Conditions: Metastatic or Unresectable Melanoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate how effective the study drugs, nivolumab (also known as Opdivo®) and talazoparib (also known as Talzenna®) are when given as a combination treatment for unresectable or metastatic melanoma. The study team wants to know the effectiveness of these drugs together in treating cancer than if each study drug was given by itself.

Detailed description:
This is a phase II, single arm, multi-institutional, open label trial in a sample size of 37 primary or recurrent, unresectable or metastatic melanoma patients progressed on prior checkpoint inhibitor therapy with germline or somatic mutations in BRCA1/2 or BRCA-ness.

The primary objective of this study is to estimate the clinical efficacy of nivolumab plus talazoparib in patients with unresectable or metastatic melanoma with BRCA1/2 or other DNA damage repair mutations (defined as BRCA-ness)

Secondary objectives and their endpoints include progression free survival (PFS) defined as time from first dose of treatment until disease progression, treatment related adverse events, anti-tumor activity , and immune-related progression free survival (irPFS).

Arms:
arm 1: Nivolumab 480mg intravenously every 4 weeks (28 days) + Talazoparib 1mg orally daily

Interventions: intervention 1: Nivolumab intervention 2: Talazoparib
Intervention descriptions: intervention 1: 480mg intravenously every 4 weeks (28 days) intervention 2: 1mg orally daily

Protocol document:
Prot_SAP_000.pdf: 
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CASE2619 Protocol v5 
05/09/2023 
 
STUDY NUMBER:  
CASE2619 
 
ClinicalTrials.gov NCT #: NCT04187833 
 
Protocol Date:  05/09/2023 
 
STUDY TITLE:  Phase II Trial of Nivolumab in Combination with Talazoparib in 
Patients with Unresectable or Metastatic Melanoma and Mutations in 
BRCA or BRCA-ness 
 
 
 
 
PRINCIPAL INVESTIGATOR:   Dr. James Isaacs, MD 
 
 
 
  Department of Hematology and Oncology 
  Cleveland Clinic Taussig Cancer Institute  
  9500 Euclid Avenue, 
 
 
 
 
  Cleveland, OH 44195 
  Ph: 
 
   
  Email: 
 
 
CO-INVESTIGATORS:  
Lucy Boyce Kennedy, MD 
 
 
 
 
Cleveland Clinic Taussig Cancer Institute 
 
Ph: 
 
Email: 
 
 
 
 
 
 
STATISTICIAN:  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY COORDINATOR: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPONSOR:  
 
 
Case Comprehensive Cancer Center  
 
 
 
 
 
SUPPORT/FUNDING: 
 
Pfizer, Inc. 
 
 
SUPPLIED AGENT: 
 
Talazoparib, Pfizer 
OTHER AGENT:  
 
Nivolumab 
 
 
 


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SUMMARY OF CHANGES 
 
Protocol 
Date 
Section 
Change 
11/4/2019 
10.1.3 
Updated number of vials to be sent to Dr. Diaz’s lab from one to three 
14.0 
Changed futility monitoring plan to a safety monitoring plan 
1/17/2020 
2.2 
Added OS as a secondary objective 
2.3 
Added ctDNA and CNV correlatives  
3.1 
Removed mini-dose escalation phase 
3.1 
Updated list of mutations/deletions for inclusion  
4.2.12 
Allowed Pg-p inhibitor with modified Tala dosing 
10.1.3 
Clarified collection of correlatives 
16.8 
Added Personal/Family history Form 
5/31/2020 
6.4 
Removed immunosuppressive agents (expect to treat adverse related 
events) 
 
4.2.2 
Add for melanoma  
12/3/2021 
4.1.1 
Add genomic marker of genomic loss of heterozygosity (gLOH) to the 
inclusion criteria 
05/09/202
3 
Cover 
page, 
8.4.1. 
Footer 
througho
ut. 
Personnel changes including the PI transition from Dr. Funchain to Dr. 
Isaacs. Protocol version number and date changed in footer throughout.  
 


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STUDY SCHEMA 
 
 
 
 
 
 
 
 


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PROTOCOL SUMMARY 
 
Protocol Number/Title 
Phase II Trial of Nivolumab in Combination with 
Talazoparib in Patients with Unresectable or Metastatic 
Melanoma with Mutations in BRCA or BRCA-ness 
Study Phase 
II  
Brief Background/Rationale 
 
 
 
Current treatment for unresectable or metastatic melanoma 
includes monotherapy with nivolumab, with an objective 
response rate (ORR) of about 40% in the first line setting 
and about 15% in the refractory setting.  Newer targeted 
therapies in melanoma are needed, especially once patients 
progress on standard therapies. 
 
“BRCA-ness” has not specifically been studied in 
melanoma; however, our own data from the only familial 
melanoma registry in the United States suggests a 
substantial presence of germline and somatic mutations in 
this patient population.  In the first 130 melanoma patients 
accrued to our Gross Family Melanoma Registry at the 
Cleveland Clinic, 19% (25) had a germline 
pathogenic/likely pathogenic mutation, of which 52% (13) 
were in genes associated with BRCA1/2 and “BRCA-ness.” 
This represents a significant proportion of patients with 
metastatic melanoma that could benefit from PARP 
inhibitor (PARPi) therapy.  These findings are confirmed in 
The Cancer Genome Atlas (TCGA).  Out of 470 
skin cutaneous melanoma patients that have germline 
sequencing data available, 52 (11%) have 
pathogenic/likely pathogenic germline mutations, and 25 
patients (5.3%) have mutations in “BRCA-ness” genes. 
Somatic mutations involving “BRCA-ness” are equally 
common in TCGA, 16% (n = 72) possess actionable/likely 
actionable mutations. 
 
Additionally, some data indicate that BRCA-ness genes 
may not be required for PARPi efficacy if a tumor is 
sensitive to immunotherapy. A recent study suggests that in 
addition to synthetic lethality, PARPi trap the PARP1/2 
enzyme at sites of damaged DNA, and thus prevent DNA 
repair, replication, and transcription. In vitro studies have 
demonstrated that the PARPi, talazoparib, has more potent 
PARP trapping than other PARPi in clinical development 
(4-5). Additionally, PARPi-mediated DNA damage by 
talazoparib has been shown to increase the immunogenicity 
of tumor cells by promoting T cell and natural killer cell 
infiltration, and increasing tumor expression of PD-L1 in 


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vitro and in vivo.  Therefore, the use of talazoparib in 
combination with the immune checkpoint inhibitor (CPI), 
nivolumab, may have a synergistic immunotherapeutic and 
antitumor effect without requiring genes conferring 
“BRCAness.” 
 
Biomarker selection strongly influences the efficacy of 
PARP inhibition. Mateo et al. looked at treatment with the 
PARPi olaparib in patients with metastatic castration-
resistant prostate cancer (mCRPC). This study showed that 
treatment with olaparib in patients with mCRPC who had 
germline defects in DNA repair genes led to a high 
response rate.  Conversely, within the mCRPC cohort 
without a “BRCA-ness” marker, only a single responder 
was observed.  Eligible alterations were in BRCA1/2, ATM, 
PALB2, CHEK2, FANCA, HDAC2, RAD51, MLH3, 
ERCC3, MRE11, and NBN. 
 
We propose that PARP inhibition with talazoparib will 
have synergistic antitumor activity in combination with 
nivolumab in unresectable and metastatic melanoma 
patients with DNA-repair defects, who have progressed on 
prior CPI therapy, and improve the ORR from 10% to 30% 
with limited toxicity. 
Primary Objective  
Determine the clinical efficacy of nivolumab plus 
talazoparib in patients who have progressed on prior CPI, 
unresectable or metastatic melanoma with BRCA1/2 or 
other DNA damage repair mutations (defined as BRCA-
ness), as measured by objective response rate (ORR).   
 
Secondary Objectives 
• Determine progression free survival (PFS) in 
unresectable or metastatic melanoma patients 
treated with nivolumab plus talazoparib. 
• Determine overall survival (OS). 
 
• Evaluate treatment-related adverse events in patients 
treated with nivolumab plus talazoparib.To assess the 
anti-tumor activity of nivolumab in combination with 
talazoparib in unresectable or metastatic melanoma 
patients with BRCA1/2 or other DNA damage repair 
mutations (defined as BRCA-ness), as measured by 
immune-related objective response rate (irORR) 
every 12 weeks for a period of approximately 12 
months.  
 


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• Determine immune-related progression free survival 
(irPFS) in unresectable or metastatic melanoma 
patients treated with nivolumab plus talazoparib. 
Correlative Objective(s) 
 
• Measure adaptive and innate cellular 
immunofiltration into tumor (by tumor biopsies) and 
peripheral circulating T cells (by PBMCs) at 
baseline (pre-treatment), after treatment initiation 
(at about 12 weeks), and at time of progression, and 
to correlate activity with response to treatment. 
   
• Assess total somatic tumor mutation burden by 
sequencing at baseline (pre-treatment), after therapy 
at 12 weeks, and at time of progression to evaluate 
DNA landscape and its effect on sensitivity of 
combination nivolumab and talazoparib therapy.  
 
• Assess patient reported outcomes for adverse events 
while on combination therapy at baseline and before 
each cycle (about every 4 weeks) of nivolumab. 
 
• Assess ctDNA, CNV at baseline, at C2D1 and 
C3D1 and at time of progression. 
 
Sample Size 
37 patients 
Disease sites/Conditions 
Metastatic or unresectable melanoma 
Interventions 
Nivolumab 480mg intravenously every 4 weeks (28 days) + 
Talazoparib 1mg orally daily  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ABBREVIATIONS  
 
 
 
 
CCCC Case Comprehensive Cancer Center 
CRF 
Case Report Form 
DCRU Dahm’s Clinical Research Unit 
DSTC 
Data Safety and Toxicity Committee 
FDA 
Food and Drug Administration 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
PRMC Protocol Review and Monitoring Committee 
SOC 
Standard of Care 
CCF 
Cleveland Clinic Foundation 
UH 
University Hospitals 
 
 


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TABLE OF CONTENTS 
 
1.0  
INTRODUCTION  
 
1.1 
Background of Melanoma and Standard Therapies  
1.2  
Nivolumab 
1.3 
Talazoparib 
1.4  
Rationale   
1.5 
Background and Rationale of Correlative Studies 
 
2.0 
OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
 
2.2  
Secondary Objectives 
2.3 
Correlative Objectives 
2.4 
Endpoints 
2.5 
Primary Endpoint 
2.6 
Secondary Endpoints 
2.7 
Correlative Endpoints 
 
3.0 
STUDY DESIGN 
3.1 
Study Design and Schema 
3.2 
Number of Subjects 
3.3 
Replacement of Subjects 
 
 
4.0  
SUBJECT SELECTION 
4.1 
Inclusion Criteria 
4.2  
Exclusion Criteria 
4.3 
Inclusion of Women and Minorities 
 
5.0 
REGISTRATION  
 
 
6.0  
TREATMENT PLAN 
6.1 
Treatment Regimen Overview  
6.4 
General Concomitant Medications and Supportive Care Guidelines 
6.5 
Criteria for Removal from Study 
6.6 
Duration of Follow-Up 
 
7.0 
DOSE DELAYS / DOSE MODIFICATIONS 
7.1 
Dose Modification for Talazoparib for Patients with Renal Impairment 
7.2 
Modifications for Nivolumab and Talazoparib Drug-Related Toxicity 
7.3 
Management of Nivolumab Related Infusion Reaction 
7.4 
Management of Immune-Related Adverse Events 
 
8.0 
ADVERSE EVENTS AND POTENTIAL RISKS 
8.1  
Talazoparib Adverse Events 
8.2 
Definitions 
8.3 
Serious Adverse Event Report Form 


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8.4 
Reporting Procedures for Serious Adverse Event  
8.5 
Serious Adverse Events and OnCoreTM    
8.6 
Data Safety Toxicity Committee 
8.7 
Data and Safety Monitoring Plan 
 
9.0 
PHARMACEUTICAL INFORMATION  
9.1 
Investigational Agent: Talazoparib 
 
9.2 
Commercial Agent:  Nivolumab 
 
10.0 
EXPLORATORY/CORRELATIVE  
10.1     Anti-Tumor Response by TILs and PDL-1 Expression 
10.2 
Analysis of Tumor Mutational Burden  
10.3  Assessment of Patient Reported Outcomes for Adverse Events 
10.4 
Additional Correlative Analysis 
 
 
11.0 
STUDY PARAMETERS AND CALENDAR 
11.1 
Study Parameters 
11.2 
Calendar 
 
12.0 
MEASUREMENT OF EFFECT  
 
13.0 
RECORDS TO BE KEPT/REGULATORY CONSIDERATIONS 
13.1 
Data Reporting 
13.2 
Regulatory Considerations  
 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
15.0 
REFERENCES 
 
16.0 
APPENDICES  
16.1  RECIST 1.1 Criteria  
16.2  Immune-related RECIST (irRECIST) Criteria 
16.3  Performance Status Scale  
16.4  NCI CTCAE v5.0  
16.5  PGP Inhibitors and Inducers 
16.6 
Pill Diary  
16.7 
PRO-CTCAE form 
16.8 
Personal/Family History of Cancer Form 
 
 
 


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1.0 
Introduction  
 
1.1 
Background of Melanoma and standard therapies  
 
Cutaneous malignant melanoma is the most aggressive form of skin cancer, accounting 
for the large majority of skin cancer-related deaths.  Incidence rates continue to increase 
for melanoma, it is the fifth most common cancer in men and women, with current 
estimate of 96,000 new diagnoses and 9,000 deaths annually in the United States.1  
Although early stage patients can be treated successfully with surgical resection in the 
majority, many will develop metastatic disease.  Overall five year survival for all stages 
of melanoma is about 92%; however five year overall survival for metastatic melanoma 
is 23%.1  
 
Prior to the advent of immunotherapy in 2011, median overall survival for metastatic 
melanoma was 6-8 months, with five year OS less than 10% with the use of dacarbazine 
or temozolomide chemotherapy.2  Recently, treatment options for patients with advanced 
melanoma have expanded greatly with the United States (US) Food and Drug 
Administration (FDA) approval in 2011-2013 of the anti-cytotoxic T-lymphocyte antigen 
4 (CTLA-4) antibody, ipilimumab, and the highly selective inhibitors of BRAFV600E, 
vemurafenib and dabrafenib.  In addition, the MEK inhibitor, trametinib, also received 
FDA approval in 2013 for the treatment of patients with BRAFV600E mutant melanoma. 
Combination  BRAF/MEK inhibitor therapy received FDA approval in 2014 based on a 
randomized Phase II study in which the combination showed superior efficacy relative to 
dabrafenib alone. 
 
Current treatment of metastatic melanoma includes combined administration of anti- 
CTLA-4 immunotherapy with ipilimumab plus anti-programmed cell death receptor 1 (PD-
1) immunotherapy with nivolumab or monotherapy with nivolumab.3–7  In a phase 3 study 
by Larkin et al. (CheckMate 067), 945 previously untreated unresectable or metastatic 
melanoma patients were randomized 1:1:1 to receive nivolumab alone, nivolumab plus 
ipilimumab, or ipilimumab alone.  The median progression-free survival was 14 months in 
the nivolumab plus ipilimumab group and in the nivolumab group, however higher adverse 
events of grade 3 or 4 toxicity were observed in the combination group (55.0%) compared 
to nivolumab monotherapy (14.3%).3 The objective response rate (ORR) was 43.7% (95% 
CI, 38.1-49.3) in the nivolumab group, and 57.6% (95% CI, 52.0-63.2) in the combination 
group. In December 2014, the FDA approved nivolumab as a single agent for treatment in 
unresectable or metastatic melanoma.  In Checkmate 066, advanced BRAF wild-type 
melanoma patients were randomized to receive nivolumab or dacarbazine as first line 
therapy.  The objective response rate was 40% in the nivolumab group and 14% in the 
dacarbazine group.8   
 
Once patients progress on prior anti-PD-1 therapy, limited treatment options are available.  
This refractory population includes patients who possess a targetable BRAF mutation and 
have already received combined BRAF/MEK inhibitor therapy and those who have 
received prior anti-PD-1 therapy, in whom response rates to salvage anti-PD-1 therapy or 
combination CTLA4/PD-1 inhibition are low.  A recent retrospective study presented at 


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ASCO 2019 (n = 200) demonstrated that treatment after anti-PD-1 monotherapy with 
combination ipilimumab and nivolumab (n = 77) had an ORR of about 19%, single agent 
ipilimumab (n = 47) 4.2%, and re-challenge with BRAF/MEK inhibitor in the BRAF 
mutant subpopulation (n = 18) 22%.9  Grade 3-4 toxicity or toxicity requiring treatment 
discontinuation was observed in 34% of patients in the combination ipilimumab/nivolumab 
arm.  This finding is consistent with a prior study where patients treated with 
ipilimumab/nivolumab (n = 37) after failure with anti-PD-1 therapy had an ORR of 21% 
and 16% in patients treated with single agent ipilimumab (n=47).10  Additionally, another 
retrospective study (n=398) presented at ASCO 2019 demonstrated that once patients 
progress on prior anti-PD-1 therapy, retreatment with anti-PD-1 achieved modest 
responses.  Of 34 patients who received a second course of anti-PD-1 therapy, only five 
(14.7%) had an objective response; specifically, two (5.9%) achieved a CR and three 
(8.8%) had tumor shrinkage.11 Ongoing trials in refractory metastatic melanoma aim to 
reach better salvage efficacy in ORR than with single agent anti-PD-1 therapy or 
combination CTLA4/PD-1 inhibition. 
 
1.2 
Nivolumab 
 
Nivolumab is a humanized monoclonal IgG4 antibody that targets the PD-1 protein. This 
monoclonal antibody was evaluated in a phase I/II study in 296 patients with a variety of 
heavily pretreated malignancies, including 107 patients with melanoma.12 Updated 
efficacy data with an additional one year follow up for the melanoma cohort showed that 
the overall ORR was 31% for the entire melanoma patient cohort and an additional 7% of 
patients had stable disease.13 No clear-cut dose response relation was observed, although a 
dose of 3mg/kg had the highest response rate (41%). Median duration of response was 24 
months.   
 
Grade 3 or 4 treatment related adverse events (AE) were observed in 32 of 296 patients 
(14%) enrolled in the study.12  A variety of autoimmune side effects were observed, 
including pneumonitis, vitiligo, hepatitis, hypophysitis, thyroiditis, and colitis.  
 
Several phase 3 trials have been conducted to evaluate the efficacy and safety of nivolumab 
in unresectable or advanced melanoma.  An international phase 3 randomized controlled 
trial by Weber et al. evaluated nivolumab as second-line or later-line therapy.  Specifically, 
if patients had progressed after ipilimumab, (and if indicated) BRAF inhibitor therapy, they 
were randomly assigned to intravenous nivolumab 3mg/kg every 2 weeks or investigator 
choice chemotherapy (ICC) with decarbazine or paclitaxel combined with carboplatin.  
From December 2012-January 2014, 272 patients were randomized to nivolumab and 133 
to chemotherapy. ORR of first 120 patient on nivolumab was 32% versus 10% in 
chemotherapy group. Grade 3-4 AEs related to nivolumab was observed in 12 (5%) of 
patients, which included increased lipase, transamintis, anemia, and fatigue.4 Updates to 
this study showed longer median duration of response for nivolumab versus ICC (32 
months vs. 13 months), and confirmed overall response rate of nivolumab (27% versus 
10% in ICC).14 Preliminary results of this study led to FDA approval of nivolumab in 
refractory melanoma on December 22, 2014.   
 


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A second phase 3 study by Robert et al. (CheckMate 066) randomly assigned 418 
previously untreated patients with metastatic melanoma without a BRAF mutation to 
receive nivolumab 3mg/kg every two weeks and dacarbazine-matched placebo every three 
weeks or dacarbazine and placebo from January 2013 to February 2014.  At one year, 
overall rate of survival was 73% in nivolumab group versus 42% in dacarbazine group.  
Median PFS was 5 months in nivolumab group versus 2.2 months in dacarbazine group. 
ORR was 40% versus 14%, respectively.15  Three-year follow up of this study showed 
median OS of 37.5 months in nivolumab group and 11.2 months in dacarbazine group; 
three-year overall survival rates were 51.2% and 21.6% respectively.  Treatment related 
grade 3/4 AEs were reported in 15.0% (31 of 206) of nivolumab treated patients, leading 
to 5% (10 of 206) discontinuing therapy.  These included pruritis, diarrhea, and rash.  Any 
grade AEs included vitiligo, erythema, hypothyroidism and infusion-related reaction.16 
This study led to FDA approval of nivolumab in treatment-naïve BRAF V600E wild-type 
unresectable or metastatic melanoma on November 23, 2015. 
 
1.3  
Talazoparib 
 
Poly ADP ribose polymerase-1 (PARP1) is a protein responsible for repairing single-strand 
breaks in DNA. Mutations in BRCA1 and BRCA2 cause errors in DNA repair. Talazoparib 
is a potent, orally bioavailable, small molecule PARP inhibitor in development for the 
treatment of a variety of human cancers.  Drugs that inhibit PARP1 cause multiple double 
strand breaks (DSBs) to form in tumors with BRCA1 and BRCA2 mutations that cannot 
be repaired, leading to cell death, a cytotoxic effect referred to as synthetic lethality. Studies 
have demonstrated clinical benefit with PARP inhibitors in treatment of germline 
BRCA1/2-mutant breast, ovarian, and prostate cancers. A more recent study suggests that 
PARP inhibitors trap the PARP1 and PARP2 enzyme at sites of damaged DNA, and thus 
prevent DNA repair, replication, and transcription.17  
 
In vitro studies have demonstrated that the PARP inhibitor, talazoparib, has more potent 
PARP trapping than other PARP inhibitors in clinical development.18,19 Additionally, 
PARP inhibitor-mediated DNA damage has been shown to increase the immunogenicity 
of tumor cells, as evidenced by talazoparib promoting T cell and natural killer cell 
infiltration in a murine model of ovarian cancer.20  Talazoparib has also been shown to 
increase tumor expression of programmed death-ligand 1 (PD-L1) in vitro and in vivo.21 
Therefore, the use of talazoparib in combination with the immune checkpoint inhibitor, 
nivolumab, may have a synergistic immunotherapeutic and antitumor effect.   
 
Talazoparib has been studied in Phase I and II (ABRAZO) trials in solid tumors, and in a 
Phase III (EMBRACA) study in locally advanced or metastatic breast cancer with germline 
BRCA mutations. In the Phase I trial, the most common adverse events related to 
talazoparib were anemia, thrombocytopenia, and mild-to-moderate fatigue.22 Overall, 
talazoparib was tolerated well in the EMBRACA trial. Of 287 patients in the talazoparib 
arm, grade 3 or 4 hematologic adverse events, primarily anemia, occurred in 55% of the 
patients. Nonhematologic adverse events like diarrhea and nausea, occurred in 32% of 
patients; however, the majority of nonhematologic adverse events in the talazoparib group 
were grade 1 in severity. Patients treated with talazoparib (1 mg QD) had significantly 


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longer median progression-free survival than those receiving physician’s choice of 
chemotherapy (8.6 vs. 5.6 months, respectively; 95% CI: 0.41–0.71; HR: 0.54; 
p<0.0001).23  Patients who received talazoparib had significant overall improvements in 
patient-reported global health status/quality of life scores and a significantly greater delay 
in time to clinical deterioration.24  Based on this study, talazoparib was approved for use 
by the US Food and Drug Administration for the treatment of adults with deleterious or 
suspected deleterious germline BRCA-mutated (gBRCAm) human epidermal growth factor 
receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in 2018. 
 
1.3.1 Talazoparib Clinical Experience 
 
Talazoparib is a potent, orally bioavailable, small molecule PARP inhibitor in development 
for the treatment of a variety of human cancers. 
 
As of 30 November 2016, approximately 439 patients have received talazoparib in 
company-sponsored studies in hematologic malignancies and solid tumors. Studies in solid 
tumors include a Phase 1 study (PRP-00122) in advanced or recurrent solid tumors, a 
Phase 1 study in advanced malignancies (PRP-002), a Phase 2 study (673-20125) in locally 
advanced and/or metastatic breast cancer patients with a germline BRCA defect, a 
Phase 3 study (673-30123) in locally advanced or metastatic breast cancer with a germline 
BRCA defect, a Phase 1 hepatic impairment study (MDV3800-02), a Phase 1 absorption, 
distribution, metabolism and excretion (ADME) study (MDV3800-0326), and a Phase 1 
study on cardiac repolarization (MDV3800-1427). 
 
As of 30 November 2016, aggregate safety data from 3 company-sponsored clinical studies 
evaluating talazoparib monotherapy at the proposed dose of 1 mg QD in patients with 
advanced malignancies (Phase 1 studies PRP-001 and MDV3800-14 and Phase 2 study 
673-201; 164 patients total) provide the basis for the most common treatment emergent 
adverse events (TEAEs).  The most common TEAEs associated with talazoparib (>20%) 
occurring in patients who received 1 mg QD talazoparib were anemia (42.1%), fatigue 
(36.6%), nausea (29.3%), thrombocytopenia (25.6%), neutropenia (20.7%), and alopecia 
(20.1%). The most common Grade 3 or higher drug-related TEAEs occurring in ≥5% of 
patients were anemia (28.0%), thrombocytopenia (16.5%), and neutropenia (12.2%). 
 
Serious AEs (SAEs) occurred in 52 of 164 patients (31.7%) who received 1 mg QD 
talazoparib. SAEs occurring in ≥2% of patients were pleural effusion (4.3%), anemia and 
dyspnea (3.7% each), and neoplasm progression and thrombocytopenia (2.4% each). 
Fourteen patients had SAEs considered related to talazoparib, which included anemia 
(3.0%); thrombocytopenia (2.4%); platelet count decreased (1.2%); and increased 
transaminases, neutropenic sepsis, and vomiting (0.6% each). 
 
A total of 12 of 164 patients (18.8%) who received 1 mg QD talazoparib had a TEAE that 
led to death (6 associated with the underlying malignancy including 1 also associated with 
bronchopneumonia; 2 dyspnea; and 1 each disease progression, lung infection, hypoxia, 
and respiratory failure). Of these events, none were assessed as related to talazoparib. 
 


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Among the 164 patients who received 1 mg QD talazoparib, 19.5% had a TEAE that led 
to dose reduction and 57.3% had a TEAE that led to dose interruption. The most common 
TEAEs that led to dose reduction or interruption were associated with myelosuppression. 
Five of 164 patients (3.0%) treated with talazoparib at a dose of 1 mg QD permanently 
discontinued talazoparib due to a TEAE. The TEAEs that led to study drug discontinuation 
were anemia, increased ALT, increased AST, metastatic breast cancer, and dyspnea. 
 
1.3.2 Clinical Efficacy of Talazoparib in Patients with Advanced Solid Tumors 
 
A total of 110 patients with advanced tumors with DNA repair pathway abnormalities, 
particularly those associated with BRCA and phosphatase tensin homolog (PTEN) 
dysfunction, were enrolled in the Phase 1 study PRP-001, which was completed in March 
2015.22 The maximum tolerated dose (MTD) of talazoparib was defined as 1 mg QD and 
it was used in the expansion phase of the study in patients with breast, ovarian/primary 
peritoneal, and pancreatic cancer with deleterious germline mutations; small cell lung 
cancer (SCLC); and Ewing sarcoma. As of 13 February 2015, the proportion of patients 
with breast, ovarian/primary peritoneal, and pancreatic cancers with BRCA mutations who 
were treated with talazoparib at 1 mg QD and had objective responses according to 
RECIST v1.1 was 50% (7 of 14; 95% CI: 23.0, 77.0), 41.7% (5 of 12; 95% CI: 15.2, 72.3), 
and 20.0% (2 of 10), respectively. Cancer patients harboring BRCA mutations who are 
resistant to platinum-based chemotherapy display decreased sensitivity to PARP 
inhibitors.28  
 
1.3.3  Clinical Efficacy of Talazoparib in Patients with Germline BRCA Mutations 
and Locally Advanced and/or Metastatic Breast Cancer 
 
The ongoing Phase 2, open-label, 2-stage, 2-cohort study, 673-201, is evaluating 
talazoparib in patients with locally advanced or metastatic breast cancer with deleterious 
germline BRCA mutations. Enrolled patients included those who were platinum-sensitive 
(Cohort 1) and patients who received at least 3 prior chemotherapy regimens and no prior 
platinum therapy (Cohort 2). As of 1 September 2016, the data cut-off for the primary 
analysis, 83 patients with locally advanced or metastatic breast cancer with deleterious 
germline BRCA mutations were tumor evaluable (48 patients in Cohort 1; 35 patients in 
Cohort 2), and 9 patients were continuing on treatment. Efficacy analyses were conducted 
by independent central radiology assessment. The ORR was 20.8% (95% CI: 10.47, 34.99) 
in Cohort 1, 37.1% (95% CI: 21.47, 55.08) in Cohort 2 and 27.7% (95% CI: 18.45, 38.62) 
overall. This response rate, which included 2 CRs and 8 PRs in Cohort 1 and 13 PRs in 
Cohort 2, is considered clinically meaningful as these populations have a poor prognosis.25 
 
The landmark EMBRACA phase 3, randomized, open-label trial for patients with advanced 
breast cancer and a germline BRCA1/2 mutation (n = 431) compared patients treated with 
single agent talazoparib (1mg daily) or standard single-agent chemotherapy of physician’s 
choice. 287 were assigned to receive talazoparib.  Median PFS was significant longer in 
the talazoparib group than in the standard-therapy group (8.6 months vs 5.6 months; HR 
0.54; 95% CI 0.41-0271 p<0.001).  The ORR was higher in the talazoparib group than in 
the standard-therapy group (62.6% vs. 27.7%; OR 5; 95% CI 2.9-8.8; p<0.001).  


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Additionally, patient-reported outcomes favored talazoparib; significant overall 
improvements and significant delays in the time to clinically meaningful deterioration were 
observed.  Grade 3-4 hematologic events (anemia) occurred in 55% of patients who 
received talazoparib and 38% of patients who received standard therapy. Nonhematologic 
adverse events like diarrhea and nausea, occurred in 32% of patients; however, the majority 
of nonhematologic adverse events in the talazoparib group were grade 1 in severity.23,24 
 
1.3.4 Pharmacokinetics of Talazoparib in Humans 
 
PK analysis for talazoparib was conducted based on 6207 PK observations of 490 patients 
with advanced cancer from 4 clinical trials, Studies PRP-001, PRP-002, 673-201, and 673-
301.  The PK of talazoparib as a single agent was evaluated in 142 adult patients with 
cancer, including 109 patients with solid tumors (Study PRP-001) and 33 with hematologic 
malignancies (Study PRP-002). Doses of 0.025 mg to 2 mg were administered orally as a 
single dose or as QD doses. This dose range bracketed the 1 mg QD dose used in ongoing 
safety and efficacy studies, and provided a framework for assessing dose linearity. As the 
PK of talazoparib was similar in patients with solid tumors and hematologic malignancies, 
and no differences were apparent between males and females, the results are summarized 
collectively. 
 
Oral absorption of talazoparib was rapid and independent of dose after administration of 
single or QD doses. Peak talazoparib concentrations were generally reached approximately 
1 to 8 hours post-dose. Exposure increased approximately dose-proportionally with 
increasing doses. At 1 mg/day, the mean t1/2 was approximately 2 days; the mean apparent 
volume of distribution (V/F) was 415 L, indicating extensive extravascular distribution. 
 
Steady state was reached in approximately 2 to 3 weeks with daily administration. 
Apparent oral clearance (CL/F) of talazoparib appeared to be dose linear, with a mean CL/F 
across doses of approximately 5 L/h. Renal excretion was a major elimination pathway for 
unchanged parent talazoparib. Following oral administration, 44% to 90.6% of the dose 
was recovered in urine as unchanged parent drug over 24 hours at steady state for doses up 
to 1 mg QD. Mean renal clearance ranged from 1.38 L/h to 4.96 L/h independent of dose, 
suggesting linear urinary elimination kinetics. 
 
Following repeated administration at 1 mg QD, talazoparib accumulated approximately 
2.4-fold relative to a single dose.  At steady state, the mean maximum plasma concentration 
(Cmax) was 21.0 ng/mL (55 nM), the mean plasma trough concentration (Ctrough) was 
3.72 ng/mL (9.87 nM), and the mean area under the plasma concentration-time curve 
(AUC) was 202 ng*h/mL (532 nM*h). The Ctrough of talazoparib at steady state at 1 mg 
QD is above the Ctrough values at the efficacious dose of 0.33 mg/kg daily used in some 
of the xenograft models (1.3 nM). 
 
PK data from a food-effect study showed that food had no effect on the extent of absorption 
of talazoparib (AUC) but decreased the rate of absorption (Cmax was 46% lower and time 
to Cmax [Tmax] was 2.63 hours later); however, this reduction in the rate of absorption 
following a single dose is not clinically relevant because talazoparib accumulates 2.4-fold 


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at steady state after 1 mg QD dosing. Furthermore, AUC or Ctrough is thought to drive 
efficacy, not Cmax; therefore, talazoparib can be taken with or without food. Talazoparib 
is being administered without regard to food in ongoing safety and efficacy studies. 
 
A preliminary population PK analysis used data from patients in Studies PRP-001 and 
PRP-002 to assess the effects of renal function on the PK of talazoparib. The talazoparib 
CL/F in patients with mild renal impairment (creatinine clearance [CLCR] 60-89 mL/min) 
was similar compared with patients with normal renal function (CLCR ≥90 mL/min). In 
patients with moderate renal impairment (CLCR 30-59 mL/min), the talazoparib CL/F was 
decreased by 44% from normal, resulting in higher talazoparib exposure.  
 
The effect of renal impairment on talazoparib PK is also being investigated in the ongoing 
study MDV3800-01. 
 
The effect of hepatic impairment on talazoparib PK is being investigated in the ongoing 
MDV3800-02 study. 
 
The potential for talazoparib to affect the PK of other drugs was assessed through in vitro 
experiments and is described in the talazoparib IB.29  For additional information on 
pharmacokinetics, metabolism, drug-drug interactions, safety, efficacy and any additional 
information on talazoparib, please refer to the investigator brochure. 
 
1.3.5 Clinical Experience in Patients with mCRPC Treated with PARP Inhibitors 
as a Single Agent or in Combination with Immunotherapy 
 
The PARP inhibitor olaparib given as single agent was evaluated in a Phase 2 study in 
50 patients with previously treated mCRPC.30 Of the 50 patients, all patients had received 
prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 
(58%) had received cabazitaxel. Of the 49 patients evaluable for response (defined either 
as an objective response according to RECIST v1.1, or as a reduction of at least 50% in the 
prostate-specific antigen (PSA) level or a confirmed reduction in the circulating tumor-cell 
count from 5 or more cells per 7.5 mL of blood to less than 5 cells per 7.5 mL), 16 patients 
achieved a response (33%; 95% CI: 20.0, 48.0). Homozygous deletions, deleterious 
mutations, or both were identified in DNA-repair genes in 16 patients (33%) and 14 of 
these patients (88%) achieved a response. 
 
The combination of olaparib with durvalumab was evaluated in a Phase 1/2 study in 
17 patients with mCRPC with and without somatic or germline DDR mutations. Overall, 
median radiographic progression-free survival (rPFS) for all patients was 16.1 months 
(95% CI: 4.5-16.1 months) with a 12-month rPFS of 51.5% (95% CI: 25.7-72.3%).  
Activity was seen in patients with alterations in DDR genes with median rPFS of 16.1 
months (95% CI: 7.8-18.1 months). 53% (n = 9) had a radiographic and/or PSA response 
(defined as ≥50% decline in PSA).  Patients with fewer peripheral myeloid-derived 
suppressor cells and with alterations in DDR genes were more likely to respond. The 12-
month PFS probability was 83% (95% CI: 27.3-94.5%) in patients with mutations, 
compared to 36.4% (95% CI: 11.2-62.7%) for those without mutations (p = 0.031).  Most 


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common treatment-related grade 3 or 4 adverse events were anemia (24%), lymphopenia 
(12%), infection (12%), and nausea (12%).  Four patients had immune-related adverse 
events (irAEs) of any grade, including two with acute onset hearing loss, one with optic 
neuritis, and one patient with synovitis.  All were treated with high-dose steroids and 
symptoms improved to near complete resolution with exception of one patient with hearing 
loss, who required use of a hearing aid.31 
 
Veliparib given as a single agent was investigated in a Phase 1 dose-finding study in 
patients with advanced solid tumors; overall, 98 patients were enrolled, of whom 78 had 
disease with a germline BRCA defect.32  Three patients with BRCA2 germline mutated 
mCRPC were enrolled at the recommended Phase 2 dose (RP2D) and were evaluable for 
response. In these patients, the ORR was 2/3 (66%) and all patients had a PSA reduction 
>50% with respect to baseline. 
 
A Phase 1 study evaluated niraparib given as a single agent in 100 patients with advanced 
solid tumors.33 A total of 23 mCRPC patients were enrolled and 21 of these received 
niraparib at 290 mg QD or 300 mg QD. No mCRPC patient achieved an objective response 
but 9 patients had SD with a median duration of 254 days (range: 124–375 days) and 1 
patient had a >50% decrease in the concentration of PSA and had remained on study for 
306 days. 
 
RP2D for talazoparib in combination with avelumab is currently being studied in Phase 
1b/2 trial NCT03330405 in patients with advanced or metastatic solid tumors.  DLT rate 
of avelumab in combination with talazoparib is also being studied in this clinical trial. 
 
Additionally, combination niraparib (200mg daily) and pembrolizumab (200mg IV every 
21 days) was recently studied in a phase 2 trial of 55 patients with advanced or metastatic 
TNBC, and showed reasonable efficacy with a tolerable safety profile.  This study found 
an ORR of 21% and DCR of 49% with a tolerable safety profile.  Most common treatment-
related adverse events of grade 3 or higher were anemia, thrombocytopenia, and fatigue; 
two patients experienced grade 3 immune-related adverse events.34 
 
 
 
 
 
1.4 
Rationale  
 
Limited studies are available to understand the role of PARP inhibitors in treatment of 
melanoma. Czyz et al. conducted in vitro studies looking at the effect of the PARP inhibitor 
olaparib in eight DSB repair genes expressed in melanoma that were identified in The 
Cancer Genome Atlas (TCGA) database. Specifically, in melanoma cells displaying down 
regulation of the DSB repair gene LIG4, PARP inhibition alone and in combination with 
dacarbazine caused accumulation of toxic DSBs and apoptosis, suggesting that the 
phenomenon of synthetic lethality could be applied in melanoma.35 Furthermore, this study 
showed that olaparib was selectively toxic to DSB repair deficient human melanoma 


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xenografts, which was further enhanced in the presence of dacarbazine.  This suggests that 
melanomas could be sensitive to PARP inhibitor-mediated synthetic lethality due to their 
putative deficiencies in DNA repair pathways. Further elaborating on this concept, in the 
B16F10 murine syngeneic melanoma model, the PARP inhibitor (ABT-888), now known 
as veliparib, strongly potentiated temozolomide (TMZ) with significant antitumor efficacy 
in a dose-proportional manner, but did not show single agent activity.36,37  Preclinical 
studies with PARP inhibitor therapy in DSB repair deficient melanoma tumors suggest a 
synthetic lethality and a synergistic effect.  
 
In vitro studies have demonstrated that the PARP inhibitor, talazoparib, has more potent 
PARP trapping than other PARP inhibitors in clinical development.18,19 Additionally, 
PARP inhibitor-mediated DNA damage has been shown to increase the immunogenicity 
of tumor cells, as evidenced by talazoparib promoting T cell and natural killer cell 
infiltration in a murine model of ovarian cancer.20  Talazoparib has also been shown to 
increase tumor expression of programmed death-ligand 1 (PD-L1) in vitro and in vivo.21 
Furthermore, olaparib has been shown to increase cytotoxic T cell infiltration by 
augmenting STING (stimulator of interferon genes) intracellular pathway, an innate 
immune response activated by cytosolic DNA (perhaps a consequence of DNA damage by 
olaparib) that can lead to enhanced interferon (IFN) production and further T cell 
recruitment and activation.38  Therefore, the use of talazoparib in combination with the 
immune checkpoint inhibitor, nivolumab, may have a synergistic immunotherapeutic and 
antitumor effect.   
 
Middleton et al. conducted a Phase II randomized, controlled, double-blinded clinical trial 
evaluating veliparib with TMZ in patients with metastatic melanoma.  Patients (n = 346) 
were randomized to veliparib 20mg with TMZ, veliparib 40mg with TMZ, or placebo with 
TMZ.39 Median PFS was 3.7 [95% CI, 3.0-3.5], 3.6 [95% CI, 1.9-4.1], and 2 [95% CI, 1.9-
3.7] months in the 20 mg, 40mg, and placebo arms, respectively. The ORR was 10.3%, 
8.7%, and 7.0%. Although not statistically significant, the PFS was almost doubled in the 
combination arms compared to the placebo arm, supporting that PARP inhibition promotes 
synthetic lethality and potentiates TMZ activity in melanoma. PFS was better in patients 
receiving veliparib with low ERCC1 expression (5.6 vs. 1.9), wildtype BRAF V600 status 
(2.4 vs. 1.8), and positive p16 status (3.8 vs. 1.8) when compared to placebo.39 ERCC1 is 
part of the nucleotide excision repair pathway.  Low ERCC1 expression coupled with 
PARP inhibition may hinder DNA repair following TMZ exposure, leading to lethal DSBs 
during replication. These data suggest that biomarker selection may influence the efficacy 
of PARP inhibition when combined with TMZ. 
 
Biomarker selection strongly influences the efficacy of PARP inhibition.  A study by 
Mateo et al. looked at treatment with the PARP inhibitor olaparib in patients with 
metastatic castration-resistant prostate cancer with DNA-repair defects.30 Of 49 patients, 
16 had a response to olaparib (33%; 95% CI, 20-48).  In these 16 patients, next-generation 
sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair 
genes, which included BRCA1/2, ATM, Fanconi anemia genes, and CHEK2.  The hazard 
ratio for radiologic progression in the biomarker-positive group as compared with the 
biomarker-negative group was 0.24 (95% CI, 0.11-0.50).  This study showed that treatment 


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with the PARP inhibitor olaparib in patients with metastatic prostate cancer who had 
germline defects in DNA-repair genes led to a high response rate.30 Eligible alterations 
were in BRCA1/2, ATM, PALB2, CHEK2, FANCA, HDAC2, RAD51, MLH3, ERCC3, 
MRE11, and NBN.  Many of these, specifically BRCA1/2, ATM, ATR, PALB2, CHEK1/2, 
RAD51, FANCA, and HDAC have been reported to have a synthetic lethal interaction with 
PARP inhibition, and have been termed “BRCA-ness.”17,40,41 
 
“BRCA-ness” has not specifically been studied in melanoma; however our imputations 
from TCGA data and our own data from a local familial melanoma registry suggest a 
substantial presence of germline and somatic mutations in this patient population. Huang 
et al. identified pathogenic germline mutations in all cancers using The Cancer Genome 
Atlas. Out of 470 skin cutaneous melanoma patients that have germline sequencing data 
available, 52 (11%) have pathogenic/likely pathogenic germline mutations, and 25 patients 
(5.3%) have mutations in BRCA1/2 or “BRCA-ness.”42  Looking at somatic mutations 
involving BRCA1/2 or “BRCA-ness” genes in melanoma in TCGA, 16% (n = 72) possess 
actionable/likely actionable mutations when variants of undetermined significance (VUS) 
are excluded.  If VUS are included, 58% (n = 255) of patients possess likely actionable 
mutations.43,44 Up to 63% of melanoma patients possess germline and/or somatic mutations 
in DSB repair genes that could be targeted with PARP inhibitor therapy.  In the first 130 
melanoma patients accrued to our Gross Family Melanoma Registry at the Cleveland 
Clinic, 19% (25) had a germline pathogenic/likely pathogenic mutation, of which 52% (13) 
were in genes associated with BRCA1/2 and “BRCA-ness.”45 This represents a significant 
proportion of patients with metastatic melanoma that could benefit from PARP inhibitor 
therapy.   
 
We propose that PARP inhibition with talazoparib at a dose of 1mg orally daily will 
have synergistic antitumor activity in combination with nivolumab 480mg 
intravenously every 4 weeks in unresectable and metastatic melanoma patients with 
DNA-repair defects in BRCA1/2 or BRCA-ness that have progressed on prior CPI 
therapy and improve the objective response rate from about 10% to 30% with limited 
toxicity.   
 
 
 
1.5 
Background and rationale of correlative studies 
 
This study intends to characterize the activity of nivolumab in combination with 
talazoparib, with the aim of increasing the clinical benefit seen historically with single 
agent nivolumab. A key mechanistic hypothesis underpinning the combination is that 
increased DNA damage and cell death mediated by talazoparib will lead to enhanced 
immune priming and tumor immunogenicity, enabling a more effective anti-tumor immune 
response to be promoted by nivolumab. Given this hypothesis, one subgroup of patients 
likely to benefit from the combination will be those whose tumors are most sensitive to 
talazoparib-mediated cell death and DNA damage.  Several biomarkers have the potential 
to identify patients with such increased sensitivity to talazoparib, one of these will be 
employed in the context of this study, the presence of pathogenic or likely pathogenic 


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germline or somatic defects in a panel of DDR genes.46  A correlative study will include 
that prior to study enrollment, we will obtain tumor-biopsy samples from all patients to 
conduct biomarker studies from both germline and somatic DNA, including sequencing to 
identify genomic aberrations and tumor mutational burden (TMB) associated with 
sensitivity to PARP inhibition in this disease. 
 
Complementing the DDR biomarkers described above, a number of assessments will be 
undertaken as correlatives to understand the immune context of patient tumors, which may 
also be a contributing factor in response to the combination of talazoparib and nivolumab. 
These include assessment of immune cell types in the tumor using immunohistochemistry, 
assessment of infiltrating immune cell number and phenotype by immunohistochemistry 
or flow cytometry, relative expression of genes representative of immune activation versus 
suppression by gene expression profiling, and assessment of mutational or neoantigen load 
within tumors.  
 
To enable the above mentioned biomarker assessments, the collection of pre-treatment 
tumor specimens, including a tumor tissue sample from a biopsy performed during, or 
within 1 year of, the screening period.  See section 4.0 for further clarification on pre-
treatment tumor specimen.  
 
Given the limited ability to assess tumor tissue-based biomarkers longitudinally, 
biomarkers will also be measured in peripheral blood at time points pre-treatment, post-
treatment and at progression. The primary aim of these measurements is to identify 
mechanistic biomarkers for the combination of nivolumab and talazoparib.  Such 
biomarkers may have value in predicting response to treatment.   
 
In the event that clinical benefit is not observed or is transient, assessment of reasons for 
lack of benefit may help guide patient selection for future development of the combination.  
For these reasons, tumor biopsies performed at the End-of-Treatment (EOT) visit or in the 
event of permanent treatment discontinuation due to disease progression, are requested 
from patients, unless clinically contraindicated. If the Sponsor considers sufficient data 
have been obtained to confirm possible causes for lack of clinical benefit, collection of 
tumor tissue from EOT tumor biopsies may be discontinued. 
 
1.5.1 Banked Biospecimen Collection Rationale 
Banked biospecimens will be collected for the purpose of conducting research; specific 
uses are described in the Banked Biospecimens section. Comparing the deoxyribonucleic 
acid (DNA), ribonucleic acid (RNA), protein, and metabolite variation patterns of patients 
who respond well and those who respond poorly to treatment may help to better define the 
most appropriate group of patients in which to target a given treatment. Collecting 
biospecimens for exploratory pharmacogenomic/genomic/biomarker analyses and 
retaining them in the Biospecimen Banking System (BBS) make it possible to better 
understand the investigational product’s mechanism of action and to seek explanations for 
differences in, for example, exposure, tolerability, safety, and/or efficacy not anticipated 
prior to the beginning of the study. 
 


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Banked biospecimens retained in the BBS also can be used in research on melanoma. 
Providing these biospecimens is a required study activity for study sites and patients, unless 
prohibited by local regulations or ethics committee (EC) decision. 
  
2.0  
Objectives 
2.1  
Primary Objective  
The primary objective is to determine the clinical efficacy of nivolumab plus 
talazoparib in patients with unresectable or metastatic melanoma with BRCA1/2 or 
other DNA damage repair mutations (defined as BRCA-ness), as measured by 
objective response rate (ORR) every 12 weeks for a period of approximately 12 
months.  
 
2.2 
Secondary Objectives 
• Determine progression free survival (PFS) in unresectable or metastatic melanoma 
patients treated with nivolumab plus talazoparib. 
 
• Determine overall survival (OS) in unresectable or metastatic melanoma patients 
treated with nivolumab plus talazoparib. 
 
• Evaluate treatment-related adverse events in patients treated with nivolumab plus 
talazoparib. 
 
• To assess the anti-tumor activity of nivolumab in combination with talazoparib in 
unresectable or metastatic melanoma patients with BRCA1/2 or other DNA damage 
repair mutations (defined as BRCA-ness), as measured by immune-related objective 
response rate (irORR) every 12 weeks for a period of approximately 12 months.  
 
• Determine immune-related progression free survival (irPFS) in unresectable or 
metastatic melanoma patients treated with nivolumab plus talazoparib. 
 
2.3 
Correlative Objectives 
• Measure adaptive and innate cellular immunofiltration into tumor (by tumor 
biopsies) and peripheral circulating T cells (by PBMCs) at baseline (pre-treatment), 
after treatment initiation (at about 12 weeks), and at time of progression, and to 
correlate activity with response to treatment. 
   
• Assess total somatic tumor mutation burden by sequencing at baseline (pre-
treatment), after therapy at 12 weeks, and at time of progression to evaluate DNA 
landscape and its effect on sensitivity of combination nivolumab and talazoparib 
therapy.  
 
• Assess patient reported outcomes for adverse events while on combination therapy 
at baseline and before each cycle (about every 4 weeks) of nivolumab. 
 
2.4 
Endpoints 
2.5 
Primary Endpoint 


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Best overall response, defined as complete response (CR) and partial response (PR) 
by RECIST 1.1 recorded from the start of the treatment until disease progression or 
recurrence. 
 
2.6 
Secondary Endpoints 
• PFS, defined as the time from the first dose of study treatment to the date of disease 
progression by RECIST 1.1 or death due to any cause, whichever occurs first. 
 
• OS, defined as the time from the first dose of study treatment to the date of death. 
 
• Number of participants with treatment-related adverse events, as assessed by 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0. 
 
• Immune-related overall response (irOR), defined as immune-related complete 
response (irCR) and immune-related partial response (irPR) by irRECIST (See 
Appendix 16.2) recorded from the start of the treatment until disease progression.  
 
• irPFS, defined as the time from the first dose of study treatment to the date of 
disease progression by irRECIST or death due to any cause, whichever occurs first. 
 
2.7 
Correlative Endpoints 
• Assess anti-tumor response by measure of immune-infiltration, including, but not 
limited to, expression of CD8, CD4, Treg (FOXP3), NK cells (CD56) into tumors, 
by flow cytometry and immunohistochemistry on tumor biopsies and peripheral 
blood mononuclear cells (PBMCs) at baseline, 12 weeks, and at progression.  
 
• Assess longitudinal genomic evolution by sequencing and gene expression analysis 
at baseline, 12 weeks, and at progression to evaluate DNA landscape and its 
correlation to response. 
 
• Assess patient reported outcomes for adverse events, as measured by PRO-CTCAE 
while on combination therapy at baseline and before each cycle (every 4 weeks) of 
nivolumab for a period of 12 months. 
 
3.0 
Study Design 
 
3.1  
Study Design and Schema 
A phase II, single arm, multi-institutional, open label trial in a sample size of 37 primary 
or recurrent, unresectable or metastatic melanoma patients progressed on prior checkpoint 
inhibitor therapy with germline or somatic mutations in BRCA1/2 or BRCA-ness.  Prior to 
study enrollment, patients will initially be screened for germline or somatic mutations in 
one of the following genes: ARID1A, ARID1B, ARID2, ATM, ATR, BAP1, BARD1, BLM, 
BRCA1, BRCA2, BRIP1, CDK4, CDK12, CHEK1, CHEK2, DSS1, EMSY, ERCC3, 
FANCA, FANCD2, HDAC2, IDH1, LIG4, LIG3, MDC1, MLH1, MLH3, MRE11, NBN, 
PALB2, PRKDC, RAD50, RAD51, RAD54,  XRCC6. Genomic markers of homologous 


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repair deficiency such as gLOH are also permitted as inclusion criteria; other markers of 
HRD may be included as determined by review by the medical monitor.  Prior to study 
enrollment, we will obtain tumor-biopsy samples to conduct biomarker studies from both 
germline and somatic DNA, including targeted panel and transcriptome sequencing to 
identify genomic aberrations associated with sensitivity to PARP inhibition in this disease.  
Patients with identified mutations listed above, will then be enrolled in the study.  Patients 
will be treated simultaneously with standard of care therapy, nivolumab 480mg 
intravenously every 4 weeks plus investigational agent, talazoparib 1mg orally once daily.  
Beginning with Cycle 1 Day 1, all patients enrolled will simultaneously begin treatment 
with talazoparib 1mg daily, unless otherwise specified, and nivolumab 480mg every 4 
weeks. 
 
 
Patients will be assessed every 4 weeks and lab work will be obtained at that time. CT 
imaging scans will be obtained every 12 weeks to assess treatment response. If a patient 
achieves a CR, treatment with nivolumab will be continued for a total of one year from 
time of CR and talazoparib will be continued.  In patients with partial response (PR) or 
stable disease (SD), treatment with both agents will be continued until the time of disease 
progression or adverse events. 
 
3.2 
Number of Subjects 
Approximately 37 analyzable subjects will be enrolled in this trial.  For sample size 
calculation please see Section 14. 
 
3.3 
Replacement of Subjects  
Patients who receive at least one dose of treatment with nivolumab and talazoparib will 
contribute to the efficacy analysis.  Any subject who receives at least one cycle or dose 
of treatment on this protocol is evaluable for toxicity.  With 10% of patients potentially 
not evaluable due to drop out or loss to follow up, 37 patients would need to be enrolled 
for a total of 33 analyzable. Patients who are not evaluable are defined as patients who 
are consented and enrolled in the study, but have physically moved away that it would 
be too burdensome to follow up with institution, those who are lost to follow up defined 
as individuals who enroll but do not receive treatment, imaging, and are not present at 
scheduled office visits. 
 
 
4.0 
Subject Selection 
Each of the criteria in the sections that follow must be met in order for a subject to be 
considered eligible for this study. Use the eligibility criteria to confirm a subject’s 
eligibility.  
 
4.1 
Inclusion Criteria 
 
 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment:  
 


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4.1.1 Subjects must have a germline or somatic DNA damage repair mutation or 
deletion including any one of the following: ARID1A, ARID1B, ARID2, ATM, ATR, 
BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDK4, CDK12, CHEK1, CHEK2, 
DSS1, EMSY, ERCC3, FANCA, FANCD2, HDAC2, IDH1, LIG3, LIG4, MDC1, 
MLH1, MLH3, MRE11, NBN, PALB2, PRKDC, RAD50, RAD51, RAD54,  XRCC6, 
or gLOH.  The result may have been obtained from one of the following test 
providers: Myriad Genetics, Invitae, Ambry, Quest, Color Genomics, IMPACT, 
Foundation Medicine (tissue or ctDNA based), Tempus, Caris, Guardant, or 
another CLIA approved tissue and/or serum based next generation sequencing-
based assay. 
 
 
 
4.1.2 Subjects must have histologically or cytologically confirmed diagnosis of 
primary or recurrent metastatic melanoma including cutaneous, mucosal, or uveal 
melanoma. 
  
 
 
4.1.3 Subjects must have received prior checkpoint inhibitor therapy (defined as 
anti-CTLA4 or anti-PD-1 or combination anti-CTLA4/anti-PD-1), either for 
metastatic or unresectable disease or adjuvant therapy. 
 
 
 
4.1.4 Age at the time of enrollment should be greater than 18 years. Because no 
dosing or adverse event data are currently available on the use of nivolumab in 
combination with talazoparib in subjects ≤18 years of age, children are excluded 
from this study. 
 
 
 
4.1.5 ECOG Performance status ≤ 2. 
 
 
 
4.1.6 Subjects must have normal organ and marrow function as defined below:   
 
▪ Hemoglobin ≥ 9.0 g/dl  
▪ Absolute neutrophil count ≥ 1,500/mcL 
▪ Platelet count ≥ 90,000/mcL 
▪ Bilirubin ≤ 1.5 x ULN (except in subjects with Gilbert Syndrome, 
who can have a total bilirubin < 3.0mg/dL) 
▪ AST (SGOT) ≤ 3.0 X upper limit of normal 
▪ ALT (SGPT) ≤ 3.0 X upper limit of normal 
▪ Serum Creatinine Clearance ≥ 30mL/minute.  See section 7.1 for 
talazoparib dose adjustment for renal impairment.  
CrCl< 30mL/minute has not been studied in talazoparib. 
 
 
 
4.1.7  Measurable disease as defined by RECIST 1.1 criteria 
 
 
 
4.1.8 During screening, while taking study drug, and until 5 months after taking the 
final dose of study drug, women of childbearing potential (WOCBP) must practice 
one of the following methods of birth control: 
• Use double-barrier contraception method defined as male use of a 
condom and female use of a barrier method (e.g., contraceptive 


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sponge, spermicidal jelly or cream, diaphragm [always use with 
spermicidal jelly/cream]).  
• Use of hormonal contraceptives (oral, parenteral, vaginal, or 
transdermal) for at least 3 months before the first study drug 
administration.  
• Use of an intrauterine device. 
• Have a male partner who has had a vasectomy (at least 6 months prior 
to study enrollment). 
• Or must abstain from sexual intercourse completely. 
 
 
 
4.1.9 During screening, while taking study drug, and until 7 months after taking the 
final dose of study drug, men who are sexually active with WOCBP must practice 
one of the following methods of birth control: 
▪   Have had a vasectomy (at least 6 months prior to study enrollment). 
▪ Use double-barrier contraception method defined as male use of a 
condom and female use of a barrier method (e.g., contraceptive 
sponge, spermicidal jelly or cream, diaphragm [always use with 
spermicidal jelly/cream]).  
▪ Partner use of an intrauterine device. 
▪ Partner use of hormonal contraceptives (oral, parenteral, vaginal, or 
transdermal) for at least 3 months before the first study drug 
administration. 
▪ Or must abstain from sexual intercourse completely 
 
 
 
4.1.10 Subjects must have the ability to understand and the willingness to sign a 
written informed consent document. 
 
 
 
4.1.11 Ability to swallow pills. 
 
 
 
 
4.2 
Exclusion Criteria 
 
The presence of any of the following will exclude a subject from study enrollment. 
 
 
 
4.2.1 Prior treatment with a PARP inhibitor. 
 
 
 
4.2.2 Prior anti-cancer therapy for melanoma less than 14 days prior to first dose of 
study drug. 
 
 
 
4.2.3 Known symptomatic brain metastases requiring steroids. Patients with 
previously diagnosed brain metastases are eligible if they have completed their 
treatment and have recovered from the acute effects of radiation therapy or surgery 


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prior to study enrollment, have discontinued corticosteroid treatment for these 
metastases for at least 4 weeks and are neurologically stable. 
 
 
 
4.2.4 Subjects with uncontrolled intercurrent illness including, but not limited to 
ongoing or active infection, poorly controlled congestive heart failure, unstable 
angina pectoris or psychiatric illness/social situations that would limit compliance 
with study requirements.  
 
 
 
4.2.5 Known HIV or AIDS-related illness  
HIV-positive subjects on combination antiretroviral therapy are ineligible because 
of the potential for pharmacokinetic interactions with talazoparib. In addition, these 
subjects are at increased risk of lethal infections when treated with marrow 
suppressive therapy. Appropriate studies will be undertaken in subjects receiving 
combination antiretroviral therapy when indicated.  
 

 
4.2.6   Prior organ transplantation including allogeneic stem-cell transplantation. 
 

 
4.2.7 Poorly controlled or uncontrolled autoimmune disease that might deteriorate 
when receiving an immunostimulatory agent. Subjects with vitiligo, type I diabetes 
mellitus, residual hypothyroidism due to autoimmune condition or prior therapy 
requiring hormone replacement, psoriasis not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to 
enroll. Patients with endocrinopathies controlled on replacement drugs are eligible. 
 

 
4.2.8 Major surgery within 4 weeks prior to study enrollment. 
 

 
4.2.9 Current use of corticosteroids at the time of study enrollment, EXCEPT for 
the following: 
a. Intranasal, inhaled, topical steroids, eye drops or local steroid injection 
(eg, intra-articular injection) 
b. Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone 
or equivalent 
c. Steroids as premedication for hypersensitivity reactions (eg, CT scan 
premedication) 
 

 
4.2.10  Diagnosis of Myelodysplastic Syndrome (MDS) 
 

 
4.2.11 Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at 
screening (positive HBV surface antigen or detectable HCV RNA if anti-HCV 
antibody screening test positive). 
 

 
4.2.12 Current or anticipated use of a P-glycoprotein (P-gp) inducer (avasimibe, 
carbamazepine, phenytoin, rifampin, and St. John’s wort), or inhibitor of breast 
cancer resistance protein (BCRP) (curcumin, cyclosporine, elacridar [GF120918], 
and eltrombopag). P-glycoprotein (P-gp) inhibitor (amiodarone, carvedilol, 
clarithromycin, cobicistat, darunavir, dronedarone, erythromycin, indinavir, 


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itraconazole, ketoconazole, lapatinib, lopinavir, propafenone, quinidine, 
ranolazine, ritonavir, saquinavir, telaprevir, tipranavir, valspodar, and verapamil) 
are allowed, but require a dose modification of talazoparib, see section 7.1.1, 
 

 
4.2.13 Inability to swallow capsules or known intolerance to talazoparib or its 
excipients.  
 

 
4.2.14  Pregnant women are excluded from this study because animal studies have 
demonstrated that nivolumab and talazoparib may cause fetal harm when 
administered to pregnant women. Breastfeeding women are excluded from this 
study because nivolumab and talazoparib may be excreted in human breastmilk 
and the potential for serious adverse reactions in nursing infants.  
 

 
4.2.15 Persisting toxicity related to prior therapy > Grade 1. 
 
 
4.3 
Inclusion of Women and Minorities  
Men, women and members of all races and ethnic groups are eligible for this trial. 
 
5.0 
Registration 
All subjects who have been consented are to be registered in the OnCore™ Database. For 
those subjects who are consented, but not enrolled, the reason for exclusion must be 
recorded. 
 
All subjects will be registered through Cleveland Clinic Lead Study Coordinator and will 
be provided a study number by contacting the study coordinator listed on the cover page.  
 
6.0  
Treatment Plan 
 
6.1 
Treatment Regimen Overview 
Treatment will be administered on an outpatient basis. 
Patients found to have a mutation in BRCA1/2 or BRCA-ness who have enrolled in the trial, 
will begin treatment with both talazoparib 1mg orally daily on Cycle 1 Day 1 and 
nivolumab 480mg intravenously every 4 weeks and continue without interruption, unless 
necessitated by an adverse event.   
 
Patients will have labs, survey, and an office visit every 4 weeks, prior to administration 
of nivolumab.  Patients will have imaging scans completed every 3 months. 
 
If a CR is achieved, treatment duration for nivolumab and talazoparib will be continued 
until one year from CR. For PR or SD, patients will continue talazoparib 1mg daily and 
nivolumab 480mg every 4 weeks until disease progression, unacceptable toxicity, or for 24 
months of therapy. 
 


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Appropriate dose modification for talazoparib is described in Section 7.0 and 7.1 for renal 
impairment.  No dose modification is permitted for nivolumab.  Dose delays are permitted 
for talazoparib and nivolumab to manage toxicity. 
 
Reported adverse events and potential risks of talazoparib and nivolumab are described in 
Section 8.0.  
 
No investigational or commercial agents or therapies other than those described below may 
be administered with the intent to treat the subject's malignancy. 
 
6.1.1 Talazoparib Administration 
 
Subjects will take Talazoparib 1mg orally on Days 1-28 of each (28 day) cycle unless 
otherwise specified.. 
Patients should self-administer talazoparib orally QD, with or without food. The capsules 
should be swallowed whole with a glass of water without chewing, dissolving, or opening 
them prior to swallowing. 
 
Patients should be instructed to take talazoparib at approximately the same time each day 
and to not take more than the prescribed dose at any time. 
 
If a patient misses a day of treatment or vomits any time after taking a dose, he/she must 
be instructed not to “make it up” but to resume subsequent doses the next day as 
prescribed. 
 
Patients should complete the Dosing Diary after taking each dose. If the patient misses a 
day of treatment or takes a dose different than was prescribed, the reason for the missed 
dose or different dose must be recorded in the Dosing Diary. The Dosing Diary should be 
returned to the site at every cycle. 
 
6.1.2 Nivolumab Administration 
Subjects will receive Nivolumab 480mg on Day 1 of each (28 day) cycle. Nivolumab will 
be administered IV over 30 (+/- 5) minutes. 
 
6.4 
General Concomitant Medications and Supportive Care Guidelines 
 
The following medications are prohibited during the study: 
  
• Prednisone greater than 10 mg (except when used in the management of adverse 
events)  
• Any concurrent antineoplastic therapy for melanoma (ie, chemotherapy, extensive 
radiation therapy, or standard or investigational agents for treatment of 
melanoma).  
• P-gp inducers or BCRP inhibitors (Appendix 5; Section 16.5) 
 


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Because there is a potential for interaction of nivolumab and talazoparib with other 
concomitantly administered drugs through the cytochrome P450 system, P-gp or BCRP 
inhibitors, the case report form must capture the concurrent use of all other drugs, over-
the-counter medications, or alternative therapies. The Principal Investigator should be 
alerted if the subject is taking any agent known to affect or with the potential to affect 
selected CYP450 isoenzymes, P-gp or BCRP inhibitors. Please refer to Appendix 5; 
Section 16.5 for a complete list.  
 
Palliative (limited-field) radiation therapy is permitted, if all of the following criteria are 
met:  
▪ The lesion being considered for palliative radiation is not a target lesion.  
 
Subjects should receive full supportive care, including transfusions of blood and blood 
products, cytokines, antibiotics, antiemetics, etc. when appropriate. 
 
6.5 
Criteria for Removal from Study 
 
Patients will be treated per protocol until: 
 
• Disease progression, 
• Immune-related RECIST v1.1 will be used to guide treatment; if imaging shows 
progressive disease, patients can continue study treatment at the investigator’s 
discretion until confirmatory assessment by imaging ≥ 4 weeks later. 
 
• Intercurrent illness that prevents further administration of treatment, 
 
• The investigator considers the cessation of treatment, for safety reasons, to be in the best 
interest of the subject.  
 
• Unacceptable adverse event(s) (Defined as unacceptable treatment related toxicity, NCI 
CTCAE version 5.0 Grade 3 or 4 that fails to recover to < Grade 3 within 4 weeks), 
 
• Subject decision to withdraw from treatment (partial consent) or from the study (full 
consent), 
 
• Lost to follow-up 
 
• Pregnancy during the course of the study for a child-bearing participant, 
 
• Death, or 
 
• Sponsor reserves the right to temporarily suspend or prematurely discontinue this study. 
The date and reason for discontinuation must be documented. Every effort should be made 
to complete the appropriate assessments.  
 
6.5.1 Withdrawal of Consent 


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If the patient refuses further visits, the patient should continue to be followed for survival 
unless the patient withdraws consent for disclosure of future information or for further 
contact. In this case, no further study specific evaluations should be performed, and no 
additional data should be collected. The Sponsor may retain and continue to use any data 
collected before such withdrawal of consent. Subjects should notify the investigator in 
writing of the decision to withdraw consent from future follow-up, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is only from further receipt of investigational 
product (in which case the withdrawal of consent form is not applicable) or also from study 
procedures and/or posttreatment study follow-up (in which case a withdrawal of consent 
form should be provided and signed). In the event that vital status (whether the subject is 
alive or dead) is being measured, publicly available information should be used to 
determine vital status only as appropriately directed in accordance with local law. 
 
6.5.2 Lost to Follow-up 
If a patient does not return for a scheduled visit, every effort should be made to contact 
the patient and report their ongoing status. The Investigator should inquire about the 
reason for withdrawal, request that the patient return all unused talazoparib, request that 
the patient return for a final visit, if applicable, and follow-up with the patient regarding 
any unresolved AEs. 
 
 If it is determined that the patient has died, the site will use locally permissible methods 
to obtain the date and cause of death. The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to 
obtain updated contact information. If, after all attempts, the patient remains lost to 
follow-up, then the last-known-alive date as determined by the Investigator should be 
reported and documented in the patient’s medical records. 
 
6.6 
Duration of Follow Up 
Subjects will be followed for toxicity for 30 days after treatment has been discontinued or 
until death, whichever occurs first.  
 
The clinical course of each event will be followed until resolution, stabilization, or until it 
has been determined that the study treatment or participation is not the cause.  
 
Serious adverse events that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome. Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study 
participation will be recorded and reported immediately. 
 
7.0  
Dose Delays/Dose Modifications 
Following dosing interruption due to toxicity at any time in the study, the talazoparib 
dose may need to be reduced, based on the worst toxicity reported, when treatment is 
resumed. 
 
Dose reduction should be made in accordance with the guidance provided in Section 7.2. 


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CASE2619 Protocol v5 
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Dose reduction of talazoparib by 1 dose level at a time will be allowed depending on the 
type and severity of toxicity encountered. Doses less than 0.5 mg are not permitted. 
Patients unable to tolerate 0.5 mg QD, will be permanently discontinued from 
talazoparib, but may continue on single agent nivolumab. Dose reductions of nivolumab 
are not permitted, however dose delays are permitted.  Available dose levels for dose 
reductions for talazoparib are listed in Table 1. 
 
 
Once a dose has been reduced for a given patient, all subsequent cycles should be 
administered at that dose level, unless further dose reduction is required. Intra-patient 
dose re-escalation is not allowed. 
 
7.1 
Dose Modification for Talazoparib for Patients with Renal Impairment 
For patients with moderate renal impairment, defined as CLcr 30-59 mL/min, the 
recommended dose of Talazoparib is 0.75 mg once daily.  Please see Section 1.3.4 for 
more information. Also described in prescriber information/package insert. 
 
7.1.1 Dose Modification for Talazoparib for use with p-glycoprotein inhibitors 
If patients must be co-administered a p-gp inhibitor (amiodarone, carvedilol, 
clarithromycin, cobicistat, darunavir, dronedarone, erythromycin, indinavir, itraconazole, 
ketoconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir, 
saquinavir, telaprevir, tipranavir, valspodar, and verapamil), the talazoparib dose should 
be reduced to 0.75mg daily. 
 
7.2 Study Treatment Modifications for Nivolumab and Talazoparib Drug-Related 
Toxicity (excluding immune-related adverse events) 
 
Recommended nivolumab and talazoparib treatment modifications in case of 
investigational product (talazoparib) related toxicity is shown in Table 2. The specific 
guidelines are applicable in cases which can be attributed to one of the therapies. The 
instructions should be followed in the column regarding the therapy that toxicity is 
attributed to. In cases where an AE is possibly related to both drugs, the guidelines in 
both columns for both drugs should be followed. Patients who stop nivolumab or 
talazoparib for unacceptable toxicity may continue treatment with the drug that is not 
considered to be responsible for the toxicity observed. 
 
 
 


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CASE2619 Protocol v5 
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Table 2 
Treatment Modifications for Nivolumab and Talazoparib Drug-
Related Toxicity (excluding immune-related adverse events) 
 
Toxicity 
Talazoparib 
Nivolumab 
Hematologic Toxicities 
 
 
Grade 1 and Grade 2 
-No requirement for dose 
interruption or dose 
reduction. 
-Continue as per schedule. 
Anemia Grade ≥ 3 
(hemoglobin < 8g/dL) 
-Hold talazoparib and 
monitor weekly until 
resolve to baseline. 
-Talazoparib may be 
reduced by 1 dose level per 
section 7.0. 
-Permanently discontinue if 
persists for >4 weeks 
without recovery to 
baseline. Refer to 
hematologist for evaluation 
including assessment of 
possible MDS/AML. 
-Hold nivolumab. 
-Re-initiate nivolumab 
once toxicity Grade ≤ 1 or 
baseline. 
-Permanently discontinue 
nivolumab if toxicity does 
not resolve to Grade ≤ 1 or 
baseline within 12 weeks 
or if the same Grade 3 
toxicity recurs (if 
talazoparib had already 
been discontinued and 
recurrent event occurs on 
nivolumab only) 
Neutropenia Grade ≥ 3 
(ANC<1000/µL) 
-Hold talazoparib and 
monitor weekly until ANC 
≥1500/µL. 
-Resume talazoparib based 
on the following recovery 
times: 
• ≤1 week: No 
change. 
• >1 week: 
Talazoparib may be 
reduced by 1 dose 
level, per Section 
7.0. 
-Permanently discontinue 
talazoparib if persists for 
>4 weeks without recovery 
to ANC ≥1500/µL. Refer 
to hematologist for 
evaluation including 
assessment of possible  
MDS/AML. 
-Hold nivolumab. 
-Re-initiate nivolumab 
once toxicity Grade ≤ 1 or 
baseline. 
-Permanently discontinue 
nivolumab if toxicity does 
not resolve to Grade ≤ 1 or 
baseline within 12 weeks 
or if the same Grade 3 
toxicity recurs (if 
talazoparib had already 
been discontinued and 
recurrent event occurs on 
nivolumab only) 
Thrombocytopenia Grade 
≥ 3  
(platelets <50,000/µL) 
-Hold talazoparib and 
monitor weekly until 
platelets ≥75,000/µL. 
-Hold nivolumab. 


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CASE2619 Protocol v5 
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-Resume talazoparib based 
on the following recovery 
times: 
•  ≤1 week: No 
change. 
• >1 week: 
Talazoparib may be 
reduced by 1 dose 
level, per Section 
7.0. 
-Permanently discontinue 
talazoparib if persists for 
>4 weeks without recovery 
to platelets  ≥75,000/µL. 
Refer to hematologist for 
evaluation including 
assessment of possible  
MDS/AML 
 
-Re-initiate nivolumab 
once toxicity Grade ≤ 1 or 
baseline. 
-Permanently discontinue 
nivolumab if toxicity does 
not resolve to Grade ≤ 1 or 
baseline within 12 weeks 
or if the same Grade 3 
toxicity recurs (if 
talazoparib had already 
been discontinued and 
recurrent event occurs on 
nivolumab only) 
Non-hematologic 
Toxicities 
 
 
Grade 1 and Grade 2 
-No requirement for dose 
interruption or dose 
reduction. 
 
-Continue as per schedule. 
Grade 3 
-Hold talazoparib. 
Resume talazoparib 
reduced by 1 dose level if 
toxicity resolves to Grade 
≤1 or baseline within 4 
weeks. 
 
-Exceptions are: 
Nausea, vomiting, or 
diarrhea lasting ≤72 hours; 
fatigue lasting <5 days; 
hypertension controlled 
with medical therapy; 
increase in indirect 
bilirubin indicative of 
Gilbert’s syndrome; serum 
lipase or amylase lasting 
≤7 consecutive days 
without 
-Hold nivolumab. 
-Resume once toxicity is 
Grade ≤1 or baseline. 
-Permanently discontinue 
if toxicities does not 
resolve to grade ≤1 or 
baseline within 12 weeks 
or if the same Grade 3 
toxicity recurs. 
 
-Exceptions are: 
Laboratory values that do 
not have any clinical 
correlate. 
-For suspected immune-
related toxicities follow 
guidance in Section 7.4. 


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CASE2619 Protocol v5 
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clinical signs or symptoms 
of pancreatitis; 
endocrinopathies 
controlled with hormonal 
therapy; laboratory values 
that do not have any 
clinical correlate. 
-If the same Grade 3 
toxicity recurs, reduce by 1 
dose level. 
-Permanently discontinue if 
toxicity does not improve 
to Grade ≤1 or baseline 
within 4 weeks. 
 
-Exceptions are: 
Laboratory values that do 
not have any clinical 
correlate. 
-Permanently discontinue if 
Grade 3 liver test 
abnormality.  
-Re-challenge may be 
considered once toxicity is 
Grade ≤1 or baseline, if an 
alternative cause for the 
abnormal liver tests (ALT, 
AST, total bilirubin) is 
identified. 
-For suspected immune-
related toxicities due to 
nivolumab that require 
nivolumab delay or 
discontinuation, talazoparib 
should also be placed on 
hold until toxicity is Grade 
≤1 or baseline. 
Grade 4 
-Permanently discontinue 
talazoparib 
    -Exceptions are: 
     Laboratory values that     
    do not have any clinical    
    correlate.        
. 
 
-Permanently discontinue 
nivolumb. 
  -Exceptions are: 
Laboratory values that do 
not have any clinical 
correlate. 
-For suspected immune-
related toxicities follow 
guidance in Section 7.4. 


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Abbreviations: AML = Acute Myeloid Leukemia; ANC=Absolute Neutrophil Count; 
MDS=Myelodysplastic Syndrome. 
 
7.3 
Management of Nivolumab Related Infusion Reaction 
For management of nivolumab related infusion reaction, follow Institutional guidelines.  
 
In the absence of any such guidelines, or per provider discretion, apply the 
following:  
 
For Grade 1 symptoms: (Mild reaction; itching, rash, hives, fever, rigors): Stop the 
infusion, notify provider and study nurse. Initiate normal saline infusion at 500ml/hr, 
titrate up to maintain systolic BP >100. Administer diphenhydramine 50mg IV. Remain 
at bedside and monitor subject until recovery from symptoms.  
 
The following prophylactic pre-medications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) at least 30 minutes before additional nivolumab administrations.  
 
For Grade 2 symptoms: (Moderate reaction such as SOB, chest tightness, back pain, 
which requires therapy or infusion interruption but responds promptly to symptomatic 
treatment): Follow above for Grade 1 and add oxygen at 2L via nasal cannula and titrate 
to keep O2 saturation > 92%, and give hydrocortisone 100mg IVP once; remain at 
bedside and monitor subject until resolution of symptoms. If symptoms progress, do not 
re-dose medications already given, move on to treatment for severe / Grade 3 reactions. If 
the infusion is interrupted, then restart the infusion at 50% of the original infusion rate 
when symptoms resolve; if no further complications ensue after 30 minutes, the rate may 
be increased to 100% of the original infusion rate.  
 
Monitor subject closely. If symptoms recur, then no further nivolumab will be 
administered at that visit. Administer diphenhydramine 50 mg IV, and remain at bedside 
and monitor the subject until resolution of symptoms. The amount of study drug infused 
must be recorded on the electronic case report form (eCRF). The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or 
equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) should be administered 
at least 30 minutes before additional nivolumab administrations. If necessary, 
corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may 
be used.  
 
For Grade 3 or Grade 4 symptoms: (Severe reaction, anaphylaxis, bronchospasm, 
stridor, wheezing, respiratory distress, angioedema, systolic BP < 80mm Hg, or LOC. 
Grade 3: prolonged [ie, not rapidly responsive to symptomatic medication and/or brief 
interruption of infusion] recurrence of symptoms following initial improvement; 
hospitalization indicated for other clinical sequelae [eg, renal impairment, pulmonary 
infiltrates]). Grade 4: (life threatening; pressor or ventilatory support indicated): 
Immediately discontinue infusion of nivolumab. Follow guidelines for Grades 1 and 2 
and add the following: Activate emergency response team as appropriate. Administer 


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CASE2619 Protocol v5 
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medications from Grade 1 and 2 reaction guidelines if not yet given and add Epinephrine 
0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 
1:10,000 solution.  
 
Subject should be monitored until the investigator is comfortable that the symptoms will 
not recur. Nivolumab will be permanently discontinued. 
 
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritis within 1 week after treatment), symptomatic treatment may be given (eg, 
oral antihistamine, or corticosteroids). 
 
7.4 
Immune-Related Adverse Events Toxicity Management 
 
For patients receiving nivolumab, any AE suspected to be immune-related (irAE) should 
be managed according to the guidance for management of irAEs per ASCO guidelines.47  
 
Treatment of irAEs is mainly dependent on severity (NCI CTCAE v5.0 grade), 
management summarized per ASCO guidelines below: 
 
• Grade 1: continue nivolumab with close monitoring. 
 
• For grade 2 toxicities, hold nivolumab.  Consider resuming when symptoms 
and/or laboratory values revert to grade 1 or less.  Corticosteroids (initial dose of 
0.5 to 1 mg/kg/day of prednisone or equivalent) may be administered. 
 
• Grades 1 to 2 (persistent): manage similar to Grades 3 to 4 AE. 
 
• Grades 3 to 4: treat with high dose corticosteroids; if suspected to be related to 
nivolumab, talazoparib should be withhold until toxicity resolves to Grade ≤1 or 
baseline. 
 
• For Grade ≥3 immune-related toxicities suspected to be related to nivolumab, 
talazoparib should be withheld until toxicity resolves to Grade ≤1 or baseline. 
Nivolumab should be held for grade 3 toxicities and high-dose corticosteroids 
(prednisone 1 to 2mg/kg/day or methylprednisolone IV 1 to 2mg/kg/day).  
Corticosteroids should be tapered over the course of at least 4-6 weeks.  If 
symptoms do not improve with 48-72 hours of high-dose corticosteroid, 
infliximab may be offered for some toxicities. 
 
• Grade 4 toxicities warrant permanent discontinuation of nivolumab, with the 
exception of endocrinopathies that have been controlled by hormone replacement. 
 
 
 
 
Table 3.   Treatment Modification for irAEs Associated with Nivolumab 


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CASE2619 Protocol v5 
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Toxicity 
Hold 
Treatment for 
Grade 
Timing for 
Restarting 
Treatment 
Treatment 
Discontinuation 
Diarrhea/Colitis 
 
2 - 3 
Toxicity resolves to 
Grade 0-1. 
Toxicity does not 
resolve within 12 
weeks of last dose or 
inability to reduce 
corticosteroid to10 mg 
or less of prednisone or 
equivalent per day 
within 12 weeks. 
4 
Permanently 
discontinue. 
Permanently 
discontinue. 
Pneumonitis 
2 
Toxicity resolves to 
Grade 0-1. 
Toxicity does not 
resolve within 12 
weeks of last dose or 
inability to reduce 
corticosteroid to10 mg 
or less of prednisone or 
equivalent per day 
within 12 weeks. 
3-4 
Permanently 
discontinue. 
Permanently 
discontinue. 
AST, ALT, or 
increased 
bilirubin 
2 
Toxicity resolves to 
Grade 0-1. 
Toxicity does not 
resolve within 12 
weeks of last dose. 
3-4 
Permanently 
discontinue. 
Permanently 
discontinue. 
Type 1 diabetes 
mellitus (if new 
onset) or 
hyperglycemia 
T1DM or 3-4 
Hold nivolumab for 
new onset T1DM or 
Grade3-4 
hyperglycemia 
associated with 
evidence of beta cell 
failure. 
Resume nivolumab 
when patients are 
clinically and 
metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to 
Grade 0-1.  Therapy 
with nivolumab can be 
continued while 
endocrine replacement 
therapy is instituted. 
Toxicity does not 
resolve within 12 
weeks of last dose or 
inability to reduce 
corticosteroid to10 mg 
or less of prednisone or 
equivalent per day 
within 12 weeks. 
Hyperthyroidism 3 
Toxicity resolves to 
Grade 0-1. 
Toxicity does not 
resolve within 12 
weeks of last dose or 


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CASE2619 Protocol v5 
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inability to reduce 
corticosteroid to10 mg 
or less of prednisone or 
equivalent per day 
within 12 weeks. 
4 
Permanently 
discontinue. 
Permanently 
discontinue. 
Hypothyroidism 
 
Therapy with 
nivolumab can be 
continued while 
thyroid replacement 
therapy is instituted. 
Therapy with 
nivolumab can be 
continued while thyroid 
replacement therapy is 
instituted. 
Renal failure or 
nephritis 
2 
Toxicity resolves to 
Grade 0-1. 
Toxicity does not 
resolve within 12 
weeks of last dose or 
inability to reduce 
corticosteroid to10 mg 
or less of prednisone or 
equivalent per day 
within 12 weeks. 
3-4 
Permanently 
discontinue. 
Permanently 
discontinue. 
Myocarditis 
1-2 
Toxicity resolves to 
Grade 0-1. 
Toxicity does not 
resolve within 12 
weeks of last dose or 
inability to reduce 
corticosteroid to10 mg 
or less of prednisone or 
equivalent per day 
within 12 weeks. 
3-4 
Permanently 
discontinue. 
Permanently 
discontinue. 
All other 
immune-related 
AEs1 
3 or severe 
Toxicity resolves to 
Grade 0-1 
Toxicity does not 
resolve within 12 
weeks of last dose or 
inability to reduce 
corticosteroid to10 mg 
or less of prednisone or 
equivalent per day 
within 12 weeks. 
4 
Permanently 
discontinue. 
Permanently 
discontinue. 
Abbreviations:  AE = Adverse Event; T1DM = Type 1 diabetes mellitus 
1Patients with intolerable or persistent Grade 2 drug-related AE may hold study 
medication at provider discretion.  Permanently discontinue study drug for persistent 


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Grade 2 adverse reactions for which treatment with study drug has been held, that do not 
recover to Grade 0-1 within 12 weeks of the last dose. 
 
 
 
8.0 
Adverse Events and Potential Risks  
 
8.1 
Talazoparib 
  
A comprehensive list of all reported adverse events and any potential risks for talazoparib 
seen alone or in combination with nivolumab is detailed in Section 7.2. The recommended 
treatment and clinical management for the commonly occurring events is outlined in 
Section 7.2.   
 
8.2 
Definitions  
 
8.2.1 
Adverse Event   
An adverse event (AE) is any unfavorable or unintended event, physical or psychological, 
associated with a research study, which causes harm or injury to a research participant as 
a result of the participant’s involvement in a research study. The event can include 
abnormal laboratory findings, symptoms, or disease associated with the research study. 
The event does not necessarily have to have a causal relationship with the research, any 
risk associated with the research, the research intervention, or the research assessments.  
 
Adverse events may be the result of the interventions and interactions used in the research; 
the collection of identifiable private information in the research; an underlying disease, 
disorder, or condition of the subject; and/or other circumstances unrelated to the research 
or any underlying disease, disorder, or condition of the subject.  
 
8.2.2   Serious Adverse Events  
A serious adverse event (SAE) is any adverse experience occurring at any dose that results 
in any of the following outcomes:  
• Results in death.  
• Is a life-threatening adverse experience.  The term life-threatening in the 
definition of serious refers to an adverse event in which the subject was at risk 
of death at the time of the event.  It does not refer to an adverse event which 
hypothetically might have caused death if it were more severe.  
• Requires 
inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization.  Any adverse event leading to hospitalization or prolongation 
of hospitalization will be considered as Serious, UNLESS at least one of the 
following expectations is met: 
o The admission results in a hospital stay of less than 24 hours OR 
o The admission is pre-planned (e.g., elective or scheduled surgery 
arranged prior to the start of the study) OR 


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o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care. 
However it should be noted that invasive treatment during any hospitalization may 
fulfill the criteria of “medically important” and as such may be reportable as a 
serious adverse event dependant on clinical judgment.  In addition where local 
regulatory authorities specifically require a more stringent definition, the local 
regulation takes precedent.  
• Results in persistent or significant disability/incapacity.  The definition of 
disability is a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
• Is a congenital anomaly/birth defect.  
• Is an important medical event.  Important medical events that may not result 
death, be life-threatening, or require hospitalization may be considered a serious 
adverse experience when, based upon appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood disease or disorders, or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency 
or drug abuse. The development of a new cancer is always considered an 
important medical event. 
 
For the purpose of this study the following events would not be considered adverse 
events and would not be recorded in the database: 
• Abnormal laboratory findings considered associated to the original disease 
 
8.2.3 Adverse Event Evaluation  
The investigator or designee is responsible for ensuring that all adverse events (both serious 
and non-serious) observed by the clinical team or reported by the subject which occur after 
the subject has signed the informed consent are fully recorded in the subject’s medical 
records. Source documentation must be available to support all adverse events.  
 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study, requiring treatment or causing apparent clinical manifestations, 
result in a delay or dose modification of study treatment, or judged relevant by the 
investigator), should be reported as an adverse event.   
 
The investigator or sub-investigator (treating physician if applicable) will provide the 
following for all adverse events (both serious and non-serious): 
• Event term (as per CTCAE) 
• Description of the event 
• Date of onset and resolution 
• Expectedness of the toxicity 
• Grade of toxicity  
• Attribution of relatedness to the investigational agent- (this must be assigned 


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by an investigator, sub-investigator, or treating physician) 
• Action taken as a result of the event, including but not limited to; no changes, dose 
interrupted, reduced, discontinued, etc. or action taken with regard to the event, i.e. 
no action, received conmed or other intervention, etc. 
• Outcome of event 
 
Descriptions and grading scales found in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting.  
 
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the 
subject. The event is usually listed in the Investigator Brochure, consent form or research 
protocol.  
 
An unexpected adverse event is an adverse event not previously known or anticipated to 
result from the research study or any underlying disease, disorder, or condition of the 
subject.  
 
Attribution is the relationship between an adverse event or serious adverse event and the 
study drug.  Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study drug. 
• Probable – The AE is likely related to the study drug. 
• Possible – The AE may be related to the study drug. 
• Unlikely – The AE is doubtfully related to the study drug. 
• Unrelated – The AE is clearly NOT related to the study drug. 
 
Protocol must specify if attribution is required for individual components of the treatment 
regimen or the treatment regimen as a whole. 
 
8.3  
SAE Report Form 
SAEs will be recorded on the FDA Form 3500A (MedWatch) but should only be reported 
as instructed below.  The electronic FDA SAE reporting forms should not be used.   
 
8.4  
Reporting Procedures for Serious Adverse Events 
For the purposes of safety reporting, all adverse events will be reported that occur on or 
after Cycle 1 Day 1 through 30 days after the final dose of study drug. Adverse events, 
both serious and non-serious, and deaths that occur during this period will be recorded in 
the source documents. All SAEs should be monitored until they are resolved or are clearly 
determined to be due to a subject’s stable or chronic condition or intercurrent illness(es). 
Related AEs will be followed until resolution to baseline or grade 1 or stabilization. 
Planned surgeries or in-patient procedures are not considered SAEs. 
 
8.4.1 SAE Reporting Requirements 
• Participating investigators (all sites) must report all serious adverse events to the 
Lead Site Principal Investigator (e.g. Sponsor-Investigator) within 24 hours of 


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discovery or notification of the event. The participating investigator must also 
provide follow-up information on the SAE until final resolution.  
o Send all SAE medwatch forms to the Dr. James Isaacs(isaacsj3@ccf.org) 
and to cancersaeinbox@ccf.org. Please cc the lead study coordinator 
within 24 hours of discovery/notification of the event. 
• The Lead Site Principal Investigator will review the SAE and report the event to 
the FDA, Pfizer, and IRB as applicable. 
o External sites are responsible for reporting SAEs to their local IRB per their 
local policies 
• It is the Sponsor-Investigator’s responsibility (e.g. lead site PI) to ensure that ALL 
serious adverse events that occur on the study (e.g. ALL SAEs that occur at each 
enrolling institution) are reported to all participating sites. 
 
Pfizer, Inc. Reporting Requirements:  
• AE reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.  
 
Institutional Review Board Reporting Requirements: 
• Investigative sites will report adverse events to their respective IRB according to 
the local IRB’s policies and procedures in reporting adverse events.  
 
8.5 
SAEs and OnCore 
• All SAEs will be entered into Overture™ and OnCore.  A copy of the SAE form(s) 
submitted to the sponsor-investigator is also uploaded into OnCore. 
 
8.6  
Data Safety and Toxicity Committee 
It is the responsibility of each site PI to ensure that ALL SAEs occurring on this trial 
(internal or external) are reported to the Case Comprehensive Cancer Center’s Data and 
Safety Toxicity Committee. This submission is simultaneous with their submission to the 
sponsor and/or other regulatory bodies.  
 
The sponsor-investigator is responsible for submitting an annual report to the DSTC as per 
CCCC Data and Safety Monitoring Plan. 
  
8.7 
Data and Safety Monitoring Plan (DSMP) 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data 
and Safety Monitoring Plan in accordance with NCI guidelines.  
 
9.0 
PHARMACEUTICAL INFORMATION  
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 7.2.  
 
9.1 Investigational Agent 
9.1.1  Name of Agent 
_______Talazoparib_________ 
 


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Other Names:   
_______Talzenna___________ 
 
Talazoparib will be provided by Pfizer. Talazoparib will be supplied as 0.25mg and 1mg 
capsules.  
Medication labels will comply with US legal requirements and be printed in English. 
They will supply no information about the patient.  
 
Talazoparib should be stored at 15°C–30°C; 59°F–86°F) or per approved local label. All 
excursions should be brought to the Sponsor-Investigator’s and Pfizer’s attention for 
assessment and authorization for continued use. Ensure that the drug is used before the 
retest expiry date provided by Pfizer.  
 
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration. Study drug will be administered only to eligible patients under 
the supervision of the investigator or identified sub investigator(s). During the study, 
Talazoparib will be administered orally as 1mg every 24 hours. Patients should be 
instructed to take their Talazoparib at about the same time each day with or without food. 
The capsules should be swallowed whole and must not be opened or dissolved. The 
investigator should instruct the patient to take the study drug exactly as prescribed (promote 
compliance). All dosages prescribed and dispensed to the patient and all dose changes 
during the study should be recorded.  
 
If the patient forgets to take his/her dose, the dose is not made up, but is instructed to 
resume subsequent doses the next day as prescribed. 
 
Drug Accountability:  
The investigator or designated study personnel are responsible for maintaining accurate 
dispensing records of the study drug. All study drugs must be accounted for, including 
study drug accidentally or deliberately destroyed. Under no circumstances will the 
investigator allow the investigational drug to be used other than as directed by the protocol. 
If appropriate, drug storage, drug dispensing, and drug accountability may be delegated to 
the pharmacy section of the investigative site.  
 
Drug Destruction:  
At the completion of the study, there will be a final reconciliation of drug shipped, drug 
consumed, and drug remaining. This reconciliation will be logged on the drug 
reconciliation form, signed and dated. Any discrepancies noted will be investigated, 
resolved, and documented prior to return or destruction of unused study drug. Drug 
destroyed on site will be documented in the study files. 
 
9.2  
Commercial Agent 
9.2.1  Name of Agent 
________Nivolumab___________ 
 
Other Names:   
________Opdivo______________ 
 


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Nivolumab will be obtained from commercial sources. Nivolumab will be supplied as a 
clear to opalescent, colorless to pale-yellow solution in a vial.  
 
Medication labels will comply with US legal requirements and be printed in English. They 
will supply no information about the patient.  
To prepare the infusion, withdraw the required volume of nivolumab and transfer into an 
intravenous container.  Dilute nivolumab with either 0.9% sodium chloride injection, USP 
or 5% dextrose injection, USP to prepare an infusion with a final concentration ranging 
from 1mg/mL to 10mg/mL.  The total volume of infusion must not exceed 160 mL.  For 
adult and pediatric patients with body weights less than 40 kg, the total volume of infusion 
must not exceed 4mL/kg of body weight.  Mix diluted solution by gentle inversion.  Do 
not shake.  Discard partially used vials or empty vials of nivolumab.  After preparation, 
store nivolumab infusion either at room temperature for no more than 8 hours from the 
time of preparation.  This includes room temperature storage of the infusion in the IV 
container and time for administration of the infusion, or under refrigeration at 2°C to 8°C 
(36°F-46°F) for no more than 24 hours from the time of infusion preparation.  Do not 
freeze.  
 
All excursions should be brought to the Sponsor-Investigator’s attention for assessment 
and authorization for continued use. Ensure that the drug is used before the retest expiry 
date provided by BMS.  
 
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration. Study drug will be administered only to eligible patients under 
the supervision of the investigator or identified sub investigator(s). During the study, 
nivolumab will be administered intravenously as 480mg every 4 weeks (28 days).  
Administer the infusion over 30 (+/- 5 minutes) minutes through an IV line containing a 
sterile, no-pyrogenic, low protein binding, in-line filter (pore size of 0.2-1.2 micrometers).  
Do not coadminister other drugs through the same IV line.  Flush the IV line at the end of 
infusion. All dosages prescribed and dispensed to the patient and all dose changes during 
the study should be recorded.  
 
Nivolumab is considered standard of care therapy.  Financial responsibility for nivolumab 
should be that of insurance company.  If insurance company is not responsible, then the 
cost of this agent will be the subject’s responsibility.  
 
10.0 
CORRELATIVE STUDIES 
 
10.1 
Anti-Tumor Response by TILs and PD-L1 Expression 
 Assess anti-tumor response by measure of immune-infiltration of cells to include, but not 
limited to, CD8, CD4, Treg (FOXP3), NK cells (CD56), MDSCs into tumors, and PD-L1 
expression on tumor by multiplex immunofluorescence, flow cytometry and 
immunohistochemistry on tumor biopsies and serum samples at baseline, 12 weeks, and 
at progression.  As additional clinical and medical knowledge is learned from this study, 
additional analysis may be performed on prior collected blood and tissue specimens. 
 


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10.1.1 Background  
Immunotherapy such as nivolumab functions to modulate the immune microenvironment. 
CD8+, CD4+ T cells, regulatory T cells (Tregs), Natural Killer cells (NK), among others 
are important contributors both to the function of and resistance to targeted therapy and 
immunotherapy.48 The tumor microenvironment as well as the peripheral blood are 
dynamic and subject to change based on changes in tumor burden and therapy. There is 
need for prospective data demonstrating correlations between changes in peripheral blood 
and changes in the tumor microenvironment. The goal of this study is to evaluate the 
hypothesis that changes in the type and behavior of immunomodulatory cells in the 
peripheral blood will reflect tumor burden and that such changes will impact tumor burden 
and response while on therapy with nivolumab and talazoparib.  Additionally, this study 
will further investigate the preclinical findings that PARP inhibitor-mediated DNA damage 
has been shown to increase the immunogenicity of tumor cells by promoting T cell and NK 
cell infiltration.21  
 
10.1.2   Rationale for Analysis 
Identifying an immunomodulatory effect by analyzing tumor infiltrating lymphocytes 
circulating immune cells will help identify patients that would respond better to 
combination therapy and decrease tumor burden.  Please see section 14 for analysis plan. 
 
10.1.3 Collection of Specimens 
Tumor biopsies (fresh frozen preferred; however, FFPE acceptable if fresh frozen not 
available) and peripheral blood samples (peripheral blood mononuclear cells (PBMC)) will 
be collected prior to treatment (at time of enrollment, or archival FFPE tumor tissue), at 12 
weeks (+/- 1 week) at time of imaging, and at time of progression will be collected.  See 
Section 11.0. Blood samples at each time point will be drawn into two 8 ml heparinized 
(green top) tubes and two 4.5 mL Na Citrate tubes. PBMCs will be isolated by Ficoll 
separation method. For fresh frozen tumor biopsies, submission of 3-4 grams of tissue 
(equivalent of 2 to 3 passes of tissue, or 3-4 core biopsies) is preferred. For FFPE tissue, 
submission of 12-15 slides of 10µm thickness preferred; however, if unable to obtain, 12 
slides of 10µm thickness or what is able to be obtained is sufficient.  
 
10.1.4 Handling of Specimens 
De-identify the specimen using a code specific for this trial and transport the specimen to 
 lab at the Cleveland Clinic. 
 
Cleveland Clinic Lerner Research Institute 
Tissue Processing and Immune Monitoring Lab 
Attn: 
 
2111 E. 96th Street, 
 
Cleveland, OH 44106  
Telephone: 
  
E-mail: 
 
 
10.1.5 Analytical Laboratory 


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The specimens will be analyzed in the laboratory of Dr. Marcela Diaz-Montero at the 
Cleveland Clinic of Case Comprehensive Cancer Center. Dr. Marcela-Diaz will provide 
overall guidance on experimental design and interpretation of results. Personnel in her 
laboratory will perform all staining, cytometry and analysis. Plasma and serum will also be 
frozen and stored for future analyses.  Address is listed in 10.1.4. 
 
10.1.6   Methods  
Flow cytometry, TCR repertoire, and single cell sequencing. 
 
10.2 
Analysis of Longitudinal Genomic Evolution 
Assess longitudinal genomic evolution by sequencing at baseline, at 12 weeks, and at 
progression to evaluate DNA landscape and its correlation to response.  As additional 
clinical and medical knowledge is learned from this study, additional analysis may be 
performed on previously collected blood and tissue specimens. 
 
10.2.1 Background  
This study intends to characterize the activity of nivolumab in combination with 
talazoparib, with the aim of increasing the clinical benefit seen historically with single 
agent nivolumab. A key mechanistic hypothesis underpinning the combination is that 
increased DNA damage and cell death mediated by talazoparib will lead to enhanced 
immune priming and tumor immunogenicity, enabling a more effective anti-tumor immune 
response to be promoted by nivolumab. Given this hypothesis, one subgroup of patients 
likely to benefit from the combination will be those whose tumors are most sensitive to 
talazoparib-mediated cell death and DNA damage.  Several biomarkers have the potential 
to identify patients with such increased sensitivity to talazoparib, one of these will be 
employed in the context of this study, the presence of pathogenic or likely pathogenic 
germline or somatic defects in a panel of DDR genes.46 Whole exome sequencing of tumor 
tissue prior to initiation of treatment, after treatment, and at progression will identify 
mutational load while on therapy.  The combination of talazoparib and nivolumab will 
increase DSBs and therefore increase levels of fragmented DNA both in the tumor and 
PBMCs, likely results in changes in mutational burden.  This was shown in prior in vitro 
and in vivo studies.49  If patients who respond to combination therapy are shown to have a 
higher tumor mutational burden, this would confirm mechanistic action of this combination 
and could generate hypothesis to further explore this combination in studies without 
mutations in BRCA1/2 or BRCA-ness and more cancer patients could potentially derive 
benefit from this combination therapy. 
 
10.2.2 Rationale for Analysis 
Discussed in Section 10.2.1 and Section 14. 
 
10.2.3 Collection of Specimens 
See Section 10.1.3. 
 
10.2.4 Handling of Specimens 
All specimens are to be shipped to the lab of Dr. Marcela-Diaz.  
 


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10.2.5 Analytical Laboratory 
Specimens will be analyzed in the lab of Dr. Marcela-Diaz. 
 
10.2.6 Methods 
DNA and RNA sequencing by NGS. 
 
10.3. Assessment of Patient Reported Outcomes for Adverse Events 
Assess patient reported outcomes for adverse events, as measured by PRO-CTCAE while 
on combination therapy at baseline and before each cycle (every 4 weeks) of nivolumab 
for a period of 12 months. 
 
 
 
10.3.1 Background  
 
Immunotherapy has transformed treatment for melanoma. A better understanding of 
toxicities, long-term effects of immunotherapy, and effect on patient’s quality of life is 
needed, especially when introducing a second anti-cancer agent to immunotherapy.  
Patient-reported outcomes (PRO’s) can help show clinical benefit in reducing disease 
related symptoms, provide more accurate estimates of toxicity, help model treatment costs 
and improve symptom management.  PRO-CTCAE provides a systematic yet flexible tool 
for descriptive reporting of symptomatic treatment side effects in clinical trials. PRO-
CTCAE can be used and reported in conjunction with the CTCAE reports gathered by 
clinicians. It provides additional information that is complementary to existing safety and 
tolerability assessments reported by clinicians using the CTCAE. 
 
10.3.2 Rationale for Analysis 
Discussed in Section 14. 
 
10.3.3 Collection of PRO-CTCAEs 
Surveys will be administered to patients beginning prior to treatment (baseline), and every 
12 weeks (at time of imaging and office visit) after treatment initiation. 
 
10.3.4 Handling of PRO-CTCAEs 
Surveys will be de-identified and sent electronically by secure email or postal mail to the 
study coordinator at the lead institution (address listed on first page of document) every 
three months until the end of the trial.  During the trial, the study coordinator at each 
institution will be responsible for maintaining the PRO-CTCAE surveys. 
 
10.3.5 Analytical Laboratory 
N/A.  
 
10.3.6 Methods 
Utilize PRO-CTCAE form designed by NCI. The National Cancer Institute's PRO-CTCAE 
measurement system was developed as a companion to the Common Terminology Criteria 
for Adverse Events (CTCAE). It is not intended to be used as a stand-alone patient-reported 


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outcome. The current standard for grading and reporting all AEs in cancer clinical trials, 
including symptomatic AEs, is clinician grading using the CTCAE.  The PRO-CTCAE 
measurement system includes an item library of 124 discrete items representing 78 
symptomatic toxicities drawn from the CTCAE. As such, it provides a systematic yet 
flexible approach to capture symptomatic adverse events in trials of new cancer therapies. 
Custom PRO-CTCAE form is in Appendix 16.7.  
10.4 Additional correlative analysis, including, but not limited to, analysis of STING 
pathway on prior collected tissue and blood specimens to evaluate effects on 
immunogenicity of combination therapy; circulating tumor DNA (ctDNA) 
measurements, and copy number variation to evaluate their association with 
response to treatment.   
10.4.1 Collection of Specimens 
Blood will be collected in four 10mL Streck tubes for cell free DNA analysis at 
each of the following time points: before treatment initiation, at Cycle 2 Day 1 of 
nivolumab, at Cycle 3 Day 1, and at progression. 
10.4.2 Handling of Specimens 
 
All specimens are to be shipped to the lab of Dr. Marcela-Diaz.  
 
10.4.3 Analytical Laboratory 
Specimens will be analyzed in the lab of Dr. Marcela-Diaz. 
 
11.0  STUDY PARAMETERS AND CALENDAR  
 
11.1 
Study Parameters 
Serum Chemistry:  
Calcium, Chloride, Potassium, Sodium, Bicarbonate, Aspartate aminotransaminase, 
Alanine 
aminotransaminase, 
Alkaline 
Phosphatase, 
Total 
Bilirubin, 
Lactate 
dehydrogenase, Creatinine, Blood urea nitrogen (BUN), Glucose, Albumin, Total protein, 
creatine kinase 
  
*Note for serum chemistries: Tests for AST, ALT, ALP and total bilirubin must be 
conducted concurrently and assessed concurrently.   
  
Hematology: White blood cell (WBC) count with differential, Red blood cell count, 
Hematocrit, Hemoglobin, Platelet count, Mean corpuscular volume (MCV), Mean 
corpuscular hemoglobin concentration (MCHC)  
 
Coagulation factors: Prothrombin time, activated partial thromboplastin time, international 
normalized ratio (INR) 
  


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Urinalysis: Color, Appearance, Specific Gravity, pH, Protein, Glucose, Ketones, Blood, 
Bilirubin. Microscopy including WBC/High power field (HPF), RBC/HPF if clinically 
indicated  
 
11.1.1 Screening Evaluation  
Screening studies and evaluations will be used to determine the eligibility of each subject 
for study inclusion. Patients will have somatic or germline testing done and known 
mutational status prior to enrollment in this study.  All screening evaluations, which include 
procedures listed below, must be completed within 4 weeks (28 days) prior to 
administration of protocol therapy unless otherwise noted 
 
Pretreatment (or screening) Visit  
The following procedures and assessments will be completed during pretreatment visit: 
• Review of medical history, including cancer history and any prior testing 
regarding cancer-related genes. 
• Review of all of the medications taken for the past month.  
• Discuss contraception (birth control).  
• Record height and weight.  
• Physical examination by provider. 
• Record blood pressure, heart rate and body temperature.  
• Assess performance status.  
• Have blood drawn for following:  
o To assess kidneys, liver, coagulation, bone marrow and thyroid function  
o To test for HBV, HCV 
o To be used for correlatives 
o CK 
• Urinalysis 
• βHCG – for WOCBP only 
• Imaging (CT scan, PET scan, MRI) of all tumors present. Scans must be done ≤4 
weeks (28 days) prior to administration of protocol therapy.    
• A tumor biopsy is needed by the time of starting this study to determine if the 
patient has a mutation in BRCA/BRCAness.  Biopsy and germline sequencing does 
not have to be completed within the 28 day screening period. 
• Tumor biopsy for correlative samples is optional. If patient has an archival biopsy 
prior to starting this study, this biopsy can be used for the screening correlative 
sample.  
 
11.1.2 Treatment Period 
The treatment period is a total of 24 months (26 cycles) maximum for each patient. If a 
patient achieves a CR, the patient will continue treatment for 12 months from the date of a 
confirmed CR (unless the 26 cycles comes first). Patients with stable disease or partial 
response, will continue on therapy for the full duration of the 24 months.  
 
Study Treatment (Cycle 1 Day 1) 
On the day study treatment is started, the following will be done: 


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• Discuss any cancer-related symptoms (such as fatigue, shortness of breath, pain, 
etc.) that patient has been experiencing for the 2 weeks prior to this day.  
• Discuss contraception  
• Record weight.  
• Complete a survey reporting any cancer-related symptoms (PRO-CTCAE) 
• Physical examination by provider  
• Record blood pressure, heart rate and your temperature.  
• Assess performance status 
• Have blood drawn for chemistry, CBC, LDH, CK, PT/PTT 
• The research center staff will give one bottle of talazoparib that contains enough 
capsules for at least 1 cycle of treatment.  
• Administer nivolumab intravenously at a standard dose of 480 mg over 30 (± 5) 
minutes.  
• Assess adverse events.  
 
These same steps will occur every cycle (every 4 weeks). Patient will need to be seen on 
Day 1 (±3 day) of each cycle. Nivolumab will be administered every 4 weeks (28±3 
days). 
 
At All Day 1 Visits: 
• Return the Dosing (Pill) Diary and any leftover talazoparib capsules in the bottle 
to the research center.  
• Discuss contraception (birth control) that is being used.  
• Record weight.  
• Complete a survey reporting any side effects of the treatment drugs (PRO-
CTCAE) 
• Interval history, vitals, and physical examination by provider.  
• Assess performance status.  
• Have blood drawn for chemistry, CBC, LDH, CK  
• Assess adverse events. 
 
At Cycle 3 Day 1 (±3 days) 
Procedures and lab tests listed above in: “At All Day 1 Visits.”  Additional procedures 
will include: 
• Have blood drawn for correlatives 
• Imaging (CT scan or PET scan, MRI if needed) of all body sites of tumor(s). This 
will be performed every 3 months (or about every 3 cycles) until progression. 
• Optional tumor biopsy for correlatives (to assess TILs and TMB) 
• Assess adverse events. 
 
End of Treatment Visit 
End of Treatment visit should occur within one week of the last treatment dose. Adverse 
events will be assessed. 
• Return the Dosing (Pill) Diary and any leftover talazoparib capsules in their bottle 
to the research center.  


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• Assess adverse events. 
• Discuss contraception being used.  
• Record weight.  
• Complete a survey reporting any side effects of the treatment drugs (PRO-
CTCAE) 
• Physical examination by provider.  
• Record blood pressure, heart rate and body temperature.  
• Assess performance status. 
• Have blood drawn for chemistry, CBC, LDH, CK  
• Imaging (CT scan or PET scan, MRI if needed) of all of your tumors may need to 
be performed, depending on the date of last scans.  
•  If patient progressed, will have a serum sample collected an optional tumor 
biopsy for correlative analysis  
 
Discontinuation 
If a patient progresses while on active treatment, the patient will come off treatment per 
physician discretion. Once off active treatment, the patient will come in for the 30 (± 7) 
day follow up/Off Study visit for safety evaluation per follow-up visit guidelines below. 
The patient will then be considered off study. Correlative samples should be collected for 
patients who progress while on treatment or during follow-up. 
 
If a patient ends treatment due to unacceptable toxicities per physician discretion, the 
patient will continued to be followed per the follow up guidelines below until the start of 
new anti-cancer therapy at which point the patient will be considered off study.  
 
Follow-Up Visits  
The first follow up visit will occur at 30 (± 7) days after last dose of study treatment. The 
remaining follow up visits will occur every 90 (± 7) days post last dose of study treatment 
for a total of 24 months in follow up. Patients that progress during the follow up phase 
will no longer be followed for the study.  
 
The following assessments will be completed: 
• Interval history, vitals including weight, and physical examination by provider.  
• Assess performance status.  
• Have blood drawn for chemistry, CBC, LDH, CK, and correlatives (if necessary).  
• Imaging (CT scan or PET scan, MRI if needed) of all body sites of tumor(s).  
• Complete a survey reporting any side effects of the treatment drugs (PRO-
CTCAE) 
• Assess adverse events. 
 
11.2 
Calendar  
Treatment cycles are 28 days long.  Screening studies are to be conducted within 28 days 
prior to administration of protocol therapy.  
 
A visit window of ±3 days is allowed for all labs and scans. 


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A visit window of ±3 days is allowed for treatment. 
A visit window of ±7 days is allowed for 3 month follow-up visits 
 
 
 




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CASE2619 Protocol v5 
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1. Pretreatment visit procedures must be completed within 28 days of Cycle 1 Day 1 
visit unless specifically stated otherwise 
2. Should occur within 7 days of discontinuation of study drug. 
3. Should occur within 30 (±7) days of last dose of drug. 
4. Patients will continue to be followed for 2 years after the last dose of treatment or 
until progression or until new anti-cancer treatment is initiated. Visits will be every 
90 (±7) days from the date of last dose of study drug.  
5. Vital signs to include temperature, pulse, respiratory rate, and blood pressure 
6. Somatic/Germline Mutation Testing for BRCA/BRCA-ness does not need to be 
completed in 28-day pre-treatment window, as long as it is completed before 
study enrollment.  
7. Includes HBV surface antigen and anti-HCV antibody test. If anti-HCV is 
positive, HCV RNA test must be performed 
8. Only needed for patients who are WOCBP 
9. Correlative Studies are only needed at screening, C3D1 (±3 days) and at 
progression, if that occurs (not needed at EOT unless patient has evidence of PD). 
With exception of correlative studies for ctDNA and CNV, which are also needed 
at C2D1 in addition to above time points. 
10. Tumor specimens are optional. 
 
12.0  MEASUREMENT OF EFFECT  
Patients must have measurable disease at screening and will be evaluated for response on the 
basis of RECIST criteria version 1.1 (Appendix 1; Section 16.1) and immune-related RECIST 
criteria (Appendix 2; Section 16.2). Tumor measurements using physical examination, spiral 
CT scan, PET/CT and/or MRI or other appropriate techniques deemed suitable by the 
investigator will be performed at screening within 28 days of patient registration and repeated 
per study calendar (Section 11). Scans can be done more frequently per MD discretion; these 
scans will be submitted on an unscheduled disease assessment CRF. 
 
13.0 
DATA REPORTING / REGULATORY CONSIDERATIONS  
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
8.0 (Adverse Events: List and Reporting Requirements). 
 
 
13.1 
Data Reporting  
The Overture and OnCore™ Databases will be utilized, as required by the Case 
Comprehensive Cancer Center, to provide data collection for both accrual entry and trial 
data management. Overture and OnCore™ are Clinical Trials Management Systems 
housed on secure servers maintained at Case Western Reserve University. Access to data 
through Overture and OnCore™ is restricted by user accounts and assigned roles. Once 
logged into the Overture or OnCore™ system with a user ID and password, Overture and 
OnCore™ define roles for each user which limits access to appropriate data. User 
PRO-CTCAE 
 
X 
X 
X 
X 
X 
X 


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CASE2619 Protocol v5 
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information and password can be obtained by contacting the OnCore™ Administrator at 
OnCore-registration@case.edu. 
 
Overture and OnCore™ are designed with the capability for study setup, activation, 
tracking, reporting, data monitoring and review, and eligibility verification. This study will 
utilize electronic Case Report Form completion in the Overture database. A calendar of 
events and required forms are available in Overture and OnCore™. 
 
13.2 
Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all applicable 
federal (including 21 CFR parts 56 & 50), state or local laws. 
13.2.1 Written Informed consent 
Provision of written informed consent must be obtained prior to any study-related 
procedures. The Principal Investigator will ensure that the subject is given full and 
adequate oral and written information about the nature, purpose, possible risks and benefits 
of the study as well as the subject’s financial responsibility. Subjects must also be notified 
that they are free to discontinue from the study at any time. The subject should be given 
the opportunity to ask questions and be allowed time to consider the information provided.  
The original, signed written Informed Consent Form must be kept with the Research Chart 
in conformance with the institution’s standard operating procedures. A copy of the signed 
written Informed Consent Form must be given to the subject. Additionally, documentation 
of the consenting process should be located in the research chart. 
13.2.2 Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or 
allow the sponsor, a regulatory authority, or Institutional Review Board access to subject’s 
medical information that includes all hospital records relevant to the study, including 
subjects’ medical history.  
 
13.2.3  Retention of records 
The Principal Investigator of The Case Comprehensive Cancer Center supervises the 
retention of all documentation of adverse events, records of study drug receipt and 
dispensation, and all IRB correspondence for as long as needed to comply with local, 
national and international regulations. No records will be destroyed until the Principal 
Investigator confirms destruction is permitted.  
 
13.2.4  Audits and inspections  
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the site to perform 
audits or inspections, including source data verification. The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, Good Clinical Practice (GCP), 


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guidelines of the International Conference on Harmonization (ICH), and any applicable 
regulatory requirements.  For multi-center studies, participating sites must inform the 
sponsor-investigator of pending audits.  
 
14.0 
STATISTICAL CONSIDERATIONS  
In this phase II, single arm, multi-institutional, open label trial in primary or recurrent, 
unresectable or metastatic melanoma patients who progressed on prior checkpoint inhibitor 
therapy with germline or somatic mutations in BRCA1/2 or BRCA-ness, we hypothesize 
that combination therapy with talazoparib and nivolumab will improve the objective 
response rate from 10% to 30% with limited toxicity.  The primary objective is to estimate 
the clinical efficacy of nivolumab plus talazoparib in patients with unresectable or 
metastatic melanoma with BRCA1/2 or other DNA damage repair mutations (defined as 
BRCA-ness), as measured by objective response rate (ORR) every 12 weeks for a period 
of approximately 12 months.  This will be assessed by best overall response (CR+PR) by 
RECIST v1.1.  Secondary objectives and their endpoints include PFS defined as time from 
first dose of treatment until disease progression, as assessed by RECIST v1.1, treatment 
related adverse events as assessed by CTCAE v5.0, anti-tumor activity as measured by 
irOR as assessed by irRECIST, and irPFS as assessed by irRECIST. 
 
The historical ORR for anti-PD-1 re-challenge after progression is about 5%-10%. ORR 
for re-challenge with combination anti-PD-1/anti-CTLA4 inhibition after progression is 
about 15%-20%.  The ORR for single agent PARP inhibitors in ovarian and breast cancer 
patients that harbor a mutation in BRCA is at least 50%; about 72% and 62% (SOLO3 and 
EMBRACA trials, respectively). 
 
Sample Size Justification 
To test this hypothesis with 90% power and a 2-sided binomial test with alpha of 0.10, 
33 patients will need to be treated to achieve an improvement in ORR from 10% to 
30%.  With 10% of patients potentially not evaluable, 37 patients would need to be 
enrolled for a total of 33 patients that are analyzable. Patients who are not evaluable 
are defined as patients who are consented and enrolled in the study, but who physically 
move away that it would be too burdensome to follow up with institution, those who 
are lost to follow up defined as individuals who enroll but do not receive treatment, 
imaging, and are not present at scheduled office visits. 
 
Bayesian Monitoring Rule for Safety 
We will use the method of Thall et al to monitor toxicity in this study.50  Unacceptable 
toxicity observed at the time the 11th patient has received three cycles of therapy is 
defined for this protocol as CTCAE Grade 3-4 non-hematological toxicities, excluding 
fatigue and endocrinopathies, which fail to resolve to Grade 1 despite appropriate 
supportive care.  A point mass of 0.65 was used as target toxicity rate.  Beta (0.65, 0.35) 
was used as non-informative prior distributions for toxicity rate. Total accrual will be 33 
patients. Patients will be monitored in cohorts of 11, starting from the 11th patients. The 
trial will stop early if an excessive toxicity rate is observed. Formally, stop the trial early 
if Pr(Toxicity rate > 65%|data) > 0.9, i.e. we will stop the trial early if the posterior 
probability of toxicity rate being higher than 65% given data is higher than 0.9. Table 1 


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and 2 summarize the stopping boundaries for toxicity and operating characteristics based 
on the stopping rules. 
 
Table 1. Summary of early stopping boundaries in cohorts of 11 for toxicity. E.g. If 9 or more 
patients experienced toxicity out of the first 11 patients, the trial will stop early; similarly, if 17 
or more out of the first 22 patients experienced toxicity, the trial will stop early for safety. 
Stop Early if #Toxicities Observed ≥ 
9 
17 
Total #Patients Treated 
11 
22 
 
Table 2. Summary of operating characteristics based on 10,000 simulations using stopping 
boundaries in table 1. For example, if the true toxicity rate is 0.65, the probability of early 
stopping is 0.26; if the true toxicity rate is 0.8, the probability of early stopping is 0.79. 
Scenario 
True Toxicity 
Rate 
Pr(Early 
Stopping) 
Average #Pts 
Treated 
Average #Toxicity 
Observed 
1 
0.50 
0.04 
32.2 
16.1 
2 
0.65 
0.26 
27.9 
18.1 
3 
0.80 
0.79 
17.5 
14.0 
 
 
Interim Analysis 
No planned interim analysis will be performed due to expected accrual rate for this 
study. 
 
Analysis Plan 
All baseline patient demographics and clinical characteristics will be summarized by 
mean/standard deviations and count/frequency for continuous and categorical variables 
respectively. All analyses will be completed as intent to treat. 
 
Patients who receive at least one dose of treatment with nivolumab and talazoparib will 
contribute to the efficacy analysis.  Any subject who receives at least one dose of 
treatment on this protocol is evaluable for toxicity.  Proportion of patients with overall 
response will be estimated with corresponding 95% confidence interval. PFS and irPFS 
curves will be based on the Kaplan-Meier method.  Overall response by irRECIST will 
be estimated as a proportion with corresponding 95% confidence interval.  
 
All subjects will be included in the safety analysis, with toxicities graded according to 
NCI CTCAE v5.0. Incidence tables will be generated to summarize incidence of 
patients reporting at least one episode of each specific adverse event, incidence of 
adverse events causing withdrawals and incidence of serious adverse events. Listing of 
adverse events by patients will include the time to onset, the duration of each event, the 
severity of each event, and the relationship of the event to study therapy, whether it was 
a serious event, and whether it caused withdrawal. 
 
Correlative Studies and Analysis Plan 
Correlative studies include, but are not limited to: assessing anti-tumor response by 
measure of immune-infiltration of CD8, CD4, Treg (FOXP3), NK cells (CD56) into 


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tumors by flow cytometry, and PD-L1 expression on tumor by immunohistochemistry 
performed on tumor biopsies at baseline, 12 weeks, and at progression; and assessing 
total somatic mutation burden by sequencing at baseline, 12 weeks, and at progression 
to evaluate DNA landscape and its correlation to response.  These studies will be 
performed on all patients enrolled in the study, unless deemed not evaluable.  
Parametric assumptions will be assessed using Shapiro-Wilk statistics and qqplots and 
non-parametric alternatives will be considered when necessary.  Tumor infiltrating 
lymphocytes (CD8, CD4, Treg, NK cells), total mutational burden, and PD-L1 
expression will be assessed using a mixed model approach, adjusting for repeated 
measurements over time and response (yes/no). If there are differences by time, 
pairwise contrasts will be utilized to assess for specific differences at various time 
points, adjusting for multiple comparisons using the Tukey method.   
 
The final correlative objective of patient reported adverse events (PRO-CTCAE) will 
be summarized as percentages and frequencies, as described above in analysis plan. 
 
Although exploratory, for 33 evaluable patients, we will be able to detect moderate 
effect sizes of 0.44 for all correlative outcomes listed above, with 90% power and two-
sided level of significance of 0.10.  
 
Accrual 
About 225 primary or recurrent metastatic or unresectable melanoma patients are seen 
annually at seven institutions in the Regional Melanoma Translational Research 
Consortium (RMTRC), which include: Cleveland Clinic, University Hospitals, 
MetroHealth, University of Pittsburgh Medical Center, Roswell Park, Penn State, and 
Ohio State University. About 50 patients per year would meet eligibility criteria.  Of 
these, about half are expected to enroll.  The estimate annual accrual rate is 25 patients 
per year. At this rate, the accrual goal of 37 patients is anticipated to be completed 
within two years. 
 


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Hoos A, Eggermont AMM, Janetzki S, et al. Improved endpoints for cancer 
immunotherapy trials. J Natl Cancer Inst. 2010;102(18):1388-1397. 
doi:10.1093/jnci/djq310 
53.  
Hodi FS, Butler M, Oble DA, et al. Immunologic and clinical effects of antibody 
blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated 
cancer patients. Proc Natl Acad Sci U S A. 2008;105(8):3005-3010. 
doi:10.1073/pnas.0712237105 
54.  
Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune 
therapy activity in solid tumors: immune-related response criteria. Clin Cancer 
Res. 2009;15(23):7412-7420. doi:10.1158/1078-0432.CCR-09-1624 
55.  
Nishino M, Jagannathan JP, Krajewski KM, et al. Personalized tumor response 
assessment in the era of molecular medicine: cancer-specific and therapy-specific 
response criteria to complement pitfalls of RECIST. AJR Am J Roentgenol. 
2012;198(4):737-745. doi:10.2214/AJR.11.7483 
56.  
Nishino M, Gargano M, Suda M, Ramaiya NH, Hodi FS. Optimizing immune-


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related tumor response assessment: does reducing the number of lesions impact 
response assessment in melanoma patients treated with ipilimumab? J Immunother 
cancer. 2014;2(1):17. doi:10.1186/2051-1426-2-17 
 
16.0 
APPENDIX  
16.1 
RECIST 1.1 Criteria  
 
The determination of antitumor efficacy during this study will be based on objective tumor 
assessments made according to the RECIST system of unidimensional evaluation.  
Adapted from E.A. Eisenhauer, et al. New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–
247.51 
 
Measurability of Tumor Lesions  
At baseline, individual tumor lesions will be categorized by the investigator as either 
measurable or non-measurable by the RECIST criteria as described below.  
 
Measurable:  
 
Tumor lesion: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:  
 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm);  
 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).  
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.  
 
Non-Measurable: All other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with 10 mm to <15 mm short axis) as well as truly non-
measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging techniques.  
 
NOTE: If measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.  
 
Recording Tumor Measurements  
 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total 
representative of all involved organs should be identified as target lesions and measured and 
recorded at baseline and at the stipulated intervals during treatment. Target lesions should be 


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selected on the basis of their size (lesion with the longest diameters) and their suitability for 
accurate repetitive measurements (either by imaging techniques or clinically).  
 
The longest diameter will be recorded for each target lesion. The sum of the longest diameter 
for all target lesions will be calculated and recorded as the baseline sum longest diameter to 
be used as reference to further characterize the objective tumor response of the measurable 
dimension of the disease during treatment. All measurements should be performed using a 
caliper or ruler and should be recorded in metric notation in centimeters.  
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements are not required and these lesions should be 
followed as “present” or “absent.”  
 
Techniques for Assessing Measurable Disease  
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at screening and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical (physical) examination when both methods have been used 
to assess the antitumor effect of a treatment.  
 
Definitions of Tumor Response  
 
Target Lesions  
 
Complete response (CR) is defined as the 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) is defined as a ≥30% decrease in the sum of the longest dimensions of 
the target lesions taking as a reference the baseline sum longest dimensions.  
 
Progressive disease (PD) is defined as a ≥20% increase in the sum of the longest dimensions 
of the target lesions taking as a reference the smallest sum of the longest dimensions recorded 
since the treatment started, or the appearance of one or more new lesions. In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 
mm.  
 
Stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as a reference the smallest sum of the longest dimensions 
since the treatment started.  
 
Non-Target Lesions  
 
Complete response (CR) is defined as the disappearance of all non-target lesions. All lymph 
nodes must be non-pathological in size (<10 mm short axis).  
Non-CR/Non-PD is defined as a persistence of ≥1 non-target lesions.  
 
Progressive disease (PD) is defined as unequivocal progression of existing non-target 
lesions, or the appearance of ≥1 new lesion.  


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The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease and progressive disease.  
 
Confirmation of Tumor Response  
To be assigned a status of PR or CR, changes in tumor measurements in patients with 
responding tumors must be confirmed by repeat studies that should be performed  
4 weeks after the criteria for response are first met. In the case of SD, follow-up 
measurements must have met the SD criteria at least once after study entry at a minimum 
interval of 8 weeks.  
 
Determination of Tumor Response by the RECIST Criteria  
When both target and non-target lesions are present, individual assessments will be recorded 
separately. Determination of tumor response at each assessment is summarized in the 
following table.  
 
Response Evaluation Criteria in Solid Tumors 
 
Determination of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest sum on study). For CR and PR, the patient’s best response assignment will 
depend on the achievement of both measurement and confirmation criteria. CR and PR 
must be confirmed by 2 measurements at least 4 weeks apart. In the case of SD, follow 
up measurements must have met the SD criteria at least once after start of the treatment at 
a minimum interval of 6 weeks. 
 
16.2 
Immune-related Response Criteria Derived From RECIST v1.1 (irRECIST) 


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Increasing clinical experience indicates that traditional response criteria may not be 
sufficient to fully characterize activity in this new era of targeted therapies and/or 
biologics. 
 
This is particularly true for immunotherapeutic agents such as anti-CTLA4 and anti-PD-
1\anti PD-L1 antibodies which exert the anti-tumor activity by augmenting activation and 
proliferation of T-cells, thus leading to tumor infiltration by T-cells and tumor regression 
rather than direct cytotoxic effects.52,53  Clinical observations of patients with advanced 
melanoma treated with ipilimumab, for example, suggested that conventional response 
assessment criteria such as Response Evaluation Criteria in Solid Tumors (RECIST) and 
World Health Organization (WHO) criteria are not sufficient to fully characterize 
patterns of tumor response to immunotherapy because tumors treated with 
immunotherapeutic agents may show additional response patterns that are not described 
in these conventional criteria.54,55 
 
Furthermore, the conventional tumor assessment criteria (RECIST and WHO criteria) 
have been reported as not capturing the existence of a subset of patients who have an OS 
similar to those who have experienced CR or PR but were flagged as PD by WHO 
criteria.54,55 
 
On these grounds, a tumor assessment system has been developed that incorporates these 
delayed or flare-type responses into the RECIST v1.1 (irRECIST).56 
 
For irRECIST, with the exception of a complete response assessment, only target and 
new measurable lesions are taken into account. 
 
In contrast to RECIST v1.1, the irRECIST: 
• Requires confirmation of both progression and response by imaging at least 4 
weeks from the date first documented, and 
 
• Does not necessarily score the appearance of new lesions as progressive disease if 
the sum of lesion diameters of target lesions (minimum of 10 mm per lesion, 
maximum of 5 target lesions, maximum of 2 per organ) and measurable new 
lesions does not increase by ≥20%. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported target lesion(s) at baseline and throughout the study. 
 
irRECIST responses are defined as follows: 
 
• Overall immune-related complete response (irCR): Complete disappearance of 
all lesions (whether measurable or not) and no new lesions. All measurable lymph 
nodes also must have a reduction in short axis to <10 mm. 
 


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• Overall immune-related partial response (irPR): Sum of the diameters (longest 
for non-nodal lesions, shortest for nodal lesions) of target and new measurable 
lesions decreases ≥30%. 
 
• Overall immune-related stable disease (irSD): Sum of the diameters (longest 
for non-nodal lesions, shortest for nodal lesions) of target and new measurable 
lesions does not meet criteria for irCR or irPR (compared to baseline), or 
immune-related progressive disease (irPD, compared to nadir). 
 
• Overall immune-related progressive disease (irPD): Sum of the diameters 
(longest for non-nodal lesions, shortest for nodal lesions) of target and new 
measurable lesions increases ≥20% (compared to nadir), confirmed by a repeat, 
consecutive observation at least 4 weeks from the date first documented. 
 
New measurable lesions: Incorporated into tumor burden (i.e., added to the target lesion 
measurements). A lymph node has to be ≥15 mm in short axis to be a measurable new 
lesion and its short axis measurement is included in the sum. Up to 2 new lesions per 
organ and up to 5 new lesions in total can be added to the measurements. 
 
New non-measurable lesions: Do not define progression but preclude irCR. 
 
Overall responses derived from changes in target, non-target, and new lesions are 
outlined in the following table. 
 
Overall Response Derived from Changes in Target, Non-target and New Lesions 
 
 


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16.3 
Performance Status 
 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
 
0 
 
Normal activity. Full active, able 
to carry on all pre-disease 
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 (e.g., 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% if waking hours. 
 
60 
Requires occasional 
assistance, but is able to care 
for most of his/her 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 more 
than 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 
 
16.4 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE)  
 
The NCI CTCAE (version 5.0, dated November 27, 2017) has been placed in the Study 
Reference Binder for this protocol. Alternatively, the NCI CTCAE may be reviewed online at 
the following NCI website:  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
 


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16.5 
P-glycoprotein (PGP) INHIBITORS AND INDUCERS 
 
 
P-gp Inhibitors: 
• Carvedilol, cladribine, clarithromyacin, cobicistat, darunavir, dronedarone, 
erythromycin, amiodarone, indinavir, itraconazole, ketoconazole, lapatinib, 
lopinavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir, telaprevir, 
tipranavir, valspodar, and verapamil 
 
P-gp Inducers: 
• avasimibe, carbamazepine, phenytoin, rifampin, and St. John’s wort 
 
Inhibitor of breast cancer resistance protein (BCRP) (curcumin, cyclosporine, elacridar 
[GF120918], and eltrombopag 
 
Notes:  
Grapefruit, grapefruit juice and other foods that are known to inhibit P-gp activity should 
be avoided during treatment.  
P-gp inhibitors require dose reduction of talazoparib to 0.75mg (see section 7.1.1). 
P-gp inducers (including St. John’s Wort also known as hypericum perforatum) are 
prohibited during treatment with talazoparib. 
 
 


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16.6 
Pill Diary 
 
 
SUBJECT PILL DIARY 
 
 
Subject Name ________________________Protocol #_____________Subject Study ID __________  
Cycle #: _______    
       Month #: _______   
                                
INSTRUCTIONS FOR THE SUBJECT: 
   1.  You will take 1 tablet of 1mg Talazoparib capsule(s) each day. Take the tablets with or without food, as you wish.  
   2.  Record the date, the number of tablets you took, and what time you took them. 
   3.  If you have any comments please record them in the “Comments” column below. 
   4.  Please bring your pill bottle and this form to your physician when you come for your next appointment.   
   5.  Please sign your name at the bottom of the diary. 
Date 
Day 
# of _____ mg Talazoparib 
capsule(s) and time taken  
Comments 
 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
 
 
 
7 
 
 
 
8 
 
 
 
9 
 
 
 
10 
 
 
 
11 
 
 
 
12 
 
 
 
13 
 
 
 
14 
 
 
 
15 
 
 
 
16 
 
 
 
17 
 
 
 
18 
 
 
 
19 
 
 
 
20 
 
 
 
21 
 
 
 
22 
 
 
 
23 
 
 
 
24 
 
 
 
25 
 
 
 
26 
 
 
 
27 
 
 
 
28 
 
Add/remove days as needed 
Subject’s Signature: ________________________________________ Date: ___________ 
 
 


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16.7 
PRO-CTCAE 
 
 
 
 


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16.8     Family/Personal History Questionnaire Form 
           *To be collected by research nurse at pre-treatment visit 
 
1. Do you have a personal history of another type of cancer, besides melanoma?  
Yes/no 
2. If yes:  How many? 
3. If yes:  What type(s) of cancer? Can choose one or multiple cancers from list 
below: 
a. Breast 
b. Ovarian 
c. Brain 
d. Colorectal 
e. Kidney 
f. Pancreas 
g. Prostate 
h. Uterine 
i. Other GU 
j. Other GI 
k. Other (field to write it other cancer) 
4. If yes:  What was/is the date of diagnosis for each cancer? 
5. Do you have a family history of cancer?  (Cancer in your parents, siblings, 
children, aunts/uncles, nephews/nieces, grandparents or grandchildren)  Yes/no 
6. If yes:   
a. Cancer in mother? Yes/no 
i. If yes: drop down type of cancer (able to select multiple) 


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b. Cancer in father? Yes/no 
i. If yes: drop down type of cancer (able to select multiple) 
c. Do the same as above (separate drop down for each type of family 
member) for cancer in siblings, children 
d. Do the same as above, also add drop down for maternal/paternal: 
grandmother, grandfather, aunts, uncles, nephews, nieces, other relative 
(specify).