Clinical trial NCT01989546
Conditions: Advanced Ovarian Cancer Primary Peritoneal Cancer Advanced Breast Cancer Advanced Solid Tumors
Keywords: DNA Damage Advanced Solid Tumors BRCA Mutations PARP Inhibitor Pharmacodynamics
Sponsor: National Cancer Institute (NCI)
Start date: 2014-02-04; Completion date: 2020-03-26
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

* The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining genomic stability by regulating a variety of deoxyribonucleic acid (DNA) damage repair mechanisms.
* Talazoparib (BMN 673) is a PARP inhibitor with greater in vitro activity than any other PARP inhibitor currently in development. BMN 673 has been shown to cause single-agent synthetic lethality in breast cancer 1 and breast cancer 2 (BRCA1/2)- and phosphatase and tensin homolog (PTEN)-deficient cell lines and has potent antitumor activity in animal models of tumors harboring mutations in DNA repair pathways.
* BMN 673 is showing promising single-agent activity in patients with advanced ovarian and breast cancer harboring deleterious BRCA mutations.
* This pilot study will evaluate the pharmacodynamic effects of BMN 673 on DNA damage and apoptosis markers in tumor biopsy tissue.

Primary Objective:

-Determine the pharmacodynamic effect of BMN 673 in tumor biopsies from patients with advanced ovarian, breast, or other solid tumor and deleterious BRCA mutations.

Secondary Objectives:

* Determine the response rate (Complete Response (CR) + Partial Response (PR) of treatment with BMN 673 in patients with advanced ovarian or primary peritoneal carcinoma and deleterious BRCA mutations.
* Determine the response rate (CR + PR) of treatment with BMN 673 in patients with advanced breast carcinoma and deleterious BRCA mutations.
* Determine the response rate (CR + PR) of treatment with BMN 673 in patients with advanced solid tumor (other than breast or ovarian) and deleterious BRCA mutations.

Eligibility:

* Adult patients with documented deleterious BRCA 1 or 2 mutations with histologically confirmed ovarian, primary peritoneal, breast, prostate, pancreas, gastric or other solid tumor whose disease has progressed following at least one standard therapy or who have no acceptable standard treatment options.
* No major surgery, radiation, or chemotherapy within 4 weeks prior to study enrollment, and recovered from toxicities of prior therapies to at least eligibility levels.
* Age greater than or equal to 18 years of age; Eastern Cooperative Oncology Group (ECOG) performance status less than equal to 2
* Adequate organ function.
* Willingness to undergo tumor biopsies.

Study Design:

* BMN 673 will be administered orally each day in 28-day cycles.
* Dosing will be at the established recommended Phase II dose of 1000 mcg/day each day for

  28 days.
* We plan to accrue a total of 12 evaluable patients per cohort for a total of 36 patients. To allow for some patients who will not be evaluable, the accrual ceiling is 42 patients.
* Tumor biopsies will be mandatory at baseline (pre-dose), and then approximately 3-6 hours post BMN 673 on day 8. An optional tumor biopsy may also be collected at time of disease progression.

SCHEMA

* BMN 673 is administered orally each day in 28-day cycles
* Tumor biopsies will be performed at baseline (pre-treatment) and 3-6 hrs post dose on cycle 1 day 8. An optional tumor biopsy may also be collected at time of disease progression. Tumor biopsies will be evaluated for protease activated receptor (PAR) levels, DNA damage response markers such as \>=H2A.X Variant Histone (H2AX), cleaved caspase 3, excision repair cross-complementing group 1 (ERCC1), pNbs1, XPF, RAD51, and pT1989ATR, and, as indicators of ataxia telangiectasia and Rad3-related protein (ATR)/ataxia telangiectasia mutated (ATM) activation, Checkpoint kinase 1 (chk1) and Checkpoint kinase 2 (chk2)
* Blood samples for circulating tumor cells (CTC) analyses will be collected at baseline (pre-treatment), on cycle 1 day 1(3-6 hours post dose), on cycle 1 day 8 (3-6 hours post dose), and on cycle 2 day 1 (3-6 hours post dose)
* Blood samples for pharmacokinetic (PK) analysis will be collected on cycle 1 day 1 pre-dose and 0.5, 1, 2, 3, 4, 6,8, and 24 hours post-dose, on cycle 1 day 8 (3-6 hours post dose), and on cycle 2 day 1 pre-dose and 3-6 hours post dose.

Detailed description:
Background:

* The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining genomic stability by regulating a variety of deoxyribonucleic acid (DNA) damage repair mechanisms.
* Talazoparib (BMN 673) is a PARP inhibitor with greater in vitro activity than any other PARP inhibitor currently in development. Talazoparib (BMN 673) has been shown to cause single-agent synthetic lethality in breast cancer 1 and breast cancer 2 (BRCA1/2)- and phosphatase and tensin homolog (PTEN)-deficient cell lines, and has potent antitumor activity in animal models of tumors harboring mutations in DNA repair pathways.
* Talazoparib (BMN 673) is showing promising single-agent activity in patients with advanced ovarian and breast cancer harboring deleterious BRCA mutations.
* This pilot study will evaluate the pharmacodynamic effects of talazoparib (BMN 673) on DNA damage and apoptosis markers in tumor biopsy tissue.

Primary Objective:

-Determine the pharmacodynamic effect of talazoparib (BMN 673) in tumor biopsies from patients with advanced ovarian, breast, or other solid tumor and deleterious BRCA mutations.

Secondary Objectives:

-Determine the response rate (Complete Response (CR) + Partial Response (PR) of treatment with talazoparib (BMN 673) in patients with deleterious BRCA mutations.

Eligibility:

* Adult patients with documented deleterious BRCA 1 or 2 mutations with histologically confirmed ovarian, primary peritoneal, breast, prostate, pancreas, gastric or other solid tumor whose disease has progressed following at least one standard therapy or who have no acceptable standard treatment options.
* No major surgery, radiation, or chemotherapy within 4 weeks prior to study enrollment, and recovered from toxicities of prior therapies to at least eligibility levels.
* Age greater than or equal to 18 years of age; Eastern Cooperative Oncology Group (ECOG) performance status less than equal to 2
* Adequate organ function.
* Willingness to undergo tumor biopsies.

Study Design:

* Talazoparib (BMN 673) will be administered orally each day in 28-day cycles.
* Dosing will be at the established recommended Phase II dose of 1000 microgram/day each day for 28 days.
* To meet the primary, pharmacodynamic endpoint of the trial, we plan to accrue a total of 12 patients with matched, evaluable baseline and day 8 biopsies. To allow for some patients whose biopsies will not be evaluable (i.e., will contain \<5% tumor content), the accrual ceiling is 24 patients. The number of patients evaluable for objective response, while relevant to the secondary objective of the trial, will not be considered in determining completion of accrual.
* Tumor biopsies will be mandatory at baseline (pre-dose), and then approximately 3-6 hours post talazoparib (BMN 673) on day 8. One optional tumor biopsy may also be collected either on day 1 (+/- 2 days) of the cycle following any restaging at which a 10-19% increase in tumor volume is observed (according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria) if the patient has been on study for at least 4 cycles, or at time of disease progression.

Arms: arm 1: Single agent
Interventions: intervention 1: BMN 673
Intervention descriptions: intervention 1: Poly (ADP-ribose) polymerase (PARP) inhibitor; has been shown to cause single-agent synthetic lethality in breast cancer 1 and breast cancer 2 (BRCA1/2)- and phosphatase and tensin homolog (PTEN)-deficient cell lines, and has potent antitumor activity in animal models of tumors harboring mutations in deoxyribonucleic acid (DNA) repair pathways.

Protocol documents:
Prot_SAP_000.pdf: 
CTEP # 9510
Clinical Center #14-C-0015
1
TITLE:  Pilot Trial of Talazoparib (BMN 673), an Oral PARP Inhibitor, in Patients With 
Advanced Solid Tumors and Deleterious BRCA Mutations
Abbreviated Title: Pilot Talazoparib (BMN 673)
Coordinating Center:
Developmental Therapeutics Clinic (NCIDTC)
National Cancer Institute
10 Center Drive
Bethesda, MD 20892
Principal Investigator:
A. P. Chen, MD A-E
31 Center Drive
Bldg 31 Room 3A44
Bethesda, MD 20892
Phone: 240-781-3320
Fax: 240-541-4515
chenali@mail.nih.gov
NIH Associate 
Investigators:
James H. Doroshow, MDA-E
DCTD, NCI
Howard Streicher, MDA-E
DCTD, NCI
Geraldine O'Sullivan Coyne, MD, PhDA-E
CCR, NCI
Naoko Takebe, MD, PhDA-E
DCTD, NCI
Sheila Prindiville, MD, MPHA-E 
CCCT, NCI
Elad Sharon, MDA-E
DCTD, NCI
Elliot Levy, MDA-E
CC, NIH
Non-NIH Associate 
Investigators:
Lamin Juwara, CRNPA,B,E
Leidos Biomed., FNLCR 
Referral Contact:
Jennifer Zlott, RN A,B,E
Bldg 10/Rm8D53
(240) 760-6046
Fax: (301) 451-5625
zlottjh@mail.nih.gov
NCI Supplied Agent: 
Talazoparib (BMN 673) (NSC 771561)
IND Number:
119558
Version Date:
August 24, 2020
NCT Number:
NCT01989546
Roles: Aobtains information by intervening or interacting with living individuals for research purposes; 
Bobtains identifiable private information about living individuals; Cobtains the voluntary informed 
consent of individuals to be subjects; Dmakes decisions about subject eligibility; Estudies, interprets, or 
analyzes identifiable private information or data/specimens for research purposes


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PRÉCIS
Background:

The poly (ADP-ribose) polymerase (PARP) family of enzymes is critical for maintaining 
genomic stability by regulating a variety of DNA damage repair mechanisms.

Talazoparib (BMN 673) is a PARP inhibitor with greater in vitro activity than any other PARP 
inhibitor currently in development.  Talazoparib (BMN 673) has been shown to cause single-
agent synthetic lethality in BRCA1/2- and PTEN-deficient cell lines, and has potent antitumor 
activity in animal models of tumors harboring mutations in DNA repair pathways.  

Talazoparib (BMN 673) is showing promising single-agent activity in patients with advanced 
ovarian and breast cancer harboring deleterious BRCA mutations. 

This pilot study will evaluate the pharmacodynamic effects of Talazoparib (BMN 673) on DNA 
damage and apoptosis markers in tumor biopsy tissue. 
Primary Objective:

Determine the pharmacodynamic effect of talazoparib (BMN 673) in tumor biopsies from 
patients with advanced ovarian, breast, or other solid tumor and deleterious BRCA mutations.
Secondary Objectives:

Determine the response rate (CR + PR) of treatment with talazoparib (BMN 673) in patients with 
deleterious BRCA mutations.
Eligibility:

Adult patients with documented deleterious BRCA 1 or 2 mutations with histologically 
confirmed ovarian, primary peritoneal, breast, prostate, pancreas, gastric or other solid tumor 
whose disease has progressed following at least one standard therapy or who have no acceptable 
standard treatment options.

No major surgery, radiation, or chemotherapy within 4 weeks prior to study enrollment, and 
recovered from toxicities of prior therapies to at least eligibility levels.

Age ≥18 years of age; ECOG performance status ≤ 2

Adequate organ function.

Willingness to undergo tumor biopsies.
Study Design:

Talazoparib (BMN 673) will be administered orally each day in 28-day cycles.  

Dosing will be at the established recommended Phase II dose of 1000 μg/day each day for 
28 days.

To meet the primary, pharmacodynamic endpoint of the trial, we plan to accrue a total of 12 
patients with matched, evaluable baseline and day 8 biopsies.  To allow for some patients whose 
biopsies will not be evaluable (i.e., will contain <5% tumor content), the accrual ceiling is 24 
patients.  The number of patients evaluable for objective response, while relevant to the 
secondary objective of the trial, will not be considered in determining completion of accrual.

Tumor biopsies will be mandatory at baseline (pre-dose), and then approximately 3-6 hours post 
talazoparib (BMN 673) on day 8.  One optional tumor biopsy may also be collected either on day 
1 ( 2 days) of the cycle following any restaging at which a 10-19% increase in tumor volume is 
observed (according to RECIST criteria) if the patient has been on study for at least 4 cycles, or 
at time of disease progression.


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SCHEMA
Talazoparib (BMN 673)
Talazoparib (BMN 673)
D1
D8
D28
D28
D1
Tumor 
biopsy
Blood for 
CTCs
Talazoparib (BMN 673) is administered orally each day in 28-day cycles
Tumor biopsies will be performed at baseline (pre-treatment) and 3-6 hrs post dose on cycle 1 
day 8.  One optional tumor biopsy may also be collected either on day 1 ( 2 days) of the cycle 
following any restaging at which a 10-19% increase in tumor volume is observed (according to 
RECIST criteria) if the patient has been on study for at least 4 cycles, or at time of disease 
progression.  Tumor biopsies will be evaluated for PAR levels, DNA damage response 
markers such as γH2AX, cleaved caspase 3, ERCC1, pNbs1, XPF, RAD51, and pT1989ATR, 
and, as indicators of ATR/ATM activation, chk1 and chk2
Blood samples for CTC analyses will be collected at baseline (pre-treatment), on cycle 1 day 1 
(3-6 hours post dose and approximately 24 hours post dose/before day 2 dose), on cycle 1 day 
8 (3-6 hours post dose), on cycle 2 day 1 (3-6 hours post dose, ± 3 days for scheduling 
conflicts), on day 1 of every subsequent cycle before drug administration (day 1 of every 3 
cycles for patients on study for more than 12 months), at the time of the optional restaging 
follow-up biopsy (if applicable), and at time of disease progression.  
*Please note: As of Amendment H (2/5/2018) blood for PK analysis will no longer be 
collected.  Blood samples for PK analysis will be collected on cycle 1 day 1 pre-dose and 0.5, 
1, 2, 3, 4, 6, 8, and 24 hours post-dose, on cycle 1 day 8 (3-6 hours post dose), and on 
cycle 2 day 1 pre-dose and 3-6 hours post dose (± 2 days for scheduling conflicts). 
Cycle 1
Cycle 2
D14
Blood for 
PK*


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TABLE OF CONTENTS
PRÉCIS............................................................................................................................................2
SCHEMA.........................................................................................................................................3
TABLE OF CONTENTS.................................................................................................................4
1
OBJECTIVES......................................................................................................................6
2
BACKGROUND .................................................................................................................6
2.1
Poly-ADP-ribosylation ............................................................................................6
2.2
Talazoparib (BMN 673)...........................................................................................8
2.3
Rationale ................................................................................................................13
2.4
Correlative Studies Background ............................................................................13
3
PATIENT SELECTION....................................................................................................14
3.1
Eligibility Criteria..................................................................................................14
3.2
Exclusion Criteria ..................................................................................................16
3.3
Inclusion of Women and Minorities ......................................................................17
3.4
Screening Evaluation .............................................................................................17
4
REGISTRATION PROCEDURES ...................................................................................18
4.1
Registration Process...............................................................................................18
5
TREATMENT PLAN........................................................................................................18
5.1
Agent Administration.............................................................................................19
5.2
General Concomitant Medication and Supportive Care Guidelines......................19
5.3
Duration of Therapy...............................................................................................21
5.4
Duration of Follow Up...........................................................................................21
5.5
Criteria for Removal from Study...........................................................................21
6
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................21
6.1
Dose Modifications................................................................................................22
7
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................22
7.1
Comprehensive Adverse Events and Potential Risks List (CAEPR).....................23
7.2
Adverse Event Characteristics...............................................................................25
7.3
Expedited Adverse Event Reporting......................................................................25
7.4
Routine Adverse Event Reporting .........................................................................30
7.5
Secondary Malignancy...........................................................................................31
7.6
Second Malignancy................................................................................................31
8
PHARMACEUTICAL INFORMATION..........................................................................31
8.1
Talazoparib (BMN 673; NSC 771561)..................................................................32
8.2
Agent Ordering ......................................................................................................33
8.3
Agent Accountability.............................................................................................34
8.4
Investigator Brochure Availability ........................................................................34
8.5
Useful Links and Contacts.....................................................................................34
9
CORRELATIVE/SPECIAL STUDIES.............................................................................34
9.1
Pharmacodynamic and Pharmacokinetic Assays...................................................35


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9.2
Sample Collection and Processing.........................................................................38
9.3
Human Data Sharing Plan......................................................................................39
10
STUDY CALENDAR .......................................................................................................39
11
MEASUREMENT OF EFFECT .......................................................................................41
11.1
Antitumor Effect – Solid Tumors ..........................................................................41
11.2
Guidelines for Evaluation of Measurable Disease.................................................43
11.3
Response Criteria...................................................................................................45
11.4
Duration of Response.............................................................................................47
12
DATA REPORTING / REGULATORY REQUIREMENTS...........................................48
12.1
Data Reporting.......................................................................................................48
12.2
CTEP Multicenter Guideline .................................................................................48
12.3
Collaborative Agreements Language.....................................................................48
13
STATISTICAL CONSIDERATIONS...............................................................................50
13.1
Study Design/Endpoints ........................................................................................50
13.2
Sample Size/Accrual Rate......................................................................................50
13.3
Analysis of Exploratory Pharmacodynamic Endpoints.........................................51
14
HUMAN SUBJECTS PROTECTIONS ............................................................................51
14.1
Justification for Subject Selection .........................................................................51
14.2
Evaluation of Benefits and Risks/Discomforts......................................................52
14.3
Consent and Assent Process and Documentation..................................................52
14.4
Procedure for Protecting Against or Minimizing Any Potential Risks..................52
14.5
Patient Advocate....................................................................................................53
15
REFERENCES ..................................................................................................................54
APPENDIX A: PERFORMANCE STATUS CRITERIA.............................................................57
APPENDIX B: PATIENT’S MEDICATION DIARY..................................................................58
APPENDIX C: PD/PK COLLECTION WORKSHEETS.............................................................60
APPENDIX D: PK SAMPLE HANDLING AND SHIPPING.....................................................64


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1
OBJECTIVES
Primary Objective:

Determine the pharmacodynamic effect of talazoparib (BMN 673) in tumor biopsies from 
patients with advanced ovarian, breast, or other solid tumor and deleterious BRCA 
mutations.
Secondary Objective:

Determine the response rate (CR + PR) of treatment with talazoparib (BMN 673) in 
patients with deleterious BRCA mutations.
2
BACKGROUND
2.1
Poly-ADP-ribosylation
Poly-ADP-ribosylation occurs after single- or double-stranded DNA damage and represents 
the posttranslational modification of histones and other nuclear proteins by poly (ADP-
ribose) polymerase (PARP) [1].  PARP has been implicated in many cellular processes, 
including replication, transcription, differentiation, gene regulation, protein degradation, 
and mitotic spindle maintenance.  Enhanced PARP-1 expression and/or activity in tumor 
cells, as compared to normal cells, has been demonstrated in malignant lymphomas [2], 
hepatocellular carcinoma [3], cervical carcinoma [4], colorectal carcinoma [5], non-
Hodgkin’s lymphoma [6], leukemic lymphocytes [7], and colon adenomatous polyps [8].  
In knockout mouse models, deletion of PARP-1 is sufficient to impair DNA repair [9-11].  
The residual PARP-dependent repair activity (~ 10%) is due to PARP-2.  This suggests that 
only PARP-1 and PARP-2 need to be inhibited to impair DNA repair [12-14].
Poly-ADP-ribosylation of proteins is a dynamic process with a short half-life (t1/2) of 
<1 min.  The enzymes responsible for degrading these polymers are poly (ADP-ribose) 
glycohydrolase (PARG), which cleaves ribose-ribose bonds, and ADP-ribosyl protein 
lyase, which removes the protein proximal to the ADP-ribose monomer.
Increased PARP activity is one of the mechanisms by which tumor cells avoid apoptosis 
caused by DNA damaging agents.  PARP activity is essential for the repair of single-
stranded DNA breaks through the base excision repair (BER) pathways [14, 15].  
Therefore, inhibition of PARP sensitizes tumor cells to cytotoxic agents (e.g., alkylators 
(temozolomide, cyclophosphamide, BCNU) and topoisomerase I inhibitors (e.g., 
irinotecan, camptothecin, topotecan) that induce DNA damage that would normally be 
repaired through the BER system.  Double-stranded breaks are strong activators of 
PARP-1, resulting in PARP-1–mediated activation of DNA-PK and Ku80, important 
components of the non-homologous end-joining double-stranded break repair pathway [16, 
17].  Small molecule inhibitors of PARP directly inhibit repair of double-stranded breaks 
[9, 18].


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Deleterious BRCA Mutations and the Concept of Synthetic Lethality
There are also data suggesting that PARP inhibitors have activity against some BRCA-
deficient cells in the absence of any DNA damaging agent [19-21].  It is possible that, in 
BRCA-deficient cells, PARP inhibition stops the BER pathway, and thus, single-stranded 
breaks are carried through DNA synthesis, resulting in double-stranded breaks.  The 
increase in double-stranded breaks cannot be repaired by homologous recombination, due 
to the lack of BRCA1 or 2, resulting in increased cell death. 
BRCA1-/- and 2 -/- embryonic stem cells were observed to be extremely sensitive to PARP 
inhibition (Figure 1) [20].  This might be due to inhibition of the BER pathway by the 
PARP inhibitor in the background of defective homologous repair in BRCA-deficient 
cancer cells (Figure 2) [21, 22].
Figure 1: Inhibition of PARP activity inhibits the survival of cells lacking wild-type 
BRCA1 or BRCA2 after 10-12 days of continuous exposure to PARP inhibitor [20].  


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Figure 2: Inhibition of PARP in tumor cells with BRCA mutations leads to persistence of 
DNA lesions normally repaired by homologous recombination [21].
These observations led to the evaluation of single-agent PARP inhibitors in patients with 
deleterious BRCA mutations [23].  Results from recent Phase II studies of single-agent 
olaparib, an oral PARP inhibitor, in patients with recurrent ovarian cancer or refractory 
breast cancer and confirmed BRCA1 or 2 mutations are encouraging.  Confirmed overall 
response rates for patients with ovarian cancer treated with 400 or 100 mg two times a day 
(BID) of olaparib were 33% and 13%, respectively; a further 33% and 29% of patients 
experienced stable disease.  It is also worth noting that median progression-free survival 
(PFS) in these two cohorts was 5.8 and 1.9 months, respectively [24].  For the companion 
trial of olaparib in patients with deleterious BRCA mutations and breast cancer, the 
objective response rate was 38% (9/24) on the 400 mg BID dose (41% [11/27] in the 
investigator’s presentation to ASCO 2009) [25].  These data support the hypothesis that 
BRCA-deficient cancer cells are sensitive to PARP inhibition.  
2.2
Talazoparib (BMN 673)
Mechanism of Action
Talazoparib (BMN 673) has been shown to be a highly selective and potent cytotoxic agent 
in human cancer cell lines and in animal models of tumors harboring mutations that 
compromise DNA repair pathways.  Talazoparib (BMN 673) inhibits PARP in vitro at a 
lower concentration 
(IC50= 0.57 nM) than the PARP inhibitors ABT 888 (IC50=4.73 nM), AG14447 (IC50=1.98 
nM), or olaparib (IC50=1.94 nM) [26, 27].
Pharmacodynamic Studies
IC50 values for the inhibition of recombinant human PARP-1 enzymatic activity are 
approximately the same for the talazoparib tosylate salt (BMN 673ts) and freebase forms 
(BMN 673fb) (0.83 and 1.2 nM, respectively), indicating that the tosylate salt does not 
affect mechanism of action of BMN 673fb.  In contrast, the enantiomeric isomer (LT-
00674) is a poor inhibitor of PARP-1 enzymatic activity (IC50>100 nM).  BMN 673fb 
inhibited PARP-2 to a comparable extent as its inhibition of PARP-1.
Assessment of BMN 673fb and related compounds for their tumor cell cytotoxicity 
revealed selective and potent cytotoxicity in human cancer cell lines harboring mutations 
that compromise DNA repair pathways.  Gene mutations that confer selective tumor cell 
cytotoxicity included BRCA1 (MX-1 mammary tumor cells), BRCA2 (Capan-1 pancreatic 
tumor cells), PTEN (MDA-MB-468 mammary, LNCap and PC-3 prostate tumor cells), and 
MLH-1 mutations (HCT-116 colorectal tumor cells) (Table 1).  The IC50 values of BMN 
673fb in these tumor cell lines were in the single-digit nanomolar or sub-nanomolar range.  
In contrast, the IC50 of talazoparib (BMN 673) against normal human primary cell MRC-5 
and several tumor cell lines that do not have reported DNA repair-related mutations are 
significantly greater (250 nM to > 1000 nM).


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Table 1.  The cytotoxicity of talazoparib (BMN 673) and reference PARP inhibitors was 
compared in normal human cells (MRC-5) or in tumor cells that either wild-type for 
BRCA‐1/BRCA‐2 (SW620, MB231), deficient in BRCA‐1 (MX‐1), or BRCA‐2 (Capan‐1).  
Cells were seeded in their recommended growth medium and allowed to grow overnight at 
37°C, then incubated in media containing increasing concentrations of PARP inhibitors for 
12-14 days.  
In the BRCA1-deficient MX-1 xenograft tumor model, oral administration of 0.33 mg/kg
BMN 673fb once daily for 28 days resulted in significant antitumor activity (tumor growth 
delay/tumor regression; Figure 3).  Dose-related inhibition of tumor growth was observed 
at lower doses, while a higher dose (1.0 mg/kg/day) induced significant body weight loss 
with associated mortality.  Consistent with the antitumor effect, profound reduction in poly 
(ADP-ribose) (PAR) level (a measure of PARP activity) was observed in MX-1 xenografts 
following oral administration.  Complete suppression of BRCA1-deficient tumor growth 
was achieved in a 3-month study dosed at 0.165 mg/kg/BID [26].  Oral administration 
(0.33 mg/kg/day for 28 days) also resulted in antitumor activity in the PTEN-deficient 
LNCap, MDA-MB-468, and PC-3 xenograft models [26].  In addition, BID oral 
administration of BMN 673fb (0.33 mg/kg/day for 28 days) delayed the growth of the 
MLH-1–deficient HCT-116 xenograft tumor in nude mice.
Figure 3.  Single-agent antitumor efficacy in the BRCA1/2-deficient MX‐1 model.  PARP 
inhibitors AZD2281, talazoparib (BMN 673), or vehicle (10% DMAc, 6% Solutol HS15 


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and 84% PBS) was administered orally once daily for 28 consecutive days beginning Day 1 
(n=6).  Purple straight line indicates the daily dosing period.  P-value compares each 
treatment group with the vehicle only group.
Assessment of various dosing schedules in the mouse xenograft models indicated that 
continuous daily administration of BMN 673fb resulted in greater antitumor activity than 
intermittent administration at the same or higher dose levels (Figure 4).  BID dosing 
resulted in extended tumor growth delay or extended tumor regression compared to single 
daily (QD) dosing at an identical total daily dose level for 28-days.  These results suggest 
that continuous suppression of PARP activity is required for optimal antitumor activity. 
Figure 4.  QD versus BID dosing in the MX-1 xenograft model.  Talazoparib (BMN 673) 
administered orally at either 0.33 mg/kg once daily or 0.175 mg/kg BID for 28 consecutive 
days beginning Day 1 (n=6).  Purple straight line indicates the daily dosing period. 
Pharmacokinetic Studies
Pharmacokinetic studies were performed in rats and dogs.  BMN 673ts (tosylate salt) was 
selected as the dosing form by comparing the bioavailability of the free base and salt forms 
in 3 dogs; thereafter, all GLP pharmacokinetic and toxicology/TK studies used the salt 
form for oral and IV administration.  The oral formulation used in the GLP studies was a 
suspension in CMC (0.5% w/v).  The clinical presentation and formulation developed for 
the Phase 1 studies is a HPMC capsule containing BMN 673ts in a dry powder blend (25, 
50, 250 and 1000 μg free base equivalents/capsule.  A GLP bridging study compared the 
PK and bioavailability of the suspension and capsule in male and female dogs using the 
250-μg capsule.  BMN 673ts’ relative bioavailability following capsule administration 
compared to the suspension was 185% and 212% for males and females, respectively; for 
males and females combined, 197%.
Oral bioavailability, calculated from the ratio of area under the concentration-time curve 
(AUC) following oral administration relative to the AUC following intravenous (IV) 
administration (AUCoral/AUCIV), was > 42.7% in rats and > 50.5% in dogs based on single 
dose comparisons.  The compound was metabolically stable.  The terminal half-life (t½) of 


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talazoparib (BMN 673) at various doses in rats and dogs ranges from 28.5 to 32.0 hour and 
69.7 to 91.2 hour, respectively, which allows for once daily dosing.  Steady state 
concentrations were reached on Day 15 in rats and on Day 20 in dogs using daily 
administration of talazoparib (BMN 673).  Comparing Day 15 and 28 with Day 1 for all 
dose levels in dogs, AUC and Cmax increased from Day 1 to Day 15 to Day 28. 
 
Preclinical Studies
Five-day repeat dose toxicity and toxicokinetic (TK) studies with 28-day recovery were 
conducted in rats and dogs.  In dogs (the most sensitive species), talazoparib (BMN 673) 
was administered at dosage levels of 0.003, 0.01, 0.03, 0.1 mg/kg/day over 5 consecutive 
days.  Severe pancytopenia was observed in dogs treated at the two highest dose groups 
(0.03 and 0.1 mg/kg/day).  At these doses, the mean reticulocyte nadir occurred on day 6 
and the platelet and WBC nadirs on day 11.  These changes were reversed in the group 
treated at 0.03 mg/kg/day on days 17-18 (i.e., 12-13 days after the last dose of the drug).  In 
contrast, some animals in the group treated at 0.1 mg/kg/day died due to bacterial 
septicemia associated with bone marrow hypocellularity and lymphoid organ depletion.  
Remaining animals in this dose group were euthanized due to hypoactivity, hyperthermia, 
hypersalivation, and/or fecal abnormalities on day 12-13.  Coagulation parameters were 
unaffected.  After repeat-dose administration of daily oral talazoparib (BMN 673) in dogs 
for 5-days, the highest non-severely toxic dose (HNSTD) was 0.03 mg/kg/day.
Twenty-eight day repeat dose toxicity and TK studies with 28-day recovery were also 
conducted in rats and dogs.  In dogs (the most sensitive species), talazoparib (BMN 673) 
was administered at dosage levels of 0.0005, 0.0015, 0.005, 0.01 mg/kg/day over 28 
consecutive days.  Talazoparib related signs included hematology findings in males and 
females given 0.005 or 0.01 mg/kg/day such as mildly lower red cell mass, mildly to 
moderately lower platelet and absolute reticulocyte counts, and minimally to mildly lower 
white blood cell counts with a generalized decrease in all leukocytes.  All of these signs 
reversed or were reversing by the end of the recovery phase.  After repeat-dose 
administration of daily oral talazoparib (BMN 673) in dog for 28 days, the HNSTD was 
0.01 mg/kg/day.
The main nonclinical dose-related findings were changes in reticulocytes, platelet, white 
and red blood cell counts in repeat dose studies in rat and dog that were indicative of bone 
marrow hypocellularity and lymphoid tissue depletion.  Findings of increased cellular 
turnover in the gastrointestinal system and focal necrosis of the liver, testes, and ovary 
were dose related in severity and incidence.  BMN 673ts related mortalities were dose 
related, categorized as secondary toxicity and were due to either 1) septicemia secondary to 
bone marrow and lymphoid organ depletion (rat and dog) or 2) at higher dose levels, 
enteropathy defined by villous atrophy (rat only).  All primary toxicity findings were 
completely or partially reversible in the 28-day recovery time frame tested—decreased 
reticulocyte, platelet, RBC, and WBC counts were sensitive and early markers of target 
organ toxicity.
Non-Clinical Pharmacokinetics


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Talazoparib (BMN 673) was assessed for activities on PARG, receptor/ion channel and 
enzyme activity, CYP450, effects on hERG cell current, respiratory and CNS systems and 
in mutagenic AMES tests, in vitro.  No significant undesired effects or talazoparib-related 
genotoxicity were observed in these studies.
Clinical Experience
The following includes potentially proprietary information from the July 2017 talazoparib 
Investigator’s Brochure:
Approximately 17 studies of talazoparib (single-agent and combination) are ongoing, and 
as of 30 Nov 2016, approximately 439 patients and 18 healthy volunteers have received 
talazoparib at doses up to 2 mg/day in company-sponsored clinical studies in hematologic 
malignancies and solid tumors. Two ongoing investigator-sponsored studies are evaluating 
the combination of talazoparib with DNA-damaging chemotherapy (temozolomide, 
irinotecan). The majority of available efficacy and safety data was obtained from studies in 
solid tumors. A Phase 1 study in patients with advanced or recurrent solid tumors defined 
the maximum tolerated dose (MTD) of talazoparib as 1 mg/day. Data from this study 
demonstrated objective responses and/or clinical benefit in patients with breast, 
ovarian/peritoneal, and pancreatic cancer; SCLC; and Ewing sarcoma. A Phase 2 study 
evaluating single-agent talazoparib in patients with locally advanced or metastatic breast 
cancer with deleterious germline BRCA mutations demonstrated single-agent activity with 
an objective response rate of 27.7%. In the cohort of patients who were previously treated 
with platinum-containing regimens (N = 48 who were tumor-evaluable), 2 patients had 
complete responses (CRs). An ongoing Phase 3 study is evaluating talazoparib and 
physician-choice therapies in patients with germline BRCA mutations who have received 
no more than 3 prior chemotherapy regimens for locally advanced or metastatic breast 
cancer. In a Phase 1 study of talazoparib in combination with temozolomide or irinotecan, 
confirmed partial responses (PRs) were observed in patients with platinum-resistant 
ovarian cancer, cervical adenocarcinoma, SCLC, and triple-negative breast cancer.
Treatment-emergent adverse events (TEAEs) of all causality reported in ≥20% of patients
administered single-agent talazoparib 1 mg/day are related to myelosuppression (anemia,
thrombocytopenia, neutropenia), GI toxicity (nausea, diarrhea, constipation), fatigue,
alopecia, and headache. TEAEs of National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE) grade ≥3 severity in ≥5% of patients were related to
myelosuppression. The adverse events (AEs) associated with talazoparib are detectable
through routine laboratory and clinical monitoring and may be managed with supportive 
care or dose reductions or interruptions as described in each study protocol. 
The pharmacokinetics (PK) of talazoparib as a single agent was evaluated in 142 adult
patients with hematologic malignancies and solid tumors at doses of 0.025 to 2 mg/day
administered orally, as a single dose or as multiple doses. The PK was similar in patients of
each cancer type and no differences were apparent between males and females. Oral
absorption of talazoparib was rapid and independent of dose after administration of single 
or multiple doses. Elimination appeared to follow biphasic kinetics; at 1 mg/day (the
recommended dose), the mean terminal half-life (t1/2) was approximately 2 days. Renal
excretion was a major elimination pathway for unchanged parent talazoparib. Following


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repeated administration at 1 mg/day, talazoparib accumulated approximately 2.4-fold 
relative to a single dose. A food-effect study showed that food had no clinically meaningful 
effect on the extent of absorption; talazoparib is being administered without regard to food 
in ongoing safety and efficacy studies.
At test concentrations in excess of therapeutic exposures (approximately 200-fold Cmax),
talazoparib does not markedly induce or inhibit CYP enzymes. Furthermore, concentrations
in excess of therapeutic exposures (approximately 20-fold Cmax) did not inhibit membrane
transporter function. Therefore, it is unlikely that talazoparib will demonstrate clinically
significant DDIs when co-administered with corresponding CYP or transporter substrates.
However, talazoparib is a substrate for P-glycoprotein (P-gp) and breast cancer resistance 
protein (BCRP), and plasma talazoparib concentrations may increase or decrease when
Co-administered with P-gp or BCRP inhibitors or inducers, respectively.
Additional ongoing Phase 1 company-sponsored clinical studies are evaluating the 
excretion and plasma PK of carbon 14 (14C)-labeled talazoparib; the PK of talazoparib in 
patients with renal impairment or hepatic impairment, DDIs, and the effects of talazoparib 
on cardiac repolarization. Clinical development of talazoparib is ongoing in solid tumors as
monotherapy and in combination with other agents.
Potential Food and Drug Interactions
Based on in vitro data, talazoparib (BMN 673) is not likely to inhibit metabolism via 
human cytochrome P450 (CYP 450) enzymes.  Effects of co-administration of repeat 
dosing of BMN 673 with other drugs are unknown.
Preliminary data from a study to evaluate the effect of food on the pharmacokinetics of 
talazoparib (BMN 673) in healthy male subjects suggest that food delayed absorption of 
talazoparib (BMN 673) as indicated by a prolonged Tmax and reduced Cmax in the fed 
compared to fasted state, but did not affect the overall extent of absorption as indicated by 
equivalent AUC0-last and AUC0-∞ values in the fed and fasted states.  Based on these 
findings, talazoparib (BMN 673) will be taken without regard to food in this current study. 
2.3
Rationale
Talazoparib (BMN 673), a highly selective and potent PARP inhibitor, has shown 
anticancer activity in preclinical models and early clinical trials in the setting of defects in 
the DNA repair pathway.  This pilot study will evaluate the pharmacodynamic effects of 
talazoparib (BMN 673) on DNA damage and apoptosis markers in tumor biopsy tissue and 
assess for the antitumor effect of treatment with talazoparib (BMN 673) in patients with 
advanced ovarian, breast, or other solid tumors, and deleterious BRCA mutations.   
2.4
Correlative Studies Background
Tumor biopsies will be mandatory and will be evaluated for pharmacodynamic (PD) 
studies for evidence of DNA damage repair and apoptosis (e.g., γH2AX, ERCC1, pNbs1, 
XPF, RAD51, pT1989ATR, activated cleaved caspase 3, and as indicators of ATR/ATM 


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activation, chk1 and chk2).  Circulating tumor cells (CTCs will be collected pre-dose and 
following study drug administration, on day 1 of every subsequent cycle (every 3 cycles for 
patients on study for more than 12 months), at the time of the optional restaging follow-up 
biopsy (if applicable), and at time of disease progression to measure any changes in the 
number of circulating CTCs and the level of γH2AX, and to evaluate whether we can 
measure changes in the phenotype over time to explore any correlation with response to 
treatment or disease progression.  Analysis will be performed in Dr. Bob Kinders’ lab at the 
Frederick National Laboratory for Cancer Research.
Histone H2AX is one of the H2A histones present in nucleosomes in normal and cancer 
tissues and is one of the earliest markers of DNA double-strand breaks [28-30].  γH2AX is 
phosphorylated at its C-terminus (serine 139 in humans) within minutes following DNA 
double-strand breaks marking the chromatin domain around the broken chromosomal DNA 
ends, thus allowing the recruitment of repair factors [28, 30-33].  The levels of γH2AX are 
directly correlated to the amounts of double-strand breaks, and can be used as a dosimeter 
and biomarker for DNA double-strand breaks.  
Because the product of the PARP enzyme is PAR molecules, a validated immunoassay will 
be used to determine the amount of cellular PAR in tumor biopsies as a clinical biomarker 
of PARP inhibition [34, 35].
Additionally, to further understand the potential for carcinomas to adapt to treatment by 
undergoing epithelial-mesenchymal transition (EMT) and the implications of initial 
epithelial-mesenchymal phenotype on the response of patients to talazoparib [36, 37], 
tumor biopsies will be evaluated for markers of epithelial/mesenchymal state, such as E-
cadherin, vimentin, and β-catenin.
3
PATIENT SELECTION
3.1
Eligibility Criteria
Adult patients with documented deleterious BRCA 1 or 2 mutations with 
histologically confirmed ovarian, primary peritoneal, breast, prostate, pancreas, 
gastric or other solid tumor whose disease has progressed following at least one 
standard therapy or who have no acceptable standard treatment options.
Patients with ovarian cancer should have one prior platinum-based 
chemotherapeutic regimen for management of primary disease containing 
carboplatin, cisplatin, or another organoplatinum compound.  This initial treatment 
may have included intraperitoneal therapy, consolidation, biologic/targeted (non-
cytotoxic) agents or extended therapy administered after surgical or non-surgical 
assessment.  Ovarian cancer patients with both platinum-sensitive and platinum-
resistant disease are eligible.  Patients with platinum-refractory disease are NOT 
eligible.
Definitions:


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
Platinum sensitive ovarian cancer is defined as patients who respond to 
platinum-based therapy (complete or partial) and then progress/recur more 
than 6 months after their last platinum dose (i.e., platinum-free interval is > 6 
months).

Platinum resistant ovarian cancer is defined as patients who respond to 
platinum-based therapy (complete or partial) and then progress/recur within 6 
months of their last platinum dose (i.e., platinum-free interval is ≤ 6 months).

Platinum refractory ovarian cancer is defined as patients who have progression 
of disease while receiving platinum-based chemotherapy or who fail to achieve 
at least a partial response to platinum-based chemotherapy (i.e., best response 
to platinum-based chemotherapy is stable disease).  
Patients with metastatic disease must have received at least one line of standard of 
care (SOC) treatment for metastatic disease prior to enrollment.
3.1.1
Age ≥18 years of age. 
3.1.2
ECOG performance status ≤ 2 (see Appendix A).
3.1.3
Life expectancy of greater than 3 months.
3.1.4
Patients must have normal organ and marrow function as defined below:
leukocytes
≥3,000/mcL
absolute neutrophil count
≥1,500/mcL
platelets
≥100,000/mcL
total bilirubin
≤1.5 X institutional upper limit of normal
AST(SGOT)/ALT(SGPT)
≤3 X institutional upper limit of normal
creatinine
≤1.5X institutional upper limit of normal
OR
‒ creatinine clearance
≥60 mL/min for patients with creatinine levels 
above institutional normal.
3.1.5
The effects of talazoparib (BMN 673) on the developing human fetus are unknown.  
For this reason and because PARP inhibitors are known to be teratogenic, women 
of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry, for 
the duration of study participation, and for 30 days after completing study 
treatment.  Should a woman become pregnant or suspect she is pregnant while she 
or her partner is participating in this study, she should inform her treating physician 
immediately.  Men treated or enrolled on this protocol must also agree to use 
adequate contraception prior to the study, for the duration of study participation, 
and for 3 months after completion of talazoparib (BMN 673) administration.
3.1.6
Patients must be able to swallow whole tablets or capsules.  Nasogastric or G-tube 
administration is not allowed.  Any gastrointestinal disease which would impair 
ability to swallow, retain, or absorb drug is not allowed.


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3.1.7
Ability to understand and the willingness to sign a written informed consent 
document.
3.1.8
Patients with HER2-positive advanced breast cancer or ovarian cancer should have 
received at least two lines of systemic therapy in the advanced setting.
3.1.9
Patients with prostate cancer can continue to receive treatment with GnRH agonists 
while on study, as long as there is evidence of disease progression on therapy. 
3.2
Exclusion Criteria
3.2.1
Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study or those who have not 
recovered from adverse events due to agents administered more than 4 weeks 
earlier.  Patients who have had prior treatment with any PARP inhibitors are 
ineligible.
3.2.2
Patients who are receiving any other investigational agents.
3.2.3
Patients with known active brain metastases or carcinomatous meningitis are 
excluded from this clinical trial.  Patients whose brain metastatic disease status has 
remained stable for ≥ 4 weeks following treatment of brain metastases are eligible 
to participate at the discretion of the principal investigator.
3.2.4
Eligibility of subjects receiving any medications or substances with the potential to 
affect the activity or pharmacokinetics of talazoparib (BMN 673) will be 
determined following review by the principal investigator.
3.2.5
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements.
3.2.6
Pregnant women are excluded from this study because the effects of the study drugs 
on the developing fetus are unknown. 
3.2.7
HIV-positive patients on combination antiretroviral therapy are ineligible because 
of the potential for pharmacokinetic interactions with talazoparib (BMN 673).  In 
addition, these patients are at increased risk of lethal infections when treated with 
marrow-suppressive therapy.  Appropriate studies will be undertaken in patients 
receiving combination antiretroviral therapy when indicated.
3.2.8
Patients who require use of coumarin-derivative anticoagulants such as warfarin are 
excluded.  Low molecular weight heparin is permitted for prophylactic or 
therapeutic use. Low-dose warfarin (≤1 mg/day) is permitted.
3.2.9
Women who are currently lactating.


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3.3
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.
Accrual Targets
Sex/Gender
Ethnic Category
Females
Males
Total
Hispanic or Latino
3
+
1
=
4
Not Hispanic or Latino
17
+
3
=
20
Ethnic Category: Total of all subjects
20 (A1)
+
4 (B1)
=
24 (C1)
Racial Category
American Indian or Alaskan Native
0
+
0
=
0
Asian
1
+
0
=
1
Black or African American
2
+
1
=
3
Native Hawaiian or other Pacific Islander
0
+
0
=
0
White
17
+
3
=
20
Racial Category: Total of all subjects
20 (A2)
+
4 (B2)
=
24 (C2)
(A1 = A2)
(B1 = B2)
(C1 = C2)
3.4
Screening Evaluation
3.4.1
Histologic confirmation of primary tumor tissue or of known recurrence will be 
required from each participant to confirm diagnosis.  Documentation of presence of 
deleterious BRCA mutations should be available at the time of enrollment.  
3.4.2
History and physical examination: Complete history and physical examination 
(including height, weight, vital signs, and performance score) will be conducted 
within 72 hours prior to enrollment. 
3.4.3
Imaging Studies (Baseline): Every participant should have an evaluation of known 
sites of disease as part of the baseline evaluation.  All patients will be required to 
undergo a CT scan of the chest/abdomen/pelvis to evaluate sites of disease within 
28 days prior to enrollment.  MRI evaluation of site of disease may be performed in 
lieu of CT evaluation at the discretion of the principal investigator if it is the 
opinion of the investigator that this modality would provide a more accurate 
assessment of disease than a CT would, for a given site.
3.4.4
Laboratory Evaluation: Baseline laboratory data are to be obtained within 72 hours 
prior to enrollment:

Hematological Profile: CBC with differential.

Biochemical Profile: albumin, total bilirubin, BUN, calcium, creatinine, 
phosphorus, SGOT [AST], SGPT [ALT], magnesium, potassium, and 
sodium.


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
Coagulation Profile: PT, PTT, INR as clinically indicated prior to tumor 
biopsy.

Serum pregnancy test for female participants of childbearing potential.
4
REGISTRATION PROCEDURES
4.1
Registration Process
Authorized staff must register an eligible candidate with NCI Central Registration Office 
(CRO) within 24 hours of signing consent.  A registration Eligibility Checklist from the 
Web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and 
sent via encrypted email to: NCI Central Registration Office (HOIS) ncicentralregistration-
l@mail.nih.gov.  After confirmation of eligibility at Central Registration Office, CRO staff 
will call pharmacy to advise them of the acceptance of the patient on the protocol prior to 
the release of any investigational agents.  Verification of Registration will be forwarded 
electronically via e-mail.  Please note that it is very important for all registrars to acquire 
encrypted e-mail from NIH Help Desk, since the verification of registration includes 
patient’s information.  A recorder is available during non-working hours.
Off Protocol Therapy and Off-Study Procedure: Authorized staff must notify the 
Central Registration Office (CRO) when a patient is taken off protocol therapy and when a 
subject is taken off-study.  A Participant Status Update Form from the Web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed 
and sent via encrypted email to: NCI Central Registration Office (HOIS) 
ncicentralregistration-l@mail.nih.gov.
5
TREATMENT PLAN
This is an open-label pilot trial of single-agent talazoparib (BMN 673), an oral PARP inhibitor, 
in patients with histologically confirmed BRCA-positive ovarian or primary peritoneal 
carcinoma; BRCA-positive breast cancer; other solid tumors (other than breast or ovarian) 
whose disease has progressed following at least one line of standard therapy or who have no 
acceptable standard treatment options. 
Reported adverse events and potential risks for talazoparib (BMN 673) are described in Section 
7.  Appropriate dose modifications for talazoparib (BMN 673) are described in Section 6.
History and physical examination can be done up to 3 days before the start of a new cycle.  
Patients will be examined at baseline and within 2 days of day 8 at the clinical center during 
the first cycle and then prior to every new cycle (up to 3 days before start of a new cycle).
Labs (CBC with differential; serum chemistries) will be performed at baseline, within 2 days of 
day 8, and during week 3 of cycle 1, and then at the start of each subsequent cycle (up to 3 
days before start of a new cycle).


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CT scans will be performed at baseline, and repeat-imaging scans will be performed every 2 
cycles.  MRI evaluation of site of disease may be performed in lieu of CT evaluation at the 
discretion of the principal investigator if it is the opinion of the investigator that this modality 
would provide a more accurate assessment of disease than a CT would for a given site.
5.1
Agent Administration
Talazoparib (BMN 673) will be administered orally at 1000 µg/day each day, which is the 
recommended Phase II dose.  Each cycle is 28 days (± 1 day for scheduling).  Patients will 
be asked to maintain a Study Medication Diary (Appendix B) and record each dose of 
study medication.  Patients will be given instructions for completing the medication diary 
and will be asked to return it to the clinic staff at the end of each cycle.  After cycle 2, 
patients may miss up to 10% of the planned doses for any cycle without causing a protocol 
violation.
Patients will be considered evaluable for the primary objective of the trial if their biopsy 
procedures yield matched, evaluable (i.e., ≥5% tumor content) baseline and day 8 tumor 
biopsies.
Reported adverse events and potential risks are described in Section 7.  Appropriate dose 
modifications are described in Section 6.  No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to treat the 
patient’s malignancy.
5.2
General Concomitant Medication and Supportive Care Guidelines
The predominant toxicity observed in clinical and non-clinical toxicology studies was bone 
marrow suppression, with effects on reticulocytes, platelets, and red and white blood cell 
counts.  Weekly blood counts will be obtained during the first cycle, and then at the start of 
each cycle.  If any weekly evaluation demonstrates grade ≥ 2 neutropenia or 
thrombocytopenia, a repeat hematology assessment will be obtained 3-5 days later.
All patients will be provided with the best available supportive care.  All concurrent 
medications should be documented prior to initiation of treatment, and be periodically 
reviewed with the patient.
Based on in vitro data, talazoparib (BMN 673) is not likely to inhibit metabolism via 
human cytochrome P450 (CYP 450) enzymes.  Because there is a potential for interaction 
with other concomitantly administered drugs, the case report form will capture the 
concurrent use of all other drugs, over-the-counter medications, or alternative therapies.
5.2.1
Nausea/Vomiting
Anti-emetics will not be administered routinely prior to talazoparib (BMN 673).  
However, if a patient develops nausea/vomiting, anti-emetics such as but not 
limited to prochlorperazine, metoclopramide, 5-HT3 antagonists may be given.  In 
addition, if a patient develops nausea and/or vomiting that is Grade 2 or greater, 


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antiemetics may be instituted prophylactically at the discretion of the investigator.  
Nausea and vomiting will be considered refractory if it does not resolve to≤ Grade 1 
with treatment with a combination of at least 2 of the antiemetics within 24 hours.
5.2.2
Diarrhea
If diarrhea develops and does not have an identifiable cause other than study drug 
administration, anti-diarrheals such as Lomotil (diphenoxylate HCl 2.5 mg + 
atropine sulfate 0.025 mg/tablet) dosed according to package insert or loperamide 4 
mg po after the first unformed stool with 2 mg po with every 2 hours as long as 
unformed stools continue (4 mg every 4 hours while asleep).  No more than 16 mg 
of loperamide should be taken during a 24-hour period).  This regimen can be 
repeated for each diarrheal episode.  Diarrhea will be considered refractory if it 
does not resolve within 24 hours ≤ to Grade 2 with the above regimen (16 mg, or 
less if there is resolution of the symptoms, of loperamide in a 24-hour period).  If 
the patient develops blood or mucus in the stool, dehydration, or hemodynamic 
instability, or fever along with the diarrhea, anti-diarrheals will be discontinued and 
the patient will be treated with IV fluids and antibiotics as medically indicated.
5.2.3
Neutropenia
To reduce the risk of severe myelosuppression events, a complete blood count 
(CBC) should be performed weekly during cycle 1, and at the start of each 
subsequent cycle (up to 3 days before start of new cycle).  Febrile neutropenia is a 
life-threatening complication requiring hospitalization and urgent broad-spectrum 
antibiotics, as well as an aggressive search for the source and microbial cause of the 
episode.  Growth factors to prevent neutropenia will not be administered 
prophylactically.  If necessary, they may be administered according to accepted 
American Society of Clinical Oncology (ASCO) guidelines to allow re-treatment.
5.2.4
Anemia
Symptomatic anemia should be treated with red blood cell transfusion and is 
recommended if the hemoglobin falls below 8 g/dL.  The initiation of erythropoietic 
therapy for the management of chemotherapy-induced anemia follows the 
American Society of Hematology/ASCO clinical practice guidelines 
(http://www.asco.org).
5.2.5
Thrombocytopenia
Thrombocytopenia will be treated conservatively.  In the absence of bleeding, or a 
necessary invasive procedure, platelet transfusions should be given for a platelet 
count ≤10,000/mm3.  If invasive procedure(s) is (are) planned, or the patient 
develops bleeding, platelet transfusions should be administered in accordance with 
the standard of practice, usually maintaining a platelet count above 50,000/mm3.


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5.3
Duration of Therapy
In the absence of treatment delays due to adverse events, treatment may continue until one 
of the following criteria applies:
•
Disease progression
•
Intercurrent illness that prevents further administration of treatment
•
Significant toxicity occurs despite 2 dose reductions as described in Section 6 
•
Pregnancy
•
Patient decides to withdraw from the study, or
•
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator.
5.4
Duration of Follow Up
Patients will be followed for 30 days after the last dose is administered or until one of the 
following occurs: patient enrolls on another protocol, patient receives standard of care, or 
death, whichever comes first.  The follow-up will consist of a phone call between Days 27-
30 after the last dose to evaluate adverse events that were ongoing and any new events that 
might be deemed related to the therapy.  Toxicities felt to be possibly, probably, or 
definitely related to the study drugs that have not resolved or stabilized by Day 30 post-
treatment will be followed until stabilization or resolution via phone calls as clinically 
indicated.
5.5
Criteria for Removal from Study
Patients will be removed from study for one of the following reasons: completed 30-day 
follow up period or toxicities are unresolved but stabilized, patient enrolls on another 
protocol, or patient receives standard of care.  The reason for study removal and the date 
the patient was removed must be documented in the medical record and communicated by 
fax to Central Registration per Section 4.
6
DOSING DELAYS/DOSE MODIFICATIONS
Toxicities should have resolved to ≤ Grade 2 prior to starting the next cycle.  Treatment may 
be delayed for a maximum of 2 weeks beyond the actual cycle length of 28 days for toxicities 
that develop and do not resolve as defined above.  Beyond two weeks, the patient will not 
receive further therapy on this protocol and will be followed for resolution of toxicities.  
Treatments may be delayed up to 7 days past the end of the previous cycle of 28 days for 
scheduling conflicts at the discretion of the investigator. 
Patients will be allowed up to 2 dose reductions per the table below.  If more than 2 dose 
reductions are required, the patient will be removed from the study.


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Dose Level
Dose (μg/day)
1
1000
-1
750
-2
500
6.1
Dose Modifications
Dose modifications are defined below:
6.1.1
Patients with creatinine clearance of 30-59 mL/min will be dose reduced to DL-1 
(750 µg/day), per the approved talazoparib package insert, and may be re-escalated 
to DL1 with a creatinine clearance ≥60 mL/min.
6.1.2
Grade 2 Drug-related toxicity: No changes will be made to the dose of talazoparib 
(BMN 673) for Grade 2 toxicities.  Therapy will not be interrupted for Grade 2 
hematologic toxicities.
6.1.3
Grade 3-4 Drug-related non-hematologic toxicities: Doses of talazoparib (BMN 
673) will be held until toxicities recover to ≤ Grade 2 or baseline prior to re-
initiating treatment at the next lower dose level.  Electrolyte abnormalities will not 
require dose reduction if resolution to Grade 2 or less is documented within 72 
hours.  Dose modifications for nausea, vomiting, and diarrhea will be made only if 
they are refractory to treatment (See Section 5.2).
6.1.4
Grade 3 Drug-related hematologic toxicities: Dose of talazoparib (BMN 673) will 
be held until hematologic toxicities, except anemia, lymphopenia, or leucopenia in 
the absence of Grade 3 or higher neutropenia, have resolved to ≤ Grade 2 prior to 
re-initiating treatment at the same dose level.
6.1.5
Grade 4 Drug-related Hematologic Toxicities: Dose of talazoparib (BMN 673) will 
be held until hematologic toxicities, except anemia, lymphopenia, or leucopenia in 
the absence of Grade 4 neutropenia, have resolved to ≤ Grade 2 prior to re-initiating 
treatment at the next lower dose level.
7
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting (via CTEP-AERS) in addition to 
routine reporting.


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7.1
Comprehensive Adverse Events and Potential Risks List (CAEPR)
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Talazoparib (BMN 
673, NSC 771561)
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset 
of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI 
(except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further 
clarification.  Frequency is provided based on 553 patients.  Below is the CAEPR for Talazoparib 
(MDV3800, BMN 673).
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the 
SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required.
Version 2.3, June 7, 2019(1)
 Adverse Events with Possible 
 Relationship to Talazoparib (MDV3800, BMN 673)
 (CTCAE 5.0 Term)
[n= 553]
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia
Anemia (Gr 2)
Febrile neutropenia
GASTROINTESTINAL DISORDERS
Abdominal pain
Abdominal pain (Gr 2)
Constipation
Constipation (Gr 2)
Diarrhea
Diarrhea (Gr 2)
Dyspepsia
Mucositis oral
Nausea
Nausea (Gr 2)
Typhlitis
Vomiting
Vomiting (Gr 2)
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Fatigue
Fatigue (Gr 2)
Fever
Fever (Gr 2)
Pain
Pain (Gr 2)
INFECTIONS AND INFESTATIONS
Infection (2)
Infection2 (Gr 2)
INVESTIGATIONS
Lymphocyte count decreased
Neutrophil count decreased
Neutrophil count decreased (Gr 4)
Platelet count decreased
Platelet count decreased (Gr 4)
White blood cell decreased
White blood cell decreased 
(Gr 3)
METABOLISM AND NUTRITION DISORDERS
Anorexia
Anorexia (Gr 2)
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)


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 Adverse Events with Possible 
 Relationship to Talazoparib (MDV3800, BMN 673)
 (CTCAE 5.0 Term)
[n= 553]
Likely (>20%)
Less Likely (<=20%)
Rare but Serious (<3%)
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Leukemia secondary to oncology 
chemotherapy
Myelodysplastic syndrome
Treatment related secondary 
malignancy
NERVOUS SYSTEM DISORDERS
Dizziness
Dizziness (Gr 2)
Headache
Headache (Gr 2)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Alopecia
Alopecia (Gr 2)
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.
2Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC.
3Neuropathy peripheral may include both Peripheral sensory neuropathy and Peripheral motor neuropathy under the 
NERVOUS SYSTEM DISORDERS SOC.
Adverse events reported on talazoparib (MDV3800, BMN 673) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that talazoparib (MDV3800, BMN 673) caused 
the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia)
CARDIAC DISORDERS - Atrial flutter; Sinus bradycardia
GASTROINTESTINAL DISORDERS - Abdominal distension; Flatulence; Intra-abdominal hemorrhage; Small 
intestinal obstruction; Toothache
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; General disorders and 
administration site conditions - Other (accidental overdose); Non-cardiac chest pain
HEPATOBILIARY DISORDERS - Hepatic failure; Sinusoidal obstruction syndrome
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase increased; Weight loss
METABOLISM AND NUTRITION DISORDERS - Hyperkalemia; Hypokalemia
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Generalized 
muscle weakness; Muscle cramp; Myalgia; Neck pain; Pain in extremity
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (glioblastoma multiforme); Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (metastatic breast cancer); Neoplasms benign, malignant and 
unspecified (incl cysts and polyps) - Other (metastases to meninges)
NERVOUS SYSTEM DISORDERS - Dysgeusia; Intracranial hemorrhage; Nervous system disorders - Other 
(neuropathy peripheral)(3); Nervous system disorders - Other (nonserious axonal sensorimotor polyneuropathy); 
Syncope; Transient ischemic attacks
PSYCHIATRIC DISORDERS - Anxiety; Insomnia; Psychiatric disorders - Other (mental status changes)
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; Epistaxis; Oropharyngeal 
pain; Pleural effusion; Respiratory, thoracic and mediastinal disorders - Other (obstructive airways disorder)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Rash maculo-papular
VASCULAR DISORDERS - Thromboembolic event


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Note: Talazoparib (BMN 673) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent.
7.2
Adverse Event Characteristics

CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 will be utilized until March 31, 2018 for AE reporting.  CTCAE version 5.0 
will be utilized for AE reporting beginning April 1, 2018.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0.  A copy of the CTCAE 
version 5.0 can be downloaded from the CTEP Web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
Attribution of the AE:

Definite – The AE is clearly related to the study treatment.

Probable – The AE is likely related to the study treatment.

Possible – The AE may be related to the study treatment.

Unlikely – The AE is doubtfully related to the study treatment.

Unrelated – The AE is clearly NOT related to the study treatment.
7.3
Expedited Adverse Event Reporting
7.3.1
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Expedited Reporting System), accessed via the CTEP Web site 
(http://ctep.cancer.gov).  The reporting procedures to be followed are presented in 
the “NCI Guidelines for Investigators: Adverse Event Reporting Requirements for 
DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from 
the CTEP Web site (http://ctep.cancer.gov).  These requirements are briefly 
outlined in the tables below (Section 7.3.2).
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to 
be made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is 
restored, the 24-hour notification phoned in must be entered electronically into 
CTEP-AERS by the original submitter at the site.
7.3.2
Expedited Reporting Guidelines
Use the NCI protocol number and the protocol-specific patient ID assigned during 
trial registration on all reports.
Note:  A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below.  Attribution to treatment or 
other cause must be provided.
Death due to progressive disease should be reported as Grade 5 “Disease 
Progression” in the system organ class (SOC) “General disorders and 


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administration site conditions”.  Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be 
submitted.
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:  
1)
Death
2)
A life-threatening adverse event 
3)
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 
24 hours 
4)
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
5)
A congenital anomaly/birth defect. 
6)
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition (FDA, 21 CFR 312.32; ICH E2A and ICH E6).
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below.
Hospitalization
Grade 1 and Grade 2 Timeframes
Grade 3-5
Timeframes
Resulting in 
Hospitalization 
≥ 24 hrs
10 Calendar Days
Not resulting in 
Hospitalization 
≥ 24 hrs
Not required
24-Hour 5 Calendar 
Days
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR.
Expedited AE reporting timelines are defined as:
o
“24-Hour; 5 Calendar Days” – The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour 
report.
o
“10 Calendar Days” – A complete expedited report on the AE must be submitted within 10 calendar days 
of learning of the AE.
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for:

All Grade 3, 4, and Grade 5 AEs
Expedited 10 calendar day reports for:

Grade 2 AEs resulting in hospitalization or prolongation of hospitalization
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period.
Effective Date:  May 5, 2011


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7.3.3
Protocol-specific expedited AE reporting exclusions
For this protocol only, certain AEs/grades are exceptions to the Expedited 
Reporting Guidelines and do not require expedited reporting (i.e., CTEP-AERS).  
These are any grade lymphopenia, any grade alopecia, Grade 2 electrolyte (sodium, 
potassium, phosphorous, magnesium) abnormalities, Grade 2 anemia, Grade 2 
hypoalbuminemia, Grade 2 hyperglycemia, Grade 2 INR, Grade 2 PTT, Grade 2 
hyperglycemia, and Grade 2 hyperuricemia will NOT be reported through CTEP-
AERS but will be reported in the routine data submissions.
7.3.4
Pregnancy, Fetal Death, and Death Neonatal
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form should be completed for 
patients who became pregnant on study, and faxed along with any additional 
medical information to 301-230-0159.  The potential risk of exposure of the fetus to 
the investigational agent(s) or chemotherapy agent(s) should be documented in the 
“Description of Event” section of the CTEP-AERS report.
7.3.4.1 Pregnancy

Because patients who become pregnant on study risk intrauterine exposure 
of the fetus to agents which may be teratogenic, DCTD/DCP is requesting 
that pregnancy should be reported in an expedited manner via CTEP-AERS 
as Grade 3 “Pregnancy, puerperium and perinatal conditions – Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal conditions 
SOC.

The pregnancy outcome for patients on study should be reported via CTEP-
AERS at the time the outcome becomes known, accompanied by the same 
Pregnancy Report Form used for the initial report.
7.3.4.2 Pregnancy loss

Pregnancy loss is defined in CTCAE as “Death in utero.” Any pregnancy 
loss should be reported expeditiously, as Grade 4 “Pregnancy loss” under 
the Pregnancy, puerperium and perinatal conditions SOC.

A pregnancy loss should NOT be reported as a Grade 5 event under the 
Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-
AERS recognizes this event as a patient death.
7.3.4.3 Death Neonatal

Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by the 
investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously.


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
A neonatal death should be reported expeditiously as Grade 4 “Death 
neonatal” under the General disorders and administration SOC.

Neonatal death should NOT be reported as Grade 5 “Death neonatal” under 
the General disorders and administration SOC.  If reported as such, the 
CTEP-AERS interprets this as a death of the patient being treated.
7.3.5
NCI-IRB Expedited Reporting of Adverse Events, Unanticipated Problems, and 
Deaths
7.3.5.1 Definitions
Adverse event
An adverse event is defined as any reaction, side effect, or untoward event that 
occurs during the course of the clinical trial associated with the use of a drug in 
humans, whether or not the event is considered related to the treatment or clinically 
significant.  For this study, AEs will include events reported by the patient, as well 
as clinically significant abnormal findings on physical examination or laboratory 
evaluation.  A new illness, symptom, sign or clinically significant laboratory 
abnormality or worsening of a pre-existing condition or abnormality is considered 
an AE.  All AEs must be recorded on the AE case report form unless otherwise 
noted in Section 7.3.3.
All AEs, including clinically significant abnormal findings on laboratory 
evaluations, regardless of severity, will be followed until satisfactory resolution.  
AEs should be reported up to 30 days following the last dose of study drug.  AEs 
that are considered treatment related, expected, continuing, but not resolvable by 30 
days after treatment completion (e.g., alopecia) will not be followed after the 30-
day period.
An abnormal laboratory value will be considered an AE if the laboratory 
abnormality is characterized by any of the following:

Results in discontinuation from the study

Is associated with clinical signs or symptoms

Requires treatment or any other therapeutic intervention

Is associated with death or another serious adverse event, including 
hospitalization

Is judged by the Investigator to be of significant clinical impact

If any abnormal laboratory result is considered clinically significant, the 
investigator will provide details about the action taken with respect to the 
test drug and about the patient’s outcome.
Suspected adverse reaction
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event.  For the purposes of IND safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 


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relationship between the drug and the adverse event.  A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which 
means any adverse event caused by a drug.
Unexpected adverse reaction
An adverse event or suspected adverse reaction is considered “unexpected” if it is 
not listed in the investigator brochure or is not listed at the specificity or severity 
that has been observed; or, if an investigator brochure is not required or available, is 
not consistent with the risk information described in the general investigational plan 
or elsewhere in the current application.  “Unexpected” also refers to adverse events 
or suspected adverse reactions that are mentioned in the investigator brochure as 
occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.
Serious 
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition 
of a Serious Adverse Event or if it compromises the safety, welfare, or rights of 
subjects or others.
Serious Adverse Advent
An adverse event or suspected adverse reaction is considered serious if in the view 
of the investigator or the sponsor, it results in any of the following:
Death,
A life-threatening adverse drug experience
Inpatient hospitalization or prolongation of existing hospitalization
Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions
A congenital anomaly/birth defect.
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.
Disability
A substantial disruption of a person’s ability to conduct normal life functions.
Life-threatening adverse drug experience
Any adverse event or suspected adverse reaction that places the patient or subject, 
in the view of the investigator or sponsor, at immediate risk of death from the 
reaction as it occurred, i.e., it does not include a reaction that had it occurred in a 
more severe form, might have caused death.
Protocol Deviation (NIH Definition)
Any change, divergence, or departure from the IRB-approved research protocol.


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Non-compliance (NIH Definition)
The failure to comply with applicable NIH Human Research Protections Program 
(HRPP) policies, IRB requirements, or regulatory requirements for the protection of 
human research subjects.
Unanticipated Problem
Any incident, experience, or outcome that:

Is unexpected in terms of nature, severity, or frequency in relation to
(a) the research risks that are described in the IRB-approved 
research protocol and informed consent document; Investigator’s 
Brochure or other study documents, and
(b) the characteristics of the subject population being studied; AND

Is related or possibly related to participation in the research; AND

Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized.
7.3.5.2 NCI IRB and Clinical Director Reporting Requirements
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and 
NCI Clinical Director:

All deaths, except deaths due to progressive disease

All protocol deviations

All unanticipated problems

All non-compliance
Reports must be received within 7 days of PI awareness via iRIS.
7.3.5.3 NCI-IRB Reporting of IND Safety Reports
Only IND Safety Reports that meet the definition of an unanticipated 
problem will need to be reported to the NCI IRB.
7.4
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions.  AEs reported 
through CTEP-AERS must also be reported in routine study data submissions.
7.4.1
NCI-IRB Requirements for PI Reporting of Adverse Events at Continuing Review
System 
Organ Class
CTCAE 
Term
Grade
# of events 
since last CR
Total # of 
events
Attribution 
to Research
Serious?
Unexpected?


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The protocol PI will report to the NCI-IRB:
1. A summary of all protocol deviations in a tabular format to include the date the 
deviation occurred, a brief description of the deviation, and any corrective action.
2. A summary of any instances of non-compliance
3. A tabular summary of the following adverse events:

All Grade 2 unexpected events that are possibly, probably or definitely 
related to the research;

All Grade 3 and 4 events that are possibly, probably or definitely related to 
the research;

All Grade 5 events regardless of attribution;

All Serious Events regardless of attribution.
NOTE: Grade 1 events are not required to be reported.
7.5
Secondary Malignancy
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS.  Three options are available to 
describe the event: 

Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML]) 

Myelodysplastic syndrome (MDS) 

Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. 
7.6
Second Malignancy
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified. 
8
PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational administered 
in this study can be found in Section 7.


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8.1
Talazoparib (BMN 673; NSC 771561)
Other Names:
BMN 673ts
Chemical Name:
3H-Pyrido[4,3,2-de]phthalazin-3-one, 5-fluoro-8-(4-
fluorophenyl)-2,7,8,9-tetrahydro-9-(1-methyl-1H-1,2,4-triazol-5-
yl)-, (8S,9R)-, 4-methylbenzenesulfonate (1:1)
Classification:
(CAS):
PARP Inhibitor
(1207456-01-6)
Mode of Action:
Talazoparib (BMN 673) is a potent and specific inhibitor of 
PARP1 and PARP2, preventing PARP-mediated DNA repair of 
single strand DNA breaks via the base-excision repair pathway.  
It has demonstrated synthetic lethality in tumors with defects in 
DNA repair pathways such as BRCA mutations and PTEN 
dysfunction.
Mol. Formula (BMN 673ts):
C26H22F2N6O4S
Mol. Weight (BMN 673ts):
552.5624
Description:
Talazoparib (BMN 673) free base is the active moiety of the 
BMN 673ts (tosylate salt) formulation.
Solubility:
Unknown
How Supplied:
Talazoparib (BMN 673) capsules are supplied by Pfizer, Inc., and 
distributed by the Pharmaceutical Management Branch, 
CTEP/DCTD/NCI.  BMN 673 is supplied as 250 mcg capsules 
(opaque white, size 4) packaged in 30-count HDPE bottles with 
an induction seal and child-resistant cap.  The hypromellose 
capsules contain a blend of BMN 673 drug substance, silicified 
microcrystalline cellulose, titanium dioxide, red iron oxide, and 
yellow iron oxide.  
Talazoparib (BMN 673) capsules may be repackaged from the 
manufacturer-supplied HDPE bottle into a pharmacy-supplied 
HDPE bottle for dispensing purposes.
Storage:
Drug product is stored at room temperature (15-30°C/59-86° F) 
and protected from light.  If a storage temperature excursion is 
identified, promptly return BMN 673 to between 15-30°C and 
quarantine the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration 
of the excursion) to PMBAfterHours@mail.nih.gov for 
determination of suitability.
Stability:
Shelf-life surveillance studies of talazoparib (BMN 673) are 


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ongoing.
Route of Administration:
Oral: talazoparib (BMN 673) can be taken without regard to food.  
Potential Drug Interaction:
Based on in vitro data, talazoparib (BMN 673) is not likely to 
demonstrate clinically significant CYP450 inhibition- or 
induction-based drug-drug interactions.  Talazoparib (BMN 673) 
is a substrate for P-glycoprotein (P-gp) and breast cancer 
resistance protein (BCRP) drug transporters.  The PK parameters 
of talazoparib (BMN 673) could be altered if talazoparib (BMN 
673) is coadministered with P-gp and BCRP inhibitors/inducers.  
Studies have shown that talazoparib (BMN 673) is not a substrate 
or an inhibitor of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, 
OAT3, MATE1, or BSEP transporters.
Availability
Talazoparib (BMN 673) is an investigational agent supplied to 
investigators by DCTD, NCI.  Talazoparib (BMN 673) is 
provided to the NCI under a Collaborative Agreement between 
the Pharmaceutical Collaborator and DCTD, NCI.
8.2
Agent Ordering
NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  If 
there are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
investigator at that institution.
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application.  Access to OAOP requires the establishment of a CTEP 
Identity and Access Management (IAM) account and the maintenance of an “active” 
account status and a “current” password.  For questions about drug orders, transfers, 
returns, or accountability, call or email anytime.  Refer to the PMB’s website for specific 
policies and guidelines related to agent management.  


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8.3
Agent Accountability
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from the 
PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(DARF) available on the CTEP forms page.  Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 
8.4
Investigator Brochure Availability
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB OAOP application.  Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account status 
and a “current” password.  Questions about IB access may be directed to the PMB IB 
Coordinator via email.
8.5
Useful Links and Contacts

CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/

NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov

PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm 

PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx 

CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/index.jsp

CTEP Associate Registration and IAM account help:  ctepreghelp@ctep.nci.nih.gov 

IB Coordinator:  IBCoordinator@mail.nih.gov 

PMB email:  PMBAfterHours@mail.nih.gov

PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET)
9
CORRELATIVE/SPECIAL STUDIES
We plan to evaluate the in vivo molecular effects of talazoparib (BMN 673) using pre- and 
post-treatment tumor biopsy specimens and CTCs.  Blood samples for CTCs will be collected 
during cycle 1 at baseline, 3-6 hours post-drug administration on day 1, approximately 24 
hours post-drug administration on day 1 (before day 2 dose), 3-6 hours post-drug 
administration on day 8, and on cycle 2 day 1, 3-6 hours post dose (± 3 days for scheduling 
conflicts), on day 1 of every subsequent cycle (every 3 cycles for patients on study for more 
than 12 months), at the time of the optional restaging follow-up biopsy (if applicable), and at 
time of disease progression.  Mandatory tumor biopsies will be collected for evaluation of 
levels of DNA-damage repair and apoptosis at baseline and 3-6 hours post-dose on day 8 
during cycle 1.  One optional tumor biopsy may also be collected either on day 1 ( 2 days) of 


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the cycle following any restaging at which a 10-19% increase in tumor volume is observed 
(according to RECIST criteria) if the patient has been on study for at least 4 cycles, or at time 
of disease progression.  
9.1
Pharmacodynamic and Pharmacokinetic Assays
Evaluation of drug effect on DNA damage response will be performed using immunoassays to 
measure PAR levels and immunofluorescence assays to measure DNA damage-repair markers 
such as γH2AX, ERCC1, pNbs1, XPF, RAD51, pT1989ATR, activated cleaved caspase 3, and, 
as indicators of ATR/ATM activation, chk1 and chk2.  Evaluation of drug effect on tumor 
epithelial-mesenchymal phenotype will be performed using immunoassays to measure 
phenotypic markers of epithelial and mesenchymal states (such as E-cadherin, vimentin, and β-
catenin).
9.1.1
Laboratory Contact
At least 24 hours prior to tumor biopsy or blood sample collection, the research 
nurse will contact the NCI Phase I/II PK/PD Support Group in NIH Building 10: E-
mail: NCIPK-PDsupportgroup@mail.nih.gov, Pager: 102-12798 Phone: 301-451-
1169 Fax: 301-480-5871.  For biopsies, tubes pre-labeled with the information 
specified in Section 9.3, biopsy date, and site of tissue biopsy will be provided.  
Initial processing and shipping of the samples will be completed as described 
below.
9.1.2
Blood Collection for CTC Studies
Whole blood will be collected aseptically by venipuncture or from a venous port 
into two 4 mL K3-EDTA tubes.  The collected blood samples are stable for up to 72 
hours at room temperature (15°C to 30°C) prior to processing.  Blood samples for 
CTCs will be collected from all patients at the following (approximate) time points:

Cycle 1 prior to treatment,

Cycle 1, day 1: 3-6 hours after dose

Cycle 1, day 1: approximately 24 hours after first dose (before second dose)

Cycle 1, day 8: 3-6 hours after dose

Cycle 2, day 1: 3-6 hours after dose (± 3 days for scheduling conflicts)

Every subsequent cycle on day 1 prior to treatment (day 1 of every 3 cycles for 
patients on study more than 12 months)

At the time of the optional restaging follow-up biopsy, if applicable

At time of disease progression
9.1.3
Tumor Biopsies
9.1.3.1 Timing of tumor biopsies
Biopsies will be mandatory.  Biopsies will be collected at the following time 
points:


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• before drug administration on study (baseline)
• on cycle 1 day 8, 3-6 hours after treatment with talazoparib (BMN 673)
• Optional: one additional biopsy either on day 1 ( 2 days) of the cycle 
following any restaging at which a 10-19% increase in tumor volume is 
observed (according to RECIST criteria) if the patient has been on study 
for at least 4 cycles, or at disease progression  
9.1.3.2 Biopsy Procedure
Serial tumor biopsies will be obtained by the Interventional Radiology team by a 
percutaneous approach.  It is preferred that up to 5 core biopsies 18-gauge in 
diameter and ≥1 cm in length will be obtained during each procedure if considered 
safe and feasible.  It is estimated that there will be between 2 million–5 million cells 
from each biopsy.  If a site is deemed appropriate for biopsy with minimal risk to 
the participant by agreement between the investigators and Interventional 
Radiology team, an attempt for biopsy will be made.  If possible, the lesion from 
which each biopsy is taken will be documented, and an attempt will be made to 
collect biopsies at subsequent timepoints from the same lesion, at the discretion of 
the Interventional Radiology team.
The use of imaging to facilitate biopsies will be decided by members of the 
Interventional Radiology team and may include ultrasound, CT scan, or MRI.  
Should a CT scan be needed for biopsy, the number of scans for each procedure 
will be limited to the minimum number needed to safely obtain a biopsy.  Tumor 
biopsies and local anesthesia will be administered only if they are considered to be 
of low risk to the participant, as determined by the investigators and Interventional 
Radiology.
If the participant chooses not to undergo tumor biopsy, he/she will still remain in 
the study and receive study medication, and all the other correlative studies will be 
performed.
Tumor biopsies are mandatory.  Baseline biopsies will be performed following 
patient enrolling on study.  If an initial attempt at percutaneous biopsy is 
unsuccessful, the patient will be given an option to proceed with a repeated attempt 
at percutaneous biopsy.  A separate consent form must be signed for each biopsy 
procedure, so patients may choose not to undergo subsequent biopsies.  If the 
baseline biopsy is unsuccessful or the patient refuses to undergo subsequent 
biopsies, no further biopsies will be performed but the patient will remain on study, 
receive study medication, and other correlative studies will be performed. 
9.1.3.3 Solid Tumor Biopsy Processing
Up to five tissue cores will be collected.  The cores will be transferred into a 1.5-
mL pre-chilled cryovial and then flash frozen in liquid nitrogen per DCTD 
SOP340507 (http://dctd.cancer.gov/ResearchResources/biomarkers/ 


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docs/par/SOP340507_Biopsy_Frozen.pdf).  Samples will be submitted to 
Dr. Kinders’ laboratory for evaluation of DNA damage markers, and H&E 
pathology evaluation.  The frozen biopsy specimens are transferred to PADIS on 
dry ice, where the core biopsy samples are stored at -80°C and subsequently 
processed within 7-10 days for analysis.  Biopsy samples will be analyzed for PAR 
levels and DNA damage response and apoptosis as described above; any additional 
cores will be flash-frozen and kept for future analysis.
9.1.4
Shipping of samples for pharmacodynamic analysis
Biopsies for PD analysis will be shipped on dry ice to:
Attention: Dan Danner
NCI-F/FNLCR
1073 Beasley Street, Building 1073
Fort Detrick
Frederick, MD 21701
Phone: 301-846-5748
NCI_PD_Support@mail.nih.gov
Blood for CTC analysis will be shipped at room temperature (15°C to 30°C) 
to:
Attention: Dan Danner
NCI-F/FNLCR
1073 Beasley Street, Building 1073
Fort Detrick
Frederick, MD 21701
Phone: 301-846-5748
NCI_PD_Support_CellSearch@mail.nih.gov
Shipment should be by CSP Courier and may be arranged by contacting Jenn 
Bangh, FNLCR, Tel.: 301-846-5893
9.1.5
Blood Collection for Pharmacokinetic Analysis
Please note: As of Amendment H (2/5/2018) blood for PK analysis will no longer 
be collected.
Whole blood will be collected aseptically by venipuncture or from a venous port 
into a 5 mL K3 EDTA vacutainer at room temperature for plasma separation per 
Appendix D.  
Blood samples will be collected from all patients at the following time points: 

cycle 1 day 1 pre-dose and then 0.5, 1, 2, 3, 4, 6, 8, and 24 hours post-dose

cycle 1 day 8 (3-6 hours post dose)

cycle 2 day 1 pre-dose and 3-6 hours post dose (± 2 days for scheduling 
conflicts)


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Plasma samples should be shipped as described in Appendix D.
9.2
Sample Collection and Processing
Biospecimens will be collected and processed using validated SOPs that will ensure 
both specimen quality and patient confidentiality pursuant to informed consent 
provisions.  Information about each specimen (e.g., blood, tumor biopsy, circulating 
tumor cells, per specific protocol) will be recorded on a PK/PD collection 
worksheet included in Appendix C.
Using a computerized inventory system and a backup hardcopy process, all 
specimen collection and processing steps will be documented and the specific 
location of each specimen will be tracked.  Each new specimen collected will be 
assigned a unique barcode identifier that can be linked to the original specimen 
collected and other relevant information within the inventory system.  To ensure 
patient confidentiality, only containers used for the initial specimen collections will 
be labeled with patient identifiers.  
Only the barcode identifier will be applied to all subsequent specimen containers.  
When specimens are processed and aliquoted, no patient information will be 
included on the new containers.  Original specimen containers will be discarded.  
Only barcode-labeled specimens without patient identifiers will be shipped for 
analysis and/or storage.  Specimen labels will indicate: CTEP protocol number, 
unique patient accession number, 3-digit sample number (see list below), collection 
time, and total volume collected, as appropriate.  Samples from sets of at least three 
patients will be grouped for scientific analysis.
Standardized 3-digit sample collection numbers:
200 series: blood for PK
400 series: blood for circulating tumor cells (CTCs)
500 series: tumor biopsies
The inventory process contains other security provisions sufficient to safeguard 
patient privacy and confidentiality.  Access to the inventory system and associated 
documents will be restricted to appropriate individuals.  Requests to use specimens 
stored in the repository must be approved.  The only patient information available 
in the inventory system will be the patient sex, diagnosis, and level of informed 
consent given.  SOPs ensure that any changes in informed consent made by a 
patient and relayed to the PI will be reflected in the inventory system to ensure that 
specimens are destroyed as appropriate.  All laboratory personnel will be trained to 
adhere to SOPs and will be monitored for high-quality performance.
Any new use of these samples will require prospective IRB review and approval.  
Access to these samples will only be granted following IRB approval of an 
additional protocol, granting the rights to use the material.


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If at any time, a patient withdraws from the study and does not wish for their 
existing samples to be utilized, the individual must provide a written request.  
Following receipt of this request, the samples will be destroyed (or returned to the 
patient, if so requested), and reported as such to the IRB.  Any samples lost (in 
transit or by a researcher) or destroyed due to unknown sample integrity (i.e., 
broken freezer allows for extensive sample thawing, etc.) will be reported as such to 
the IRB.
9.3
Human Data Sharing Plan
What data will be shared?
We will share human data generated in this research for future research as follows:
X De-identified data in an NIH-funded or approved public repository
X Identified data in BTRIS (automatic for activities in the Clinical Center)
X De-identified or identified data with approved outside collaborators under
appropriate agreements
How and where will the data be shared?
Data will be shared through:
X An NIH-funded or approved public repository: clinicaltrials.gov
X BTRIS (automatic for activities in the Clinical Center)
X Approved outside collaborators under appropriate individual agreements
X Publication and/or public presentations
When will the data be shared?
X At the time of publication or shortly thereafter
10 STUDY CALENDAR
Baseline evaluations are to be conducted within 72 hours prior to start of protocol therapy.  
Scans and x-rays must be done ≤ 4 weeks prior to the start of therapy.  Start of next cycle may 
be delayed for up to 1 week to accommodate scheduling conflicts.  History and physical 
examination and laboratory evaluations can be performed up to 3 days before the start of the 
next cycle.  


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Study Treatment 
Cycle 1 
Cycle 2 and subsequent 
cycles
Off 
Treatment
Study Procedure
Screen
Wk 1
Wk 2
Wk 3
Wk 4
Wk 1
Wk 2
Wk 3
Wk 4
Talazoparib (BMN 673)a
X
X
X
X
X
X
X
X
Informed consent
X
Demographics
X
Medical history
X
Concurrent meds
X
X-----------------------------------------------------------------------X
Physical examb
X
X
X
X
Vital signs
X
X
X
X
Height
X
Weight
X
X
X
Performance status
X
X
X
CBC w/diff, pltsc
X
X
X
X
X
Serum chemistryc
X
X
X
X
X
PT, INR, PTTd
X
β-HCGe
X
Adverse event evaluation
X
X----------------------------------------------------------------------X
Tumor measurements
X
Tumor measurements are repeated every 2 cycles.  
Documentation (radiologic) must be provided for patients 
removed from study for progressive disease.
X
Tumor biopsyf
X
X
Circulating tumor cellsg
X
X
X
X
Blood for PKh


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a. Talazoparib (BMN 673) will be administered orally at 1000 µg/day each day for 28 days.
b. Physical examination at the Clinical Center should be performed at the start of each cycle (up to 3 days 
before start of a new cycle and within 2 days of day 8 during cycle 1.
c. Serum chemistry (albumin, total bilirubin, calcium, creatinine, creatine clearance, phosphorus, 
magnesium, potassium, sodium, SGOT [AST], SGPT [ALT]); CBC w/diff, platelets at baseline, within 
2 days of day 8, and during week 3 of cycle 1, then every 4 weeks at the start of each subsequent cycle 
(up to 3 days before start of a new cycle).  If clinically indicated, labs may be obtained with more 
frequency with subsequent cycles.
d. PT/INR, PTT prior to biopsy.
e. Serum pregnancy test (women of childbearing potential) within 1 week prior to enrollment and as 
clinically indicated.
f. Tumor biopsies will be prior to treatment and 3-6 hrs after the talazoparib (BMN 673) dose on day 8.  
One optional tumor biopsy may also be obtained either on day 1 (± 2 days) of the cycle following any 
restaging at which a 10-19% increase in tumor volume is observed (according to RECIST criteria) if the 
patient has been on study for at least 4 cycles, or at disease progression.
g. CTCs will be obtained prior to drug administration; 3-6 hours and then approximately 24 hours post drug 
administration (prior to day 2 dose) on day 1, 3-6 hours post drug administration on day 8 in cycle 1, 
and 3-6 hours post drug administration on day 1 of cycle 2 (± 3 days for scheduling conflicts), on day 1 
of every subsequent cycle (every 3 cycles for patients on study more than 12 months) before drug 
administration, and at time of disease progression
h  Please note: As of Amendment H (2/5/2018) blood for PK analysis will no longer be collected.
  
11 MEASUREMENT OF EFFECT
11.1
Antitumor Effect – Solid Tumors
Although response is not the primary endpoint of this trial, patients with measurable 
disease will be assessed by standard criteria.  For the purposes of this study, patients should 
be re-evaluated for response every 8 weeks (every 2 cycles).  In addition to a baseline scan, 
confirmatory scans should also be obtained at least 4 weeks following initial 
documentation of objective response.
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in the RECIST criteria.
11.1.1 Definitions
Evaluable for toxicity.  All patients will be evaluable for toxicity from the 
time of their first treatment with talazoparib (BMN 673).
Evaluable for objective response.  Only those patients who have 
measurable disease present at baseline, have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered 
evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit 


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objective disease progression prior to the end of cycle 1 will also be 
considered evaluable.)
Evaluable Non-Target Disease Response.  Patients who have lesions 
present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions.
11.1.2 Disease Parameters
Measurable disease.  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥20 mm by chest x-ray or as ≥10 mm with CT scan, MRI, or 
calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters).
Malignant lymph nodes.  To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15 mm in short axis when assessed by 
CT scan (CT scan slice thickness recommended to be no greater than 5 
mm).  At baseline and in follow-up, only the short axis will be measured 
and followed.
Non-measurable disease.  All other lesions (or sites of disease), including 
small lesions (longest diameter <10 mm or pathological lymph nodes with 
≥10 to <15 mm short axis), are considered non-measurable disease.  Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-
measurable.
Note:  Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions (neither 
measurable nor non-measurable) since they are, by definition, simple 
cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability 
described above.  However, if non-cystic lesions are present in the same 
patient, these are preferred for selection as target lesions.
Target lesions.  All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with 


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the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance 
the next largest lesion which can be measured reproducibly should be 
selected.  A sum of the diameters (longest for non-nodal lesions, short axis 
for nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease.
Non-target lesions.  All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted 
throughout follow-up.
11.2
Guidelines for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.  Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam.
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable. 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).  
As with CT, if an MRI is performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of disease.  Furthermore, as 
with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence.  It is beyond the scope of 


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the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and 
the image acquisition protocol should be followed as closely as possible to prior scans.  
Body scans should be performed with breath-hold scanning techniques, if possible.
PET-CT  At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements.  
However, if the site can document that the CT performed as part of a PET-CT is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed.  
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement.  Ultrasound examinations cannot be reproduced in their entirety 
for independent review at a later date and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances.
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint.
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  
In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000].
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain).
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 (an effusion may 
be a side effect of the treatment) and progressive disease.


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FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity.
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image.
11.3
Response Criteria
11.3.1 Evaluation of Target Lesions
Complete Response (CR):
Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-
target) must have reduction in short axis to <10 mm.
Partial Response (PR):
At least a 30% decrease in the sum of the diameters 
of target lesions, taking as reference the baseline sum 
diameters.
Progressive Disease (PD):
At least a 20% increase in the sum of the diameters 
of target lesions, taking as reference the smallest sum 
on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also 
considered progressions).


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Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study.
11.3.2 Evaluation of Non-Target Lesions
Complete Response (CR):
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm 
short axis).
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to be 
considered in complete clinical response.
Non-CR/Non-PD:
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits.
Progressive Disease (PD):
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, not a 
single lesion increase.    
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator).
11.3.3 Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria.
For Patients with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response 
when Confirmation is 
Required*
CR
CR
No
CR
≥4 wks. Confirmation**
CR
Non-
CR/Non-PD
No
PR
≥4 wks. Confirmation**


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CR
Not 
evaluated
No
PR
PR
Non-
CR/Non-
PD/not 
evaluated
No
PR
SD
Non-
CR/Non-
PD/not 
evaluated
No
SD
Documented at least once 
≥4 wks. from baseline**
PD
Any
Yes or 
No
PD
Any
PD***
Yes or 
No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
*
See RECIST 1.1 manuscript for further details on what is evidence of a 
new lesion.
**
Only for non-randomized trials with response as primary endpoint.
***
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression.
Note:
Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment.
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials so to 
assign this category when no lesions can be measured is not advised
11.4
Duration of Response
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that progressive disease is objectively documented.


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Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements. 
12 DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements).
12.1
Data Reporting
12.1.1 Method
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  
Data will be collected in the Center for Cancer Research C3D database and will be 
transmitted to CTMS electronically at least once every 2 weeks.
Note: All adverse events that have occurred on the study, including those reported 
through CTEP-AERS, must be reported via the monitoring method identified 
above.
12.1.2 Responsibility for Data Submission
N/A
12.2
CTEP Multicenter Guideline
N/A 
12.3
Collaborative Agreements Language
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to 
the provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within 
the terms of award, apply to the use of the Agent(s) in this study:
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the clinical 
study.  Collaborator(s) data for Agent(s) are confidential and proprietary to 
Collaborator(s) and shall be maintained as such by the investigators.  The protocol 
documents for studies utilizing Agents contain confidential information and should 
not be shared or distributed without the permission of the NCI.  If a copy of this 


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protocol is requested by a patient or patient’s family member participating on the 
study, the individual should sign a confidentiality agreement.  A suitable model 
agreement can be downloaded from http://ctep.cancer.gov.
2. For a clinical protocol where there is an investigational Agent used in combination 
with (an)other Agent(s), each the subject of different Collaborative Agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data”): 
a. NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with NCI, the 
design of the proposed combination protocol, and the existence of any obligations 
that would tend to restrict NCI's participation in the proposed combination protocol.
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its 
own Agent.
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own Agent.
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy of 
Individually Identifiable Health Information set forth in 45 C.F.R. Part 164.
4. When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them.
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial.
6. Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP by the Group office for Cooperative Group studies or by the principal 
investigator for non-Cooperative Group studies for immediate delivery to 
Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to an 


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additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three 
(3) days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings.  Press releases and other media presentations must 
also be forwarded to CTEP prior to release.  Copies of any manuscript, abstract 
and/or press release/ media presentation should be sent to:
E-mail: ncicteppubs@mail.nih.gov
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information.
13 STATISTICAL CONSIDERATIONS
13.1
Study Design/Endpoints
Patients will receive talazoparib (BMN 673) orally at 1000 µg/day, each day, in 28-day 
cycles.  Tumor biopsies will be mandatory predose and 3-6 hours post talazoparib (BMN 
673) dose on cycle 1 day 8. 
Up to 24 patients will be accrued to assure at least 16 patients with matched, evaluable 
baseline and day 8 biopsies (with 97% likelihood). The primary endpoint will be the 
percent of patients who achieve a sustained PD response, defined to be at least 4% nuclear 
area positive (NAP) γH2AX at the day 8 biopsy.  In clinical testing, this level of γH2AX is 
seen less than 5% of the time at baseline (in the absence of an active agent) [38].  If we 
observe at least 3 out of the 16 (19%) patients with evaluable baseline and day 8 biopsies 
achieving such a sustained PD response, we will declare the agent promising by means of 
the PD assay.  This design will give us 90% power to detect a true 30% sustained PD 
response rate, across patients with less than .04 probability of a false positive in the event 
that the agent has no effect and the true likelihood of such a sustained PD response, for an 
individual patient, is less than 5%.  [Note: As of 3/24/2020, this study has closed to accrual.  
The PD response rate will be determined and tested against the null hypothesis of 5% (the 
rate of false positivity for the threshold value of 4% NAP γH2AX).]
13.2
Sample Size/Accrual Rate
A total of 16 patients with matched, evaluable baseline and day 8 biopsies will be enrolled.  
Patients who have at least 4% NAP at the pre-treatment biopsy will not be included in the 
primary analysis and for sample size calculations would not be considered evaluable.  In 
order to allow for some patients who will not be evaluable, the accrual ceiling for the study 
is 24 patients.  As of July, 2017, 9 patients have been enrolled with 6 having evaluable 


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matched biopsy pairs.  Additional patients will be enrolled, up to an accrual ceiling of 15 
(or 24 total patients), yielding a 99% likelihood of accruing 12 patients with evaluable 
biopsy pairs.
It is anticipated that 2-3 patients may be enrolled per month onto this study.  It is expected 
that an additional 8-12 months (as of July, 2017) will be required to accrue the number of 
patients necessary to complete the trial.
13.3
Analysis of Exploratory Pharmacodynamic Endpoints
Mean and SD of change in % NAP, from pre-treatment baseline to day 8 among all patients 
and among patients who achieve a sustained PD response. 
Mean and SD of ERCC1 at pre-treatment baseline and at day 8 among all patients and 
among patients who achieve a sustained PD response. 
14 HUMAN SUBJECTS PROTECTIONS
14.1
Justification for Subject Selection
This study will be open to all individuals regardless of gender, ethnicity, or race, provided 
that the aforementioned inclusion and exclusion criteria are met.  Patients for this study will 
be recruited through internal referral, our physician referral base, and through various 
cancer information hotlines (i.e., Clinical Studies Support Center, 1-800-4Cancer).  To 
date, there is no information that suggests that differences in drug metabolism or effect on 
tumor would be expected in one ethnic group compared to another.  Efforts will be made to 
extend accrual to each representative population, but a balance must be struck between 
participant safety considerations and limitations on the number of individuals exposed to 
potentially ineffective treatments on the one hand and the need to explore racial/ethnic 
aspects of clinical research on the other hand.  If differences in outcome that correlate to 
ethnic identity are noted, a follow-up study may be written to investigate those differences 
more fully.
Due to lack of knowledge of the effects of talazoparib (BMN 673) on the fetus or infants, 
as well as the possibility of teratogenic effects, pregnant and nursing women will be 
excluded from this trial.  Patients with unstable or serious medical conditions are excluded 
due to the possibility that talazoparib (BMN 673) may worsen their condition and the 
likelihood that the underlying condition may obscure the attribution of adverse events to 
talazoparib (BMN 673).  HIV-positive patients on combination antiretroviral therapy are 
excluded from the study because of possible PK interactions with talazoparib (BMN 673).
14.1.1 Participation of Children
This study includes patients 18 years of age and older.  Because insufficient dosing 
or adverse event data are currently available on the use of talazoparib (BMN 673) in 
patients <18 years of age, children are excluded from this study, but may be eligible 
for future pediatric trials.  Studies will be performed in patients <18 years of age 
when it is appropriate to do so.


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14.2
Evaluation of Benefits and Risks/Discomforts
There may or may not be any clinical benefit to a patient from participation in this trial.  
Their participation will benefit future cancer patients.  Potential risks include the possible 
occurrence of any of a range of side effects that are listed in the consent document.  The 
procedure for protecting against or minimizing risks will be to medically evaluate patients 
as described in Sections 5 and 6.  Although no compensation is available, any injury will be 
fully evaluated and treated in keeping with the benefits or care to which participants are 
entitled under applicable regulations.
14.3
Consent and Assent Process and Documentation
An associate or principal investigator on the trial will inform patients of the purpose, 
alternatives, drug administration plan, research objectives, and follow-up of this trial.  The 
patient will be provided an IRB-approved consent for review and signature and his/her 
questions will be answered.  After a decision is made to enroll into the study, a signature 
will be obtained from the patient.  The original signed consent goes to Medical Records; a 
copy will be placed in the research record. Patients will not be consented by telephone.
All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before entering on 
study.
14.3.1 Participation of subjects unable to give consent
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-
consent may be necessary and there is a possibility, though unlikely, that subjects could 
become decisionally impaired. For this reason and because there is a prospect of direct 
benefit from research participation, all subjects ≥ age 18 at the NCI only will be offered the 
opportunity to fill in their wishes for research and care, and assign a substitute decision 
maker on the “NIH Advance Directive for Health Care and Medical Research 
Participation” form so that another person can make decisions about their medical care in 
the event that they become incapacitated or cognitively impaired during the course of the 
study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team for 
evaluation.  For those subjects that become incapacitated and do not have pre-determined 
substitute decision maker, the procedures described in MEC Policy 87-4 for appointing a 
surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who 
do not have a legal guardian or durable power of attorney, will be followed.
14.4
Procedure for Protecting Against or Minimizing Any Potential Risks
All care will be taken to minimize side effects, but they can be unpredictable in nature and 
severity.  This study may involve risks to patients, which are currently unforeseeable.  All 
patients will be monitored for side effects from taking study medication.  This research 
represents a greater than minimal risk to participants, but presents the prospect of direct 
benefit to individual subjects.


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The research component of this study required to obtain 3 CT tumor biopsies confers 
radiation exposure at an effective dose of 2.4 rem.  This dose is below NIH RSC guidelines 
of less than 5.0 rem per year in adults, and represents a slightly greater than minimal risk to 
patients.
14.5
Patient Advocate
The patients’ rights representative is available to patients receiving treatment on this 
protocol at the NIH Clinical Center at (301) 496-2626 in Building 10 of the Clinical 
Research Center, Room 1-3521, on the Bethesda NIH campus.  Patients will be informed 
that they can contact the study PI or RN at any time with questions about their medical 
care, and that the patients’ rights representative is also available to answer non-medical 
questions about the study.


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Fukushima, M., et al., Poly(ADP-ribose) synthesis in human cervical cancer cell-
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Alderson, T., New targets for cancer chemotherapy--poly(ADP-ribosylation) processing 
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Wielckens, K., et al., ADP-ribosylation of nuclear proteins in normal lymphocytes and in 
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Berger, N.A., et al., Synthesis of DNA and poly(adenosine diphosphate ribose) in normal 
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Hirai, K., K. Ueda, and O. Hayaishi, Aberration of poly(adenosine diphosphate-ribose) 
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Fernet, M., et al., Poly(ADP-ribose) polymerase, a major determinant of early cell 
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Shall, S. and G. de Murcia, Poly(ADP-ribose) polymerase-1: what have we learned from 
the deficient mouse model? Mutat Res, 2000. 460(1): p. 1-15.
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Masutani, M., et al., The response of Parp knockout mice against DNA damaging agents. 
Mutat Res, 2000. 462(2-3): p. 159-66.
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Ame, J.C., et al., PARP-2, A novel mammalian DNA damage-dependent poly(ADP-ribose) 
polymerase. J Biol Chem, 1999. 274(25): p. 17860-8.
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Menissier de Murcia, J., et al., Functional interaction between PARP-1 and PARP-2 in 
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Schreiber, V., et al., Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient 
base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem, 2002. 277(25): p. 
23028-36.
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Memisoglu, A. and L. Samson, Base excision repair in yeast and mammals. Mutat Res, 
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Ruscetti, T., et al., Stimulation of the DNA-dependent protein kinase by poly(ADP-ribose) 
polymerase. J Biol Chem, 1998. 273(23): p. 14461-7.
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Galande, S. and T. Kohwi-Shigematsu, Poly(ADP-ribose) polymerase and Ku autoantigen 
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274(29): p. 20521-8.
18.
Boulton, S., S. Kyle, and B.W. Durkacz, Interactive effects of inhibitors of poly(ADP-
ribose) polymerase and DNA-dependent protein kinase on cellular responses to DNA damage. 
Carcinogenesis, 1999. 20(2): p. 199-203.
19.
Bryant, H.E., et al., Specific killing of BRCA2-deficient tumours with inhibitors of 
poly(ADP-ribose) polymerase. Nature, 2005. 434(7035): p. 913-7.
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Farmer, H., et al., Targeting the DNA repair defect in BRCA mutant cells as a therapeutic 
strategy. Nature, 2005. 434(7035): p. 917-21.
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Iglehart, J.D. and D.P. Silver, Synthetic lethality--a new direction in cancer-drug 
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Drew, Y. and H. Calvert, The potential of PARP inhibitors in genetic breast and ovarian 
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Fong, P.C., et al., Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA 
mutation carriers. N Engl J Med, 2009. 361(2): p. 123-34.
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Audeh, M.W., et al., Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in 
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Tutt, A., Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced 
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Wang, B., et al., Novel PARP Inhibitors with Potent Anti-tumor Activity as Single-agent 
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Fernandez-Capetillo, O., et al., H2AX: the histone guardian of the genome. DNA Repair, 
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Rogakou, E.P., et al., DNA double-stranded breaks induce histone H2AX phosphorylation 
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Paull, T.T., et al., A critical role for histone H2AX in recruitment of repair factors to 
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31.
Bassing, C.H. and F.W. Alt, H2AX may function as an anchor to hold broken chromosomal 
DNA ends in close proximity. Cell Cycle, 2004. 3(2): p. 149-153.
32.
Redon, C., et al., Histone H2A variants H2AX and H2AZ. Current Opinion in Genetics & 
Development, 2002. 12(2): p. 162-169.
33.
Celeste, A., et al., Genomic instability in mice lacking histone H2AX. Science, 2002. 
296(5569): p. 922-927.
34.
Kummar, S., et al., Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor 
ABT-888 in patients with advanced malignancies. J Clin Oncol, 2009. 27(16): p. 2705-11.
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Kummar, S., et al., A phase I study of veliparib in combination with metronomic 
cyclophosphamide in adults with refractory solid tumors and lymphomas. Clinical Cancer 
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36.
Allison Stewart, C., et al., Dynamic variations in epithelial-to-mesenchymal transition 
(EMT), ATM, and SLFN11 govern response to PARP inhibitors and cisplatin in small cell lung 
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37.
Stark, T.W., et al., Predictive value of epithelial-mesenchymal-transition (EMT) signature 
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Wilsker, D.F., et al., Evaluation of Pharmacodynamic Responses to Cancer Therapeutic 
Agents Using DNA Damage Markers. Clin Cancer Res, 2019. 25(10): p. 3084-3095.


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APPENDIX A: PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Grade
Descriptions
0
Normal activity.  Fully active, able to carry on 
all pre-disease performance without restriction.
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).
2
In bed <50% of the time.  Ambulatory and 
capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 
50% of waking hours.
3
In bed >50% of the time.  Capable of only 
limited self-care, confined to bed or chair more 
than 50% of waking hours.
4
100% bedridden.  Completely disabled.  Cannot 
carry on any self-care.  Totally confined to bed 
or chair.
5
Dead.


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APPENDIX B: PATIENT’S MEDICATION DIARY
Today’s Date _____________________Cycle #______  Daily BMN 673 Dose_______µg
Patient Name_____________________(initials acceptable)  Patient Study ID _________________
INSTRUCTIONS
1.
Complete one form for each cycle of treatment.
2.
Swallow each capsule whole with a full glass of water with or without food.  Do not chew or open the 
capsules.  If capsule is broken and the powder of the capsules gets on skin, wash the exposed area with 
as much water as necessary.  Inform investigator or nurse if that occurs.
3.
Record the date and time you took the drugs. 
4.
If you have any comments or notice any side effects, please record them in the Comments column.
5.
Please bring this form and your bottle of talazoparib (BMN 673) with when you return for your 
appointment.
6.
In case of errors, please place a single slash mark through the error and initial it.  Please do not white 
out any error or scribble it out with ink.  Please do not write the correct information directly over the 
error, but on a separate line next to the error.
Day
Date
Time 
of dose
Number of 
capsules taken 
250 µg
Comments
1
2
3
4
5
6
7
8
9
10
11
12


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Day
Date
Time 
of dose
Number of 
capsules taken 
250 µg
Comments
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Patient’s signature: _____________________________________________________________


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APPENDIX C: PD/PK COLLECTION WORKSHEETS


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Date: 
SAMPLE COLLECTION SHEET: Cycle 1 DAY 1/2
CTEP Protocol 9510
Ht: 
Research Nurse: 
Talazoparib (BMN 673) Dose:
Wt:  
Phone: 
Patient ID:
BSA:  
Page 102-12798 for Sample 
Pick-up
Lab phone: 301-451-1169
PI: A. P. Chen, MD      
  Phone: 301 768-2749   
 PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION
Day
Time
Instructions
Ideal Time
Actual Time
Record comments (i.e., if collection missed), and sign 
each time you collect a sample
Day 1
Prior to drug 
administration
PD 400 2x 4 mL K3 EDTA
Label tube: sample number, date and time
Administer talazoparib (BMN 673);  Time:__________
Day 1
3-6 hours after 
drug
PD 401 2x 4 mL K3 EDTA 
Label tube: sample number, date and time
 
Day 1
24 hours after 
drug
PD 402 2x 4 mL K3 EDTA 
Label tube: sample number, date and time
Date: 
SAMPLE COLLECTION SHEET: Cycle 1 Day 8
CTEP Protocol 9510
Ht: 
Research Nurse: 
Talazoparib (BMN 673) Dose:
Wt:  
Phone: 
Patient ID:
BSA:  
Page 102-12798 for 
Sample Pick-up
Lab phone: 301-451-1169
PI: A. P. Chen, MD     
  Phone: 301 768-2749     
 PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION
Day
Time
Instructions
Ideal Time
Actual Time
Record comments (i.e., if collection missed), and sign 
each time you collect a sample
Administer talazoparib (BMN 673); Time:____________
Day 8
3-6 hours after 
drug
PD 403 2x 4 mL K3 EDTA 
Label tube: sample number, date and time
 
 


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Date: 
SAMPLE COLLECTION SHEET: Cycle 2 Day 1
CTEP Protocol 9510
Ht: 
Research Nurse: 
Talazoparib (BMN 673) Dose:
Wt:  
Phone: 
Patient ID:
BSA:  
Page 102-12798 for 
Sample Pick-up
Lab phone: 301-451-1169
PI: A. P. Chen, MD  
  Phone: 301 768-2749    
 PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION
Day
Time
Instructions
Ideal Time
Actual Time
Record comments (i.e., if collection missed), and sign 
each time you collect a sample
Administer talazoparib (BMN 673); Time:____________
Day 1
3-6 hours after 
drug
PD 404 2x 4 mL K3 EDTA
Label tube: sample number, date and time


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Date: 
SAMPLE COLLECTION SHEET: Cycle 3 and onwards Day 1/Per PI
CTEP Protocol 9510
Ht: 
Research Nurse: 
Talazoparib (BMN 673) Dose:
Wt:  
Phone: 
Patient ID:
BSA:  
Page 102-12798 for 
Sample Pick-up
Lab phone: 301-451-1169
PI: A. P. Chen, MD  
  Phone: 301 768-2749    
 PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION
Day
Time
Instructions
Ideal Time
Actual Time
Record comments (i.e., if collection missed), and sign 
each time you collect a sample
Day 1
Prior to drug 
administration
PD 40X 2x 4 mL K3 EDTA
Label tube: sample number, date and time
Date: 
SAMPLE COLLECTION SHEET: Day of restaging follow-up or progression biopsy
CTEP Protocol 9510
Ht: 
Research Nurse: 
Talazoparib (BMN 673) Dose:
Wt:  
Phone: 
Patient ID:
BSA:  
Page 102-12798 for 
Sample Pick-up
Lab phone: 301-451-1169
PI: A. P. Chen, MD  
  Phone: 301 768-2749    
 PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION
Day
Time
Instructions
Ideal Time
Actual Time
Record comments (i.e., if collection missed), and sign 
each time you collect a sample
Day 1
Prior to drug 
administration
PD 40X 2x 4 mL K3 EDTA
Label tube: sample number, date and time


CTEP # 9510
Clinical Center #14-C-0015
64
APPENDIX D: PK SAMPLE HANDLING AND SHIPPING
Please note: As of Amendment H (2/5/2018) blood for PK analysis will no longer be collected.
Pharmacokinetic Blood Sampling and Plasma Sample Preparation

Affix completed sample labels lengthways to vacutainer and cryovials.  Each blood sample 
must be processed within 1 hour of draw.

Collect approximately 5 mL of blood in K3 EDTA vacutainer tubes at room temperature.

Invert vacutainer gently 8-10 times. 

Centrifuge at 1500 x g for 10 minutes at room temperature.

Transfer 0.8 mL of plasma into each of three 2-mL cryovials.  To avoid contamination, 
always use a new transfer pipette for each sample, and do not remove the plasma near the 
precipitate.

Transfer plasma samples to -70oC freezer (within 2 hours of collection). 

Ship 2 cryovials of plasma (primary samples) on dry ice (shipping instructions below).  Ship 
backup samples on dry ice in a separate shipment. 
PK Sample Shipping Log and Instructions

Ship PK plasma samples every 3 months or when requested.  

Use an electronic manifest for each shipment (see below).  Each manifest should indicate the 
subject ID, time points, and number of samples included in the shipment.

Place samples grouped by subject in cryobox.  Ensure the cryobox is closed and remains so 
in transit using shipping tape.  Place the cryobox in a sealable Biohazard bag with an 
appropriate amount of absorbent.

Each shipment should be prepared in accordance with IATA regulations.  Samples must be 
shipped at least 3 days prior to US National Holiday.  

Frozen samples should be shipped via Fed Ex, Monday through Wednesday.  No shipments 
should be made later than Wednesday of any given week.  (Samples should arrive by 
Friday, not on the weekend, because it is closed on weekends.)

For questions regarding sample shipment, contact Lara Graham, 610-296-3152,  
lgraham@alliancepharmaco.com. 

On the day of shipment, e-mail the completed electronic manifest, the tracking number and 
other appropriate paperwork to Lara Graham (lgraham@alliancepharmaco.com)  
Lara Graham
Sample management
Alliance Pharma          
17 Lee Blvd.
Malvern, PA19355
Ph: 610-296-3152
lgraham@alliancepharmaco.com  


CTEP # 9510
Clinical Center #14-C-0015
65
Sample PK Shipment Manifest: Talazoparib (BMN 673) Plasma Samples from Study NCI/CTEP #9510 
To: lgraham@alliancepharmaco.com  
Sponsor:  National Cancer Institute/CTEP P9510
Date Shipped:
No. of items shipped:
Shipped by:  
Item 
No
Pt/Sample ID
Description
Day
Time Point
Cycle
Draw Date and 
Time
Unit
Quantity
Volume
1
Plasma PK
cryovial
2
Plasma PK
cryovial
3
Plasma PK
cryovial
4
Plasma PK
cryovial
5
Plasma PK
 
 
cryovial
6
Plasma PK
 
 
cryovial
7
Plasma PK
 
 
cryovial
8
Plasma PK
 
 
cryovial
9
Plasma PK
cryovial
10
Plasma PK
cryovial
11
Plasma PK
cryovial
12
Plasma PK
cryovial
13
Plasma PK
cryovial
14
Plasma PK
 
 
cryovial
15
Plasma PK
 
 
cryovial
16
Plasma PK
 
 
cryovial
17
Plasma PK
 
 
cryovial
18
Plasma PK
 
 
cryovial

ICF_001.pdf: 
MEDICAL RECORD
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or
•Parent, for Minor Patient
INSTITUTE:
National Cancer Institute
STUDY NUMBER:
14-C-0015
PRINCIPAL INVESTIGATOR:
A. P. Chen, MD
STUDY TITLE: 
Pilot Trial of Talazoparib (BMN 673), an Oral PARP Inhibitor, in Patients with 
Advanced Solid Tumors and Deleterious BRCA Mutations
Continuing Review Approved by the IRB on 05/06/19 
Amendment Approved by the IRB on 08/26/19 (J)
Date Posted to Web: 09/06/19
Standard
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY
•
Adult Patient or
•Parent, for Minor Patient
NIH-2514-1 (07-09)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent (1)
INTRODUCTION
We invite you to take part in a research study at the National Institutes of Health (NIH).
First, we want you to know that:
Taking part in NIH research is entirely voluntary. 
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation.
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future.
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study.
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.  
Why is this study being done?
We are doing this study to develop better treatments for cancer.  In this study, an experimental 
drug, talazoparib (BMN 673), will be given to you.  The purpose of this study is to determine 
what effects, good and/or bad, this drug may have on you and your cancer.  This study will also 
look at how talazoparib (BMN 673) may affect the levels of certain proteins in your tumor and 
how well the drugs work against cancer cells by examining cells from a small piece of your 
tumor taken before the drug is given and again after talazoparib (BMN 673) is given.


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 14-C-0015
CONTINUATION: page 2 of 14 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
Talazoparib (BMN 673) is thought to work by preventing DNA repair in tumor cells.  It is an 
experimental drug that has shown some anti-cancer effects against tumor cells in experimental 
animals and in patients with defects in their DNA-repair pathways.  This drug is in the beginning 
stages of being tested in humans.  About 600 patients have received talazoparib (BMN 673) to 
date.  Although we hope this experimental therapy will decrease the size of your tumor, we 
cannot promise or predict the benefits of the treatment at this time.
Why are you being asked to take part in this study?
You are being asked to take part in this research study because you have ovarian or primary 
peritoneal carcinoma, breast carcinoma, or another type of cancer that has progressed after 
receiving standard treatment, or for which no effective therapy exists, and your tumor has a 
particular gene variation (a BRCA mutation) that changes how your tumor repairs DNA.   
How many people will take part in this study?
Up to 24 patients will participate in this study. 
Description of Research Study
What will happen if you take part in this research study?
Before you begin the study
You will need to have the following examinations, tests, or procedures to find out if you can be 
in the study.  Most of these examinations, tests, or procedures are part of your regular cancer care 
and may be done by your health care team, even if you do not join the study.  If you have had 
them recently, they may not need to be repeated.  This will be up to your study doctor.  You will 
have the examinations, tests, and procedures listed below to see if you can take part in the study 
(this is called the screening or baseline evaluation).

Complete medical history.

Physical examination: including height, weight, blood pressure, pulse, and temperature.

Standard blood tests: (requiring about 1 tablespoon of blood in total), which include 
measurement of your white blood cells, red blood cells, platelets, blood sugar and 
electrolytes, how your liver and kidneys work, and how well your blood clots.

Pregnancy test: A blood test will be done to check for pregnancy in women who are able 
to become pregnant.

CT scans: of your chest, abdomen, and pelvis to measure your tumor(s).  Other imaging 
tests may be done as needed.


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 14-C-0015
CONTINUATION: page 3 of 14 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
During the study
If you are accepted and you choose to take part, you will begin receiving talazoparib (BMN 673).  
You will take talazoparib (BMN 673) by mouth once per day for 28 days.  The drug is given in 
cycles; each cycle is 28 days (4 weeks) long.  You can take the drug with or without food.  
You will be asked to maintain a diary to document the exact time you took the study drug, and to 
report any side effects that you may have.  If you miss or vomit the dose, please make a note of 
this in your diary and contact your team immediately to receive further instructions.  Please bring 
the study diary with you to each clinic visit. 
You will also have tests and procedures done because you are in the study to see how talazoparib 
(BMN 673) is affecting your body.  This will include repeating some of the imaging studies (e.g., 
CT scans, a computerized x-ray examination) every 8 weeks to find out if your cancer has 
responded.  Descriptions of the tests and procedures that will be performed during the study are 
listed below.  Please see the Study Chart below for more details.  
Clinical Center Visits: We will ask that you come to the Clinical Center at the beginning of 
cycle 1, and weeks 1, 2, and 3 during cycle 1; and at the beginning of week 1 for all other cycles.  
While you are at the Clinical Center we will perform study tests and procedures to see how the 
study drug is affecting your body.  If you develop any side effects, you may be asked to visit 
more often.
Standard procedures being done because you are in this study; these may be done more 
often because you are in the study:

Clinic visit: to ask how you are feeling and to evaluate you with a physical examination 
during weeks 1 and 2 of cycle 1 and week 1 for all subsequent cycles.

Vital signs and physical examinations: will be performed during the clinic visits.

Blood tests: Measurement of your white blood cells, red blood cells, platelets, blood 
sugar, electrolytes, and of how your liver and kidneys work will be done during weeks 1, 
2, and 3 of cycle 1; and then at the beginning of all subsequent cycles.  Approximately 
1 tablespoon (15 mL) of blood will be drawn per visit.

CT scans (or other imaging tests):  such as ultrasound (an examination using sound 
waves) or MRI (an examination using magnetic field and radio waves) that detect your 
tumor will be done before the study and every 8 weeks while you are receiving study 
drugs.  This is done so that any benefit of the treatment can be determined, and if your 
cancer is not responding to the treatment, the study team can tell you and discuss other 
treatment options (discussed further below). 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 14-C-0015
CONTINUATION: page 4 of 14 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
 
Tests and procedures that are either being tested in this study or being done to see how the 
drug is affecting your body:

Research blood samples: We will collect blood samples to find out the effects of the 
drug on any tumor cells in the blood.  Blood samples will be collected at the beginning of 
the study and then several times during cycle 1 and cycle 2, and at the start of all other 
cycles.  Please see the study chart for more details.  The total blood for all these tests will 
be about 7 tablespoons (100 mL).

Tumor biopsy: After you are accepted to take part in the study, you will be asked to 
undergo imaging-directed biopsy of your tumor (removal of a small bit of tissue for 
microscopic examination) once before you receive the study drug and after you have 
taken the drug on day 8.  We are collecting biopsy samples to study the effects of 
talazoparib (BMN 673) on your tumor.  Biopsies are an important part of this trial and are 
done for research purposes.  Willingness to undergo tumor biopsies is required for taking 
part in this study.  We may also ask you for an optional third biopsy if your disease 
comes back during treatment. 
After the first biopsy, if you decide not to have further biopsies, you will still receive 
study drugs and have other tests that are part of the study.  You will be asked to sign a 
separate consent form for each biopsy procedure.
Tumor biopsies are only collected by trained personnel.  Biopsies are collected using a 
small needle under imaging guidance (CT, MRI, or ultrasound as deemed appropriate by 
the interventional radiologist performing the biopsy).  Imaging helps the specialized 
radiologist know that the needle has been placed into the tumor mass.  
The biopsy to be performed is exclusively for research purposes and will not benefit you.  
It might help other people in the future.  Even if you sign "yes" to have the biopsy you 
can change your mind at any time.  Please read the sentence below and think about your 
choice.  After reading the sentence, circle and initial the answer that is right for you.
I agree to allow biopsies for research purposes: 
Yes              No               Initials_________


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 14-C-0015
CONTINUATION: page 5 of 14 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
When you are finished taking the drugs
When you have finished taking talazoparib (BMN 673), your study doctor will watch you 
carefully for up to 30 days after the last treatment or until another treatment is started.  You will 
need these tests and procedures at that time:

Vital signs and a physical examination

Blood tests

CT scans or other imaging tests such as ultrasound or MRI
You will be followed for 30 days after taking the last dose of study drugs.  We will call you 
between days 27-30 to ask about any side effects that were ongoing when you stopped therapy, 
or any new side effects that might be related to the study therapy.  If you have side effects that 
might be related to the study drugs that have not gotten better after 30 days, we will call you 
every 2 weeks until the side effects have become stable or gotten better.  The follow-up period 
will end if you enroll in another study or start receiving standard therapy.
Study Chart
The study drug is given over 28-day periods of time called cycles.  The chart below and on the 
next page shows what will happen to you during cycle 1 and future cycles after you sign the 
consent form and start the study.  Each cycle is numbered in consecutive order.  The left-hand 
column shows the day in the cycle and the right-hand column shows what will happen on that day.
Day
What to do and what will happen to you
Before 
starting 
study drug

Check in at the Outpatient Clinic

Get routine blood tests

Pregnancy test for women who are able to become pregnant

Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider

CT or MRI scan will be done

Tumor biopsy will be taken

Blood sample for research will be taken
Cycle 1, 
Day 1

Admitted to the Clinical Center

Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider (does not need to be repeated if done within 3 days 
before starting treatment)

Get routine blood tests (does not need to be repeated if done within 3 days 
before starting treatment)

Begin taking talazoparib (BMN 673) by mouth


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 14-C-0015
CONTINUATION: page 6 of 14 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
Day
What to do and what will happen to you

Blood samples for research will be taken 30 minutes and then 1, 2, 3, 4, 6, 8, 
and 24 hours after you take talazoparib (BMN 673)
Cycle 1, 
Day 8

Get routine blood tests

Blood sample for research will be taken 3-6 hours after you take talazoparib 
(BMN 673)

Continue taking talazoparib (BMN 673)

Tumor biopsy will be taken
Cycle 1, 
Week 3

Get routine blood tests

Continue taking talazoparib (BMN 673)
Cycle 2 
and 
onwards, 
Day 1

Check in at the Outpatient Clinic

Have a history taken of how you feel and undergo a physical examination by a 
Health Care Provider

Get routine blood tests

CT scan or MRI to determine how your tumor is responding to the treatment 
will be done every 2 cycles (8 weeks)

Blood sample for research will be taken before taking talazoparib (BMN 673) 
(every 3 cycles if you have been on study for more than a year)

Continue taking talazoparib (BMN 673) 

Blood sample for research will be taken 3-6 hours after you take talazoparib 
(BMN 673) (cycle 2 only)
Birth Control
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child.  If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice an effective form of birth control before starting study treatment, during 
study treatment, and for 30 days after you finish study treatment.  Men participating in this study 
must also agree to use adequate contraception prior to the study, for the duration of study 
participation, and for 3 months after finishing study treatment.  If you think that you or your 
partner is pregnant, you should tell your study doctor or nurse at once.
Effective forms of birth control include:

abstinence

intrauterine device (IUD)

vasectomy

tubal ligation

hormonal (birth control pills, injections, or implants)


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 14-C-0015
CONTINUATION: page 7 of 14 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
Risks or Discomforts of Participation
What side effects or risks can I expect from being in this study? 
You may have side effects while on this study.  Everyone taking part in the study will be 
watched carefully for any side effects.  But, doctors do not know all the side effects that may 
happen when taking talazoparib (BMN 673).  There may be other side effects that we cannot 
predict.  Side effects may be mild or very serious.  Your health care team may give you 
medicines to help lessen side effects.  Many side effects go away with those medicines, and 
others can go away soon after you stop taking the study drug.  In some cases, side effects can be 
serious, long lasting, may never go away, or may result in death.  You should talk to your study 
team about all side effects that you have while taking part in the study.  
Risks and side effects related to talazoparib (BMN 673) may include: 
COMMON, SOME MAY BE SERIOUS  
In 100 people receiving talazoparib (BMN 673), more than 20 and up to 100 may have:

Anemia which may require blood transfusion

Diarrhea, nausea, vomiting

Tiredness

Bruising, bleeding

Headache

Hair loss
OCCASIONAL, SOME MAY BE SERIOUS  
In 100 people receiving talazoparib (BMN 673), from 4 to 20 may have:

Pain

Constipation, heartburn

Sores in the mouth which may cause difficulty swallowing

Fever

Infection, especially when white blood cell count is low

Loss of appetite

Dizziness
RARE, AND SERIOUS
In 100 people receiving talazoparib (BMN 673), 3 or fewer may have:


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 14-C-0015
CONTINUATION: page 8 of 14 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent

Swelling of the bowels which may require surgery

Cancer of bone marrow caused by chemotherapy

Damage to the bone marrow (irreversible) which may cause infection, bleeding, may 
require transfusions

A new cancer resulting from treatment of earlier cancer
Because many of the adverse events seen in patients taking talazoparib (BMN 673) were 
decreased numbers of the cells you need to fight infection, please tell your study team 
immediately if you have any of the symptoms of a fever, sore throat, or other signs of an 
infection.
Potential Risks Related to Research-Related Imaging Studies: 
This research study involves exposure to radiation from up to 3 CT scans (used in biopsy 
collections).  This radiation exposure is not required for your medical care and is for research 
purposes only.  The amount of radiation you will receive in this study is 2.4 rem, which is below 
the guideline of 5 rem per year allowed for research subjects by the NIH Radiation Safety 
Committee.  The average person in the United States receives a radiation exposure of 0.3 rem per 
year from natural sources, such as the sun, outer space, and the earth's air and soil.  If you would 
like more information about radiation, please ask the investigator for a copy of the pamphlet, An 
Introduction to Radiation for NIH Research Subjects.
While there is no direct evidence that the amount of exposure received from participating in this 
study is harmful, there is indirect evidence it may not be completely safe.  There may be a very 
slight increase in the risk of cancer. 
Please tell your doctor if you have had any radiation exposure in the past year, either from other 
research studies or from medical tests or care, so we can make sure that you will not receive too 
much radiation.  Radiation exposure includes x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive materials 
were injected into your body. 
If you are pregnant you will not be permitted to participate in this research study.  
Potential Benefits of Participation
Are there benefits to taking part in this study?
Taking part in this study may or may not make your health better.  We do not know if you will 
receive personal, medical benefit from taking part in this study.  These potential benefits could 
include shrinking of your tumor or lessening of your symptoms, such as pain, that are caused by 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 14-C-0015
CONTINUATION: page 9 of 14 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
the cancer.  Because there is not much information about the drug’s effect on your cancer, we do 
not know if you will benefit from taking part in this study, although the knowledge gained from 
this study may help others in the future who have cancer.
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study? 
Instead of being in this study, you have these options:

Getting treatment or care for your cancer without being in a study

Taking part in another study

Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems, and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible.
Please talk to your doctor about these and other options.
Research Subject’s Rights
What are the costs of taking part in this study? 
If you choose to take part in the study, the following will apply, in keeping with the NIH policy:

You will receive study treatment at no charge to you.  This may include surgery, 
medicines, laboratory testing, x-rays or scans done at the Clinical Center, National 
Institutes of Health (NIH), or arranged for you by the research team to be done outside the 
Clinical Center, NIH if the study related treatment is not available at the NIH. 

There are limited funds available to cover the cost of some tests and procedures performed 
outside the Clinical Center, NIH.  You may have to pay for these costs if they are not 
covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or paid for by the 
Clinical Center, NIH.

Once you have completed taking part in the study, medical care will no longer be provided 
by the Clinical Center, NIH.

The NCI will supply the talazoparib (BMN 673) at no charge while you take part in this 
study.  The NCI does not cover the cost of getting the talazoparib (BMN 673) ready and 
giving it to you, so you or your insurance company may have to pay for this. 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 14-C-0015
CONTINUATION: page 10 of 14 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent

Even though it probably won’t happen, it is possible that the manufacturer may not 
continue to provide the talazoparib (BMN 673) to the NCI for some reason.  If this would 
occur, other possible options are:
•
You might be able to get the talazoparib (BMN 673) from the manufacturer or your 
pharmacy but you or your insurance company may have to pay for it.
•
If there is no talazoparib (BMN 673) available at all, no one will be able to get more 
and the study would close.

If a problem with getting talazoparib (BMN 673) occurs, your study doctor will talk to 
you about these options.
Will your medical information be kept private?
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include:

The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people.

National Institutes of Health Institutional Review Board.

Pharmaceutical Collaborator.
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the Web 
site will include a summary of the results.  You can search this Web site at any time. 
Stopping Therapy
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if your disease comes back during treatment

if you have side effects from the treatment that your doctor thinks are too severe

if new information shows that another treatment would be better for you

if too many patients in the study experience severe side effects

if you become pregnant
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time.  However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first.


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 14-C-0015
CONTINUATION: page 11 of 14 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you.  However, according to FDA guidelines, 
information collected on you up to that point may still be provided to the agent manufacturer, 
Pfizer, or designated representatives.  If you withdraw your consent and leave the trial, any 
samples of yours that have been obtained for the study and stored at the NCI can be destroyed 
upon request.  However, any samples and data generated from the samples that have already 
been distributed to other researchers or placed in the research databases cannot be recalled and 
destroyed.  
Conflict of Interest
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest. 
The National Institutes of Health and the research team for this study are using talazoparib 
(BMN 673) developed by Pfizer through a joint study with your researchers and the company.  
This means it is possible that the results of this study could lead to payments to NIH scientists 
and to the NIH.  By law, government scientists are required to receive such payments for their 
inventions.  You will not receive any money from the development of talazoparib (BMN 673).
Use of Specimens and Data for Future Research
We would like to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers.  We will not contact you to ask about each of 
these future uses.  These specimens and data will be identified by a number and not your name.  
Your specimens and data will be used for research purposes only and will not benefit you.  


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 14-C-0015
CONTINUATION: page 12 of 14 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
Researchers use specimens and data stored in scientific databases to advance science and learn 
about health and disease.  It is also possible that the stored specimens and data may never be 
used.  Results of research done on your specimens and data will not be available to you or your 
doctor.  It might help people who have cancer and other diseases in the future.  
If you decide now that your specimens and data can be kept for research and shared, you can 
change your mind at any time.  Just contact us and let us know that you do not want us to use 
your specimens and/or data.  Then any specimens that have not already been used or shared will 
be destroyed and your data will not be used for future research. 
Please read the sentence below and think about your choice.  After reading the sentence, circle 
and initial the answer that is right for you.  No matter what you decide to do, it will not affect 
your care.
My specimens and data may be kept and shared for use in research to learn about, prevent, or 
treat cancer or other health problems. 
Yes              No               Initials_________


MEDICAL RECORD
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or
•Parent, for Minor Patient
STUDY NUMBER: 14-C-0015
CONTINUATION: page 13 of 14 pages
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet)
•
Adult Patient or
•Parent, for Minor Patient
NIH-2514-1 (07-09)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
OTHER PERTINENT INFORMATION
1.
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance.
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations.
2.
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action.
3.
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines.
4.
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Dr. Alice Chen, 31 Center Drive, Building 31, room 3A44, Bethesda, 
Maryland, Telephone: 240-781-3320.  If you have any questions about the use of your specimens 
or data for future research studies, you may also contact the Office of the Clinical Director, 
Telephone:  240-760-6070.  You may also call the Clinical Center Patient Representative at 301-
496-2626.
5.
Consent Document.  Please keep a copy of this document in case you want to read it 
again.


MEDICAL RECORD
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or
•Parent, for Minor Patient
STUDY NUMBER: 14-C-0015
CONTINUATION: page 14 of 14 pages
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet)
•
Adult Patient or
•Parent, for Minor Patient
NIH-2514-1 (07-09)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
COMPLETE APPROPRIATE ITEM(S) BELOW:
A. Adult Patient’s Consent
B. Parent’s Permission for Minor Patient.
I have read the explanation about this 
study and have been given the 
opportunity to discuss it and to ask 
questions.  I hereby consent to take part 
in this study.
I have read the explanation about this study and 
have been given the opportunity to discuss it and to 
ask questions.  I hereby give permission for my 
child to take part in this study.  
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.)
Signature of Adult Patient/     Date
Legal Representative
Print Name
Signature of Parent(s)/Guardian
Date
Print Name
C. Child’s Verbal Assent (If Applicable)
The information in the above consent was described to my child and my child agrees to 
participate in the study.
Signature of Parent(s)/Guardian    Date
Print Name
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE 
FROM MAY 06, 2019 THROUGH MAY 06, 2020. 
Signature of Investigator            Date
Print Name
Signature of Witness                     Date
Print Name