to germline mutations, a recent study found that the incidence of inherited 
DNA-repair gene alterations in metastatic prostate cancer to be significantly higher (11.8%) 
than in both men with localized prostate cancer (4.6%) and in the general population at 
large (2.7%).(11) Specifically, mutations in 7 genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, 
RAD51D, GEN1) were significantly enriched in patients with metastatic prostate cancer 
compared to the general population. These findings suggest that a subset of men are more 
likely to develop metastatic prostate cancer (i.e. those with germline mutations in DNA-
repair genes) and may potentially benefit from PARPi therapy.  
The clinical activity of PARPi in patients with DNA-repair mutations and metastatic prostate 
cancer has now been established. We hypothesize that targeted therapy with PARPi should 
be sufficient to induce a clinical response irrespective of hormonal (castration-sensitive or 
castration-resistant) or metastatic (M1 or M0 ) status.  Our hypothesis is based largely on 
the data from Mateo et al showing a clinical response rate of 88% in a heavily pre-treated 
population of mCRPC patients with a DNA repair mutation, with the most pronounced 
responses being in men with germline inactivation.  For men with either BCR or mHSPC, 
this trial would also provide an alternative to ADT.  Identification of a non-hormonal based 
therapy is warranted as ADT is associated with a shorter time to castration resistance in 
men harboring a germline DNA repair mutation versus those with intact DNA repair.(12) 


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However, given that primary ADT (in mHSPC and in certain instances of high-risk BCR) is a 
standard first-line therapy, all patients on trial must be ineligible for or decline standard-
of-care hormonal treatment.  For patients with mHSPC who do not respond to PARPi, we 
will build safety rules into the trial design to take patients off study at first signs of 
progression.  Primary ADT would still remain a treatment option upon progression. 
 
1.3.2 
Rationale for dosage selection 
Rucaparib will be administered at a dose of 600mg by mouth twice daily in tablet 
formulation.  This is the FDA-approved dose of rucaparib described in the USPI. 
1.3.3 
Rationale for correlative studies 
1.3.3.1 Genetic mutation analysis in tumor 
We hypothesize that inactivation or loss of the second allele in the gene of interest 
(i.e. homologous recombination gene with germline mutation) is required for 
response to PARPi.  Tumors will be analyzed using the FoundationOne platform by 
Foundation Medicine  (Cambridge, MA).  This test sequences provides mutation 
analysis in 315 selected genes and rearrangement analysis in 28 genes.  The genes 
include those commonly mutated (BRCA2, ATM, BRCA1, etc.).  The analysis provides 
a depth of coverage of 500X, and is reported by variant analysis with regard to likely 
pathogenicity.  By cataloging the mutations present in the primary tumors for 
subjects in the study, correlative analysis associating response with specific 
mutations can be performed.  The testing will be inclusive of a sub-panel of genes of 
particular interest (BRCA1, BRCA2, ATM, CHEK2, NBN, BRIP1, RAD50, RAD51C, 
RAD51D, PALB2, MRE11, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, 
FANCI, FANCL, and FANCM).  We will also collect and examine ctDNA before 
treatment and at progression.  Reversion mutations are a known mechanism of 
resistance to PARP inhibitors, which may give insight into the etiology of clinical 
progression while on rucaparin in this clinical setting. 
1.3.3.2 mRNA expression array analysis in tumor 
An alternative possibility for tumor sensitivity to rucaparib is through epigenetic 
gene expression changes that may not be identified through genetic mutation 
analysis alone.  In conjunction with the DNA mutation testing planned to be 
performed through Foundation Medicine, subjects will have tissue tested for RNA 
expression arrays for associating response to rucaparib.  For this assay, samples will 
be tested by GenomeDx (San Diego, CA) using the Decipher GRID microarray 
platform.  The gene expression profile will be inclusive of a metastasis signature and 
PARP-sensitivity signature.  The metastatic signature has been validated in a cohort 
of patients with high risks for recurrence after primary prostate cancer therapy 
(13,14), as well as in a cohort of patients undergoing salvage radiation therapy after 
biochemical recurrence of prostate cancer (15).  A post-hoc analysis will be 
performed to evaluate these signatures, and further determine a gene expression 
profile that predicts response to rucaparib. 
1.3.3.3 PARP-1, PARP-2, γH2AX, RAD51, 53BP1 mRNA/ protein levels in tumor 
Beyond the underlying genetic mutations in DNA repair genes and the associated 
RNA expression profiles, we are exploring whether baseline assessment of the 
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RNA in situ hybridization is predictive of response.  γH2AX, RAD51, and 53BP1 are 
proteins that serve as a marker for double strand DNA breaks.  PARP-1 is the 
primary molecular target for rucaparib. 
 
 
2. OBJECTIVES 
2.1 
Primary Objective 
The primary objective is to estimate the PSA response rate (PSA50) to rucaparib in 
homologous repair-deficient patients with either metastatic hormone sensitive prostate 
cancer (mHSPC) or high-risk biochemical recurrence.  This will serve as an initial 
exploration of rucaparib’s activity in these disease states. 
2.2 
Secondary Objectives 
• 
Safety/Tolerability, defined as incidence of CTCAE v5.0 grade ≥3 toxicities experienced by 
patients on the trial. 
• 
PSA progression-free survival, defined as a time from initiation on rucaparib therapy until 
PSA increase of 25%, confirmed with another measurement at least 4 weeks later (PCWG3). 
• 
Progression-free survival: time to radiographic or clinical progression or death, whichever 
comes first.  Based on RECIST version 1.1 and PCWG3 definitions including: 1. Progression 
of soft tissue lesions according to RECIST 1.1; 2. Progression of bony lesions detected by 
bone scan according to PCWG3 criteria; 2. Radiographically-confirmed spinal cord 
compression or pathological fracture due to malignant progression, or other clinical event 
deemed to be cancer-related. 
• 
Objective response rate, defined as the proportion of patients with measurable disease at 
baseline, achieving a complete/partial response in target lesions (RECIST 1.1). 
 
2.3 
Correlative/Exploratory/Tertiary Objectives 
• 
To measure the quantitative change in gamma-H2AX, RAD51, 53BP1 formation in tumor 
tissue following treatment with rucaparib (only in patients undergoing biopsy). 
• 
To develop an mRNA expression signature associated with response to rucaparib. 
• 
To estimate the percentage of patients with a loss-of-function mutation or total allelic loss 
of second (somatic) gene allele (i.e. biallelic inactivation). 
• 
To investigate any association between PARP-1 and PARP-2 protein and mRNA expression 
levels in tumor with response to rucaparib. 
• 
To investigate any association between acquired reversion mutations with clinical 
progression on rucaparib. 
 
3. 
PATIENT SELECTION 
3.1 
Target Population 
The target population is men with hormone sensitive prostate cancer, either biochemically 
recurrent or metastatic.  All patients must have an mutation in a homologous recombination 
DNA repair gene (BRCA1, BRCA2, ATM, CHEK2, NBN, BRIP1, RAD50, RAD51C, RAD51D, 
PALB2, MRE11, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, 
FANCM). 


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3.2 
Expected Enrollment 
A total of 30 patients will be included in this study. Of these, we will include up to a 
maximum of 10 patients with non-BRCA1 or -BRCA2 mutations in this study.  This will 
ensure a minimum of 20 men with BRCA1/BRCA2 mutations.  The first patients are expected 
to be enrolled in May 2018. Accrual is expected to be completed in 24 months once the 
protocol has been approved by the IRB at each participating institution. 
3.3 
Inclusion Criteria 
To be included in this study, patients should meet all of the following criteria: 
• 
Willing and able to provide written informed consent and HIPAA authorization for 
the release of personal health information. 
NOTE: HIPAA authorization may be either included in the informed consent or 
obtained separately. 
• 
Males aged 18 years of age and above 
• 
Histological or cytologic proof of adenocarcinoma of the prostate  
• 
Pathogenic mutation in one or more homologous recombination DNA-repair genes 
(BRCA1, BRCA2, ATM, CHEK2, NBN, BRIP1, RAD50, RAD51C, RAD51D, PALB2, MRE11, 
FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM) as 
documented by a clinical CLIA-grade, saliva, tissue or blood-based (i.e leukocyte 
DNA) genetic or molecular test (including but not limited to Invitae, Foundation 
One, Color Genomics, etc). Germline and/or molecular testing will not be offered as 
an eligibility screen. 
• 
All patients must be ineligible for or have declined androgen deprivation therapy 
(ADT)-based systemic treatment, if indicated  
• 
Absolute PSA ≥2.0 ng/ml at screening.   
• 
Either (1) Metastatic disease as defined for one or more bone metastases confirmed 
by bone scintigraphy or radiographic soft tissue metastasis by CT and/or bone scan, 
performed within 8 weeks.. Or (2) biochemically recurrence disease as defined by a 
PSA >0.2 ng/ml post prostatectomy or a PSA rise of 2ng/ml or more from the nadir 
after radiation therapy. 
• 
Serum testosterone ≥ 100 ng/dl. 
• 
Participants must have normal organ and bone marrow function measured within 
28 days prior to administration of study treatment as defined below: 
o Hemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days   
o Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
o Platelet count ≥ 100 x 109/L 
o Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) 
o Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) < 3.0 x 
institutional upper limit of normal  


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Note: Patients with elevations in bilirubin, AST, or ALT should be thoroughly 
evaluated for the etiology of this abnormality prior to entry and patients 
with evidence of viral infection should be excluded. 
o Participants must have creatinine clearance estimated using the Cockcroft-
Gault equation of ≥51 mL/min: 
Estimated creatinine clearance = 
(140-age [years]) x weight (kg) 
 
 
 
 
 
 
serum creatinine (mg/dL) x 72 
Note: Patients with creatinine clearance between 51- 80 mL/min either at trial 
enrolment or during the course of the trial should be monitored every 2 weeks 
for laboratory assessment and toxicity evaluation. 
• 
ECOG Performance Status <2(Appendix A: Performance Status Criteria) 
• 
Participants must have a life expectancy ≥ 12 months. 
• 
Male participants and their partners, who are sexually active and of childbearing 
potential, must agree to the use of two highly effective forms of contraception in 
combination [see appendix E for acceptable methods], throughout the period of 
taking study treatment and for 6 months after last dose of study drug to prevent 
pregnancy in a partner. 
3.4 
Exclusion Criteria 
Patients that meet any of the criteria listed below will not be eligible for study entry: 
• 
Current active second malignancy (history of non-melanoma skin cancers and 
superficial bladder cancers are allowed) 
• 
Prior ADT in the past 6 months.  Prior ADT in context of neoadjuvant/adjuvant 
primary is allowed; prior ADT for biochemical recurrence is also allowed, as long as 
no ADT has been administered in past 6 months and testosterone has recovered 
(>100 ng/dl).  The total duration of prior ADT should not exceed 24 months. 
• 
Prior treatment with anti-androgens (e.g., bicalutamide, nilutamide, enzalutamide, 
apalutamide) or androgen synthesis inhibitors (e.g., abiraterone, orteronel) at 
therapeutic dosing for more than one month within the past 6 months is not 
permitted. If used for less than one month, the subject may be enrolled.  The use of 
5-alpha reductase inhibitor therapy (e.g., finasteride, dutasteride) is allowed, as long 
as the subject has been on a steady dose of the medication for the past 6 months and 
has tolerated it satisfactorily. 
• 
Presence of visceral (i.e. lung or liver) metastases >3cm in long-axis dimension. 
• 
Pain due to bone metastases requiring narcotic analgesics. 
• 
Prior treatment with intravenous chemotherapy. 
• 
Use of any prohibited concomitant medications (Appendix B: Medications With the 
Potential for Drug-Drug Interactions) within the prior 2 weeks. 
• 
Involvement in the planning and/or conduct of the study (applies to both Clovis 
Oncology staff and/or staff at the study site) 
• 
Previous enrollment in the present study 


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• 
Participation in another clinical study with an investigational product during the 
last 1 month. 
• 
Any previous treatment with a PARP inhibitor, including rucaparib. 
• 
Resting ECG with QTc > 480 msec on 2 or more time points within a 24 hour period 
or family history of long QT syndrome 
• 
Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) 
grade 2) caused by previous cancer therapy, excluding alopecia. 
• 
Patients with myelodysplastic syndrome/acute myeloid leukemia or with features 
suggestive of MDS/AML. 
• 
Major surgery within 2 weeks of starting study treatment, and patients must have 
recovered from any effects of any major surgery. 
• 
Poor medical risk due to a serious, uncontrolled medical disorder, non-malignant 
systemic disease or active, uncontrolled infection.  Examples include, but are not 
limited to, uncontrolled ventricular arrhythmia, recent (within 6 months) 
myocardial infarction, uncontrolled major seizure disorder, extensive interstitial 
bilateral lung disease, or any psychiatric disorder that prohibits obtaining informed 
consent. 
• 
Unable to swallow orally administered medication or gastrointestinal disorders 
likely to interfere with absorption of the study medication. 
• 
Immunocompromised patients, e.g., patients who are known to be serologically 
positive for HIV. Known active hepatitis (i.e. Hepatitis B or C) due to risk of 
transmitting the infection through blood or other body fluids 
• 
Known hypersensitivity to rucaparib or any of the excipients of the product. 
• 
Whole blood transfusions in the last 30 days prior to entry to the study. 
4. 
PATIENT REGISTRATION AND ENROLLMENT PLAN 
4.1 
Registration Procedure 
After eligibility screening and confirmation that a patient is eligible, patients who are 
selected to participate will be registered with the Lead Center Johns Hopkins, with their 
local study site/institution. A record of patients who fail to meet entry criteria (i.e., screen 
failures) will be maintained. Patient registration must be complete before beginning any 
treatment or study activities. A complete, signed study consent and HIPAA consent are 
required for registration. 
4.1.1 
Registration at Johns Hopkins 
Confirm eligibility as defined in Section 3. 
Patient Selection.  
Obtain informed consent, by following procedures in Section 11.3 
Written 
Informed Consent. 
Patient will be entered into CRMS system and enrolled in trial.  
4.1.2 
Multicenter/Participating site registration 
Central registration for this study will take place at Johns Hopkins. 


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Patient registration at each study site/institution will be conducted according to the 
institution’s established policies. Before registration, patients will be asked to sign 
and date an Institutional Review Board (IRB)-approved consent form and a research 
authorization/HIPAA form. Patients must be registered with their local 
site/institution and also with the sponsor or Lead Site before beginning any 
treatment or study activities. 


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5. 
TREATMENT/INTERVENTION PLAN 
The following assessments and procedures will occur during the study. A schedule of assessments is provided in Table 1. 
Table 1 Study Calendar 
Abbreviations: CBC, complete blood count; CT, computerized tomography; MRI, magnetic resonance imaging; PSA, prostate-specific antigen 
a 
Informed consent and radiologic assessments should be obtained within 8 weeks of study start date.  EKG should be obtained within 28 days of study start date. 
b 
Radiographic evaluations (CT A/P and NM Bone Scan) every 3 months (if metastatic disease) or every 6 months (for BCR) while enrolled in the study).  They are needed within 8 weeks of 
screening; if previously performed then they are to be performed at screening.  CT A/P and NM Bone Scan are to be performed at off-treatment visit if they have not been performed in the prior 
month. 
c 
CBC w/diff, Complete Metabolic Panel, PSA, lipid panel at each visit.  Testosterone, PT/INR, PTT, and Urinalysis at screening visit only and should be obtained within 28 days of study start date. 
d 
Subjects will be followed after completion of rucaparib therapy monthly until toxicities resolve to grade 0-1. No post treatment follow up visit needed otherwise.  
e 
Only for patients with metastatic disease: MANDATORY soft tissue Core tumor biopsy performed pretreatment (Day -7 +/- 7 days), bone biopsies are optional at pretreatment.  OPTIONAL soft 
tissue and bone tumor biopsy on C4D1 (+/- 7 days)  
f 
C1D1 routine labs (CBC w/diff, Comprehensive Metabolic Panel, PSA, lipid panel) are only required if >7 days since screening labs.   
g               ctDNA will be collected once at before starting treatment and once at the time of progression. 
 
  
Pre-
study 
Study Period 
On Treatment Assessments (Every 28 days)I 
Off Treatment / Follow-up 
 
Day -7a, h 
C1D1h (±3 
d) 
C2D1h (±3 d) 
C3D1h (±3 d) 
CnD1h (±3 d) 
 
Every 28 days d, h 
(±3 d) 
(±7days) 
Informed consent 
X 
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
Medical history 
X 
  
  
  
  
  
EKG 
X 
  
  
  
  
  
Focused Medical history 
  
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
Vital signs (P, BP, RR, T) 
X 
X 
X 
X 
X 
X 
Height 
X 
  
  
  
  
  
Weight 
X 
X 
X 
X 
X 
X 
Performance status 
X 
  
X 
X 
X 
X 
Toxicity assessment 
X 
  
X 
X 
X 
X 
Concomitant meds 
X 
X 
X 
X 
X 
X 
Metastatic tumor biopsy  
Xe 
  
  
  
(X)e 
  
ctDNA (10ml) 
  
Xg 
  
  
  
Xg 
Radiologic testsb 
X 
  
  
  
Xb 
Xb 
Laboratory testsc 
X 
Xf 
X 
X 
X 
X 
Rucaparib 
  
X 
X 
X 
X 
  
Adverse events 
  
  
X 
X 
X 
X 


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h 
In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for inperson clinical trial visits or portions of clinical trial visits where determined to be appropriate 
and where determined by the investigator not to increase the participants risks. Prior to initiating telemedicine for study visits the study team will explain to the participant, what a telemedicine visit entails 
and confirm that the study participant is in agreement and able to proceed with this method. Telemedicine acknowledgement will be obtained in accordance with the Guidance for Use of Telemedicine in 
Research. In the event telemedicine is not deemed feasible, the study visit will proceed as an in-person visit. Telemedicine visits will be conducted using HIPAA compliant method approved by the Health 
System and within licensing restrictions. 
I        Patients who remain on treatment for >12 months can begin to have their clinic visits, safety labs (including CBC w/diff, Comp), PSA, and toxicity assessments  every 3 months. 
  
 
 
 
 
 
 
 
 
 
 


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5.1 
Screening/Pretreatment Assessment (Day -7 ± 7 days) 
Before initiating any screening activities, the scope of the study should be explained to each 
patient. Patients should be advised of any known risks inherent in the planned procedures, 
any alternative treatment options, their right to withdraw from the study at any time for 
any reason, and their right to privacy. After this explanation, patients should be asked to 
sign and date a Notice of Privacy Practice research authorization/HIPAA form and an IRB-
approved statement of informed consent that meets the requirements of the Code of 
Federal Regulations (Federal Register Vol. 46, No. 17, January 27, 1981, part 50).
The screening visit will determine patient eligibility according to the inclusion and 
exclusion criteria (sections 3.3 Inclusion Criteria & Exclusion Criteria). The following 
assessments will be performed at this visit:  
• 
obtain informed consent and research authorization 
• 
record demographics (including age) and medical history (including prior 
treatment for prostate carcinoma) 
• 
conduct physical exam (including vital signs, height/weight) 
• 
obtain histologic and radiologic confirmation of disease.  If radiographic studies 
have not been performed in prior 4 weeks, they must be obtained as part of 
screening 
• 
obtain history regarding prior treatment history for prostate cancer (including 
history of ADT, history of radiation therapy or other local therapy). 
• 
perform laboratory tests (Complete blood count w/Diff, PSA, Comprehensive 
metabolic panel, urinalysis, PT/INR, PTT, testosterone, lipid panel). 
• 
assess performance status (ECOG). (Appendix A) 
• 
Perform 12-lead EKG. ECGs are required within 14 days prior to starting study 
treatment and when clinically indicated. 
o Twelve-lead ECGs will be obtained after the patient has been rested in a 
supine position for at least 5 minutes in each case.  The Investigator or 
designated physician will review the paper copies of each of the timed 
12-lead ECGs on each of the study days when they are collected. 
o ECGs will be recorded at 25 mm/sec.  All ECGs should be assessed by the 
investigator as to whether they are clinically significantly abnormal / not 
clinically significantly abnormal.  If there is a clinically significant 
abnormal finding, the Investigator will record it as an AE on the eCRF.  
The original ECG traces must be stored in the patient medical record as 
source data. 
• 
determine suitability for rucaparib. 
• 
Confirm/schedule CT guided biopsy of a metastatic site of disease if applicable 
(i.e. soft tissue, lymph node, bone) – further described in section 5.1.1 
• 
Confirmation of a pathogenic mutation in a homologous recombination DNA 
repair gene of interest , as documented by a CLIA-grade, saliva, tissue or blood 
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PALB2, MRE11, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, 
FANCL, FANCM) is necessary prior to proceeding with enrollment.  
• 
discuss concurrent medications (see Appendix B for a listing of medications with 
the potential for drug interactions) 
 
Relevant information should be documented. The institutional registration should be 
finalized, and appropriate documents (i.e. signed informed consent, research 
authorization/HIPAA form, and supporting source documentation for eligibility questions) 
faxed or emailed to the lead site/sponsor.  
5.1.1 
Surgical Procedures 
A core needle biopsy of a metastatic site of disease, in those patients with metastatic 
disease, (soft tissue, lymph node, or bone) will be performed before C1D1 of 
treatment (Day -7 +/- 7 days).   Patients will be referred to the Johns Hopkins Biopsy 
Service for an image guided core biopsy.  At least 4 standard core biopsies should be 
obtained from a metastatic site (soft tissue, lymph node, or bone).  Fine needle 
aspiration is unlikely to yield adequate tumor tissue for molecular analysis, and should 
only be attempted when core biopsy is not feasible.  A unique identifier code system, 
in which no names and other personal healthy information will be used to identify 
the samples, will be used to assign a subject number to each of the biopsy samples.  
Each specimen of collected tissue will be submitted as formalin-fixed paraffin-
embedded (FFPE) tissue according to standard procedures.  To minimize tissue 
autolysis, a dedicated tissue technician will be called/paged to the biopsy room to 
initiate processing steps including FFPE preparation, which should be done within 
30 minutes of biopsy collection.  All samples will be evaluated for adequacy and 
assessment of tumor –to-normal ratio by the urologic pathologist on the study (Dr. 
Tamara Lotan).  FFPE specimens will be processed according to the standard FFPE 
procedures in the Pathology department. 
Special considerations for optional bone biopsies 
In patients with metastatic bone lesions only, the following guidelines should be 
considered when obtaining a bone biopsy.(16) These guidelines have been 
established by a Johns Hopkins musculoskeletal pathologist with over 30 years of 
experience interpreting bone biopsies. 
• 
Bone biopsies should preferably be obtained using CT guidance. 
• 
Osteolytic lesions should be targeted preferentially over osteoblastic 
lesions. 
• 
Metastases in the pelvic bones and long bones (e.g. femur, humerus) 
should be targeted preferentially over vertebral or rib metastases. 
• 
At least 4 cores from different zones of the lesions should be 
performed. 
• 
Bone biopsies should not be decalcified, due to degradation of 
nucleic acids during the decalcification process. 
5.1.1.1 Potential biopsy complications 
Potential complications include: infection, bleeding, and pain at the biopsy 
site. 


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5.2 
Treatment/Intervention Period (Day 1 of each 28 day cycle +/- 3 days, ongoing) 
Patients will be seen on D1 of each cycle of rucaparib (consisting of 28 days, +/- 3 days).  
The following assessments will be performed at each visit:  
• 
conduct physical exam (including vital signs, weight) 
• 
obtain any medical history changes from prior assessment 
• 
assess performance status (ECOG). (Appendix A) 
• 
review concurrent medications (see Appendix B for a listing of medications with 
the potential for drug interactions)  
• 
Patients who remain on treatment for >12 months can begin to have their clinic 
visits, safety labs (including CBC w/diff, Comp), PSA, and toxicity assessments  
every 3 months. 
 
 
5.2.1 
Clinical and laboratory assessments 
On Day 1 of each cycle, patients will have a non-fasting blood drawn for the 
following values:  Repeat labs are not needed on C1D1 as long as visit is within 7 
days of screening values. 
• 
CBC  
• 
Comprehensive chemistry panel 
• 
PSA 
• 
Lipid panel 
• 
ctDNA blood collection (10ml) (C1D1 only) 
Every 3 cycles for patients with metastatic disease or every 6 cycles for patients 
with BCR, patients will have radiographic studies: 
• 
CT Abdomen and Pelvis with contrast 
• 
NM Bone scan 
Laboratory Safety Assessments: 
Full hematology assessments for safety (hemoglobin, red blood cells [RBC], 
platelets, mean cell volume [MCV], mean cell hemoglobin concentration [MCHC], 
mean cell hemoglobin [MCH], white blood cells [WBC], absolute differential white 
cell count (neutrophils, lymphocytes, monocytes, eosinophils and basophils) and 
absolute neutrophil count or segmented neutrophil count and Band forms should be 
performed at each visit and when clinically indicated.  If absolute differentials not 
available, will check % differentials. Coagulation [activated partial thromboplastin 
time (APTT) and international normalized ratio (INR)] will be performed at baseline 
and if clinically indicated. 
Biochemistry assessments for safety (sodium, potassium, calcium, glucose, 
creatinine, total bilirubin, alkaline phosphatase [ALP], aspartate transaminase 
[AST], alanine transaminase [ALT], urea or blood urea nitrogen [BUN], total protein, 
albumin.• 


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Urinalysis by dipstick should be performed at baseline and then only if clinically 
indicated. Microscopic analysis should be performed by the hospital’s local 
laboratory if required. 
These tests will be performed by the hospital’s local laboratory.  Additional analyses 
may be performed if clinically indicated. 
Any clinically significant abnormal laboratory values should be repeated as clinically 
indicated and recorded on the eCRF. 
In case a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN please 
refer to Appendix F ‘Actions required in cases of combined increase of 
Aminotransferase and Total Bilirubin – Hy’s Law’, for further instructions 
5.2.2 
Surgical Procedures 
         
               A core needle biopsy will be performed on C4D1 +/- 7 days at the same site of      
 
 
metastatic disease previously biopsied at screening for patients with metastatic  
 
 
disease.  This biopsy is optional.  Further description of this biopsy can be found in  
 
 
section 5.1.1. 
5.2.3 
Safety assessments 
Adverse events (AEs) will be monitored at each scheduled visit and throughout the 
study. Toxicity will be assessed using the most recent National Cancer Institute 
(NCI) guidance: the most recent version of Common Terminology Criteria for 
Adverse Events (CTCAE).  
5.3 
Treatment-Limiting Adverse Event 
A treatment-limiting adverse event is any AE related to protocol therapy experienced 
during the study resulting in treatment termination. Such events include dose adjustments 
for each drug (i.e., increases, decreases, delaying, or omitting therapy) related to the AE 
after therapy has been initiated or AEs because of other therapies, such as surgery and 
radiation therapy. 
 
5.4 
Dosing and Dose Modifications 
 
5.4.1 Dosing 
Rucaparib camsylate (formerly known as PF-01367338 and AG-014447) is an oral 
formulation with a molecular weight of 555.67 Daltons. Rucaparib tablets for oral 
administration will be supplied by Clovis. A brief description of the investigational product 
is provided below. 
 


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Drug Name: 
Rucaparib 
 
 
 
 
 
 
 
 
INN: 
Rucaparib 
 
 
 
 
 
 
 
Formulation: 
Tablet; film coated; 200 mg, 250 mg, 300 mg 
 
 
 
 
 
 


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How Supplied: 
200, 250, and/or 300 mg strength (based on free base) in 
high-density polyethylene bottles or equivalent with child-
resistant caps. Patients may receive 1 or more strengths. 
Each bottle contains 60 tablets 
 
 
 
Storage 
Conditions: 
15–30 °C (59 and 86° F)  
 
 
 
Patients will take 600 mg rucaparib orally twice a day (BID), as close as possible to 12 hours 
apart 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.  If a patient 
misses a dose (i.e., 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. If vomiting occurs shortly after the rucaparib tablets 
are swallowed, the dose should only be replaced if all of the intact tablets can be seen and 
counted.   
Patients will be instructed to record daily doses taken or not taken in a patient diary. 
Treatment with rucaparib is continuous and each cycle will comprise 28 days. 
 
5.4.2 Dose Modifications 
Patients enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in 
Section 6. The most recent NCI CTCAE will be used to grade adverse events. 
At each study visit for the duration of their participation in the study, patients will be 
evaluated for adverse events (all grades), serious adverse events (SAEs), and adverse events 
that require study drug interruption or discontinuation. Patients discontinued from the 
treatment phase of the study for any reason will be evaluated approximately 30 days after 
the last dose of the study drug. 
5.4.2.1 Dose Modifications for Toxicities 
Any toxicity observed during the course of the study could be managed by interruption of 
the dose of study treatment or dose reductions.  
Patients who require an interruption in rucaparib for >2 weeks due to toxicity must 
discontinue study drug unless discussed with Protocol Chair.  


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Adverse events possibly related to study drug must be resolved to grade 1 or baseline prior 
to resumption of dosing. 
Study treatment can be dose reduced to 500 mg twice daily as a first step, to 400 mg twice 
daily as a second step and 300mg twice daily as a third step. If the reduced dose of 300 mg 
twice daily is not tolerable, no further dose reduction is allowed and study treatment should 
be discontinued.  
Once dose is reduced, escalation is not permitted. 
5.4.2.1.1 Management of hematological toxicity 
Management of anemia 
Table 2 
Management of anaemia 
Haemoglobin 
Action to be taken 
Hb < 10 but ≥ 8 g/dl 
(CTCAE Grade 2) 
Give appropriate supportive treatment and investigate causality.  
Investigator judgement to continue rucaparib with supportive treatment 
(e.g. transfusion) or interrupt dose for a maximum of 2 weeks.  
If repeat Hb< 10 but ≥ 8 g/dl, dose interrupt (for max of 2 weeks) until Hb 
≥ 10 g/dl and upon recovery dose reduction to 500 mg twice daily as a 
first step and to 400 mg twice daily as a second step may be considered. 
Hb < 8 g/dl 
(CTCAE Grade 3) 
Give appropriate supportive treatment (e.g. transfusion) and investigate 
causality.  
Interrupt rucaparib for a maximum of 2 weeks until improved to Hb ≥ 10 
g/dl. 
Upon recovery dose reduce to dose should be reduced to 500 mg twice 
daily as first step. If the reduced dose of 500 mg twice daily is not 
tolerable, further dose reduction to 400mg BID as a second step may be 
considered. 
 
Common treatable causes of anemia (e.g., iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed. In some cases 
management of anemia may require blood transfusions.  
 
Management of neutropenia, leukopenia and thrombocytopenia 
Table 3 
Management of neutropenia, leukopenia and thrombocytopenia 
Toxicity 
Study treatment dose adjustment 
CTCAE Grade 1-2 
Investigator judgement to continue treatment or if dose interruption, this 
should be for a maximum of 2 weeks; appropriate supportive treatment 
and causality investigation 


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Toxicity 
Study treatment dose adjustment 
CTCAE Grade 3-4 
Dose interruption until recovered to CTCAE gr 1 or better for a maximum 
of 2 weeks. If repeat CTCAE grade 3-4 occurrence, dose reduce rucaparib 
to 500 mg twice daily as a first step and 400 mg twice daily as a second 
step 
Discontinue therapy in cases of febrile neutropenia and thrombocytopenia 
associated with haemorrhage. 
Adverse event of neutropenia and leukopenia should be managed as deemed appropriate by 
the investigator with close follow up and interruption of study drug if CTC grade 3 or worse 
neutropenia occurs. 
Primary prophylaxis with Granulocyte colony-stimulating factor (G-CSF) is not 
recommended, however, if a patient develops febrile neutropenia, study treatment should 
be stopped and appropriate management including G-CSF should be given according to local 
hospital guidelines. Please note that G-CSF should not be used within at least 24 h (7 days 
for PEGylated G-CSF) of the last dose of study treatment unless absolutely necessary. 
Platelet transfusions, if indicated, should be done according to local hospital guidelines. 
Management of prolonged hematological toxicities while on study treatment 
Discontinue rucaparib if a patient develops prolonged hematological toxicity such as: 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse anaemia 
and/or development of blood transfusion dependence 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse neutropenia 
(ANC < 1 x 109/L) 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (Platelets < 
50 x 109/L) 
Adverse events possibly must be resolved to grade 1 or baseline prior to resumption of 
dosing. 
Check weekly differential blood counts including reticulocytes and peripheral blood smear. 
If any blood parameters remain clinically abnormal after 2 weeks of dose interruption, the 
patient should be referred to hematologist for further investigations. Bone marrow analysis 
and/or blood cytogenetic analysis should be considered at this stage according to standard 
hematological practice. Development of a confirmed myelodysplastic syndrome or other 
clonal blood disorder should be reported as an SAE and full reports must be provided by the 
investigator to Clovis Oncology. Rucaparib treatment should be discontinued if patient’s 
diagnosis of MDS and/or AML is confirmed. 
Bone marrow or blood cytogenetic analysis 


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Bone marrow or blood cytogenetic analysis may be performed according to standard 
hematological practice for patients with prolonged hematological toxicities. Bone marrow 
analysis should include an aspirate for cellular morphology, cytogenetic analysis and flow 
cytometry, and a core biopsy for bone marrow cellularity.  If it is not possible to conduct 
cytogenetic analysis or flow cytometry on the bone marrow aspirate, then attempts should be 
made to carry out the tests on a blood sample.  If findings are consistent with MDS/AML, study 
drug should be discontinued and a full description of findings should be submitted with an SAE 
report by the investigator to Clovis Oncology for documentation on the Patient Safety 
database.   Presence or absence of blood cytogenetic abnormalities and flow cytometry will be 
documented on the clinical database.  
5.4.2.1.2 Management of non-hematological toxicity 
Dose interruptions are allowed as required, for a maximum of 2 weeks. Patients who 
require an interruption in rucaparib for >2 weeks due to toxicity must discontinue study 
drug. Where toxicity reoccurs following re-challenge with study treatment, then the patient 
should be considered for dose reduction or must permanently discontinue study treatment. 
Study treatment can be dose reduced to 500 mg bid as a first step , to 400 mg bid as a 
second step and 300mg bid as a third step. Treatment must be interrupted if any NCI-
CTCAE grade 3 or 4 adverse event occurs which the investigator considers to be related to 
administration of study treatment. 
Adverse events possibly related to study drug must be resolved to grade 1 or baseline prior 
to resumption of dosing. 
Management of nausea and vomiting 
No routine prophylactic anti-emetic treatment is required at the start of study treatment, 
however, patients should receive appropriate anti-emetic treatment at the first onset of 
nausea or vomiting and as required thereafter, in accordance with local treatment practice 
guidelines.   
As per international guidance on anti-emetic use in cancer patients (ESMO, NCCN), 
generally a single agent antiemetic should be considered eg dopamine receptor antagonist, 
antihistamines or dexamethasone. 
Management of AST/ALT Elevations 
Grade 3 ALT/AST elevations have been successfully treated with treatment interruption 
and/or a reduction in dose. The data reported as of the data cut-off date suggest that many 
patients have been able to continue treatment with 600 mg BID following a dose 
interruption, without any further elevation or recurrence of Grade 3 ALT/AST. The 
following guidelines have been suggested for managing Grade 3/4 ALT/AST elevations.  
Grade 4 ALT/AST elevations: Patients should stop taking rucaparib until values have 
returned to Grade 2 or better, then resume rucaparib with a dose reduction to 500mg BID. 
Monitor liver function tests weekly for 3 weeks after rucaparib has been restarted. If a 
Grade 4 ALT/AST elevation is again observed at 500mg BID, Patients should stop taking 
rucaparib until values have returned to Grade 2 or better, then resume rucaparib with a 
dose reduction to 400mg BID. Dose reductions to 300mg BID will be allowed.   


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Grade 3 ALT/AST elevations, in the absence of other signs of liver dysfunction, should be 
managed as follows:  
 
- Monitor liver function tests weekly until resolution to ≤ Grade 2.  
 
-Continuation of rucaparib with elevation of ALT/AST up to Grade 3 is permitted 
 
provided bilirubin is < ULN and alkaline phosphatase is < 3 x ULN.  
 
- If patient has Grade 3 ALT/AST and continues on rucaparib, and levels do not 
 
decline within 2 weeks or they continue to rise, treatment interruption and 
 
resolution to ≤ Grade 2 will be required before rucaparib can be resumed, either at 
 
the at a reduced dose (500mg BID (if currently taking 600mg BID), 400mg BID (if  
 
currently taking 500mg BID), 300mg BID (if currently taking 400mg BID).  
Interruptions for intercurrent non-toxicity related events 
Study treatment dose interruption for conditions other than toxicity resolution should be 
kept as short as possible. If a patient cannot restart study treatment within 4 weeks for 
resolution of intercurrent conditions not related to disease progression or toxicity, the case 
should be discussed with Principle Investigator. 
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF.  
Study treatment should be stopped at least 3 days prior to a planned surgery. After surgery 
study treatment can be restarted when the wound has healed. No stoppage of study 
treatment is required for any needle biopsy procedure. 
5.5 
End of Treatment/Treatment Discontinuation Visit 28 days after last dose +/- 3 days) 
• 
Conduct physical exam (including vital signs, height/weight) 
• 
perform laboratory tests: Complete blood count w/Diff, PSA, Comprehensive metabolic 
panel 
• 
ctDNA blood collection (10ml) 
• 
assess performance status (ECOG). (Appendix A) 
• 
review concurrent medications  
• 
assess AEs 
• 
if patient is discontinuing participation in study, perform radiographic tests: CT A/P and 
NM Bone Scan (if these have not been performed in the prior 3 months) 
5.6 
Follow-up (At least every 28 days while active AEs) 
Patients will be followed every 28 days beyond the end of treatment visit if they have 
withdrawn from study because of AEs.  Patients withdrawn from the study because of AEs 
will be followed until the adverse event has either resolved or stabilized. Reasons for 
premature withdrawal should be determined and noted.  To be performed at each visit will 
be: 
• 
conduct physical exam (including vital signs, height/weight) 


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• 
perform laboratory tests (CBC w/diff, Comprehensive metabolic panel) only as indicated 
by AEs requiring follow-up 
• 
assess performance status (ECOG). (Appendix A) 
• 
review concurrent medications  
• 
reassess AEs. 
• 
When patient will discontinuing participation in study, perform radiographic tests: CT A/P 
and NM Bone Scan (if these have not been performed in the prior 3 months) 
5.7 
Correlative/Special Studies 
5.8.1. DNA sequencing 
FFPE biopsy tissue will be sent to Foundation Medicine for next generation sequencing, 
based upon their commercially available platform.   
 
5.8.2. mRNA expression profiling 
A sample of FFPE biopsy tissue will be sent to GenomeDx for RNA expression profiling.   
 
5.8.3. PARP-1, PARP-2, γH2AX, RAD51, 53BP1 mRNA/ Protein Analysis 
A sample of biopsy will be sent to the Lotan laboratory for analysis. 
5.8 
Concomitant Medications 
Because of the potential for drug-drug interaction, the concurrent use of all other drugs, 
over-the-counter medications, or alternative therapies must be documented on the case 
report form (CRF).  
Hematopoietic Growth Factors and Blood Products 
Erythropoietin, darbepoetin alfa, and/or hematopoietic colony-stimulating factors for 
treatment of cytopenias should be administered according to institutional guidelines. 
Transfusion thresholds for blood product support will be in accordance with institutional 
guidelines. 
 
CYP450 Isoenzyme Inhibitors, Inducers, and Substrates 
Based on results of in vitro CYP interaction studies, caution should be used for concomitant 
medications with narrow therapeutic windows that are substrates of CYP2C19, CYP2C9, 
and/or CYP3A.  Selection of an alternative concomitant medication is recommended.   
 
Examples of CYP Substrates with Narrow Therapeutic Range 
CYP Enzyme 
Substrates with Narrow Therapeutic Range a 
CYP2C9 
Warfarin, phenytoin  
CYP2C19 
S-mephenytoin  


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CYP3A 
Alfentanil, astemizole, cisapride, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus, terfenadine 
The table is based on the Draft FDA Guidance on Drug Interaction Studies — Study Design, 
Data Analysis, Implications for Dosing, and Labeling Recommendations, 2012.  
a CYP substrates with narrow therapeutic range refers to drugs whose exposure-response 
relationship indicates that small increases in their exposure levels by the concomitant use 
of CYP inhibitors may lead to serious safety concerns (eg, Torsades de Pointes). 
Anticoagulants 
Caution should be exercised in patients receiving rucaparib and concomitant warfarin 
(Coumadin) as rucaparib showed a mixed inhibition of CYP2C9 in vitro. If appropriate, low 
molecular weight heparin should be considered as an alternative treatment. Patients taking 
warfarin should have international normalized ratio (INR) monitored regularly per 
standard clinical practice. 
Anti-emetics/Anti-diarrheals 
If a patient develops nausea, vomiting and / or diarrhea, then these symptoms should be 
reported as AEs and appropriate treatment of the event given. 
Administration of other anti-cancer agents 
Patients must not receive any other concurrent anti-cancer therapy, including 
investigational agents, while on study treatment.  
Subsequent therapies for cancer  
Details of first and subsequent therapies for cancer and/or details of surgery for the 
treatment of the cancer, after discontinuation of treatment, will be collected.  Reasons for 
starting subsequent anti-cancer therapies including access to other PARP inhibitors or 
investigational drugs will be collected and included in the exploratory assessments of 
survival. 
5.8.1 Prohibited before enrollment and during administration of study treatment 
Medications that are prohibited during study treatment and in the prior 6 months prior to 
enrollments: LHRH agonist / antagonist therapy, androgen receptor antagonists, and 
androgen synthesis inhibitors.  5-alpha reductase inhibitors are allowed if subject has been 
taking stable dose of medication for prior 6 months.   
5.9 
Contraception 
Patients with partners of child bearing potential, who are sexually active, must agree to the 
use of two highly effective forms of contraception throughout period of taking study 
treatment and for 3 months after last dose of study drug. 
For details refer to Appendix E Acceptable Birth Control Methods. 
 


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6. 
THERAPEUTIC/DIAGNOSTIC AGENT(S)/MODALITY(-IES) 
 
6.1 
Description of Treatments 
The drug to be tested in this clinical protocol is rucaparib (IND #).  Rucaparib will be 
supplied by Clovis Oncology. 
 
6.2 
Pharmacokinetics 
 
Dose proportional PK were observed up to 600 mg BID. The mean Tmax and mean T1/2 were 
 
approximately 4 hours and 17 hours, respectively. Oral administration of 600 mg rucaparib 
 
with a high-fat meal resulted in a moderate increase of Cmax and AUC of rucaparib compared 
 
with that under fasted conditions. The increases in rucaparib exposures were not 
 
considered clinically significant, thus rucaparib can be taken with or without food.  
 
6.3 
Dosage Selected, Preparation, and Schedule of Administration 
Rucaparib will be dosed based upon guidelines in Section 5.  Treatment will be 
administered on an outpatient basis.  Rucaparib is dosed twice daily.  Patients will be asked 
to keep a drug diary and present bottles for assessment at each assessment. 
6.3.1 
Supply, storage requirements, and special handling 
 
6.3.1.1 Supply and packaging 
 
Rucaparib camsylate (formerly known as PF-01367338 and AG-014447) is 
an oral formulation with a molecular weight of 555.67 Daltons.  
 
 
 
 
 
 
 
Rucaparib tablets for oral administration will be supplied by Clovis. A brief  
 
 
 
description of the investigational product is provided below. 
Drug Name: 
Rucaparib 
INN: 
Rucaparib 
Formulation: 
Tablet; film coated; 200 mg, 250 mg, 300 mg 
How Supplied: 
200, 250, and/or 300 mg strength (based on free base) in high-
density polyethylene bottles or equivalent with child-resistant caps. 
Patients may receive 1 or more strengths. Each bottle contains 60 
tablets 
 


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6.3.1.2 Storage requirements 
 
All tablets are provided in high-density polyethylene (HDPE) bottles with 
child-resistant caps and should be stored in the provided containers. 
between 15° and 30° C (59 and 86° F).  
 
6.3.1.3 Labeling 
Labels will be prepared in accordance with Good Manufacturing Practice 
(GMP) and local regulatory guidelines.  The labels will fulfill GMP Annex 13 
requirements for labeling.  Label text will be translated into local language.  
 
6.4 
Removing Patients from the Protocol 
In the absence of treatment delays because of adverse events, treatment will continue for 
until one of the following criteria applies: 
• 
Patient decision.  The patient is at any time free to discontinue treatment, without prejudice 
to further treatment 
• 
Severe non-compliance with the study protocol  
• 
Bone marrow findings consistent with myelodysplastic syndrome (MDS)/acute myeloid 
leukaemia (AML) 
• 
Potential Hy’s Law cases (AST or ALT ≥3x ULN and TBL ≥2xULN with no other reason) 
• 
PSA doubling from baseline value, confirmed by a second value at least 4 weeks apart, with 
a minimum time since initiation of therapy of 12 weeks. 
• 
Disease progression by symptomatic or radiographic assessment.  Patient requiring 
palliative radiation therapy will be considered to have disease progression and removed 
from the study. 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse events that may or may not be directly related to treatment but that, 
in the judgment of the treating physician, makes it dangerous for the patient to be retreated. 
• 
Adverse events requiring cessation of rucaparib, with inability to restart therapy within 14 
days. 
• 
General or specific changes in the patient’s condition that render the patient unacceptable 
for further treatment, in the judgment of the investigator 
Because an excessive rate of withdrawals can render the study uninterpretable, 
unnecessary withdrawal of patients should be avoided. When a patient discontinues 
treatment early, the investigator should make every effort to contact the patient and to 
perform a final evaluation. The reason(s) for withdrawal should be recorded. 
 
7. 
ADVERSE EVENTS 
 


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7.1 
Definitions 
7.1.1 
Adverse Event (AE) 
 
 
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). 
 
7.1.2 
Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence that occurs at any dose (or, occurs after 
informed consent is given and prior to dosing if the SAE is related to a study procedure) 
that: 
• 
Results in death. Any event resulting in death during the reporting period (from date of first 
dose of study drug through 28 days after last dose) must be treated as an SAE and reported 
as such. An event related to a study procedure that occurs after informed consent, but prior 
to dosing that results in death must also be reported as an SAE. 
• 
Is life-threatening (patient is at immediate risk of death from the event as it occurred) 
• 
Requires in-patient hospitalization (formal admission to a hospital for medical reasons) or 
prolongation of existing hospitalization 
• 
Results in persistent or significant disability/ incapacity 
• 
Results in a congenital anomaly or birth defect 
Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home or 
the development of drug dependency or drug abuse. 


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7.1.2.1 Events or Outcomes Not Qualifying as Serious Adverse Events 
 
 
The following are not considered SAEs and therefore do not need to be reported as 
 
such: 
• 
Pre-planned or elective hospitalization including social and/ or convenience 
situations (eg, respite care) 
• 
Hospital visits of less than 24 hours duration (eg, patient presents to the 
emergency room, but is not admitted to a ward) 
• 
Overdose of either Clovis study drug 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 a serious adverse event unless the 
outcome is fatal within the safety reporting period. If the event has a fatal 
outcome within the safety reporting period, then the event of Progression of 
Disease must be recorded as an AE and as a SAE with CTCAE Grade 5 (fatal 
outcome) indicated. 
 
7.1.3 
Medical significance 
An event that is not fatal or life-threatening and that does not necessitate 
hospitalization may be considered serious if, in the opinion of the investigator, it 
jeopardizes the patient’s status and might lead to medical or surgical intervention to 
prevent any of the outcomes described in section 7.1.2. Such medically significant 
events could include allergic bronchospasm requiring intensive treatment in the 
emergency room or at home, blood dyscrasias that do not result in inpatient 
hospitalization, or the development of drug dependency or abuse. 
 
7.1.4 
Adverse Events of Special Interest (AESI) 
 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 expeditiously. 
 


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7.1.5 
Progression of malignancy 
Progression of a patient’s malignancy should not be considered an AE or SAE, unless 
in the investigator’s opinion, study treatment resulted in an exacerbation of the 
patient’s condition. If disease progression results in death or hospitalization while 
on study or within 28 days of the last dose, progressive disease will be considered 
an SAE. 
7.1.6 
Life-threatening events 
A life-threatening event is any AE that places the patient at immediate risk of death 
from the reaction as it occurs. It is not a reaction that had it occurred in a more 
severe form, might have caused death. 
7.1.7 
Hospitalization or prolongation of hospitalization 
Hospitalization encompasses any inpatient admission (even for less than 24 hours) 
resulting from a precipitating, treatment-emergent adverse event. For chronic or 
long-term patients, inpatient admission also includes transfer within the hospital to 
an acute or intensive care inpatient unit. Hospitalizations for administrative reasons 
or a non-worsening preexisting condition should not be considered AEs (e.g. 
admission for workup of a persistent pretreatment laboratory abnormality, yearly 
physical exam, protocol-specified admission, elective surgery). Preplanned 
treatments or surgical procedures should be noted in the baseline documentation. 
Hospitalization because of an unplanned event will be deemed an SAE. 
Prolongation of hospitalization is any extension of an inpatient hospitalization 
beyond the stay anticipated or required for the original reason for admission. 
7.1.8 
Significant disability 
Disability is a substantial disruption of the patient’s ability to conduct normal life 
functions. 
7.1.9 
Pregnancy 
Male participants should refrain from fathering a child or donating sperm during the 
study and for 6 months following the last dose. 
Pregnancy of the patient’s partners is not considered to be an adverse event. 
However, the outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth or congenital abnormality) should if 
possible be followed up and documented.  
The outcome of any conception occurring from the date of the first dose until 6 
months after the last dose should be followed up and documented. 
All outcomes of pregnancy should be reported to Clovis Oncology. 
7.1.10 Deaths 
All deaths that occur during the study, or within the protocol-defined 30-day 
post-study follow-up period after the administration of the last dose of study 
treatment, must be reported as follows: 


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Death that is clearly the result of disease progression should be reported to the 
study monitor at the next monitoring visit, be documented, and reported as an SAE. 
Where death is not due (or not clearly due) to progression of the disease under 
study, the AE causing the death must be reported to the study monitor as a SAE 
within 24 hours. The report should contain a comment regarding the 
co-involvement of progression of disease, if appropriate, and should assign main 
and contributory causes of death.   
Deaths with an unknown cause should be reported as a SAE., but followup should be 
done to determine the cause of death.  If a cause of death is determined, the event 
term of “death” must be updated at that time.    A post mortem maybe helpful in the 
assessment of the cause of death, and if performed a copy of the post-mortem 
results should be forwarded to Clovis Oncology within the usual timeframes. 
The most recent version of the NCI CTCAE v.5.0 handbook will be used for adverse event 
descriptions and grading. 
 
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 study drug. Any SAEs, AESIs, and treatment-related Grade 3/4 AEs must be followed 
until resolution or stabilization, or until lost to follow-up. After the 28-day window, 
treatment-related SAEs and all AESIs, irrespective of causality, need to be reported.  
 
7.2 
Expectedness 
 
Adverse events can be considered, “expected,” or, “unexpected.” 
 
7.2.1  
Expected Adverse Events 
Expected adverse events are those that have been previously identified as resulting 
from administration of the agent. An adverse event can be considered expected 
when it appears in the same nature severity and specificity as what is in the current 
adverse event list of the Investigator’s Brochure (Reference Safety Information [RSI] 
section). 
 
7.2.2 
Unexpected Adverse Events 
An adverse event can be considered unexpected when the nature, intensity or 
frequency of which is not consistent with the current adverse event list of the 
Investigator’s Brochure, contact the lead site, principal investigator or sponsor to 
confirm unexpected adverse events when necessary.   
 


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7.3 
Recording and Grading 
7.3.1 
Recording 
All observed or volunteered adverse events, regardless of treatment group, severity, 
suspected causal relationship, expectedness, or seriousness will be documented. 
A clinically significant change in a physical examination finding or an abnormal test 
result (i.e., laboratory, x-ray, EKG) should be recorded as an AE, if it: 
• 
is associated with accompanying symptoms 
• 
is suggestive of organ toxicity 
• 
requires additional diagnostic testing or medical or surgical intervention 
• 
leads to a change in study dosing or discontinuation from the study 
• 
is considered clinically significant by the investigator. 
An abnormal test result that is subsequently determined to be in error does not 
require recording as an adverse event, even if it originally met one or more of the 
above criteria. 
7.3.2 
Grading severity 
All adverse events will be graded for intensity on a scale of 0 to 5. Severity grades 
will be recorded and based on the most recent version of the NCI CTCAE v.5.0 
handbook. 
7.3.3 
Attributing causality 
 
 
Medical judgment should be used to determine the cause of the AE considering  
 
 
all relevant factors such as, but not limited to, the underlying study indication,  
 
 
coexisting disease, concomitant medication, relevant history, pattern of the AE,  
 
 
temporal relationship to the study medication, dechallenge or rechallenge with  
 
 
the study drug (Table 4).  
Table 4 Relationship of Adverse Event to Study Drug 
 
Not Related To 
Study Drug 
• An AE that is clearly due to extraneous causes (eg, concurrent disease, 
concomitant medications, disease under study, etc.) 
• It does not follow a reasonable temporal sequence from administration 
of the study drug. 
• It does not follow a known pattern of response to study drug 
• It does not reappear or worsen when study drug is restarted. 
• An alternative explanation is likely, but not clearly identifiable. 


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Related to 
Study Drug 
• An AE that is difficult to assign to alternative causes. 
• It follows a strong or reasonable temporal sequence from administration 
of study drug. 
• It could not be reasonably explained by the patient’s clinical state, 
concurrent disease, or other concomitant therapy administered to the 
patient.  
• It follows a known response pattern to study drug 
• It is confirmed with a positive rechallenge or supporting laboratory data. 
 
 
7.4 
Reporting Adverse Events 
7.4.1 
Reporting serious adverse events 
 
All SAEs and AESIs, regardless of relationship to study drug, must be reported to the 
 
lead site within 48 business hours of knowledge of the event, during the study 
 
through 30 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 Clovis or the Sponsor-Investigator’s study-specific 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-Investigator is responsible for submitting reports of AEs associated with 
 
the use of the drug that are both serious and unexpected to the U.S. Food and Drug 
 
Administration (FDA), according to 21 Code of Federal Regulations (CFR) 312.32 ; to 
 
the Japanese Pharmaceuticals and Medical Devices Agency (PMDA); to the European 
 
regulatory authorities according to the European Commission Clinical Trials Directive 
 
(2001/20/EC); and to other applicable regulatory authorities, according to national 
 
law and/or local regulations. All investigators participating in ongoing clinical studies 
 
with the study medication will receive copies of these reports for prompt submission to 
 
their IRB or IEC. In accordance with the European Commission Clinical Trials Directive 
 
(2001/20/EC), Clovis 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-Investigator will submit all safety updates and periodic reports to the 
 
regulatory authorities as required by applicable regulatory requirements. 
7.4.2 
Reporting SAEs at multi-site/participating institutions  
SAEs should be reported to the lead site. 


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8. 
CRITERIA FOR OUTCOME ASSESSMENT/THERAPEUTIC RESPONSE 
8.1 
Outcome Assessment 
All baseline evaluations will be performed as closely as possible to the beginning of 
treatment (within 7 days). For subsequent evaluations, the method of assessment and 
techniques will be the same as those used at baseline. 
Note: Any bone lesions, however, that are identified on the baseline CT or MRI 
studies and judged as providing meaningful information about nontarget disease 
status on the basis of their size or other features should be considered for inclusion 
in the follow-up assessments of nontarget lesions by the same imaging modality. 
• 
Conventional CT, Bone Scan 
CT Chest, abdomen, pelvis and Bone scans will be used to measure tumor response 
as a secondary endpoint per RECIST 1.1 criteria (metastatic disease only). 
• 
Tumor markers 
       PSA measurements will be used to assess the primary endpoint  
8.1.1 
Primary endpoint 
The primary endpoint is defined as a PSA50 response, defined as a decline in PSA to 
≥50% of baseline level, confirmed with a second measurement at least 4 weeks 
later. 
8.1.2 
Secondary endpoints 
8.1.2.1.  Safety: this endpoint is defined as incidence of grade 3-5 toxicities based 
upon CTCAE v5.0 standard grading scales. 
 
 
8.1.2.2.  PSA Progression-Free Survival (PFS): PSA progression (PSA progression-free  
 
 
survival; PSA–PFS) will be defined per PCWG3 guidelines 
 
 
 
For those subjects showing an initial decline in PSA from baseline, is   
 
 
 
defined as an increase in PSA that is ≥25% and ≥2 ng/mL above the nadir,  
 
 
 
and which is confirmed by a second value 3 or more weeks later (i.e., a  
 
 
 
confirmed rising trend). 
 
 
 
For those subjects with no decline in PSA from baseline, is defined as an  
 
 
 
increase in PSA that is ≥25% and ≥2 ng/mL after 12 weeks. 
 
 
8.1.2.3.  Radiographic Progression–free survival: time to radiographic or clinical  
 
 
 
progression or  death, whichever comes first. Based on RECIST version 1.1  
 
 
 
and PCWG3 definitions including: Progression of soft tissue lesions   
 
 
 
according to RECIST 1.1; Progression of bone lesions detected with bone  
 
 
 
scan according to PCWG3 criteria; Radiologically‐confirmed spinal cord  
 
 
 
compression or pathological fracture due to malignant progression, or other  
 
 
 
clinical event deemed to be cancer‐related. 
 
 
8.1.2.4 Objective response rate (metastatic disease only): defined as the proportion  
 
 
 
of patients achieving a  complete/partial response in target lesions (RECIST  


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1.1) 
 
8.2 
Therapeutic Response 
Response and progression will be evaluated in this study using a combination of the 
international criteria proposed by the Response Evaluation Criteria in Solid Tumors 
(RECIST) Committee(17) and the guidelines for prostate cancer endpoints developed by the 
Prostate Cancer Clinical Trials Working Group (PCWG3).(18)
Patients will need to be reevaluated for response every cycle according to the guidelines 
below.
8.2.1 
PSA 
Perform PSA testing at a minimum of 1-week intervals with the threshold PSA level 
at 2.0 ng/mL. To report PSA-based outcomes, PCWG3 recommends that the percent 
of change in PSA from baseline to 12 weeks (or earlier for those who discontinue 
therapy) and the maximum decline in PSA that occurs at any point after treatment 
be reported for each patient using a waterfall plot. PSA measurements obtained 
during the first 12 weeks should not be used as the sole criterion for clinical 
decision making. 
8.2.2 
Measurable disease 
According to RECIST 1.1, measurable disease is defined as at least 1 lesion > 10mm 
in its longest diameter as measured with conventional techniques (i.e., CT with slice 
cut of 5mm, MRI). All tumor measurements will be taken using a ruler or calipers 
and recorded in millimeters (or decimal fractions of centimeters).  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 no 
greater than 5 mm).  
8.2.3 
Nonmeasurable disease 
Following RECIST, all other lesions (or sites of disease) will be considered 
nonmeasurable disease. This includes small lesions (longest diameter < 10 mm 
using spiral CT scan) lymph nodes (shortest diameter >10mm to <15mm) and any 
of the following: 
• 
bone lesions 
• 
ascites 
• 
pleural or pericardial effusion 
• 
lymphangitis cutis or pulmonis 
• 
abdominal masses that are not confirmed and followed by imaging techniques 
• 
cystic lesions 
• 
lesions occurring within a previously irradiated area unless they are 
documented as new lesions since the completion of radiation therapy 


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Note: If only a single, asymptomatic bone lesion is present at baseline, and 
will be irradiated, the metastatic nature of this lesion must be confirmed by 
x-ray, CT, or MRI. 
8.2.4 
Target (nodal and visceral) lesions 
Following RECIST, progression in a nodal or visceral site (i.e., liver and lung) is 
sufficient to document disease progression. The presence or absence of nodal and 
visceral disease before and after treatment should be recorded separately. 
All measurable lesions (up to a maximum of 2 lesions per organ and 5 lesions in 
total) will be identified as target lesions to be measured and recorded at baseline. 
The target lesions should be representative of all involved organs. Target lesions 
will be selected on the basis of size (i.e., the largest area) and suitability for accurate, 
repeated measurements (either by imaging techniques or clinically). The sum of the 
longest diameter (LD) of all target lesions will be calculated and reported as the 
baseline sum LD. The baseline sum LD will be used as a reference by which to 
characterize the objective tumor response. 
Because small lymph nodes are difficult to measure accurately and may not be 
malignant, 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 no greater than 5 mm). 
8.2.5 
Bone lesions 
When the bone scan is the sole indicator of progression, disease progression in bone 
is defined as 2 or more new lesions seen on bone scan compared with a prior scan 
for used trial entry. In situations where scan findings suggest a flare reaction or 
where new lesion(s) may represent trauma, confirm these results with other 
imaging modalities (eg, MRI or fine-cut CT). If many new areas of uptake are 
observed, confirmation is generally not necessary. 
8.2.6 
Nontarget lesions 
All other lesions (or sites of disease) will be identified as nontarget lesions and 
recorded at baseline. Nontarget lesions will include measurable lesions that exceed 
the maximum number per organ (2) or total of all involved organs (5), as well as 
nonmeasurable lesions. The presence or absence of these lesions will be recorded 
on the CRF and should be evaluated at the same assessment time points as all target 
lesions. 
8.2.7 
New lesions 
 
The appearance of new malignant lesions denotes disease progression.   There are 
 
no specific criteria for the identification of new radiographic lesions; however, the 
 
finding of a new lesion should be unequivocal: i.e. not attributable to differences in 
 
scanning technique, change in imaging modality or findings thought to represent 
 
something other than tumour (for example, some ‘new’ bone lesions may be simply 
 
healing or flare of pre-existing lesions).  
8.3 
Response Criteria for Primary and Secondary Endpoints 
8.3.1. 
Measurable soft-tissue lesions 
When evaluating soft-tissue lesions, the definitions in Table 5 apply. 


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Table 5 RECIST1.1 response criteria for target lesions 
Response 
Evaluation of Soft-Tissue Lesions 
Complete response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
<10 mm. 
Partial response (PR) 
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive disease (PD)  
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new 
lesions is also considered progression). 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while 
on study. 
 
In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of complete response depends on this 
determination, it is recommended that the residual lesion be investigated (eg, fine 
needle aspirate or biopsy) before confirming the complete response status. 
Changes in nodal and visceral sites should be recorded and reported separately, and 
lymph nodes in the pelvis must measure at least 1.5 cm in shortest diameter to be 
considered target lesions. Complete elimination of disease at a particular site 
should be recorded separately. Any favorable change should be confirmed using a 
second follow-up scan. 
8.3.2 
PSA 
For each patient, use a waterfall plot to report the percent change in PSA from 
baseline to 12 weeks (or earlier for those who discontinue therapy) and the 
maximum decline in PSA that occurs at any point after treatment.  We will also 
report the proportion of patients to achieve a 50% of greater decrease in PSA from 
baseline (i.e. PSA50 response rate) 
8.3.3 
Bone 
Record post-treatment changes as either “no new lesions” or “new lesions.” 
In the absence of clearly worsening soft-tissue (nodal and visceral) disease or 
disease-related symptoms, progression at the first scheduled assessment should be 
confirmed on a second scan performed 6 or more weeks later. In the rare case where 
visible lesions disappear, this too should be confirmed. 
8.3.4 
Nontarget lesions 
When assessing nontarget lesions, the definitions in Table 6 will apply. 
 


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Table 6 RECIST1.1 response criteria for nontarget lesions 
Response 
Evaluation of Nontarget Lesions 
Complete response (CR) 
the disappearance of all nontarget lesions and normalization of tumor 
marker levels.  All lymph nodes must be non-pathological in size 
(<10mm short axis) 
Non-CR/non-PD 
the persistence of one or more nontarget lesions and/or maintenance 
of tumor marker levels above the normal limits 
Progressive disease (PD) 
the appearance of one or more new lesions and/or unequivocal 
progression of existing nontarget lesions 
 
 
8.4 
Criteria for Progressive Disease. 
8.4.1. 
Measurable soft-tissue lesions 
When evaluating soft-tissue lesions, the definitions in Table 5 apply: 
In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of complete response depends on this 
determination, it is recommended that the residual lesion be investigated (e.g. fine 
needle aspirate or biopsy) before confirming the complete response status. 
Progression in a nodal or visceral site should be defined using RECIST1.1 (Table 5).  
8.4.2 
PSA 
 
Per the PCWG3, PSA progression is defined as the date that a 25% or greater 
increase and an absolute increase of 2 ng/mL or more from the nadir is documented 
and confirmed by a second value obtained 3 or more weeks later. Where no decline 
from baseline is documented, PSA progression is defined as a 25% increase from the 
baseline value along with an increase in absolute value of 2 ng/mL or more after 12 
weeks of treatment. 
8.4.3 
Bone 
Progressing disease on bone scan is considered when at least 2 new lesions are 
observed. Yet, progression remains unconfirmed unless at least 2 additional new 
lesions appear at a subsequent time point. 
Unless clinically indicated, there is no need to perform a follow-up bone scan before 
12 weeks of treatment. To define disease progression requires a confirmatory scan 
(which shows additional new lesions compared with the first follow-up scan) 
performed 6 or more weeks later. When further progression is documented on the 
confirmatory scan, the date of progression recorded for the trial is the date of the 
first scan that shows the change. 
8.4.4 
Nontarget lesions 
When assessing nontarget lesions, the definitions in Table 6 apply.


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9. 
DATA REPORTING AND REGULATORY REQUIREMENTS 
 
 
 
Multicenter Guidelines 
 
The Protocol Chair 
 
The Protocol Chair, Dr. Mark Markowski is responsible for performing the following tasks: 
• 
Coordinating, developing, submitting, and obtaining approval for the protocol as 
well as its subsequent amendments 
 
• 
Assuring that all participating institutions are using the correct version of the 
protocol 
 
• 
Taking responsibility for the overall conduct of the study at all participating 
institutions and for monitoring the progress of the study 
 
 
• 
Reviewing and ensuring reporting of Serious Adverse Events (SAEs) 
 
• 
Reviewing data from all sites 
Lead Center 
The Lead Center (Johns Hopkins) is responsible for performing the following tasks: 
• 
Ensuring that IRB approval has been obtained at each participating site prior to the 
first patient registration at that site, and maintaining copies of IRB approvals from 
each site. 
 
• 
Managing central patient registration 
 
• 
Collecting and compiling data from each site 
 
• 
Establishing procedures for documentation, reporting and submitting of AE’s and 
SAE’s to the Protocol Chair and all other applicable parties. 
 
• 
Facilitating audits by securing selected source documents and research records 
from participating sites for audit, or by auditing at participating sites. 
 
 
 
 
 
 
 
 


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Participating PCCTC Sites 
 
Participating sites are responsible for performing the following tasks: 
 
• 
Following the protocol as written, and the guidelines of Good Clinical Practice (GCP). 
 
• 
Submitting data to the Lead Center  
 
• 
Registering all patients with the Lead Center by submitting patient registration 
form, and signed informed consent promptly 
 
• 
Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the protocol 
 
• 
Maintaining regulatory binders on site and providing copies of all required 
documents to the Lead Center  
 
• 
Collecting and submitting data according to the schedule specified by the protocol 
 
9.1 
Data Entry 
Data collected during this study will be entered into a secure database. Staff at Johns 
Hopkins will be responsible for the initial study configuration and setup in the CRMS 
database and for any future changes. 
9.1.1 
Case report forms completion  
 
Case report forms will be generated by the coordinating center for the collection of 
all study data. Investigators will be responsible for ensuring that the CRFs are kept 
up-to-date. 
The paper Eligibility Checklist CRF must be completed using black ink.  Any errors 
must be crossed out so that the original entry is still visible, the correction clearly 
indicated and then initialed and dated by the individual making the correction. 
 
eCRFs will be completed within 2 weeks of the patient coming to the clinic and all 
relevant supporting documentation such as scans, progress notes, nursing notes, 
blood work, pathology reports, etc., will be submitted via email to the Study 
Manager for remote monitoring approximately every 4-6 weeks when requested.  
All patient names or other identifying information will be removed prior to being 
sent to the Coordinating Center (SKCCC) or non- redacted source documents can be 
sent via a password -protected/ secured document transfer based on each 
institution’s guidelines.  
 


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Authorized representatives of the Coordinating Center (SKCCC) may visit the 
satellite sites to perform audits or inspections, including source data verification. 
The purpose of these audits or inspections is to systematically and independently 
examine all trial-related activities and documents to determine whether these 
activities were conducted and data were recorded, analyzed, and accurately 
reported according to the protocol, Good Clinical Practice (GCP), and any applicable 
regulatory requirements. 
9.1.2 
Source documents 
Study personnel will record clinical data in each patient’s source documents (i.e., the 
patient’s medical record). Source documentation will be made available to support 
the patient research record. Study monitors will review entries on the CRFs at 
regular intervals, comparing the content with source documents. 
9.1.3 
Record retention 
The investigator will maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified. 
After study closure, the investigator will maintain all source documents, study-
related documents, and the CRFs. Because the length of time required for retaining 
records depends upon a number of regulatory and legal factors, documents should 
be stored until the investigator is notified that the documents may be destroyed. In 
this study, records are to be retained and securely stored for a minimum of 5 years 
after the completion of all study activities. 
9.2 
Data Management 
9.2.1 
Lead research program coordinators 
A Lead research program coordinator at the coordinating center will be assigned to 
the study. A Lead Research Program Coordinator will manage the study activities at 
each of the participating sites. The responsibilities of the Lead Research Program 
Coordinator include project compliance, data collection, data entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordination of 
the activities of the protocol team. 
 
9.3 
Clinical Trial Agreement 
This trial is being conducted under one or more clinical trial agreements that contain, 
among other terms, the publication policy, indemnity agreements, and financial 
arrangements for the study. 
 
9.4          Study Monitoring 
                 Study calls between sites will be held every 3 months to discuss accrual goals and     
 
 AE/toxicity data.  Interim analysis will be performed as described in Section 10. 
            
10. 
STATISTICAL CONSIDERATIONS 
The primary endpoint will be the proportion of subjects who achieve a PSA response, 
defined as a 50% or greater decline in PSA from baseline, confirmed on a subsequent 


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measurement at least 3 weeks apart. The treatment regimen would be considered of 
insufficient activity for further study in this population if the PSA response rate is 50% or 
less. The sample size is calculated to detect an improved PSA response rate from 50% to 
75%. An optimal Simon two stage design is planned. A total of 12 patients will be entered in 
the first stage with a planned analysis for futility performed 12 weeks after the last patient 
began rucaparib. The number of patients allowed with a non-BRCA1, -BRCA2, or –ATM 
mutation in stage 1 will be capped at 3.  If 6 or fewer subjects have a PSA response, the 
study will be terminated and we will conclude the regimen is ineffective. If ≥7 subjects 
respond, then an additional 16 patients will be studied, for a total of 28 patients.  If a total of 
17 or fewer subjects respond in stage one and two combined, we consider this regimen 
ineffective. If a total of 18 or more respond, we conclude the regimen is promising and 
warrants further study. The maximum sample size will be increased to 30 patients to 
account for possible dropouts.  The total number of patients (stage 1 and 2) allowed with a 
non-BRCA1/ -BRCA2 mutation will be capped at 10; this will ensure that at least 20 men 
will be enrolled with germline BRCA1/BRCA2mutations.    
 
This design provides 90% power to detect an absolute 25% increase in PSA response rate 
with a one-sided type I error of 0.1. The probability of early stopping is 0.61 under the null 
hypothesis that the PSA Response Rate is 50%.  
 
10.1 
Study Endpoints 
10.1.1 Analysis of the primary endpoint 
The primary endpoint of this study is PSA50 response, defined as a decrease in the PSA to 
50% less than the baseline PSA upon enrollment in the trial.  The decrease must be 
confirmed by a second measurement at least 4 weeks apart.  For purposes of meeting the 
primary endpoint, patients will be considered to have done so if they have a PSA50 response 
only while on therapy with rucaparib.  PSA values will be measured each cycle during the 
trial.  All patients who are administered at least one dose of rucaparib will be considered 
evaluable for the primary endpoint.  If patients do not have follow-up PSAs after initiation 
rucaparib therapy due to stopping therapy for toxicity or withdrawing consent, for example, 
then they will be replaced.   
We will estimate the PSA50 response rate, along with the exact 95% confidence interval, for 
the population of patients.   
10.1.2 Analysis of secondary endpoints 
 
10.1.2.1. Safety 
Patients will be assessed for toxicities at each clinical evaluation.  Toxicities will 
graded according to CTCAE v5.0 standardized grading scales.  The incidence of 
grade 3-5 toxicities will be reported.  Patients will be assessed for toxicity as long as 
they are taking rucaparib, and patients will continue to be followed if rucaparib is 
discontinued for toxicity until the toxicities improve to grade 1 or resolve 
Toxicities will be reported as a tabulated table by type and grade. 
 
10.1.2.2. PSA progression-free survival (PFS)  


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A standard definition of PSA progression per PCWG3 will be used.  PSA PFS will be 
defined as an increase in 25% over a nadir value, confirmed by a follow-up PSA at 
least 4 weeks apart.  If patients are removed from study prior to PSA progression, 
then they will be censored at that time. 
 
We will use the Kaplan-Meier method to estimate the median PSA PFS. 
   
10.1.2.3. Radiographic progression-free survival (rPFS) 
Progression-free survival will be measured from the time of first dose to objective 
tumor progression as defined by RECIST 1.1 for progressive disease or death and 
summarized using a Kaplan-Meier curve. Progression will be assigned to the earliest 
observed time. Patients whose disease has not progressed at follow-up will be 
censored at the date when the last tumor assessment determined a lack of 
 
progression.  
 
We will use the Kaplan-Meier method to estimate the median PFS. 
 
10.1.2.4 Objective response rate 
 
The objective response rate is defined as the percentage of patients with 
 
measureable disease who achieve an objective response by RECIST1.1 criteria (i.e.  
 
Complete response or Partial Response) to rucaparib.   
We will estimate the objective response rate, along with the exact 95% confidence 
interval, for the population of patients.   
10.1.3 Analysis of exploratory endpoints 
 
 
10.1.3.1. Estimate the percentage of patients with a loss-of-function mutation or total 
 
allelic loss of second (somatic) gene allele (i.e. biallelic inactivation): 
 
 The DNA mutations present in the tumor will be identified through Foundation 
 
Medicine sequencing.  Patients with a  somatic alteration including: protein 
 
truncating mutations, splice site mutations, homozygous deletions, large protein 
 
truncating rearrangements, and deleterious missense alterations in the pre-
 
specified gene list (BRCA1, BRCA2, ATM, CHEK2, NBN, BRIP1, RAD50, RAD51C, 
 
RAD51D, PALB2, MRE11, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, 
 
FANCI, FANCL, FANCM) will be considered biomarker positive.  For biomarker 
 
positive and biomarker negative subjects, we will calculate PSA50 response rates 
 
with confidence intervals for hypothesis generation.   
  
 
10.1.3.2 mRNA expression profile signature positive and negative PSA50 response 
 
calculations:  
 
Similarly to above, subjects will have tumor tested with RNA expression 
 
profiling and scored for likelihood for response to rucaparib per the Decipher GRID 
 
platform (GenomeDx).  For subjects considered to have a positive RNA expression 
 
signature based upon a binary score assigned via the GenomeDx proprietary 
 
algorithm, a PSA50 response rate will be calculated.  Similarly, a calculation will be 
 
performed for subjects considered to have a negative RNA expression signature.  


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10.1.3.3 PARP-1, PARP-2, γH2AX, RAD51, 53BP1 mRNA/protein levels:  
 
Subjects will have pretreatment and on-treatment tumor specimens analyzed.  IHC 
 
and RNA in situ hybridization staining PARP-1 and PARP-2 will be performed on the 
 
pretreatment samples and scored on scale of 0 (none) to 3 (intense staining), and 
 
the results will be associated with responses for both proteins, separately, using 
 
descriptive statistics and Fisher’s Exact Tests.   Immunofluorescence  will be used to 
 
quantify the median intensity of each H2AX, RAD51 and 53BP1 foci per cell as 
 
well determine the median number of foci per cell on the pretreatment biopsies.  
 
Using analytical microscopy, Drs. Meeker and Heaphy have developed imaging 
 
software, which can isolate single nuclei and quantify both the intensity and number 
 
of immunofluorescent foci per nucleus (i.e. per cell). Using FFPE tissue obtained at 
 
biopsy, we will examine the change in DNA damage foci number and intensity 
 
(reported as median percent change) induced by PARPi in PSA50 responders versus 
 
non-responders using a T-test.   
  
 
10.1.3.4 Reversion Mutations: 
  
 
Subjects will have ctDNA examined by FoundationACT testing before starting  
  
 
treatment and at clinical progression while on rucaparib.  We will report the  
  
 
incidence and describe the observed reversion mutation, a known mechanism of  
  
 
resistance to PARP inhibition. 
 
10.2 
Analysis Populations 
10.2.1 Intent-to-treat/Response-to-treatment/Evaluable population 
All patients who meet eligibility criteria and receive at least 1 dose of rucaparib will 
be included in the main analysis of the response rate, even if there are major 
protocol deviations (eg, incorrect treatment schedule or drug administration). Each 
patient will be assigned to one of the following categories: 
Table 7 Categories for Response to Treatment 
Category 
Response 
1 
Complete response 
2 
Partial response 
3 
Stable disease 
4 
Progressive disease 
5 
Early death from malignant disease 
6 
Early death from toxicity 
7 
Early death from other causes 
9 
Unknown (not assessable/insufficient data) 
NOTE: By arbitrary convention, category 9 designates unknown status in a clinical database. Patients in response 
categories 4 to 9 will be considered to have treatment failure (disease progression). 
 
Conclusions are to be based on the population of all eligible patients. Subanalyses 


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may be performed on various subsets of patients, such as those with no major 
protocol deviations or those who continued in the study for the entire treatment 
period (i.e., did not withdraw prematurely). Subanalysis will not serve as the basis 
for drawing conclusions concerning treatment efficacy. 
10.2.2 Safety population 
All patients enrolled in the study will be included in the safety analysis population 
and considered evaluable for toxicity and safety from the time of their first dose. 
Demographic and baseline characteristics for the safety population will be 
summarized by number and percent for categorical data (eg, sex, race/ethnicity) 
and by descriptive statistics for continuous data (eg, weight, vital signs, EKG 
readings, disease status). 
10.3 
Safety Analysis 
10.3.1 Evaluation of adverse events 
Treatment-emergent adverse events will be translated from investigator terms to 
MedDRA v20.1 terminology and summarized (number and percentage of patients) 
for all patients who receive at least 1 dose. Adverse event summaries will be 
organized by body system, frequency of occurrence, intensity (i.e., severity grade), 
and causality or attribution. Patients who experience an adverse event more than 
once will be counted only once. The occurrence with the maximum severity will be 
used to calculate intensity. 
10.3.2 Evaluation of serious adverse events and premature withdrawals 
Adverse events deemed serious and those resulting in treatment withdrawal or 
death will be summarized separately. Narrative paragraphs will be generated to 
describe the circumstances surrounding each SAE and death. 
10.3.3 Evaluation of laboratory parameters and assays 
Selected clinical laboratory parameters will be summarized and clinically significant 
changes from baseline will be discussed. 
10.3.4 Extent of exposure 
Treatment exposure will be summarized for all patients, including dose 
administration, number of cycles, dose modifications or delays, and duration of 
therapy. 
11. 
PROTECTION OF HUMAN SUBJECTS 
11.1 
Ethical Considerations 
This study will be conducted in compliance with the protocol, GCP guidelines established by 
the International Conference on Harmonization, and the ethical standards set forth in the 
Declaration of Helsinki 2004 (available at: www.laakariliitto.fi/e/ethics/helsinki.html). 
11.2 
Protocol Amendments 
Before starting the study, the protocol must be approved by each institution’s IRB or 
Independent Ethics Committee (IEC). Amendments to the protocol may be made only with 
consent of the lead site/sponsor and principal investigator and are subject to IRB approval 
before instituting. 


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11.3 
Written Informed Consent 
Before obtaining consent, members of the study team will review the rationale for the 
treatment program with the patient. The discussion will review the alternatives available 
(including hormonal therapy, chemotherapy, or supportive care as appropriate), the 
potential benefits of this program, the risks and the probability of their occurrence, and the 
procedures to minimize these risks. Should an adverse event occur, the provisions available 
to ensure medical intervention will also be reviewed. Why the risks are reasonable in 
relation to the anticipated benefits, incentives, or costs that will or may be incurred as a 
result of participating in the study, as well as the efforts to maintain confidentiality, will also 
be discussed with the patient. 
Patients will be required to sign and date (in triplicate) a statement of informed consent 
that meets the requirements of the Code of Federal Regulations (Federal Register Vol. 46, 
No. 17, January 27, 1981, part 50) and the IRB. The medical record will include a statement 
that written informed consent was obtained (and document the date that it was obtained) 
before the patient is enrolled in the study. The original signed document will become part of 
the patient’s medical record, a copy will be forwarded to the lead site/sponsor pursuant to 
sponsor registration and a copy will be sent home with each patient. 
The consent form will include the following: 
• 
the nature and objectives, potential toxicities, and benefits of the intended study 
• 
the length of therapy and likely follow-up required 
• 
alternatives to the proposed therapy (including available standard and 
investigational therapies) 
• 
the name of the investigator(s) responsible for the protocol 
• 
the right of the patient to accept or refuse treatment and to withdraw from 
participation in this study 
• 
Text regarding the consortium and the coordinating center should be added to 
all institutional informed consent documents and sections in the research 
authorization/HIPAA forms (eg, “Prostate Cancer Clinical Trial Consortium, 
Coordinating Center at Memorial Sloan-Kettering Cancer Center, New York, NY”) 
11.4 
Protection of Privacy 
Patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. After this discussion, they 
will be asked to sign a Notice of Privacy Practice research authorization/HIPAA form. The 
original signed documents will become part of the patient’s medical records, and each 
patient will receive a copy of the signed documents. The use and disclosure of protected 
health information will be limited to the individuals described in the research authorization 
form. The research authorization form must be completed by the principal investigator and 
approved by the IRB. 
11.5 
Terminating or Modifying the Study 
Adverse event and laboratory data from this trial will be assessed by the medical monitor 
(Dr. Mark Markowski) on an ongoing basis. At least quarterly, data from the clinical 
database will be reviewed. The results of this review will be shared with all investigators 
either in writing or as part of a teleconference. SAEs will be reviewed as they are reported 


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to the lead site/sponsor, and the medical monitor will make an assessment regarding the 
safety of continuing or modifying the study. This assessment will be shared with the 
investigators either in writing or as part of a teleconference. Should the assessment of 
either the lead site/sponsor or the principal investigator be that the study should be 
terminated, the study will be closed to further accrual. Patients who are receiving rucaparib 
will be assessed individually by the investigator to see if it is in the patients’ best interest to 
continue, which might be the case for a patient that is responding to the intervention. 
Follow-up safety assessments will be performed for all patients who are terminated from 
the study prematurely. 


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12. 
REFERENCES 
 
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Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, Nava Rodrigues D, 
Robinson D, Omlin A, Tunariu N, Boysen G, Porta N, Flohr P, Gillman A, Figueiredo I, 
Paulding C, Seed G, Jain S, Ralph C, Protheroe A, Hussain S, Jones R, Elliott T, McGovern U, 
Bianchini D, Goodall J, Zafeiriou Z, Williamson CT, Ferraldeschi R, Riisnaes R, Ebbs B, Fowler 
G, Roda D, Yuan W, Wu YM, Cao X, Brough R, Pemberton H, A'Hern R, Swain A, Kunju LP, 
Eeles R, Attard G, Lord CJ, Ashworth A, Rubin MA, Knudsen KE, Feng FY, Chinnaiyan AM, 
Hall E, de Bono JS. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. The New 
England journal of medicine 2015;373(18):1697-1708. 
2. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: a cancer journal for clinicians 
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Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, Antonarakis ES, Beer TM, 
Carducci MA, Chi KN, Corn PG, de Bono JS, Dreicer R, George DJ, Heath EI, Hussain M, Kelly 
WK, Liu G, Logothetis C, Nanus D, Stein MN, Rathkopf DE, Slovin SF, Ryan CJ, Sartor O, Small 
EJ, Smith MR, Sternberg CN, Taplin ME, Wilding G, Nelson PS, Schwartz LH, Halabi S, Kantoff 
PW, Armstrong AJ. Trial Design and Objectives for Castration-Resistant Prostate Cancer: 
Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin 
Oncol 2016;34(12):1402-1418. 
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James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, Ritchie AW, Parker 
CC, Russell JM, Attard G, de Bono J, Cross W, Jones RJ, Thalmann G, Amos C, Matheson D, 
Millman R, Alzouebi M, Beesley S, Birtle AJ, Brock S, Cathomas R, Chakraborti P, Chowdhury 
S, Cook A, Elliott T, Gale J, Gibbs S, Graham JD, Hetherington J, Hughes R, Laing R, McKinna F, 
McLaren DB, O'Sullivan JM, Parikh O, Peedell C, Protheroe A, Robinson AJ, Srihari N, 
Srinivasan R, Staffurth J, Sundar S, Tolan S, Tsang D, Wagstaff J, Parmar MK, investigators S. 
Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in 
prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, 
platform randomised controlled trial. Lancet 2015. 
5. 
Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, Wong YN, Hahn N, Kohli 
M, Cooney MM, Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia JA, DiPaola RS. 
Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. The New 
England journal of medicine 2015;373(8):737-746. 
6. 
Farmer H, McCabe N, Lord CJ, Tutt ANJ, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, 
Hickson I, Knights C, Martin NMB, Jackson SP, Smith GCM, Ashworth A. Targeting the DNA 
repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434(7035):917-
921. 
7. 
Tanihara Y, Masuda S, Sato T, Katsura T, Ogawa O, Inui K. Substrate specificity of MATE1 
and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. 
Biochem Pharmacol 2007;74(2):359-371. 
8. 
Lepist EI, Zhang X, Hao J, Huang J, Kosaka A, Birkus G, Murray BP, Bannister R, Cihlar T, 
Huang Y, Ray AS. Contribution of the organic anion transporter OAT2 to the renal active 
tubular secretion of creatinine and mechanism for serum creatinine elevations caused by 
cobicistat. Kidney Int 2014;86(2):350-357. 
9. 
Cancer Genome Atlas Research N. The Molecular Taxonomy of Primary Prostate Cancer. Cell 
2015;163(4):1011-1025. 
10. 
Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, Montgomery B, 
Taplin ME, Pritchard CC, Attard G, Beltran H, Abida W, Bradley RK, Vinson J, Cao X, Vats P, 


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Kunju LP, Hussain M, Feng FY, Tomlins SA, Cooney KA, Smith DC, Brennan C, Siddiqui J, 
Mehra R, Chen Y, Rathkopf DE, Morris MJ, Solomon SB, Durack JC, Reuter VE, Gopalan A, Gao 
J, Loda M, Lis RT, Bowden M, Balk SP, Gaviola G, Sougnez C, Gupta M, Yu EY, Mostaghel EA, 
Cheng HH, Mulcahy H, True LD, Plymate SR, Dvinge H, Ferraldeschi R, Flohr P, Miranda S, 
Zafeiriou Z, Tunariu N, Mateo J, Perez-Lopez R, Demichelis F, Robinson BD, Schiffman M, 
Nanus DM, Tagawa ST, Sigaras A, Eng KW, Elemento O, Sboner A, Heath EI, Scher HI, Pienta 
KJ, Kantoff P, de Bono JS, Rubin MA, Nelson PS, Garraway LA, Sawyers CL, Chinnaiyan AM. 
Integrative clinical genomics of advanced prostate cancer. Cell 2015;161(5):1215-1228. 
11. 
Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, Garofalo A, Gulati R, 
Carreira S, Eeles R, Elemento O, Rubin MA, Robinson D, Lonigro R, Hussain M, Chinnaiyan A, 
Vinson J, Filipenko J, Garraway L, Taplin ME, AlDubayan S, Han GC, Beightol M, Morrissey C, 
Nghiem B, Cheng HH, Montgomery B, Walsh T, Casadei S, Berger M, Zhang L, Zehir A, Vijai J, 
Scher HI, Sawyers C, Schultz N, Kantoff PW, Solit D, Robson M, Van Allen EM, Offit K, de Bono 
J, Nelson PS. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. 
The New England journal of medicine 2016;375(5):443-453. 
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Annala M, Struss WJ, Warner EW, Beja K, Vandekerkhove G, Wong A, Khalaf D, Seppala IL, So 
A, Lo G, Aggarwal R, Small EJ, Nykter M, Gleave ME, Chi KN, Wyatt AW. Treatment Outcomes 
and Tumor Loss of Heterozygosity in Germline DNA Repair-deficient Prostate Cancer. 
European urology 2017;72(1):34-42. 
13. 
Erho N, Crisan A, Vergara IA, Mitra AP, Ghadessi M, Buerki C, Bergstralh EJ, Kollmeyer T, 
Fink S, Haddad Z, Zimmermann B, Sierocinski T, Ballman KV, Triche TJ, Black PC, Karnes RJ, 
Klee G, Davicioni E, Jenkins RB. Discovery and Validation of a Prostate Cancer Genomic 
Classifier that Predicts Early Metastasis Following Radical Prostatectomy. Plos One 
2013;8(6). 
14. 
Karnes RJ, Bergstralh EJ, Davicioni E, Ghadessi M, Buerki C, Mitra AP, Crisan A, Erho N, 
Vergara IA, Lam LL, Carlson R, Thompson DJS, Haddad Z, Zimmermann B, Sierocinski T, 
Triche TJ, Kollmeyer T, Ballman KV, Black PC, Klee GG, Jenkins RB. Validation of a Genomic 
Classifier that Predicts Metastasis Following Radical Prostatectomy in an At Risk Patient 
Population. J Urology 2013;190(6):2047-2053. 
15. 
Freedland SJ, Choeurng V, Howard L, De Hoedt A, du Plessis M, Yousefi K, Lam LL, Buerki C, 
Ra S, Robbins B, Trabulsi EJ, Shah NL, Abdollah F, Feng FY, Davicioni E, Dicker AP, Karnes RJ, 
Den RB. Utilization of a Genomic Classifier for Prediction of Metastasis Following Salvage 
Radiation Therapy after Radical Prostatectomy. European urology 2016. 
16. 
McCarthy EF. CT-guided needle biopsies of bone and soft tissue tumors: a pathologist's 
perspective. Skeletal radiology 2007;36(3):181-182. 
17. 
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van 
Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. New guidelines to evaluate the 
response to treatment in solid tumors. European Organization for Research and Treatment 
of Cancer, National Cancer Institute of the United States, National Cancer Institute of 
Canada. Journal of the National Cancer Institute 2000;92(3):205-216. 
18. 
Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, Antonarakis ES, Beer TM, 
Carducci MA, Chi KN, Corn PG, de Bono JS, Dreicer R, George DJ, Heath EI, Hussain M, Kelly 
WK, Liu G, Logothetis C, Nanus D, Stein MN, Rathkopf DE, Slovin SF, Ryan CJ, Sartor O, Small 
EJ, Smith MR, Sternberg CN, Taplin ME, Wilding G, Nelson PS, Schwartz LH, Halabi S, Kantoff 
PW, Armstrong AJ, Prostate Cancer Clinical Trials Working G. Trial Design and Objectives for 
Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer 
Clinical Trials Working Group 3. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 2016;34(12):1402-1418. 


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APPENDIX A: PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Description 
% 
Description 
0 
Normal activity. Fully active, able to 
continue all predisease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease 
90 
Able to carry on normal activity, minor 
signs or symptoms of disease 
1 
Symptoms, but ambulatory. Restricted in 
physically strenuous activity but 
ambulatory and able to carry out work of a 
light or sedentary nature (eg, light 
housework, office work). 
80 
Normal activity with effort, some signs or 
symptoms of disease 
70 
Cares for self, unable to carry on normal 
activity or to do active work 
2 
In bed < 50% of the time. Ambulatory and 
capable of all self-care but unable to carry 
out any work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance but is able 
to care for most needs 
50 
Requires considerable assistance and 
frequent medical care 
3 
In bed > 50% of the time. Capable of only 
limited self-care, confined to bed or chair  
> 50% of waking hours. 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization indicated. 
Death not imminent. 
4 
100% bedridden. Completely disabled, 
cannot carry on any self-care, totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. Death 
not imminent. 
10 
Moribund, fatal processes progressing 
rapidly 
5 
Dead 
0 
Dead 
 
 
 


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APPENDIX B: MEDICATIONS WITH THE POTENTIAL FOR DRUG-DRUG INTERACTIONS 
 
CYP Enzyme 
Substrates with Narrow Therapeutic Range  
CYP2C9 
Warfarin, phenytoin  
CYP2C19 
S-mephenytoin  
CYP3A 
Alfentanil, astemizole, cisapride, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus, terfenadine 
 
 


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APPENDIX C: LABORATORY MANUAL 
Pathology will be reviewed and processed centrally at Johns Hopkins. Biopsy specimens will be 
handled and sampled in a uniform fashion. 
 
The lead pathologist at Johns Hopkins, Dr. Tamara Lotan, will perform the central review and 
prepare tissue for correlative analysis.   
 
All slides listed below should be sent to Dr. Tamara Lotan’s lab for central handling at: 
 
Department of Pathology 
 
 
1550 Orleans St. 
 
 
Cancer Research Building II, Room 343 
 
 
Baltimore, MD 21231 
 
 
• 
10 unstained slides and 1 H&E slide representative of tumor will be prepared and send to 
Foundation Medicine for FoundationOne testing.  Tumor will be placed in the 
FoundationOne specimen kit and mailed to: 
Foundation Medicine, Inc. 
7010 Kit Creek Road 
Morrisville, NC 27560 
Phone: 888.988.3639 
 
• 
10 unstained slides representative of tumor will be prepared and send to the Lotan 
Laboratory for PARP-1, PARP-2, gamma-H2AX, 53BP1, and RAD51 analysis. 
 
• 
10 unstained slides will be stored at 4deg C until placement in cooler shipping box with ice 
packs and mailed to: 
GenomeDx Biosciences Laboratory 
10355 Science Center Drive 
Suite 240 
San Diego, CA 92121 
 
• 
5 unstained slides representative of tumor will be prepared and banked, for those subjects 
consenting to optional tissue banking for future research. 
 
• 
ctDNA specimens will be analyzed by FoundationACT.  Lab kits will be provided by Johns 
Hopkins study team. 
 
 
For Subjects with metastatic bone disease only 
 
Subjects who decline  the bone biopsy are asked permission to obtain 30-35 unstained slides from 
their prior prostatectomy.  If agreed, the unstained slides received will be apportioned in the same 
manner above. 
 


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APPENDIX D: GLOSSARY OF ABBREVIATIONS AND ACRONYMS 
 
17-AAG 
17-allylamino-17-demethoxygeldanamycin 
17-DMAG 
17-dimethylaminoethylamino-17-demethoxygeldanamycin 
2-MPPA 
2-(3-mercaptopropyl) Pentanedioic acid  
AdEERS 
Adverse Event Expedited Reporting System  
ADR 
adverse drug reaction 
ADT 
androgen-deprivation therapy 
AE 
adverse event 
AGA 
androgenetic alopecia 
AI 
accumulation index 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
APTT 
activated partial thromboplastin time 
AR 
androgen receptor 
ASAEL 
Agent Specific Adverse Event List 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC(INF) 
area under the concentration-time curve from time zero extrapolated to infinite time 
AUC(0-T) 
area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration 
AUC(TAU) 
area under the concentration-time curve in one dosing interval 
AUMC(INF) 
area under the moment concentration time curve extrapolated to infinity 
A-V 
atrioventricular 
-HCG 
beta-human chorionic gonadotrophin 
%BE 
percent biliary excretion 
bid 
bis in die (twice a day) 
BLQ 
below limit of quantification 
BMI 
body mass index 
BP 
blood pressure 
BSA 
Body Surface Area 
BUN 
blood urea nitrogen 
C 
Celsius 
Ca++ 
calcium 
caBIG 
Cancer Biomedical Informatics Grid 


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CAEPR 
Comprehensive Adverse Event and Potential Risks 
CALGB 
Cancer and Leukemia Group B 
CBC 
complete blood count 
CCC 
Clinical Consortium Committee 
CCD 
Central Consortium Database 
CDE 
common data element 
CDUS 
Clinical Data Update System  
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cl- 
chloride 
Clcr 
creatinine clearance 
CLNR 
nonrenal clearance 
CLR 
renal clearance 
CLT 
total body clearance 
CLT/F 
apparent total body clearance 
Cm 
centimeter 
Cmax 
maximum plasma concentration 
Cmin 
trough observed concentration 
COSTART 
Coding Symbols for Thesaurus of Adverse Reaction Terms 
CNS 
central nervous system 
CR 
complete response 
CRC 
Clinical Research Center 
CRDB 
Clinical Research Database 
CRF 
case report form 
CRMIS 
Clinical Research Management Information System 
CRPC 
castration resistant prostate cancer 
CT 
computerized tomography 
CTC 
circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTMS 
Clinical Trials Monitoring Service 
CTO 
Clinical Trials Office 
CV 
coefficient of variation 
CYP 
cytochrome p-450 
DCTD 
Division of Cancer Treatment and Diagnosis 
DEV 
deviation from the nominal value 
%DEV 
percent deviation 
dL 
deciliter 
DHEA 
dehydroepiandrosterone 


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DHEA-S 
dehydroepiandrosterone sulfate 
DHT 
dihydrotestosterone 
DLT 
dose-limiting toxicity 
DSM 
data and safety monitoring 
EA 
extent of absorption 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EEG 
electroencephalogram 
EKG 
electrocardiogram 
EORTC 
European Organization  for Research and Treatment of Cancer 
ESF 
eligibility screening form 
ESR 
expedited safety report 
F 
bioavailability 
FDA 
Food and Drug Administration 
FDG-PET 
2-[18F]fluoro-2-deoxyglucose positron emitting tomography 
FDHT 
18-fluoro-dehydrotestosterone 
%FE 
percent fecal excretion 
FISH 
fluorescence in situ hybridization 
FSH 
follicle stimulating hormone 
GAPDH 
glyseraldehayde-3-phophate dehydrogenase 
GC 
gas chromatography 
GCP 
good clinical practice 
GCPII 
glutamate carboxypeptidase II enzyme 
GFR 
glomerular filtration rate 
 
 
GnRH 
gonadotropin-releasing hormone  
HAT 
histone acetyltransferases 
HCO3- 
bicarbonate 
HDAC 
histone deacetylase 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HL7 
American National Standards Institute’s Health Level Seven 
HPF 
high power field 
HPLC 
high-performance liquid chromatography 
HR 
heart rate 
HRPC 
hormone-refractory prostate cancer 
HRT 
hormone replacement therapy 
HSP90 
heat-shock protein 90 


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ICD 
International Classification of Diseases 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IHC 
immunochemical 
IM 
intramuscular 
IMSL 
International Mathematical Statistical Library 
IND 
investigational new drug 
INR 
international normalized ratio 
IP 
intraperitoneal 
IRB 
Institutional Review Board 
ITT 
intent-to-treat population 
IV 
intravenous 
K 
slope of the terminal phase of the log concentration-time curve 
K+ 
potassium 
K3EDTA 
potassium ethylenediaminetetraacetic acid 
KLK1 
kallikrein 1 
LBD 
ligand-binding domain 
LC 
liquid chromatography 
LCM 
laser capture microdissection 
LC-MS 
liquid chromatography/mass spectrometry 
LD 
longest diameter 
LDH 
lactate dehydrogenase 
LLQ 
lower limit of quantitation 
ln 
natural logarithm 
LOCF 
last observation carried forward 
LOI 
letter of intent 
LPF 
low power field 
MAD 
maximum administered dose 
MDS 
myelodysplasia 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
minimum inhibitory concentration 
MMP 
matrix metalloproteinase 
MRI 
magnetic resonance imaging 
MRT 
mean residence time 
MRT(INF) 
mean residence time adjusted for infusion time 
MRT(PO) 
mean residence time following oral administration 
MRT(SS) 
mean residence time at steady-state 
MSKCC 
Memorial Sloan-Kettering Cancer Center 
MS 
mass spectrometry 


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MTD 
maximum tolerated dose 
N 
number of subjects or observations 
NA 
not applicable 
N/A 
not available 
NBN 
National Biospecimen Network 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NOAEL 
no observed adverse effect level 
NOS 
not otherwise specified 
NSAID 
nonsteroidal anti-inflammatory drug 
NTX 
N-telopeptide cross-link 
NVB 
neurovascular bundle 
OCR 
Office of Clinical Research at MSKCC 
PCCTC 
Prostate Cancer Clinical Trials Consortium 
PCRP 
Department of Defense Prostate Cancer Research Program 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PI 
principal investigator 
PIN 
prostatic intraepithelial neoplasia 
PK 
pharmacokinetics 
PMB 
Pharmaceutical Management Branch 
PO 
per os (by mouth) 
PR 
partial response 
PSA 
prostate-specific antigen 
PSA-DT 
prostate-specific antigen doubling time 
PSMA 
prostate specific membrane antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QC 
quality control 
qd 
quaque die (every day) 
qRT-PCR 
quantitative reverse transcription-polymerase chain reaction 
QOL 
quality of life 
RBC 
red blood cell 
RC 
Research Council 
RDBMS 
Relational Database Management System 
RDRC 
Radioactive Drug Research Committee 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP 
radical prostatectomy  


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RPC 
eResearch Program Coordinator 
RSA 
Research Study Assistant 
RSD 
relative standard deviation 
%RSD 
percent relative standard deviation 
SAE 
serious adverse event 
SAHA 
suberoylanilide hydroxamic acid 
SC 
subcutaneous 
SD 
standard deviation 
SD 
stable disease 
Seq 
sequence 
SHBG 
sex hormone binding globulin 
SKI 
Sloan-Kettering Institute for Cancer Research 
SMD 
stable metabolic disease 
SOP 
Standard Operating Procedures 
SPORE 
Specialized Programs of Research Excellence 
STAR 
Symptom Tracking and Reporting 
SUV 
standardized uptake value 
t 
temperature 
t1/2 
terminal half-life  
T 
time 
TAUC(TAU) 
trapezoidal area under the concentration-time curve in one dosing interval 
TAUC(0-T) 
trapezoidal area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration 
TDP 
time to disease progression 
TGP 
prostate-specific transglutaminase  
tid 
ter in die (3 times a day) 
TMA 
tissue microarray  
Tmax 
time of maximum observed concentration 
TMPRSS2 
transmembrane protease, serine 2 
TNM 
tissue, lymph node, metastases 
TX 
treatment 
ULN 
upper limit of normal 
ULQ 
upper limit of quantitation 
UR 
urinary recovery 
VEGF 
vascular endothelial growth factor 
Vss 
volume of distribution at steady-state 
WBC 
white blood cell 
WHO 
World Health Organization 


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APPENDIX E. ACCEPTABLE BIRTH CONTROL METHODS 
 
Rucaparib is regarded as a compound with medium/high fetal risk.  Subjects with partners of 
childbearing potential, who are sexually active, must agree to the use of TWO highly effective forms 
of contraception (defined as a method that can achieve a failure rate of <1% per year when used 
consistently and correctly) in combination [as listed below], throughout the period of taking study 
treatment and for at least 4 month after last dose of study drug(s), or they must totally/truly 
abstain from any form of sexual intercourse (see below).   
 
Highly Effective Non-hormonal birth control methods include: 
• 
Total sexual abstinence. Abstinence must continue for the total duration of study treatment 
and for at least 1 month after the last dose. Periodic abstinence (eg, calendar ovulation, 
symptothermal post ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
• 
Vasectomised sexual partner PLUS male condom. With participant assurance that partner 
received post-vasectomy confirmation of azoospermia. 
• 
Tubal occlusion PLUS male condom 
• 
IUD PLUS male condom. Provided coils are copper-banded 
 
Highly Effective hormonal methods: 
• 
Normal and low dose combined oral pills PLUS male condom 
• 
Cerazette (desogestrel) PLUS male condom. Cerazette is currently the only highly 
efficacious progesterone based pill. 
• 
Hormonal shot or injection (eg., Depo-Provera) PLUS male condom 
• 
Etonogestrel implants (e.g., Implanon, Norplant) PLUS male condom 
• 
Norelgestromin / EE transdermal system PLUS male condom 
• 
Intrauterine system [IUS] device (eg., levonorgestrel releasing IUS -Mirena®) PLUS male 
condom 
• 
Intravaginal device (e.g., EE and etonogestrel) PLUS male condom. 
 
 


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APPENDIX F. ACTIONS REQUIRED IN CASES OF COMBINED INCREASE OF 
AMINOTRANSFERASE AND TOTAL BILIRUBIN – HY’S LAW 
 
1. 
INTRODUCTION 
 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a patient meets potential 
Hy’s Law (PHL) criteria at any point during the study.  The Investigator participates, together with 
Clovis Oncology clinical project representatives, in review and assessment of cases meeting PHL 
criteria to agree whether Hy’s Law (HL) criteria are met. HL criteria are met if there is no 
alternative explanation for the elevations in liver biochemistry other than Drug Induced Liver 
Injury (DILI) caused by the Investigational Medicinal Product (IMP). The Investigator is responsible 
for recording data pertaining to PHL/HL cases and for reporting Adverse Events (AE) and Serious 
Adverse Events (SAE) according to the outcome of the review and assessment in line with standard 
safety reporting processes. 
 
 
2. 
DEFINITIONS 
 
Potential Hy’s Law (PHL) 
• 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) and Total Bilirubin (TBL) ≥ 2xULN at any point during the study irrespective 
of an increase in Alkaline Phosphatase (ALP).  
 
Hy’s Law (HL) 
• 
AST or ALT ≥ 3x ULN and TBL ≥ 2xULN, where no other reason, other than the IMP, can be 
found to explain the combination of increases, eg, elevated ALP indicating cholestasis, viral 
hepatitis, another drug.  
 
 
3. 
IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
 
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any patient who meets any of the following identification criteria in isolation or in 
combination: 
• ALT ≥ 3xULN 
• AST ≥ 3xULN 
• TBL ≥ 2xULN 
 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
• 
Determine whether the patient meets PHL criteria (see Section 2 of this Appendix for 
definition) by reviewing laboratory reports from all previous visits 
• 
Promptly enter the laboratory data into the laboratory CRF 
 
 


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4. 
FOLLOW-UP 
 
Potential Hy’s Law Criteria not met 
If the patient does not meet PHL criteria the Investigator will: 
• 
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol. 
 
Potential Hy’s Law Criteria met 
If the patient does meet PHL criteria the Investigator will: 
• 
Notify the Clovis Oncology representative who will then inform the central Study Team. 
• 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data. Subsequent to 
this contact the Investigator will: 
• 
Monitor the patient until liver biochemistry parameters and appropriate clinical symptoms 
and signs return to normal or baseline levels, or as long as medically indicated 
• 
Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician 
• 
Complete the three Liver CRF Modules as information becomes available 
• 
If at any time (in consultation with the Study Physician) the PHL case meets serious criteria, 
report it as an SAE using standard reporting procedures 
 
 
5. 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES 
 
The instructions in this Section should be followed for all cases where PHL criteria are met.  No 
later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP. Clovis Oncology and the Principal Investigator will also be 
involved in this review together with other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
 
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 
• 
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly and 
follow the Clovis Oncology standard processes 
 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
• 
Report an SAE (report term ‘Hy’s Law’) according to Clovis Oncology standard processes. 
− The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply 
− As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
 


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If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until such time as an informed decision can be made: 
• 
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above 
• 
Continue follow-up and review according to agreed plan. Once the necessary supplementary 
information is obtained, repeat the review and assessment to determine whether HL 
criteria are met. Update the SAE report according to the outcome of the review 
 
 
6. 
ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL HY’S LAW 
 
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit.   
 
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence. 
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
• 
Was the alternative cause for the previous occurrence of PHL criteria being met chronic or 
progressing malignant disease? 
 
− If No: follow the process described in Section 4 of this Appendix 
 
− If Yes: Determine if there has been a significant change in the patient’s condition# 
compared with when PHL criteria were previously met 
▪ 
If there is no significant change no action is required 
▪ 
If there is a significant change follow the process described in Section 4 of 
this Appendix 
# A ‘significant’ change in the patient’s condition refers to a clinically 
relevant change in any of the individual liver biochemistry parameters (ALT, 
AST or total bilirubin) in isolation or in combination, or a clinically relevant 
change in associated symptoms. The determination of whether there has 
been a significant change will be at the discretion of the Investigator, this 
may be in consultation with the Study Physician if there is any uncertainty. 
 
 
7. 
REFERENCES 
 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical 
evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM174090.pdf 
 
 
 

ICF_001.pdf: 
Trial of Rucaparib in Patients With 
Metastatic Hormone-Sensitive Prostate 
Cancer Harboring Germline DNA Repair 
Gene Mutations
NCT03413995
3/31/2022


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 31, 2022 
Principal Investigator: Mark Markowski M.D. Ph.D. 
Application No.: IRB00156514 
 
 
Page 1 of 17 
Combined Informed Consent/Authorization June 2015 Version 15                                             TRIUMPH Protocol v7.0 dated 03/04/22 
 
 
NCT03413995 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RESEARCH PARTICIPANT INFORMED CONSENT AND PRIVACY 
AUTHORIZATION FORM 
 
Protocol Title:  
Phase II Trial of Rucaparib in Patients with Metastatic and Non-
Metastatic Hormone-Sensitive Prostate Cancer Harboring DNA 
Repair Gene Mutations (TRIUMPH) 
 
Application No.:      
IRB00156514 
 
Sponsor: 
Clovis Oncology 
 
Principal Investigator:   Mark C. Markowski M.D., Ph.D. 
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center 
401 North Broadway 
Baltimore, MD 21231 
Phone: 410 955-8893 
Fax: 410 955-8587             
  
1. 
What you should know about this study: 
• You are being asked to join a research study. This consent form explains the research study and your 
part in it. Please read it carefully and take as much time as you need. Ask your study doctor or the 
study team to explain any words or information that you do not understand. 
• You are a volunteer.  If you join the study, you can change your mind later.  There will be no penalty 
or loss of benefits if you decide to quit the study.   
• During the study, we will tell you if we learn any new information that might affect whether you 
wish to continue to participate. 
• If we think your participation in this study may affect your clinical care, information about your 
study participation will be included in your medical record, which is used throughout Johns Hopkins.   
Doctors outside of Johns Hopkins may not have access to this information.  You can ask the research 
team to send this information to any of your doctors. 
• When Johns Hopkins is used in this consent form, it includes The Johns Hopkins University, The 
Johns Hopkins Hospital, Johns Hopkins Bayview Medical Center, Howard County General Hospital, 
Johns Hopkins Community Physicians, Suburban Hospital, Sibley Memorial Hospital and All 
Children’s Hospital.  
• Biospecimens will be collected in this study.  Biospecimens may include any of the following: 
blood, tissue, saliva, urine, bone marrow, cells, etc.  Most biospecimens contain DNA, which is the 
genetic code for each person. 
If appropriate for this study, a scanned copy of 
the signed consent form should be uploaded to 
the participant’s Epic/EMR record. 
 
 
 
 
 
Patient I.D. plate 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 31, 2022 
Principal Investigator: Mark Markowski M.D. Ph.D. 
Application No.: IRB00156514 
 
 
Page 2 of 17 
Combined Informed Consent/Authorization June 2015 Version 15                                             TRIUMPH Protocol v7.0 dated 03/04/22 
• A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law.  This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.  
• If you would like to review the information for this study, or a summary of the results, ask the study 
team doctor for the ClinicalTrials.gov study registration number. 
 
2. 
Why is this research being done? 
This aim of this research is to find out if the study drug rucaparib lowers prostate-specific antigen (PSA) 
levels in men with recurrence of prostate cancer that has not yet been treated with androgen deprivation 
therapy (also referred to as a biochemical recurrence [if there is no evidence of cancer on staging 
imaging] or metastatic hormone sensitive prostate cancer [if cancer is evident on imaging]) and who 
have a mutation in a gene involved in repairing DNA damage.  The research will also examine if 
rucaparib is safe in individuals with recurrent prostate cancer. 
 
Prior research studies have shown that drugs like rucaparib can be of benefit to patients with advanced 
metastatic prostate cancer who are resistant to androgen deprivation therapy AND who carry a mutation 
in a DNA repair gene.  We are studying if rucaparib will be effective for these patients earlier in their 
treatment course (for example, prior to the start of medicines that lower testosterone levels).   
 
It is unknown whether rucaparib will have the same benefit in men with metastatic or biochemically 
recurrent prostate cancer carrying a mutation in a DNA repair gene, prior to the use of medicines that 
lower testosterone levels.  Medicines that lower testosterone levels (also known as androgen deprivation 
therapy) is a Food and Drug Administration (FDA) approved therapy for metastatic prostate cancer and 
results in patients living longer.  It may also be used in patients with biochemically recurrent prostate 
cancer in certain circumstances. 
 
Participants in this research study will be refusing life-prolonging therapy. Medicines that lower 
testosterone levels (androgen deprivation therapy +/- docetaxel +/- abiraterone) will not be given 
to participants on this study.   
 
Participants will remain eligible to receive androgen deprivation therapy after completing or 
withdrawing from this study.  
 
Rucaparib tablets are approved by the FDA for the treatment of metastatic ovarian cancer that has 
progressed after at least 2 lines of prior chemotherapy, for patients with certain known DNA mutations.  
Rucaparib is also FDA- approved for use in metastatic prostate cancer that have become resistant to 
testosterone based therapies such as androgen deprivation therapy. The FDA is allowing the use of 
rucaparib in this research study. 
 
All participants who enroll in the study will have the same procedures and receive the same study drug 
(rucaparib). 
 
Men 18 years or older with metastatic prostate cancer, who have a mutation in a gene that affects repair 
of DNA damage and normal testosterone levels, may join the study. 
 
How many people will be in this study? 
Up to 30 participants are expected to enroll in this study. About 20 of these participants are expected to 
be enrolled at Johns Hopkins.  
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 31, 2022 
Principal Investigator: Mark Markowski M.D. Ph.D. 
Application No.: IRB00156514 
 
 
Page 3 of 17 
Combined Informed Consent/Authorization June 2015 Version 15                                             TRIUMPH Protocol v7.0 dated 03/04/22 
3. 
What will happen if you join this study? 
If you agree to be in this study, we will ask you to do the following things: 
 
Screening Period:  
There will be a screening period to see if you can participate in the study. During the screening period 
the following procedures will be performed: 
• The study team will ask you questions about your medical history and health and review your 
medical record. 
• A physical examination and vital signs (body temperature, blood pressure, pulse, respiratory rate, 
weight). 
• Eastern Cooperative Oncology Group (ECOG) performance status score: This is a scale used to 
assess how your cancer is progressing, and how your cancer affects your daily living abilities. 
• Review of other medications you are currently taking. 
• Collection of a blood sample (about 3 tablespoons of blood) for laboratory tests which measure 
your blood chemistry, including kidney and liver function, count your red and white blood cells 
and platelets. Lab test to measure how long it takes your blood to clot.  
• Collection of urine sample for routine analysis. 
• Electrocardiogram (ECG): This test gives a picture of the electrical action of your heart. 
• CT scan and bone scan (if these have not been performed in the past 8 weeks).  Computed 
tomography (CT) scan or magnetic resonance imaging (MRI) of the known areas of disease.  
These pictures will allow your doctor to monitor your disease before, during and after you 
receive the study drugs. In addition, bone scans will be completed to measure your disease 
• If you are eligible for the study and choose to participate, you will be scheduled for a biopsy of 
your cancer, which is required prior to the start of rucaparib. 
o Bone biopsies are optional in this study. If you have tumor only in your bones, you have 
the option to decline the biopsy. 
• Will you give permission to take part in the screening tumor biopsy of your bone?  
 
 
 
 
 
YES     _______________________________  
 
 
 
 
Signature of Participant 
 
 
 
 
 
 
 
 
 
 
NO      _______________________________  
 
 
 
 
Signature of Participant 
 
 
 
 
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 31, 2022 
Principal Investigator: Mark Markowski M.D. Ph.D. 
Application No.: IRB00156514 
 
 
Page 4 of 17 
Combined Informed Consent/Authorization June 2015 Version 15                                             TRIUMPH Protocol v7.0 dated 03/04/22 
o If no, will you give permission to obtain pathology slides from your previous prostatectomy 
surgery? 
 
 
 
 
 
YES     ___________________________   
 
 
 
                                                   Signature of Participant 
 
 
 
 
 
 
 
 
 
 
 
NO      ____________________________  
 
 
 
              Signature of Participant 
 
 
There are many different gene defects that can affect DNA repair. These genetic defects can be inherited 
or just be isolated to your tumor.  To be able to participate on this study, you must have had prior 
genetic testing confirming the presence of a genetic alteration that can be inherited (called a germline 
mutation).   
 
You will not be screened for inheritable genetic alterations as part of this study. If you have not been 
tested or do not have an inheritable genetic mutation in a gene that affects DNA repair, you are not 
eligible for this study. 
 
If you qualify to continue to participate in the study based on the results of the screening visit tests and 
procedures, you will be scheduled for a clinic visit after which you will start on the rucaparib regimen.   
 
All participants who enroll in the study will have the same procedures and receive the same study drug 
(rucaparib). 
 
Study Drug Administration Period: 
If you are found to be eligible to continue to participate in the study, you will return to the clinic to begin 
taking the study drugs. You will take two doses of study drug at the same time each day, morning and 
evening, about 12 hours apart, with one glass of water and with or without food.  The tablets should be 
swallowed whole and not chewed, crushed, dissolved or divided. 
 
If vomiting occurs shortly after the study drug tablets are swallowed, the dose should only be replaced if 
all of the intact tablets can be seen and counted.  Should you miss a scheduled dose for whatever reason 
(such as forgetting to take the tablets or vomiting), you will be allowed to take the scheduled dose up to 
a maximum of 2 hours after that scheduled dose time.  If greater than 2 hours after the scheduled dose 
time, the missed dose is not to be taken and you should take your next dose at the next scheduled time. 
 
You will visit the study doctor as instructed. Each study drug cycle is about 4 weeks. The study doctor 
or staff will discuss with you when and on which days to report to the clinic. 
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 31, 2022 
Principal Investigator: Mark Markowski M.D. Ph.D. 
Application No.: IRB00156514 
 
 
Page 5 of 17 
Combined Informed Consent/Authorization June 2015 Version 15                                             TRIUMPH Protocol v7.0 dated 03/04/22 
During Cycles (Every 4 weeks)  
You will return to the clinic every 4 weeks.  At each visit, the following tests and procedures will be 
performed: 
• Review of any changes in your health and medications since your last visit. 
• You will be asked about the symptoms you are having from your disease and side effects you 
may be experiencing. 
• Measurement of your weight and vital signs. 
• An evaluation of your ability to carry out daily activities will be performed. 
• A physical examination. 
• Collection of a blood sample (about 2 tablespoons of blood) for laboratory tests which measure 
your blood chemistry, including kidney and liver function, count your red and white blood cells 
and platelets. 
 
Every 3 months or 6 months:  
You will have a CT scan and bone scan every 3 months if you have metastatic disease and every 6 
months if you do not have metastatic disease while you are enrolled in the study, as well as a CT and 
bone scan at the end of the study (if it has been at least 1 month since your last CT and bone scan).   
 
The following tests will be done for research:  
• Collection of a blood sample (about 1 tablespoon) for research at screening and at the time of 
disease worsening (progression).  
 
Change to Every 3 month Clinic Visits after more than 12 months of study drug: 
Once you have been on the study for 12 months, you will return to the clinic every 3 months (12 weeks) 
for your study visits.  At each visit, the following tests and procedures will be performed: 
• Review of any changes in your health and medications since your last visit. 
• You will be asked about the symptoms you are having from your disease and side effects you 
may be experiencing. 
• Measurement of your weight and vital signs. 
• An evaluation of your ability to carry out daily activities will be performed. 
• A physical examination. 
• Collection of a blood sample (about 2 tablespoons of blood) for laboratory tests which measure 
your blood chemistry, including kidney and liver function, count your red and white blood cells 
and platelets. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 31, 2022 
Principal Investigator: Mark Markowski M.D. Ph.D. 
Application No.: IRB00156514 
 
 
Page 6 of 17 
Combined Informed Consent/Authorization June 2015 Version 15                                             TRIUMPH Protocol v7.0 dated 03/04/22 
Optional tumor biopsy: 
We would like your permission to perform a second tumor biopsy after 12 weeks of receiving rucaparib.  
This procedure is optional. If you refuse to have a biopsy, this will not affect your participation on this 
study nor will it affect your future care. 
 
Will you give permission to take part in this optional tumor biopsy after 12 weeks of rucaparib? 
 
 
 
 
 
YES     ________________________   
 
 
 
Signature of Participant 
 
 
 
 
 
 
 
 
 
 
NO      __________________  
 
 
 
Signature of Participant 
 
 
 
 
 
 
End of Study Drug Regimen Visit/28-Day Follow-up Visit  
If you complete all of the study drug regimen/intervention cycles or if you are withdrawn from the study 
at any time, you will come in for an end of study drug regimen visit 28 days after your last dose of study 
drug to have the following procedures done:  
 
• Review of any changes in your health and medications since your last visit. 
• Measurement of your weight and vital signs. 
• An evaluation of your ability to carry out daily activities will be performed. 
• A physical examination. 
• Collection of a blood sample (about 2 tablespoons of blood) for laboratory tests which 
measure your blood chemistry, including kidney and liver function, count your red and white 
blood cells and platelets. 
• Imaging tests: CT or MRI of the abdomen and pelvis, CT or MRI of the chest (or chest x-
ray), and bone scan, as determined by the study doctor. 
 
The procedures and visits in this clinical trial are different from the standard treatments.  If you choose 
to join the study, there are more frequent clinic visits (every month instead of every 3 months), more 
frequent blood tests (monthly, then every month instead of every 3-6 months), and receiving rucaparib 
instead of standard treatments.  The standard treatments are medicines that lower testosterone with the 
addition of chemotherapy in certain patients.  You will not be receiving an FDA approved medication 
that has been shown in clinical studies to make patients with your type of cancer live longer. 
 
The results from all study tests (blood tests, CT and bone scans) will be given to you and be available to 
your physicians.  Genetic counseling (discussing of what the tests may mean for your health and the 
health of any family members who may also have the same genetic changes) will be available to you at 
your request. 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 31, 2022 
Principal Investigator: Mark Markowski M.D. Ph.D. 
Application No.: IRB00156514 
 
 
Page 7 of 17 
Combined Informed Consent/Authorization June 2015 Version 15                                             TRIUMPH Protocol v7.0 dated 03/04/22 
Request to collect and store biospecimens for future research  
As part of this research study, we would like to ask you to let us store your biospecimens and health 
information for future research.  This research could involve other diseases and involve research tools 
such as gene sequencing or creation of cell lines.  These samples may also be distributed to other 
researchers, but they will not contain any information that could be used to identify you.  You may limit 
the future use of any banked samples by contacting the study doctor. 
 
The research may involve research tools such as gene sequencing or the creation of cell lines.  
• Gene sequencing of your DNA provides researchers with the code to your genetic material.   
• Cell lines are living tissue samples that can be grown in a laboratory.  A cell line can provide an 
unlimited supply of cells in the future without requiring more samples from you.  Each cell contains 
your complete DNA. 
 
The Genetic Information Nondiscrimination Act (GINA) may help protect you from health insurance or 
health-related employment discrimination based on genetic information.   
 
The law provides that health insurance companies and group health plans  
• may not ask for genetic information from this research and  
• may not use genetic information when making decision about eligibility or premiums 
 
The law will not stop health insurance companies from using genetic information to decide whether to 
pay claims. The law does not apply to other types of insurance (such as life, disability or long-term 
care).  
 
Despite the GINA protections and the best efforts of the research team to protect your information, you 
may still be at risk if information about you were to become known to people outside of this study. 
 
The study doctor can provide you with additional information if you have questions.  Also, further 
information about our use of your biospecimens can be found in this consent document under the 
heading What happens to Data and Biospecimens that are collected in the study? 
 
Will you allow us to store the biospecimens we collect for this study for use in future research? 
 
 
 
 
 
YES     ________________________   
 
 
 
Signature of Participant 
 
 
 
 
 
 
 
 
 
 
NO      __________________  
 
 
 
Signature of Participant 
 
 
 
 
 
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 31, 2022 
Principal Investigator: Mark Markowski M.D. Ph.D. 
Application No.: IRB00156514 
 
 
Page 8 of 17 
Combined Informed Consent/Authorization June 2015 Version 15                                             TRIUMPH Protocol v7.0 dated 03/04/22 
Incidental Findings 
The imaging you are having as part of this research study will be reviewed by a qualified person just as 
it would be if you were having the imaging as part of your routine medical care. 
 
There is a possibility that while reviewing your imaging we may see an abnormality that we did not 
expect to see in this study. This is what is called an “incidental finding.” 
 
We will let you know if we see such an incidental finding.  Depending on the type of incidental finding, 
we may contact you by mail or by phone. In the case of a potential serious emergency, someone may go 
to your home. 
 
A qualified person (usually a member of the research team) will talk to you if there is an incidental 
finding. You do not have an option to decline information about an incidental finding. 
 
If you want, we will give information about this incidental finding to your primary doctor or we will 
refer you to an appropriate doctor for further evaluation. 
• 
An incidental finding may cause you to feel anxious.   
• 
Since an incidental finding will be part of your medical record, it may affect your current or future 
life or health insurance coverage.  This risk will vary depending on the type of insurance plan 
involved.  
• 
The costs for any care that will be needed to diagnose or treat an incidental finding would not be 
paid for by this research study.  These costs would be your responsibility. 
 
How long will you be in the study? 
We anticipate that most participants will be on the study for about 12 months.  Some participants may be 
a part of the study for a shorter time period and some may be for a longer time period. 
 
4. 
What are the risks or discomforts of the study? 
It is important that you tell the study staff about any other medicines, vitamins, nutritional or herbal 
supplements you are taking before and during the study.  It is possible that your study drug could affect 
your other medication and there are certain medications that you will not be allowed to take with the 
study drug during the study, including other anti-cancer therapies and certain vaccines. Your study 
doctor will provide you with a list of medications that you must avoid while you are taking your study 
drug, so it is important to consult your study doctor before taking anything new. 
 
Side effects can be mild, moderate or severe (these are explained below).  
• Mild: You are aware of the side effect but it doesn’t really bother you 
• Moderate: You need to take some sort of action (like painkillers for a headache) 
• Severe: The side effect stops you doing what you normally would be doing 
 
Rucaparib has been associated with the following laboratory findings and/or clinical symptoms, 
generally of mild or moderate severity and generally not requiring treatment to be stopped.  
 
You may experience none, some or all of the side effects listed below. 
 
Very common side effects (occur in 10% or more of patients): 
• Nausea or vomiting (feeling sick or actually being sick):  If required, you will be offered 
medication to control these symptoms. 
• Fatigue: Including asthenia (feeling tired, weary, exhausted, lack of or loss of energy, weakness).  


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 31, 2022 
Principal Investigator: Mark Markowski M.D. Ph.D. 
Application No.: IRB00156514 
 
 
Page 9 of 17 
Combined Informed Consent/Authorization June 2015 Version 15                                             TRIUMPH Protocol v7.0 dated 03/04/22 
• Low blood counts (red blood cells, white blood cells, and platelets).  Sometimes fever occurs with 
the low blood counts. These low blood count effects may be more likely to occur after multiple 
cycles of treatment. 
Anemia: The number of red cells in your blood may decrease, which may cause shortness of 
breath and in some instances may require blood transfusions (when you are given new blood or 
blood-based products from a donor). Low red blood cell count may make you feel tired or dizzy.  
If you feel dizzy while taking rucaparib, you should avoid potentially hazardous tasks such as 
driving or operating machinery. 
 
o Neutropenia: A low white blood cell count puts you at higher risk for bacterial or viral 
infections.  Having a high temperature or fever while your white blood cell count is low is a 
medical emergency and you must proceed to the nearest emergency room as soon as possible. 
 
o Thrombocytopenia: The number of platelets (another type of cell) in your blood may decrease 
which could lead to bleeding events. Symptoms include but are not limited to easy bruising, 
prolonged bleeding from cuts, blood in stools or urine, or nose bleeding. 
• A low phosphate level in your blood.  Usually there are no symptoms but if the levels are critically 
low, you may notice trouble breathing, confusion, muscle weakness, and/or irritability. 
• Increase in cholesterol:  If required, you will be offered medication to lower your cholesterol.   
• Changes in kidney and liver function blood tests.  These changes will be evaluated by your study 
doctor along with any in the context of other side effects that you are experiencing as well as other 
test results 
o Increase in AST/ALT in your blood.   These are enzymes produced by your liver.  This will 
be monitored by the laboratory safety tests that will be done in this study because this does 
not normally have any symptoms.  If necessary, you will be told to stop taking rucaparib until 
your AST/ALT values return to normal.   
o Increase in creatinine in your blood: (A laboratory test to measure how well your kidney is 
functioning): This will be monitored by the laboratory safety tests that will be done in this 
study. The increase in creatinine observed in patients receiving rucaparib was mild and did 
not result in impaired kidney function.  Your doctor will monitor your creatinine levels 
during the study and may decide if you need any further tests. 
• Dysgeusia: Taste changes which may affect the way food normally tastes. 
• Stomach-related effects such as constipation, vomiting, diarrhea, decreased appetite, stomach pain 
(epigastric pain), and indigestion. 
• Dyspnea: Shortness of breath 
• Dizziness: If required, you will be offered medication to control these symptoms. 
• Photosensitivity:   
o It is possible that rucaparib may make your skin and eyes more sensitive to sunlight. You 
should take all of the usual sun protection precautions when going outside. It is advised that 
you avoid excessive sun exposure, wear protective clothing (including wearing a hat and 
sunglasses), and use sunscreens regularly (sun protection factor 50 or greater).   
• Fever sometimes can occur independent of a low blood count. If you experience an elevation of your 
temperature, please refer to your study doctor for fever management. 
• Difficulty sleeping  
 
Common side effects: (occur in 1 to less than 10% of patients): 
• Rasha: which will appear as changes in your skin color (e.g. redness) and texture (e.g. bumps, 
blisters, peeling).  Some rashes may be itchy, painful, or cause no symptoms at all.  This can vary in 
severity from mild to severe.   


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 31, 2022 
Principal Investigator: Mark Markowski M.D. Ph.D. 
Application No.: IRB00156514 
 
 
Page 10 of 17 
Combined Informed Consent/Authorization June 2015 Version 15                                             TRIUMPH Protocol v7.0 dated 03/04/22 
• Pruritisa:  Feeling or sensation of itchiness on your skin.  
• Upper Airway Infection (like the common cold)  
o You may experience infections involving the nose, pharynx, larynx, and sinuses. 
Symptoms include a blocked (congested) nose, a runny nose, and sneezing.  You may 
also have clear discharge (mucus) from the nose.  You may feel generally unwell and 
may also be associated with fever.  Treatment is usually supportive but if symptoms 
persist please inform your doctor 
• Hand-Foot Syndrome (Plantar erythrodysaesthesia syndrome): When a small amount of drug 
leaks out of the blood vessels, it damages the surrounding tissues.  Symptoms may include tingling, 
burning, redness, flaking, swelling, blistering, and sores of the hands and feet due to the increased 
friction and heat your extremities are exposed to.  If you experience these symptoms, apply ice packs 
and elevate hands and feet, then contact your study doctor immediately for treatment. 
 
Uncommon side effects: (Occurring in 0.1% up to less than 1% of patients): 
• Myelodysplastic syndrome (MDS)a and acute myeloid leukemia (AML)a have been reported in a 
very small number of patients treated with rucaparib during the safety period (while on treatment 
with rucaparib and 28 days after last dose).  MDS is a pre-cancerous condition where the bone 
marrow is not as good at producing blood cells (red and/or white blood cells and/or 
platelets).  People with MDS need transfusions (red blood cells and/or platelets) and/or other 
treatments.  In some cases, MDS can progress to AML, which is a cancer of the bone marrow where 
more abnormal and immature white blood cells (also called blasts) are made than normal white 
blood cells.  People with AML need treatment with chemotherapy and/or a bone marrow 
transplant.  Patients may develop AML without first being diagnosed with MDS. 
• Events of MDS and AML have also been reported with PARP inhibitors similar to rucaparib.  At this 
time it is not known whether rucaparib or other PARP inhibitors cause MDS or AML, or if these 
developed as a result of previous chemotherapy these patients received.  Your study doctor will 
closely monitor your blood cell levels during treatment.  If he/she has any concerns about your blood 
counts you may be asked to have a biopsy of your bone marrow. 
 
a   These risks have not yet been determined by Clovis as related to rucaparib. Some of these risks 
have been reported in a high frequency of patients in clinical trials involving rucaparib (e.g. itchy 
skin, rash), others have been reported in a small number of patients but pose significant risk (e.g. 
MDS/AML) or are generally known to be caused by other anti-cancer treatments (e.g. palmar-
plantar erythrodysaesthesia). 
 
The Study Doctor may decide to interrupt and/or reduce your rucaparib dose if you experience certain 
side effects.  If your dose is reduced you will be given a new bottle of tablets. 
 
There may be risks involved in taking this drug that have not yet been discovered.  There is always a risk 
involved in taking an experimental drug but every precaution will be taken.  If you suffer any side effects 
or injuries, or your condition gets worse, tell your study doctor immediately so you can receive appropriate 
care.     
 
Imaging Risks: 
This research study includes exposure to radiation from x-rays or gamma rays.  This radiation exposure is 
for research purposes only and is not part of your medical care. X-rays and gamma rays from natural or 
medical sources can damage the genetic material (DNA) in your cells. At low doses, the body is usually 
able to repair the damage.   


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 31, 2022 
Principal Investigator: Mark Markowski M.D. Ph.D. 
Application No.: IRB00156514 
 
 
Page 11 of 17 
Combined Informed Consent/Authorization June 2015 Version 15                                             TRIUMPH Protocol v7.0 dated 03/04/22 
The total radiation exposure may be up to 4.2 rem (a rem is a unit of absorbed radiation).  The radiation 
exposure that you will get from screening CT guided biopsy is 0.8 rem. If you agree to the optional biopsy 
of your cancer and this is done by CT guided biopsy, you will receive an additional radiation exposure of 
0.8 rem.  You may receive an additional radiation exposure if you have one extra bone scan (0.8 rem) and 
one extra CT scan (1.8 rem) at the time of disease worsening (progression).   
 
This is more than the 0.3 rem that the average person in the United States gets each year from natural 
sources like the sun, outer space, air, food and soil.  It is less than the 5 rems of radiation that is allowed 
each year for people who are exposed to radiation in their jobs. 
 
The radiation exposure described here is what you will get from this research study only. It does not 
include any exposure you may have received or will receive from other tests outside of this study that are 
a part of your medical care. Radiation risk builds up with each exposure. You should think about your 
own history of radiation exposure from tests (like x-rays or CT scans) in deciding about the radiation in 
this study.  If you have questions about the total amount of radiation you will be receiving, you should ask 
your doctor. 
 
Other Risks in the Study: 
Your cancer may continue to grow if you elect to participate in this trial.  You may develop symptoms 
from cancer or the cancer may spread during this clinical trial. 
 
Allergic Reactions 
As with any drug, it is possible that you could have allergic reactions to study drug, such as itching, skin 
rash, facial swelling, and/or a severe or sudden drop in blood pressure.  A sudden drop in blood pressure 
could lead to shock with loss of consciousness and/or possible seizures, including the possibility of 
death.  If you have any of the above symptoms, seek medical attention right away. 
 
Blood Draw: Taking blood may cause discomfort, bleeding or bruising where the needle enters the 
body. In rare cases, it may result in fainting. There is a small risk of infection. 
 
Confidentiality: There is the risk that information about you may become known to people outside this 
study. 
 
Genetic information is unique to you and your family, even without your name or other identifiers.   
Johns Hopkins follows procedures to prevent people who work with your DNA information from being 
able to discover it belongs to you. However, new techniques are constantly being developed that may in 
the future make it easier to re-identify genetic data, so we cannot promise that your genetic information 
will never be linked to you. 
 
There may be side effects and discomforts that are not yet known.   
 
5. 
Are there risks related to pregnancy? 
Rucaparib may cause harm to a fetus. Participants with partners capable of becoming pregnant who 
subsequently become pregnant may risk problems in the fetus. While taking the study drug, and for 4 
months after stopping the study drug, you must use a condom when having sexual intercourse with a 
female partner, even if they are pregnant. Your female partner must also use a suitable method of 
contraception. Highly effective birth control is considered to be a method with a less than  1% per year 
failure rate and is defined in this study as established use of progesterone-only injectable or implantable 
contraceptives (e.g. Depo Provera, Implanon, Nexplanon), placement of an intrauterine device (IUD) or 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 31, 2022 
Principal Investigator: Mark Markowski M.D. Ph.D. 
Application No.: IRB00156514 
 
 
Page 12 of 17 
Combined Informed Consent/Authorization June 2015 Version 15                                             TRIUMPH Protocol v7.0 dated 03/04/22 
intrauterine system (IUS), surgical sterilization, or true, complete (as opposed to periodic) abstinence.  If 
this applies to you, please discuss your plan for birth control with the investigator or study staff. 
 
Transfer of Drug through Semen 
Male patients must use a condom when having sex to avoid passing rucaparib to your partner through 
semen. You must also not make semen donations for 6 months following the last dose of rucaparib/study 
drug because rucaparib might damage sperm. 
 
Tell your study doctor immediately if your partner becomes pregnant while taking you are on the study 
drug regimen or within 6 months for after your last dose of study drug. Please discuss with your doctor 
suitable methods of birth control.  
 
This research may hurt an embryo or fetus in ways we do not currently know.  
 
6. 
Are there benefits to being in the study? 
You may or may not directly benefit from being in this study. If you take part in this study, you may 
help others in the future. 
 
7. 
What are your options if you do not want to be in the study? 
If you decide not to join this study, other options are available.  You do not have to join this study to get 
treatment. Other treatments include androgen deprivation therapy with or without chemotherapy 
(Docetaxel) along with blood work, CT scans, and bone scans. 
 
You do not have to join this study.  If you do not join, your care at Johns Hopkins will not be affected. 
 
8. 
Will it cost you anything to be in this study?  
You will receive a separate Insurance and Research Participant Financial Responsibility Information 
Sheet (Sheet).  
 
This Sheet will give you the following information: 
• The procedures, tests, drugs or devices that are part of this research and that will be paid for by 
the study (no cost to you).   
• The procedures, tests, drugs or devices that will be billed to you and/or your health insurer.  If 
you have health insurance, you will be responsible for any co-pays or deductibles not covered by 
your insurance.  
 
9. 
Will you be paid if you join this study? 
You will not be paid to join this study. 
 
10. 
Can you leave the study early? 
• You can agree to be in the study now and change your mind later. 
• If you wish to stop, please tell us right away. 
• Leaving this study early will not stop you from getting regular medical care.  
 
If you leave the study early, Johns Hopkins may use or give out your health information that it has 
already collected if the information is needed for this study or any follow-up activities.  
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 31, 2022 
Principal Investigator: Mark Markowski M.D. Ph.D. 
Application No.: IRB00156514 
 
 
Page 13 of 17 
Combined Informed Consent/Authorization June 2015 Version 15                                             TRIUMPH Protocol v7.0 dated 03/04/22 
11. 
Why might we take you out of the study early?  
You may be taken out of the study if: 
• Staying in the study would be harmful. 
• You need treatment not allowed in the study. 
• You fail to follow instructions. 
• The study is cancelled. 
• There may be other reasons to take you out of the study that we do not know at this time.  
 
If you are taken out of the study or stop taking the study drug, we will ask you to come in for a final visit 
about 1 month after your last dose of study drug.  You will have a physical exam, blood tests, review of 
your medications, CT, and bone scan.   
 
If you are taken out of the study early, Johns Hopkins may use or give out your health information that it 
has already collected if the information is needed for this study or any follow-up activities. 
 
12. 
How will your privacy be protected?  
We have rules to protect information about you.  Federal and state laws and the federal medical Privacy 
Rule also protect your privacy.  By signing this form you provide your permission, called your 
“authorization,” for the use and disclosure of information protected by the Privacy Rule. 
The research team working on the study will collect information about you.  This includes things learned 
from the procedures described in this consent form.  They may also collect other information including 
your name, address, date of birth, and information from your medical records (which may include 
information about HIV status, drug, alcohol or STD treatment, genetic test results, or mental health 
treatment). 
 
The research team who may be a part of Johns Hopkins Health System, Johns Hopkins University or the 
Johns Hopkins Applied Physics Laboratory will know your identity and that you are in the research 
study.  Other people at Johns Hopkins, including your doctors, may also see or give out your 
information. We make this information available to your doctors for your safety.    
 
People outside of Johns Hopkins may need to see or receive your information for this study.  Examples 
include government agencies (such as the Food and Drug Administration), safety monitors, other sites in 
the study and companies that sponsor the study.  
 
If you are in a cancer study that receives federal funding, the National Cancer Institute (NCI) now 
requires that we report identifiable information (such as, zip code) about your participation.  You may 
contact the NCI if you have questions about how this information is used.  
 
We cannot do this study without your authorization to use and give out your information.  You do not 
have to give us this authorization.  If you do not, then you may not join this study. 
 
We will use and disclose your information only as described in this form and in our Notice of Privacy 
Practices; however, people outside Johns Hopkins who receive your information may not be covered by 
this promise or by the federal Privacy Rule.  We try to make sure that everyone who needs to see your 
information keeps it confidential – but we cannot guarantee that your information will not be re-
disclosed. 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 31, 2022 
Principal Investigator: Mark Markowski M.D. Ph.D. 
Application No.: IRB00156514 
 
 
Page 14 of 17 
Combined Informed Consent/Authorization June 2015 Version 15                                             TRIUMPH Protocol v7.0 dated 03/04/22 
The use and disclosure of your information has no time limit. You may revoke (cancel) your permission 
to use and disclose your information at any time by notifying the Principal Investigator of this study by 
phone or in writing.  If you contact the Principal Investigator by phone, you must follow-up with a 
written request that includes the study number and your contact information.  The Principal 
Investigator’s name, address, phone and fax information are on page one of this consent form.  
 
If you do cancel your authorization to use and disclose your information, your part in this study will end 
and no further information about you will be collected. Your revocation (cancellation) would not affect 
information already collected in the study, or information we disclosed before you wrote to the Principal 
Investigator to cancel your authorization. 
 
13. 
Will the study require any of your other health care providers to share your health 
information with the researchers of this study? 
As a part of this study, the researchers may ask to see your health care records from your other health 
care providers.   
 
14. 
What treatment costs will be paid if you are injured in this study?  
Johns Hopkins does not have a program to pay you if you are hurt or have other bad results from being 
in the study.  However, medical care at Johns Hopkins is open to you as it is to all sick or injured people.   
 
The costs for any treatment or hospital care you receive as the result of a study-related injury that are not 
covered by a health insurer will be billed to you. 
 
By signing this form you will not give up any rights you have to seek compensation for injury.  
 
15. 
What other things should you know about this research study? 
a. What is the Institutional Review Board (IRB) and how does it protect you?  
The Johns Hopkins Medicine IRB is made up of: 
• Doctors 
• Nurses 
• Ethicists 
• Non-scientists 
• and people from the local community.  
 
The IRB reviews human research studies. It protects the rights and welfare of the people taking part 
in those studies.  You may contact the IRB if you have questions about your rights as a participant or 
if you think you have not been treated fairly.  The IRB office number is 410-955-3008. You may 
also call this number for other questions, concerns or complaints about the research. 
 
When the Johns Hopkins School of Medicine Institutional Review Board (IRB) reviews a study at 
another site, that site (institution) is solely responsible for the safe conduct of the study and for 
following the protocol approved by the Johns Hopkins IRB.   
 
b. What do you do if you have questions about the study?    
Call the principal investigator, Dr. Mark C. Markowski at 410-955-8893. If you wish, you may 
contact the principal investigator by letter or by fax.  The address and fax number are on page one of 
this consent form. If you cannot reach the principal investigator or wish to talk to someone else, call 
the IRB office at 410-955-3008.   


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 31, 2022 
Principal Investigator: Mark Markowski M.D. Ph.D. 
Application No.: IRB00156514 
 
 
Page 15 of 17 
Combined Informed Consent/Authorization June 2015 Version 15                                             TRIUMPH Protocol v7.0 dated 03/04/22 
c. What should you do if you are injured or ill as a result of being in this study?  
If you think you are injured or ill because of this study, call Dr. Mark C. Markowski at 410-955-
8893 during regular office hours.  
 
If you have an urgent medical problem related to your taking part in this study, call the medical 
oncology clinic at 410-955-8893 during regular office hours and at 410-955-4331 after hours and on 
weekends.  
  
d. What happens to Data and Biospecimens that are collected in the study?  
Johns Hopkins and our research partners work to understand and cure diseases. The biospecimens 
and/or data you provide are important to this effort. 
 
If you join this study, you should understand that you will not own your biospecimens or data, and 
should researchers use them to create a new product or idea, you will not benefit financially.  
 
With appropriate protections for privacy, Johns Hopkins may share your biospecimens and 
information with our research sponsors and partners.    
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 31, 2022 
Principal Investigator: Mark Markowski M.D. Ph.D. 
Application No.: IRB00156514 
 
 
Page 16 of 17 
Combined Informed Consent/Authorization June 2015 Version 15                                             TRIUMPH Protocol v7.0 dated 03/04/22 
16. 
What does your signature on this consent form mean?  
Your signature on this form means that: You understand the information given to you in this form, you 
accept the provisions in the form and you agree to join the study. You will not give up any legal rights 
by signing this consent form.  
 
 
WE WILL GIVE YOU A COPY OF THIS SIGNED AND DATED CONSENT FORM 
 
 
 
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Participant                                                                           (Print Name)                                                 
 
Date/Time  
 
 
 
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Person Obtaining Consent                                                  (Print Name)                                               
 
Date/Time 
 
 
 
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Witness to Consent Procedures                                         (Print Name) 
 
Date/Time 
 
(optional unless IRB or Sponsor required) 
 
 
 
I have received the separate Insurance and Research Participant Financial Responsibility Information Sheet.   
 
 
 
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Participant, LAR or Parent/Guardian                               (Print Name)                                                        Date/Time 
 
 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR AND A COPY 
MUST BE GIVEN TO THE PARTICIPANT.  IF APPROPRIATE FOR THIS STUDY, A SCANNED COPY OF THE SIGNED CONSENT 
FORM SHOULD BE UPLOADED TO THE PARTICIPANT’S EPIC/EMR RECORD (UNLESS NO MEDICAL RECORD EXISTS OR 
WILL BE CREATED).  
 
 
 


Do not use this form for consenting research 
participants unless the Johns Hopkins Medicine 
Logo appears here. 
Date: March 31, 2022 
Principal Investigator: Mark Markowski M.D. Ph.D. 
Application No.: IRB00156514 
 
 
Page 17 of 17 
Combined Informed Consent/Authorization June 2015 Version 15                                             TRIUMPH Protocol v7.0 dated 03/04/22 
DOCUMENTATION OF PHYSICIAN/MID-LEVEL PROVIDER CONSENT PROCESS 
 
My signature below indicates that I have discussed the risks, benefits, and alternatives, answered any 
questions, and believe the participant is able to make an informed choice to join the study. 
 
 
 
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Physician/Mid-Level Provider                     (Print Name)                                                                     
 
Date/Time   
 
 
 
 
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Participant                                                    (Print Name)                                                                    
 
Date/Time     
 
 
 
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Witness to Consent Procedures                                         (Print Name) 
 
Date/Time 
 
(optional unless IRB or Sponsor required) 
 
 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR AND A COPY 
MUST BE GIVEN TO THE PARTICIPANT.  IF APPROPRIATE FOR THIS STUDY, A SCANNED COPY OF THE SIGNED CONSENT 
FORM SHOULD BE UPLOADED TO THE PARTICIPANT’S EPIC/EMR RECORD (UNLESS NO MEDICAL RECORD EXISTS OR 
WILL BE CREATED).