Clinical trial NCT03343054
Conditions: Neoplasms Breast Neoplasms
Keywords: Phase 1 talazoparib PF-06944076 MDV3800 BMN673 PARP inhibitor Japanese solid tumors breast cancer C3441030
Sponsor: Pfizer
Start date: 2017-11-30; Completion date: 2024-07-18
Enrollment: 28 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 1 study which consists of 2 parts; Dose Escalation part and Expansion part.

The dose escalation part is open-label, and evaluates safety, preliminary efficacy and PK of single-agent talazoparib in sequential cohorts of adult patients with advanced solid tumors who are resistant to standard therapy or for whom no standard therapy is available.

In the dose escalation part, up to 18 (minimum 3) patients are expected to be enrolled depending on the observed DLTs.

The expansion part is designed to assess the efficacy, safety and PK of single-agent talazoparib at RP2D determined in the dose escalation part in adult patients with locally advanced or metastatic breast cancer who have deleterious or suspected deleterious germline BRCA1 or BRCA2 mutations.

In the expansion part, a minimum of 17 patients will be enrolled evaluable for the primary endpoint.

Detailed description:

Arms: arm 1: 0.75 mg/day or 1.0 mg/day
Interventions: intervention 1: talazoparib
Intervention descriptions: intervention 1: Talazoparib will be administered orally on a continuous basis. Talazoparib may be taken with or without food. Each cycle will consist of 28 days.

Protocol documents:
Prot_000.pdf: 
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`
A PHASE 1 STUDY OF THE SAFETY, PHARMACOKINETICS AND ANTI-TUMOR 
ACTIVITY OF TALAZOPARIB, POLY (ADP-RIBOSE) POLYMERASE (PARP) 
INHIBITOR, IN JAPANESE PATIENTS WITH ADVANCED SOLID TUMORS
Investigational Product Number:
PF-06944076 (MDV3800/BMN673)
Investigational Product Name:
talazoparib
United States (US) Investigational New 
Drug (IND) Number:
Not Applicable
European Clinical Trials Database 
(EudraCT) Number:
Not Applicable
Protocol Number:
C3441030
Phase:
1
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.


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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 2
28 Feb 2019
The expansion part was added to evaluate the 
efficacy, the safety and PK at RP2D of single agent 
talazoparib in Japanese patients with gBRCA 
mutated advanced/metastatic breast cancer.  Most of 
the sections were updated and modified to reflect the 
design of the expansion part.
y
Schedule of Activities 
y
Introduction
y
Study Objectives and Endpoints
y
Study Design
y
Patient Eligibility Criteria 
y
Dose Reductions
y
Study Procedures
y
Pharmacokinetics Assessments
y
Tumor Response Assessments 
y
Data Analysis/Statistical Methods.  
y
New sections were added: Assessment of 
germline BRCA mutations for eligibility,
 
In addition, administrative changes were made 
throughout the protocol associated with the 
expansion part including;
y
Background and Rationale have been updated to 
provide updated clinical data from the 
completed and ongoing clinical studies and with 
the current information about breast cancer.
y
Determination of Best Overall Response was 
added to Appendix 3.  RECIST version 1.1 
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Guidelines 
The following sections were updated according to 
the updated IB

Background and Rationale (safety and PK)

Lifestyle Requirements

Concomitant Treatment(s)
Minor editorial changes were made for consistencies 
throughout the document.
Amendment 1
12 Sep 2017
Based on the requirement of Pharmaceuticals and 
Medical Devises Agency (PMDA), the following 
changes were incorporated.

Section 3.1 Study Overview
For clarification, added the statement that RP2D 
may not be determined in some cases 

Section 3.1.2.  Criteria for Dose Escalation
Updated the statement to clarify the process of 
dose escalation and RP2D determination.  All of 
the safety data is potentially used for 
determination of dose escalation

Section 3.2.  DLT Definition
Grade 3 anemia requiring blood transfusion 
would be a DLT

7.1.3.  Laboratory Safety Assessment
Added Red blood cell and Hematocrit in the 
hematology panel
In overall, minor typographical error were corrected 
including reference update.
Original protocol
23 May 2017
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
APPENDICES ...........................................................................................................................8
1. INTRODUCTION ...............................................................................................................25
1.1. Mechanism of Action/Indication.............................................................................25
1.2. Background and Rationale ......................................................................................25
1.2.1. Role of BRCA and PARP in DNA repair...................................................25
1.2.2. Mechanism and clinical use of PARP inhibitor to BRCA mutated 
cancer...............................................................................................................26
1.2.3. Talazoparib and available non-clinical/clinical data ..................................27
1.2.4. The study rationale .....................................................................................29
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................30
2.1. Dose Escalation part (Solid Tumor)........................................................................30
2.2. Expansion part (gBRCAm breast cancer) ...............................................................31
3. STUDY DESIGN.................................................................................................................31
3.1. Study Overview.......................................................................................................31
3.1.1. Starting Dose (Dose Escalation part only)..................................................32
3.1.2. Criteria for Dose Escalation (Dose Escalation part only)...........................32
3.2. DLT Definition (Dose Escalation part only)...........................................................33
4. PATIENT ELIGIBILITY CRITERIA.................................................................................35
4.1. Dose Escalation part................................................................................................35
4.1.1. Inclusion Criteria ........................................................................................35
4.1.2. Exclusion Criteria.......................................................................................36
4.2. Expansion part.........................................................................................................38
4.2.1. Inclusion Criteria ........................................................................................38
4.2.2. Exclusion Criteria.......................................................................................39
4.3. Lifestyle Requirements ...........................................................................................41
4.4. Sponsor’s Qualified Medical Personnel..................................................................42
5. STUDY TREATMENTS.....................................................................................................42
5.1. Allocation to Treatment ..........................................................................................42
5.2. Patient Compliance .................................................................................................43
5.3. Investigational Product Supplies.............................................................................43


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5.3.1. Dosage Form(s) and Packaging..................................................................43
5.3.2. Preparation and Dispensing........................................................................43
5.4. Administration.........................................................................................................44
5.4.1. Recommended Dose Modifications............................................................44
5.4.2. Dosing Interruptions...................................................................................44
5.4.3. Dose Delays................................................................................................45
5.4.4. Dose Reductions .........................................................................................46
5.5. Investigational Product Storage ..............................................................................50
5.6. Investigational Product Accountability...................................................................51
5.6.1. Destruction of Investigational Product Supplies ........................................51
5.7. Concomitant Treatment(s).......................................................................................51
5.7.1. Other Anti-tumor/Anti-cancer or Experimental Drugs...............................52
5.7.2. Supportive Care ..........................................................................................52
5.7.3. Hematopoietic Growth Factors...................................................................52
5.7.4. Anti-Diarrheal, Anti-Emetic Therapy.........................................................52
5.7.5. Anti-Inflammatory Therapy........................................................................52
5.7.6. Corticosteroids............................................................................................53
5.7.7. Surgery........................................................................................................53
6. STUDY PROCEDURES .....................................................................................................53
6.1. Screening.................................................................................................................53
6.2. Study Period ............................................................................................................53
6.3. Follow-up ................................................................................................................54
6.4. Patient Withdrawal..................................................................................................54
7. ASSESSMENTS..................................................................................................................56
7.1. Safety Assessment...................................................................................................56
7.1.1. Pregnancy Testing ......................................................................................56
7.1.2. Adverse Events...........................................................................................56
7.1.3. Laboratory Safety Assessment ...................................................................56
7.1.4. Vital Signs and Physical Examination........................................................57
7.1.5. (12-Lead) Electrocardiogram......................................................................57
7.2. Pharmacokinetics Assessments...............................................................................58
7.2.1. Plasma for PK analysis of talazoparib........................................................58


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7.3. Tumor Response Assessments ................................................................................59
7.4. Assessment of germline BRCA mutations for eligibility (Expansion part 
only)...........................................................................................................................60
8. ADVERSE EVENT REPORTING......................................................................................62
8.1. Requirements...........................................................................................................62
8.1.1. Additional Details On Recording Adverse Events on the CRF..................63
8.1.2. Eliciting Adverse Event Information..........................................................63
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Patient Withdrawal section).............................................................................63
8.1.4. Time Period for Collecting AE/SAE Information......................................64
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................64
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................64
8.1.5. Causality Assessment .................................................................................64
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................65
8.2. Definitions...............................................................................................................65
8.2.1. Adverse Events...........................................................................................65
8.2.2. Abnormal Test Findings .............................................................................66
8.2.3. Serious Adverse Events ..............................................................................66
8.2.4. Hospitalization............................................................................................67
8.3. Severity Assessment................................................................................................69
8.4. Special Situations ....................................................................................................69
8.4.1. Potential Cases of Drug-Induced Liver Injury............................................69
8.4.2. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................71
8.4.2.1. Exposure During Pregnancy......................................................71
8.4.2.2. Exposure During Breastfeeding ................................................72
8.4.2.3. Occupational Exposure .............................................................72
8.4.3. Medication Errors .......................................................................................72
8.4.3.1. Medication Errors......................................................................73
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................73
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9.1. Analysis Sets ...........................................................................................................73
9.2. Statistical Methods and Properties ..........................................................................74
9.3. Sample Size Determination.....................................................................................75
9.4. Efficacy Analysis ....................................................................................................75
9.4.1. Analysis of Primary and Secondary Efficacy Endpoints............................75
9.5. Analysis of Pharmacokinetics and Pharmacodynamics ..........................................77
9.5.1. Analysis of Pharmacokinetics.....................................................................77
9.5.1.1. Single-Dose and Steady-State Talazoparib 
Pharmacokinetic Analysis .................................................................77
9.5.2. Population Pharmacokinetic Analysis or 
Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling ................................78
9.6. Safety Analysis........................................................................................................78
9.6.1. Analysis of DLT (the Primary Endpoint for the dose escalation part).......78
9.6.2. Analysis of Secondary Safety Endpoints....................................................78
9.6.3. Electrocardiogram.......................................................................................79
9.7. Interim Analysis ......................................................................................................79
9.8. Data Monitoring Committee ...................................................................................79
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................80
11. DATA HANDLING AND RECORD KEEPING .............................................................80
11.1. Case Report Forms/Electronic Data Record .........................................................80
11.2. Record Retention...................................................................................................81
12. ETHICS..............................................................................................................................81
12.1. Institutional Review Board/Ethics Committee......................................................81
12.2. Ethical Conduct of the Study ................................................................................81
12.3. Patient Information and Consent...........................................................................82
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................82
13. DEFINITION OF END OF TRIAL...................................................................................82
14. SPONSOR DISCONTINUATION CRITERIA ................................................................83
15. PUBLICATION OF STUDY RESULTS..........................................................................83
15.1. Communication of Results by Pfizer ....................................................................83
15.2. Publications by Investigators ................................................................................84
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16. REFERENCES ..................................................................................................................85
LIST OF TABLES
Table 1.
Available Dose Levels..........................................................................................46
Table 2.
Dose Modifications for Investigational Product-Related Toxicity (Dose 
Escalation part only).............................................................................................47
Table 3.
Dose Modification of Talazoparib Due to Adverse Events (Expansion part 
only)......................................................................................................................48
Table 4.
Criteria for Temporary Withholding of Study Drug in Association With 
Liver Test Abnormalities......................................................................................50
Table 5.
Safety Laboratory Tests........................................................................................57
Table 6.
Probability of Escalating Dose .............................................................................74
Table 7.
Number of Confirmed Objective Responders for Unblinded Reviews................79
APPENDICES
Appendix 1.  Abbreviations.....................................................................................................88
Appendix 2.  Bone Marrow Reserve in Adults........................................................................92
Appendix 3.  RECIST (Response Evaluation Criteria In Solid Tumors) version 1.1 
Guidelines.............................................................................................................94
Appendix 4.  ECOG Performance Status*...............................................................................99


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PROTOCOL SUMMARY
Background and Rationale
Cancer represents a disease area with a high-unmet medical need with more than 14.1 million 
people diagnosed annually worldwide, and an associated mortality that exceeds 8.2 million 
individuals1.  The discovery and development of new anti-cancer therapies effective either in 
single-agent or combination treatment settings is still desperately needed.
Talazoparib (PF-06944076 also known as MDV3800 or BMN 673) is a potent, orally 
bioavailable, small molecule poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP)
inhibitor in development for the treatment of a variety of human cancers.  Talazoparib is 
cytotoxic to human cancer cell lines harboring gene mutations that compromise 
deoxyribonucleic acid (DNA) repair, an effect referred to as synthetic lethality.  In breast 
cancer MX-1 cells that are breast cancer susceptibility gene I (BRCA1) -deficient, 
talazoparib inhibits cell growth in vitro and inhibits tumor growth and/or induces tumor 
regression in mouse xenografts.  Anti-tumor activity was also demonstrated in small cell lung 
cancer (SCLC) cell lines and xenograft models; single-agent talazoparib reduced tumor 
growth to a similar extent as the cytotoxic chemotherapy drug cisplatin in 2 independent 
SCLC xenograft models.  
The main nonclinical toxicology findings with talazoparib were early hematologic changes 
and subsequent bone marrow and lymphoid organ depletion; focal atrophy and degeneration 
of the testes, epididymis, and seminiferous tubules; and dose-dependent apoptosis/necrosis in 
the gastrointestinal (GI) tract and liver after repeat-dose administration of talazoparib.  These 
findings are consistent with the exaggerated pharmacology of talazoparib and its tissue 
exposure pattern.  The hematologic findings were generally reversible and the early 
hematologic changes represent sensitive and early markers of target organ toxicity.  
Talazoparib caused fetal malformations, structural variations, and death in an embryo-fetal 
development study in rats.  
As of 31 January 2018, approximately 659 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.  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 the C3441030 study demonstrated objective responses and/or clinical benefit in patients 
with breast, ovarian/peritoneal, and pancreatic cancer; SCLC; and Ewing sarcoma.  
Treatment-emergent adverse drug reactions (ADRs) 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, vomiting, abdominal 
pain, and decreased appetite), fatigue, headache, and alopecia.  Grade 3 or 4 ADRs of 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) in 5% of patients were associated with myelosuppression. The ADRs associated 
with talazoparib are generally detected through routine laboratory and clinical monitoring 
and may be managed using symptomatic therapies, supportive care, or dose reductions or 
interruptions.


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The pharmacokinetics (PK) of talazoparib as a single agent was evaluated in 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; the mean terminal half life (t½) was 
approximately 4 days.  Talazoparib accumulated after 1 mg quaque die (QD) dosing with a 
median accumulation ratio (Rac) ranging from 2.33 to 5.15, consistent with its t½.  Steady 
state was reached around 3 weeks after the start of talazoparib dosing.  Talazoparib 
undergoes minimal hepatic metabolism in humans.  Renal excretion was a major elimination 
pathway for unchanged parent talazoparib.  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 therapeutic exposures, talazoparib did not markedly induce or inhibit cytochrome P450 
(CYP450) enzymes or transporters and is therefore unlikely to demonstrate clinically 
significant CYP450 inhibition- or induction-based drug-drug interactions (DDIs) or drug
transporter inhibition-based DDIs when coadministered with corresponding substrates.  
However, talazoparib is a substrate for P-glycoprotein (P-gp) and breast cancer resistance 
protein (BCRP), and plasma talazoparib concentrations may increase when coadministered 
with P-gp or BCRP inhibitors, respectively.  
A phase 2 (ABRAZO, 673-201, C3441008) and a phase 3 (EMBRACA, 673-301, 
C3441009) study evaluated single-agent talazoparib in patients with locally advanced or 
metastatic breast cancer with deleterious germline BRCA mutations (gBRCAm).  
EMBRACA met primary endpoint and is following-up for OS.  However Japanese patients 
were not included in these studies and there was no clinical experience with talazoparib in 
Japanese patients, at the time of study initiation.  Therefore, the current C3441030 study was 
initially designed to evaluate the safety, tolerability, preliminary efficacy, and PK profile of 
talazoparib as a single agent in Japanese patients with advanced solid tumors (the dose 
escalation part).
As of 24 January 2019, a total of 9 patients were enrolled in the dose escalation part of the 
C3441030 study.  Dose limiting toxicities (DLT) were not reported in any patients receiving
0.75 mg/day (n=3) or 1.0 mg/day (n=6).  Therefore, the recommended Phase 2 dose (RP2D) 
of single-agent talazoparib was determined to be 1.0 mg/day in Japanese patients with 
advanced solid tumors.  Overall the safety profile in the dose escalation part was similar to 
the adverse events (AEs) observed in global studies of talazoparib.  Most common AEs of 
single-agent talazoparib in Japanese patients were hematological toxicities and 
hepatotoxicities. Based on the preliminary PK analysis results (n=3 each in 0.75 and 
1.0 mg/day), the PK profile of single-agent talazoparib in Japanese patients was comparable 
with that in Western population.  These data also supported RP2D in Japanese patients.
EMBRACA is a pivotal, randomized, open label, 2 arm, Phase 3 study that evaluated 
talazoparib versus protocol specified physician’s choice treatment (PCT) in patients with 
gBRCAm HER2-negative locally advanced or metastatic breast cancer.  PCT included single 
agent capecitabine, eribulin, gemcitabine, or vinorelbine and was determined by the treating 
physician for each patient before randomization.  The primary objective of the study was to 


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compare progression-free survival (PFS) by blinded independent central review (BICR) 
assessment between the talazoparib and PCT arms.  As of data cutoff date of 15 September 
2017, the study met its primary objective demonstrating that talazoparib was superior to 
chemotherapy in prolonging PFS by BICR assessment, with the median PFS of 8.6 months 
[95% confidence interval (CI): 7.2, 9.3] in talazoparib arm compared with 5.6 months (95% 
CI: 4.2, 6.7) in PCT arm.  There was a 46% reduction in relative risk of disease progression 
or death, with an observed hazard ratio (HR) of 0.54 (95% CI: 0.41, 0.71; p<0.0001 [2-sided 
by stratified log-rank test]).  The primary analysis of objective response rate (ORR) was 
conducted in the intent-to-treat (ITT) with measurable disease population, based on 
investigator assessment.  ORR was 62.6% (95% CI: 55.8, 69.0) in the talazoparib arm vs 
27.2% (95% CI: 19.3, 36.3) in PCT arm.  The odds ratio was 4.99 (95% CI: 2.9, 8.8) with a 
p-value from the 2-sided stratified Cochran-Mantel-Haenszel test of <0.0001 in favor of the 
talazoparib arm.  Although confirmation was not required for this randomized trial, the 
confirmed ORR by investigator’s assessment was 50.2% (95% CI: 43.4, 57.0) in talazoparib 
arm and 18.4% (95% CI: 11.8, 26.8) in PCT arm.  An interim analysis of overall survival 
(OS) was conducted (163 deaths had occurred).  Median OS was 22.3 months (95% CI: 18.1, 
26.2) in the talazoparib arm and 19.5 months (95% CI: 16.3, 22.4) in the PCT arm with the 
estimated HR of 0.76 (95% CI: 0.55, 1.06; p=0.1053 [2-sided by stratified log-rank test]).
Following on the encouraging results of EMBRACA and the determination of RP2D in 
Japanese patients, the C3441030 study will be expanded to further evaluate efficacy, safety 
and PK at RP2D in Japanese patients with gBRCAm HER2-negative locally advanced or 
metastatic breast cancer in protocol amendment 2.  It will also explore biomarkers in blood 
and tumor samples that includes attempts to characterize sensitivity and resistance to 
talazoparib.
Objectives and Endpoints
Dose Escalation Part (Solid Tumor)
Primary Objective
•
To assess safety and tolerability at increasing dose levels of talazoparib in successive 
cohorts of patients with solid tumors in order to select the RP2D/schedule in Japanese 
patients
Secondary Objectives
•
To evaluate the overall safety profile
•
To characterize the single and steady state PK of single-agent talazoparib 
•
To assess preliminary evidence of anti-tumor activity of single-agent talazoparib
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Endpoints
Primary Endpoint
•
First-cycle DLTs
Secondary Endpoints
•
AEs as characterized by type, frequency, severity (as graded by the NCI CTCAE, 
Version 4.03), timing, seriousness, and relationship to talazoparib
•
Laboratory abnormality as characterized by type, frequency and severity (graded by the 
NCI CTCAE, Version 4.03), and timing
•
Vital signs
•
Pharmacokinetic parameters of talazoparib 
•
Single Dose (SD) - Cmax, Tmax, AUClast, AUCτ, CL/F, Vz/F, t½, and AUCinf as data permit
•
Multiple Dose (MD) (assuming steady state is achieved) - Css,max, Tss,max, AUCss,τ, CL/F, 
Rac (AUCss,τ /AUCsd,τ), Css,min and Rss (AUCss,τ /AUCsd,inf) as data permit
•
Objective Response (OR), as assessed using the Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1
•
Time to event endpoints: Duration of Response (DoR) and PFS if applicable
Expansion Part (gBRCAm breast cancer)
Primary Objective
•
To evaluate the anti-tumor activity of single agent talazoparib in Japanese patients with 
gBRCAm HER2-negative locally advanced or metastatic breast cancer
Secondary Objectives
•
To further evaluate anti-tumor activity
•
To evaluate the overall safety profile of talazoparib 
•
To characterize the PK of single-agent talazoparib
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Endpoint 
Primary Endpoint
•
Confirmed OR as assessed using RECIST version 1.1 by Investigator Assessment 
Secondary Endpoints
•
AEs including laboratory abnormalities as characterized by type, frequency, severity (as 
graded by the NCI CTCAE, version 4.03), timing, seriousness, and relationship to 
talazoparib
•
Trough concentrations of talazoparib
•
OR as assessed using RECIST version 1.1 by BICR
•
Disease Control defined as patients with a confirmed complete response (CR), confirmed 
partial response (PR) and stable disease (SD) at 16 and 24 weeks
•
Time to event endpoints: Time-to-tumor response (TTR), DoR, PFS, and OS
Study Design
This is a Phase 1 study which consists of 2 parts; Dose Escalation part and Expansion part.  
The dose escalation part is open-label, and evaluates safety, preliminary efficacy and PK of 
single-agent talazoparib in sequential cohorts of adult patients with advanced solid tumors 
who are resistant to standard therapy or for whom no standard therapy is available.  
Successive cohorts of patients received escalating doses of talazoparib on an outpatient basis 
starting from 0.75 mg/day.  This part evaluated 2 dose levels; 0.75 mg/day and 1.0 mg/day.  
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Single-dose safety and single-dose PK assessments of talazoparib in a lead-in period 
preceding the continuous daily doses have been included in the dose escalation part.  In the 
7-day lead-in period, a single lead-in dose was given on Day -7.  No talazoparib was 
administered during the interval between the lead-in single dose and Day 1 of the first cycle.  
Study treatment is given as on outpatient basis, however a patient is required to stay 
overnight at the study site during any intensive PK collection period (i.e.  Day -7 and Day 22 
in Cycle 1).  
In the dose escalation part, a total of 9 patients were enrolled.  No DLTs were observed in 
any patients receiving 0.75 mg/day (n=3) or 1.0 mg/day (n=6).  Therefore enrollment was 
completed for dose escalation part.
Protocol amendment 2 includes the addition of an expansion part which is designed to assess 
the efficacy, safety and PK of single-agent talazoparib at RP2D determined in the dose 
escalation part in adult patients with locally advanced or metastatic breast cancer who have 
deleterious or suspected deleterious germline BRCA1 or BRCA2 mutations.  The patients in 
the expansion part will receive 1.0 mg/day of talazoparib which was RP2D identified in the 
dose escalation part of the study.  The expansion part will include BICR assessment for the 
efficacy evaluation.  All radiographic images taken during the study must be available and be 
submitted for central review.
In the expansion part, a minimum of 17 patients will be enrolled evaluable for the primary 
endpoint.
In all study parts, treatment with talazoparib will continue until either disease progression, 
unacceptable toxicity or withdrawal of consent.
Study Treatments
Talazoparib will be administered on a continuous basis once daily taken at the same time 
with or without food.  A cycle is defined as the time from Day 1 dose of one cycle to the next 
Day 1 dose of the next Cycle.  If there are no treatment delays, a cycle will be 28 days.  
Talazoparib will be provided as capsules for oral administration.  The 0.25 mg capsules will 
be supplied in separate bottles (or blister cards, as appropriate) and labeled according to local 
regulatory requirements.  For the expansion part, 1.0 mg capsule will also be supplied as a 
starting dose; 0.25 mg capsule should only be used for patients who require dose reduction.
Statistical Methods
DLT is the primary endpoint of the dose escalation part of the study.  The occurrence of 
DLTs observed in the first cycle of each cohort is used to evaluate the RP2D as described in 
the Study Design section.  AEs constituting DLTs will be listed per dose level.
For the expansion part, the confirmed ORR assessed using RECIST version 1.1 by 
Investigator Assessment and the exact two-sided 90% CI will be calculated.


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the Assessments section of the 
protocol for detailed information on each assessment required for compliance with the protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the schedule of activities table in order to conduct 
evaluations or assessments required to protect the well-being of the patient.
[Dose Escalation part]
Lead in
CYCLE 1
CYCLE 2
Visit Identifier (Visit 
or Assessment 
window [days] unless 
otherwise noted) a
Screening b
(28 days prior 
to Lead-in)
Day -7 (-1)
Day 1(-1)
Day 8 
(1)
Day 15 
(1)
Day 22 
(1)
Day 1(2) c
End of 
Treatment d
Follow- up e
Informed consent f
X
(X)
Tumor history
X
Medical history
X
Physical examination
X
X
X
X
X
Baseline signs and 
symptoms g
X
Height
X
Weight
X
X
X
X
X
Vital signs h
X
X
X
X
X
Performance status i
X
X
X
X
Laboratory
Hematology j
X
X
X
X
X
X
X
X
Blood Chemistry k
X
X
X
X
X
X
X
X
Urinalysis l
X
X
Pregnancy test m
X
X
X
X
X
Virus test 
(HBV/HCV/HIV) n
X
Contraception check o
X
X
X
X
X
(12 lead) ECG p
X
X
X
X
X
X


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Lead in
CYCLE 1
CYCLE ≥2
Visit Identifier (Visit 
or Assessment 
window [days] unless 
otherwise noted) a
Screening b
(≤28 days prior 
to Lead-in)
Day -7 (-1)
Day 1(-1)
Day 8 
(±1)
Day 15 
(±1)
Day 22 
(±1)
Day 1(±2) c
End of 
Treatment d
Follow- up e
Registration and 
Treatment 
Registration q
X
Study treatment r
X
X
→
→
→
→
Tumor assessments
X
X
X
CT or MRI scan or 
equivalent s
X
X
X
Other clinical 
assessments
Serious and non-serious 
adverse event monitoring t
X
→
→
→
→
→
→
→
→
Concomitant treatment(s) u
X
→
→
→
→
→
→
→
X
Other samplings
Pharmacokinetics v
X
X
X
X
X
Abbreviations: →= ongoing/continuous event; CT = computed tomography; ECG = electrocardiogram; HBV = hepatitis B virus; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; MRI = magnetic resonance imaging.
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a.
Day relative to start of study treatment (Day 1).  
b.
Screening: To be obtained within 28 days prior to Cycle 1 Day -7 (C1D-7).
c.
For Cycle 2 Day 1 (C2D1), “-2 days” window is not applicable.
d.
End of Treatment Visit: Obtain these assessments if not completed in the last week (last 6 weeks for tumor assessments)
e.
Follow-up: At least 28 calendar days, and no more than 35 calendar days, after discontinuation of treatment, patients will return to undergo review of 
concomitant treatments, vital signs, and assessment for resolution of any treatment-related toxicity.  Patients continuing to experience toxicity at this point 
following discontinuation of treatment will continue to be followed until resolution or determination, in the clinical judgment of the investigator and 
consultation with the sponsor, that no further improvement is expected.  Pregnancy test will be performed for women of childbearing potential only.
f.
Informed Consent: Must be obtained prior to undergoing any study-specific procedures.  Procedures performed as standard of care prior to signed and dated 
informed consent document (ICD), and within the 28 day screening window may be used for study eligibility.  Patients must be also asked to sign an 
additional consent document before starting treatment on C2D1 for confirmation of their willingness to continue participation in the study beyond Cycle 1.
g.
Baseline Signs & Symptoms: Patients will be asked about any signs and symptoms experienced within the 14 days prior to PK lead-in dose.  Clinically 
significant baseline signs and symptoms will be recorded on the Adverse Event case report form (CRF) page.
h.
Vital Signs: Blood pressure (BP) and pulse rate to be recorded in sitting position.
i.
Performance Status: Use Eastern Cooperative Oncology Group (ECOG) – see Appendix 4
j.
Hematology: No need to repeat on C1D-7 if baseline assessment performed within 7 days prior to that date.  Additional hematology may be performed as 
clinically indicated.  Frequency should be increased as clinically indicated to monitor neutropenia, thrombocytopenia, and anemia.  See Assessments section 
for Laboratory Tests list.
k.
Blood Chemistry: No need to repeat on C1D-7 if baseline assessment performed within 7 days prior to that date.  Additional chemistries may be performed 
as clinically indicated.  See Assessments section for Laboratory Tests list.
l.
Urinalysis: Dipstick is acceptable.  Microscopic analyses if dipstick abnormal.  No need to repeat on C1D-7 if baseline assessment performed within 7 days 
prior to that date.  Additional urinalysis may be performed as clinically indicated.  See Assessments section for Laboratory Tests list.
m. Pregnancy Test (for women of childbearing potential only): described in the Pregnancy Testing section.  
n.
Virus (HBV/HCV/HIV) test: Perform within 28 days prior to the first study treatment.
o.
The contraception check is an opportunity to confirm that contraception, if assigned, is used consistently and correctly.  Also, for studies enrolling adult 
patients, it is the opportunity to assess changing potential to father/bear children and allows for altering contraception if new disease contraindicates a 
selected method of contraception or if nonchildbearing status is achieved.
p.
12-Lead ECG: A single 12-lead ECG will be performed.  No need to repeat on C1D-7 if baseline assessment performed within 7 days prior to that date.  
When coinciding with blood sample draws for PK, ECG assessment should be performed prior to blood sample collection, such that the blood sample is 
collected at the nominal time.  If the QTcF is prolonged (>500 msec), 3 consecutive ECGs will be performed approximately 2 minutes apart to determine 
mean QTcF interval to confirm presence of QTc prolongation and the ECGs should be re-evaluated by a qualified person at the institution for confirmation.  
Additional ECGs may be performed as clinically indicated.  
q.
Registration: patient number and dose level allocation assigned by Pfizer Inc.  


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r.
Study Treatment: described in the Study Treatments section.  A single dose of tralazoparib is administered on C1D-7, then continuous dose will begin from 
C1D1.
s.
Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging may include chest, abdomen, and pelvis CT or MRI 
scans.  Brain scans and bone scans will be performed at baseline if disease is suspected and on study as appropriate to follow disease.  Baseline central 
nervous system (CNS) imaging is not required with the exception of symptomatic patients to rule out CNS metastases.  CT or MRI scans to be done on 
C2D1 and Day 1 of every other cycle (e.g.  C4, C6, C8, C10 and C12) ±7 days window.  No need to repeat if the start of new cycle delays (e.g.  due to 
treatment related toxicity).  After completion of Cycle 12, tumor assessment will be done per local standard practice.  Tumor assessment should be repeated 
at the end of study visit if more than 6 weeks have passed since the last evaluation.  Given the exploratory nature of the dose escalation part, confirmation of 
response (complete response [CR]/partial response [PR]) is not required.  As clinically indicated, CT/MRI will be repeated by investigator’s discretion.
t.
Adverse Event (AE) Assessments: AEs should be documented and recorded at each visit using the NCI CTCAE version 4.03.  The time period for actively 
eliciting and collecting AEs and SAEs (“active collection period”) for each patient begins from the time the patient provides informed consent through and 
including a minimum of 28 calendar days after the last investigational product administration.  If the patient begins a new anti-cancer therapy, the period for 
recording non-serious AEs on the CRF ends at the time the new treatment is started.  However, any SAEs occurring during the active collection period must 
still be reported to Pfizer Safety and recorded on the CRF, irrespective of any intervening treatment.
u.
Concomitant Treatments: all concomitant medications and NonDrug Supportive Interventions should be recorded on the CRF.
v.
PK Sampling: Blood will be collected for PK sampling of talazoparib.  In lead in phase, after a single dose of tarazoparib, samples at predose and 0.50, 0.75, 
1, 2, 3, 4, 6, 8, 10 hour (h) on C1Day -7.  After that, 24, 48, 72 and 96 h post dose samples will be collected on through C1D-6 to C1D-3.  Pre-dose sample 
will be collected on C1D1 dosing as 168 h post dose sample.  Pre-dose samples will be collected on C1Day 15.  Serial PK samples after multiple dose will 
be collected on C1D22 at predose, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10 h.  Pre-dose samples will be collected on C1D23 and Day 1 of Cycles 3 and 4.  Details are in 
Pharmacokinetic Sampling Schema.
 
 
 
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Pharmacokinetic Sampling Schema
Visit Identifier 
Lead in
CYCLE 1
CYCLE 3
CYCLE 4
Study Day
Day -7
-6
-5
-4
-3
Day 1
15
22
23
Day 1
Day 1
Hours Before/After Dose
0 a 0.5 0.75
1
2
3
4
6
8
10 24 48 72 96
168 a
0 a 0 a 0.5 0.75
1
2
3
4
6
8
10 24 a
0 a
0 a
Study treatment administration
X
X
X
X
X
X
X
PK blood sampling 
X
X
X
X X X X X X
X
X
X
X
X
X
X
X
X
X
X X X X X X
X
X
X
X
Abbreviation: PK = pharmacokinetic.
a.
Predose sample collection.  Study treatment administration should be after the PK blood sampling.


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[Expansion part]
Screening a
CYCLEs 1 and 2 b
CYCLEs 
3 b
End of Treatment c
Long-Term Follow-Up d
Procedure/Assessment (visit window) e
(-28 days
prior to 
first dose of 
study 
treatment)
Day 1
(-3 days)
Day15 
(±3 days)
Day1
(-3 days)
28 days postdose
(+7 days)
See footnote d for 
schedule
Informed consent f
X
Medical history g
X
Vital signs h
X
X
X
X
X
Physical examination i
X
X
X
X
ECOG Performance Status
X
X
X
X
Tumor assessment j
X
X (See footnote j)
X 
Bone scan j
X
[X] (See footnote j)
[X]
PK blood sampling k
X 
X 
Clinical laboratory tests
Hematology l
X
X
X
X
X
Serum chemistry l
X
X
X
X
Urinalysis l
X
Calculated creatinine clearance l
X
Virus test (HBV/HCV/HIV) m
X
Pregnancy test n
X
X
X
X
Serious and non-serious adverse event 
monitoring o
X
X
X
X
X
Contraception check p
X
X
X
X
(12 lead) ECG q
X
X
Concomitant medications r
X
X
X
X
X
Patient contact: survival, obtain cancer 
treatment 
X 
Talazoparib treatment s
Once-daily dosing 


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Screening a
CYCLEs 1 and 2 b
CYCLEs 
≥3 b
End of Treatment c
Long-Term Follow-Up d
Procedure/Assessment (visit window) e
(-28 days
prior to 
first dose of 
study 
treatment)
Day 1
(-3 days)
Day15 
(±3 days)
Day1
(-3 days)
28 days postdose
(+7 days)
See footnote d for 
schedule
Documentation of germline BRCA1 or 
BRCA2 mutation t
[X]
Blood sample (germline BRCA assay) u
X
 
[X] denotes an optional test.  Abbreviations: AE = adverse event; BRCA = breast cancer susceptibility gene; CT = computed tomography; 
 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; HBV = hepatitis B virus; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; MRI = magnetic resonance imaging; NCI CTCAE = the National Cancer Institute Common Terminology Criteria for 
Adverse Events; PK = pharmacokinetics; SAE = serious adverse event.  
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a.
Screening: The Screening visit must occur within 28 days before starting study treatment.  Screening and baseline procedures may be performed on the same 
day as long as it is within 7 days before starting therapy.  
b.
The first day of treatment in each Cycle is defined as Day 1.  
c.
End of treatment visit: Obtain these assessments at the time of treatment discontinuation if not completed in the last week.  Pregnancy test will be performed 
for women of childbearing potential only.  
At least 28 calendar days, and no more than 35 calendar days, after discontinuation of treatment, patients will return to undergo review of concomitant 
treatments and assessment for resolution of any treatment related toxicity.  Patients continuing to experience toxicity at this point following discontinuation 
of treatment will continue to be followed until resolution or determination, in the clinical judgment of the investigator and consultation with the sponsor, that 
no further improvement is expected.  
d.
Long-term Follow-up: Patient contact for: survival, cause of death, and additional cancer treatment every 3 months (±7 days) after last dose for 1 year, every 
6 months (±14 days) thereafter, or whenever requested by the Sponsor.
e.
All assessments will be performed before dosing except as indicated.  Additional tests/procedures and/or unscheduled visit can be performed as clinically 
indicated.
f.
Informed Consent: Must be obtained prior to undergoing any study-specific procedures.  Procedures performed as standard of care prior to signed and dated 
informed consent document (ICD), and within the 28-day screening window may be used for this study.  Written informed consent for only the BRCA1/2 
mutation testing blood test may be obtained at any time (including prior to the screening period).
g.
Medical History: Includes full oncologic history, prior treatments, and demographics.  Clinically significant baseline signs and symptoms will be recorded as 
medical history.
h.
Vital Signs: Systolic and diastolic blood pressure, pulse rate to be recorded as defined in the Schedule of Activities and weight at Screening, Day 1 of each 
cycle and End of Treatment; height at Screening only.
i.
Physical Examinations: Screening physical examination to be a complete exam; subsequent examinations to be focused on physical examinations at the 
discretion of the Investigator based on the patient's clinical condition.
j.
Imaging includes chest, abdomen, and pelvis CT (recommended) or MRI scans.  A brain MRI or CT is to be performed at Screening to evaluate patients for 
presence/absence of brain metastases.  Newly diagnosed CNS metastases at Screening makes a patient ineligible until such time as it can be adequately 
treated, at which point the patient may be re-screened.  If adequately treated metastatic disease to the brain is present at Screening, an MRI or CT will be 
performed during the study as clinically indicated.  Post-baseline assessments should be performed using the same technique used at Screening.  CT/MRI 
scans performed as standard of care before the main ICD was signed and within the 28-day screening period may be used as the Screening tumor 
assessments if the scans were completed per the specific study requirements.
Tumor assessment to be performed every 6 weeks (±7 days) from the date of initial study treatment (C1D1) for the initial 24 weeks and every 8 weeks (±7 
days) thereafter, until objective disease progression or treatment discontinuation, regardless of any dose interruptions or dose delays.  According to RECIST 
ver 1.1, complete response (CR) and partial response (PR) must be confirmed by a second image at least 4 weeks from the initial imaging showing response.  
Tumor assessment should be repeated at the end of treatment visit if more than 6 weeks have passed since the last evaluation.  Tumor assessments can occur 
as clinically indicated anytime during the study, and at the time of clinical suspicion of disease progression.  Post-baseline tumor assessments should be 
performed using the same technique used at Screening/baseline.
Bone scan will be performed at Screening (a bone scan obtained up to 12 weeks before starting study treatment may be substituted).  If metastatic disease to 
the bone is present at Screening, a bone scan will be performed every 12 weeks (±7 days) for the initial 24 weeks and every 16 weeks (±7 days) thereafter, 


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and as clinically indicated.  Post-baseline assessments should be performed using the same technique used at Screening.
All scans taken for this study have to be submitted for Blinded Independent Central Review (BICR).  Once study endpoints are summarized and they are
notified by Sponsor, tumor assessment including brain and bone scan can be done per local standard practice and the requirement of imaging submission is 
no longer applicable.
k.
PK blood sampling: Trough PK samples will be collected on Day 1 of Cycles 2 through 4.  In the event of a dose delay on the day of PK sampling, the 
pre-dose PK sample should be drawn on the day the patient resumes their next dose of talazoparib.  
l.
Hematology: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date.  Frequency should be increased as clinically 
indicated to monitor neutropenia, thrombocytopenia, and anemia.  See Assessments section for Laboratory Tests list.
Serum chemistry: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date.  See Assessments section for Laboratory 
Tests list.
Urinalysis (dipstick): Microscopic analyses if dipstick abnormal.  See Assessments section for Laboratory Tests list.
Calculated creatinine clearance: to be performed at Screening.  Use local laboratory results or calculate by Cockcroft-Gault formula.
m. Virus (HBV/HCV/HIV) test: Perform within 28 days prior to the first study treatment.
n.
Pregnancy test (for women of child-bearing potential only): Local urine or serum (as per local regulations/practice) pregnancy test should be performed at 
Day 1 of each cycle, prior to administration of study medication; if a urine pregnancy test is positive, study drug must be interrupted and a serum pregnancy 
test must be performed.  Additional pregnancy testing may be performed throughout the study as clinically indicated.
o.
AE assessments: AEs should be documented and recorded at each visit using NCI CTCAE version 4.03.  The time period for actively eliciting and collecting 
AEs and SAEs (“active collection period”) for each patient begins from the time the patient provides informed consent through and including a minimum of 
28 calendar days after the last investigational product administration.  If the patient begins a new anti-cancer therapy, the period for recording non-serious 
AEs on the CRF ends at the time the new treatment is started.  However, any SAEs occurring during the active collection period must still be reported to 
Pfizer Safety and recorded on the CRF, irrespective of any intervening treatment.
p.
The contraception check is an opportunity to confirm that contraception, if assigned, is used consistently and correctly.  Also, for studies enrolling adult 
patients, it is the opportunity to assess changing potential to father/bear children and allows for altering contraception if new disease contraindicates a 
selected method of contraception or if nonchildbearing status is achieved.
q.
12-Lead ECG: 12-lead ECG to be performed at Screening and End of Treatment, if clinically indicated.  When coinciding with blood sample draws for PK, 
ECG assessment should be performed prior to blood sample collection, such that the blood sample is collected at the nominal time.  If the QTcF is prolonged 
(>500 msec), 3 consective ECGs will be performed approximately 2 minutes apart to determine mean QTcF interval to confirm presence of QTc 
prolongation and the ECGs should be re-evaluated by a qualified person at the site for confirmation.  Additional ECGs may be performed as clinically 
indicated.  
r.
Concomitant treatments: All concomitant medications or therapies, including herbal supplements, taken from 28 days before study treatment to 28 days after 
the last dose will be recorded on the CRF.  
s.
Talazoparib treatment: Talazoparib will be administered orally daily for 28 days in repeated 28-day cycles.  On selected days of clinic visits, the drug will be 
taken at the clinic to allow pre-dose collection of safety data.
t.
With Sponsor preapproval, results (documentation of a deleterious, suspected deleterious, or pathogenic germline BRCA1 or BRCA2 mutation) generated 
previously using the BRACAnalysis CDx test, may be provided to meet this molecular enrollment criterion.


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u.
For patients who must undergo prospective BRCA germline testing, blood sample must be collected for testing as early as possible during the screening 
period.  BRCA germline testing can be done outside of 28-day Screening period for patients who provide ICD for the BRCA1/2 mutation testing.
 
 
 
 
 
 
 
 
  
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Talazoparib is a poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor 
that is currently being investigated in patients with solid tumors including germline breast 
cancer susceptibility gene mutation (gBRCAm) locally advanced and metastatic breast 
cancer.  
1.2. Background and Rationale
Cancer represents a disease area with a high-unmet medical need with more than 14.1 million 
people diagnosed annually worldwide, and an associated mortality that exceeds 8.2 million 
individuals1.  Breast cancer is the second most common cause of cancer deaths in women, 
despite improvements in screening and treatment regimens.  According to the World Health 
Organization, in 2012, 1.7 million women were diagnosed with breast cancer and over 
522,000 women died due to the disease2.  In Japan, it was estimated that approximately 
13,000 women died due to breast cancer, which was approximately 9% of total death in 
cancer death in 20133.  The discovery and development of new anti-cancer therapies effective 
either in single-agent or combination treatment settings is still desperately needed.
1.2.1. Role of BRCA and PARP in DNA repair
Cancers are caused by multiple genetric and/or environmental factors.  Consequent genome 
instability and deficiency of DNA repair mechanism (e.g.  base excision repair, mismatch 
repair, homologous recombination etc) enable tumor development.  BRCA1 and BRCA2 are
tumor suppressor gene, and the product of BRCA genes play an important role of 
maintaining genomic stability in part by contributing to DNA repair of double-stranded 
breaks.  Loss of BRCA function due to pathogenic mutations in BRCA may cause 
homologous recombination deficiency (HRD).  
Breast cancer is a biologically diverse and genetically heterogeneous disease4,5.  Germline 
mutations in BRCA1/2 result in a lifetime risk of breast cancer by age of 70, of up to 80%6.  
It was suspected that approximately 5% to 10% of breast cancer in women are associated 
with germline BRCA1 or BRCA2 mutations.  Estrogen receptor negative, progesterone 
receptor (PgR) negative, HER2-negative tumors are known as triple negative breast cancer 
(TNBC).  Characterization of BRCA1 mutated breast cancers are known to be TNBC (70%), 
solid-tubular carcinoma and high histopathological grade7.  Hormone receptor-positive 
tumors were more frequent in BRCA2 mutation carriers8.  
PARPs comprise a family of at least 17 enzymes that transfer ADP-ribose groups to target 
proteins to regulate various cellular processes, including DNA repair; PARP1 and PARP2 
play important roles in DNA repair9,10.  Following DNA damage, PARP1 and PARP2 bind to 
single-strand DNA breaks, cleave nicotinamide adenine dinucleotide (NAD+), and attach 
multiple ADP-ribose units to target proteins, including itself11,12,13,14.  The outcome is a 
highly negatively charged protein, which leads to the unwinding of the DNA strands and 
recruitment of proteins to repair the damaged DNA through the base excision repair (BER) 
process.  When PARP1 and PARP2 are inhibited, single-strand DNA breaks persist, resulting 


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in PARP trapping, stalled replication forks and conversion of single-strand breaks into 
double-strand breaks.  These breaks must be repaired by homologous recombination or 
nonhomologous end joining or they may become lethal.  
1.2.2. Mechanism and clinical use of PARP inhibitor to BRCA mutated cancer
PARP inhibitors exert cytotoxic effects by 2 mechanisms, (1) inhibition of PARP catalytic 
activity and (2) PARP trapping, whereby PARP protein bound to a PARP inhibitor does not 
readily dissociate from DNA, preventing DNA repair, replication, and transcription15.  
Inhibition of PARP catalytic activity results in persistent single-strand breaks that require 
homologous recombination DNA repair for survival.  When trapped, PARP-DNA complexes 
inhibit DNA repair, replication, and transcription, and are more cytotoxic than unrepaired 
single-strand breaks because they do not readily dissociate.  Importantly, the ability to trap 
PARP-DNA complexes varies widely across the different PARP inhibitors, correlates with 
cell toxicity in tissue culture, and does not correlate with PARP catalytic inhibition.
DNA instability is an important characteristic of many tumor types, often times a 
consequence of defects in DNA repair16.  Although a single DNA repair pathway defect may 
not be lethal to the cell, the combination of 2 pathway defects may be lethal.  This outcome is 
an example of synthetic lethality17.  PARP inhibitors induce synthetic lethality in tumor cells 
bearing mutations and/or deletions in genes involved in homologous recombination DNA 
repair pathways, including BRCA1, BRCA2,  FANCA, PTEN, RAD51, MLH1, MSH2, 
ATM, MRE11, and PALB218,19,20,21,22,23,24,25.  In BRCA1- and BRCA2-deficient cells, 
treatment with a PARP inhibitor results in cell cycle arrest and apoptosis26,27,28.  
Proof-of-concept clinical studies in patients with ovarian, breast, and prostate cancers 
showed responses to PARP inhibitor therapy in those with BRCA1 and BRCA2 
mutations29,30,31,32, establishing the clinical relevance of PARP inhibitor-induced synthetic 
lethality in patients with tumors harboring BRCA mutations.  
The prevalence of DNA repair deficiencies contributing to synthetic lethality varies with 
tumor type.  In metastatic castration-resistant prostate cancer, analysis of somatic and 
germline mutation status demonstrated that 22.7% of cases had mutations in DNA repair 
genes associated with sensitivity to a PARP inhibitor including BRCA2, BRCA1, CDK12, 
FANCA, RAD51B, RAD51C, MLH1, and ATM33.  In an independent phase 2 study, 16 of 
49 evaluable patients (33%) with metastatic castration-resistant prostate cancer had mutations 
and/or deletions in genes involved in homologous recombination or other DNA repair 
pathways.  Of the 16 patients (33%) who responded to treatment with olaparib, 14 (88%) had 
mutations in DNA repair genes26.  These data suggest that PARP inhibition may be a useful 
strategy in a broad array of tumor types bearing diverse DNA repair pathway deficiencies 
that extend beyond BRCA1/2 mutations.  
In gBRCAm metastatic breast cancer, positive outcomes have been reported in a global phase 
3 study of olaparib (a PARP inhibitor) comparing to the standard single-agent chemotherapy, 
demonstrating statistically significant prolongation of progression-free survival (PFS) in the 
olaparib arm which supported the approval by the US Food and Drug Administration (FDA) 
and the Japan Ministry of Health, Labour and Welfare (MHLW) for use in patients with 
deleterious or suspected deleterious gBRCAm, HER2-negative metastatic breast cancer.


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1.2.3. Talazoparib and available non-clinical/clinical data
Talazoparib (PF-06944076 also known as MDV3800 or BMN 673) is a potent, orally 
bioavailable, small molecule PARP inhibitor in development for the treatment of a variety of 
human cancers.  Talazoparib is cytotoxic to human cancer cell lines harboring gene 
mutations that compromise DNA repair, an effect referred to as synthetic lethality.  In breast 
cancer MX-1 cells that are BRCA1-deficient, talazoparib inhibits cell growth in vitro and 
inhibits tumor growth and/or induces tumor regression in mouse xenografts.  Anti-tumor 
activity was also demonstrated in small cell lung cancer (SCLC) cell lines and xenograft 
models; single-agent talazoparib reduced tumor growth to a similar extent as the cytotoxic 
chemotherapy drug cisplatin in 2 independent SCLC xenograft models.  
The main nonclinical toxicology findings with talazoparib were early hematologic changes 
and subsequent bone marrow and lymphoid organ depletion; focal atrophy and degeneration 
of the testes, epididymis, and seminiferous tubules; and dose-dependent apoptosis/necrosis in 
the GI tract and liver after repeat-dose administration of talazoparib.  These findings are 
consistent with the exaggerated pharmacology of talazoparib and its tissue exposure pattern.  
The hematologic findings were generally reversible and the early hematologic changes 
represent sensitive and early markers of target organ toxicity.  Talazoparib caused fetal 
malformations, structural variations, and death in an embryo-fetal development study in rats.  
As of 31 January 2018, approximately 659 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.  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 the C3441030 study demonstrated objective responses and/or clinical benefit in patients 
with breast, ovarian/peritoneal, and pancreatic cancer; SCLC; and Ewing sarcoma.  
Treatment-emergent adverse drug reactions (ADRs) 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, vomiting, abdominal 
pain, and decreased appetite), fatigue, headache, and alopecia.  Grade 3 or 4 ADRs of
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) in 5% of patients were associated with myelosuppression. The ADRs associated 
with talazoparib are generally detected through routine laboratory and clinical monitoring 
and may be managed using symptomatic therapies, supportive care, or dose reductions or 
interruptions.
The pharmacokinetics (PK) of talazoparib as a single agent was evaluated in 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; the mean terminal half life (t½) was 
approximately 4 days.  Talazoparib accumulated after 1 mg quaque die (QD) dosing with a 
median accumulation ratio (Rac) ranging from 2.33 to 5.15, consistent with its t½.  Steady state 
was reached around 3 weeks after the start of talazoparib dosing.  Talazoparib undergoes 


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minimal hepatic metabolism in humans.  Renal excretion was a major elimination pathway 
for unchanged parent talazoparib.  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 therapeutic exposures, talazoparib did not markedly induce or inhibit cytochrome P450 
(CYP450) enzymes or transporters and is therefore unlikely to demonstrate clinically 
significant CYP450 inhibition- or induction-based drug-drug interactions (DDIs) or drug 
transporter inhibition-based DDIs when coadministered with corresponding substrates.  
However, talazoparib is a substrate for P-glycoprotein (P-gp) and breast cancer resistance 
protein (BCRP), and plasma talazoparib concentrations may increase when coadministered 
with P-gp or BCRP inhibitors, respectively.  
A phase 2 (ABRAZO, 673-201, C3441008) and a phase 3 (EMBRACA, 673-301, 
C3441009) study evaluated single-agent talazoparib in patients with locally advanced or 
metastatic breast cancer with deleterious gBRCAm.  
EMBRACA is a pivotal, randomized, open label, 2 arm, Phase 3 study that evaluated 
talazoparib versus protocol specified physician’s choice therapy (PCT) in patients with 
gBRCAm HER2-negative locally advanced or metastatic breast cancer.  PCT included single 
agent capecitabine, eribulin, gemcitabine, or vinorelbine and was determined by the treating 
physician for each patient before randomization.  The primary objective of the study was to 
compare PFS by Blinded Independent Central Review (BICR) assessment between the 
talazoparib and PCT arms.  As of data cutoff date of 15 September 2017, the study met its 
primary objective demonstrating that talazoparib was superior to chemotherapy in prolonging 
PFS by BICR assessment, with the median PFS of 8.6 months [95% confidence interval (CI): 
7.2, 9.3] in talazoparib arm compared with 5.6 months (95% CI: 4.2, 6.7) in PCT arm.  There 
was a 46% reduction in relative risk of disease progression or death, with an observed hazard 
ratio (HR) of 0.54 (95% CI: 0.41, 0.71; p<0.0001 [2-sided by stratified log-rank test]).  The 
primary analysis of objective response rate (ORR) was conducted in the intent-to-treat (ITT) 
population with measurable disease population, based on Investigator assessment.  ORR was 
62.6% (95% CI: 55.8, 69.0) in the talazoparib arm vs 27.2% (95% CI: 19.3, 36.3) in PCT 
arm.  The odds ratio was 4.99 (95% CI: 2.9, 8.8) with a p-value from the 2-sided stratified 
Cochran-Mantel-Haenszel test of <0.0001 in favor of the talazoparib arm.  Although 
confirmation was not required for this randomized trial, the confirmed ORR by investigator’s 
assessment was 50.2% (95% CI: 43.4, 57.0) in talazoparib arm and 18.4% (95% CI: 11.8, 
26.8) in PCT arm.  An interim analysis of overall survival (OS) was conducted (163 deaths 
had occurred). Median OS was 22.3 months (95% CI: 18.1, 26.2) in the talazoparib arm and 
19.5 months (95% CI: 16.3, 22.4) in the PCT arm with the estimated HR of 0.76 (95% CI: 
0.55, 1.06; p=0.1053 [2-sided by stratified log-rank test]).
The new drug application in the US and the marketing authorisation applications in the EU 
were submitted based on these results and priority review was granted in the US.  On 16 
October 2018, the FDA approved talazoparib for patients with deleterious or suspected 
deleterious gBRCAm, HER2-negative locally advanced or metastatic breast cancer.  Patients 
must be selected for therapy based on an FDA-approved companion diagnostic for 
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1.2.4. The study rationale
As there was no clinical experience with talazoparib in Japanese patients at the time of study 
initiation, the current Phase 1 study was initially designed to evaluate the safety, tolerability, 
preliminary efficacy, and PK profile of talazoparib as a single agent in Japanese patients with 
advanced solid tumors.  On the amendment 2, this part is called the dose escalation part.
In the global phase 1 (PRP-001), the MTD and recommended dose (RP2D) as a single-agent 
was investigated using dose escalation scheme starting from 0.025 mg/day up to 1.1 mg/day.  
Total of 3 dose limiting toxicities (DLTs) in Cycle 1 were observed at dose level of 0.9 
mg/day (n=1, Grade 3 thrombocytepenia) and 1.1 mg/day (n=2, Grade 3 and 4 
thrombocytopenia) when administered continuously with the cycle length of 28 days.  The 
MTD/RP2D was determined as 1.0 mg/day.  Based on these results, the starting dose selected 
in the C3441030 study is 0.75 mg/day where no DLT was observed and one level lower than 
the MTD/RP2D.  Talaroparib will be administered once daily in continuous dosing regimen 
with the treatment cycle of 28 days.  
The dose escalation part of the C3441030 study applied modified 3+3 dose escalation 
scheme to identify the RP2D in Japanese patients.  The dose was escalated to the next dose 
level (1.0 mg/day) according to the pre-defined dose escalation scheme and based on the 
incidence of DLTs at the initial dose level (0.75 mg/day).  However, the highest dose used in 
the study was 1.0 mg/day.  The dose over the MTD determined in Study PRP-001 was not 
explored.  The study also includes Lead-in PK period.  A single dose of talazoparib was 
administered 7 days prior to Cycle1 Day1 and multiple PK samples were collected as defined 
in the Schedule of Activities.
As of 24 January 2019, a total of 9 patients were enrolled in the dose escalation part of the 
C3441030 study.  DLT were not reported in any patients receiving 0.75 mg/day (n=3) or
1.0 mg/day (n=6).  Therefore, the RP2D of single-agent talazoparib was determined to be 
1.0 mg/day in Japanese patients with advanced solid tumors.  Overall the safety profile in the 
dose escalation part was similar to the adverse events (AEs) observed in global studies of 
talazoparib.  Most common AEs of single-agent talazoparib in Japanese patients were 
hematological toxicities and hepatotoxicities.  Based on the preliminary PK analysis results 
(n=3 each in 0.75 and 1.0 mg/day), the PK profile of single-agent talazoparib in Japanese 
patients was comparable with that in Western population.  These data also supported RP2D 
in Japanese patients.
Following on the encouraging results of EMBRACA and determination of RP2D in Japanese 
patients, the C3441030 study will be expanded to further evaluate efficacy, safety and PK at 
RP2D in Japanese patients with gBRCAm HER2-negative locally advanced or metastatic 
breast cancer in protocol amendment 2.  
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for the C3441030 study is the investigator’s brochure.  
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2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Dose Escalation part (Solid Tumor)
Primary Objective(s): 
Primary Endpoint(s): 
• To assess safety and tolerability at increasing dose 
levels of talazoparib in successive cohorts of patients 
with solid tumors in order to select the RP2D/schedule
in Japanese patients.
• First-cycle DLTs.
Secondary Objective(s): 
Secondary Endpoint(s): 
• To evaluate the overall safety profile.  
• Adverse Events as characterized by type, frequency, 
severity (as graded by NCI CTCAE version 4.03), timing, 
seriousness, and relationship to talazoparib.
• Laboratory abnormalities as characterized by type, 
frequency, severity (as graded by NCI CTCAE version
4.03),  and timing.
• Vital Signs.  
• To characterize the single and steady-state 
pharmacokinetics (PK) of single-agent talazoparib.
• Pharmacokinetic parameters of talazoparib: 
• Single Dose (SD) - Cmax, Tmax, AUClast, AUCτ, CL/F, 
and Vz/F and t½, and AUCinf as data permit.  
• Multiple Dose (MD) (assuming steady state is 
achieved) - Css,max, Tss,max, Css, min, AUCss,τ, CL/F, Rac 
(AUCss,τ /AUCsd,τ) and Rss (AUCss,τ /AUCsd,inf) as data 
permit.
• To assess preliminary evidence of anti-tumor activity 
of single agent talazoparib.
• Objective response (OR), as assessed using the Response 
Evaluation Criteria in Solid Tumors (RECIST) version 
1.1
• Time-to-event endpoints: eg, DoR and PFS if applicable
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2.2. Expansion part (gBRCAm breast cancer)
Primary Objective(s): 
Primary Endpoint(s): 
• To evaluate the anti-tumor activity of single agent 
talazoparib in Japanese patients with gBRCAm HER2-
negative locally advanced or metastatic breast cancer.
• Confirmed OR as assessed using RECIST version 1.1 by 
Investigator Assessment.
Secondary Objective(s): 
Secondary Endpoint(s): 
• To further evaluate anti-tumor activity.
• Objective response (OR) as assessed using RECIST 
version 1.1 by BICR.
• Disease Control defined as patients with a confirmed 
complete response (CR), confirmed partial response (PR) 
and stable disease (SD) at 16 and 24 weeks.
• Time to event endpoints: Time-to-tumor response (TTR), 
DoR, PFS, and OS.
• To evaluate the overall safety profile of talazoparib.
• AEs including laboratory abnormalities as characterized 
by type, frequency, severity (as graded by the NCI 
CTCAE, version 4.03), timing, seriousness, and 
relationship to talazoparib.
• To characterize the PK of single-agent talazoparib.
• Trough concentrations of talazoparib.
3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1 study which consists of 2 parts; Dose Escalation part and Expansion part.  
The dose escalation part is open-label and evaluates safety, preliminary efficacy and PK of 
single-agent talazoparib in sequential cohorts of adult patients with advanced solid tumors 
who are resistant to standard therapy or for whom no standard therapy is available.  
Successive cohorts of patients received escalating doses of talazoparib on an outpatient basis 
starting from 0.75 mg/day.  This part evaluated 2 dose levels; 0.75 mg and 1.0 mg.  To 
understand the single-dose safety and single-dose PK assessments of talazoparib, a lead-in 
period preceding the continuous daily doses have been included in the dose escalation part.  
In the 7-day lead-in period, a single lead-in dose was given on Day -7.  No talazoparib was
administered during the interval between the lead-in single dose and Day 1 of the first cycle.  
Study treatment is given as on outpatient basis, however a patient is required to stay 
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overnight at the study site during any intensive PK collection period (i.e.  Day -7 and Day 22 
in cycle 1).  
In the dose escalation part, a total of 9 patients were enrolled.  No DLTs were observed in 
any patients receiving 0.75 mg/day (n=3) or 1.0 mg/day (n=6).  Therefore enrollment was 
completed for dose escalation part.
Protocol amendment 2 includes the addition of an expansion part.  The expansion part is an 
open-label, multicenter, efficacy, safety and PK study of single-agent talazoparib at RP2D 
determined in the dose escalation part in adult patients with locally advanced or metastatic 
breast cancer who have deleterious or suspected deleterious germline BRCA1 or BRCA2 
mutations.  The patients in the expansion part will receive 1.0 mg/day of talazoparib which 
was RP2D identified in the dose escalation part of the C3441030 study.  The expansion part 
will include BICR assessment for the efficacy evaluation.  All radiographic images taken 
during the study must be available and be submitted for central review.
In the expansion part, a minimum of 17 patients will be enrolled evaluable for the primary 
endpoint.
In all study parts, treatment with talazoparib will continue until either disease progression, 
unacceptable toxicity or withdrawal of consent.
3.1.1. Starting Dose (Dose Escalation part only)
The starting dose was 0.75 mg given once daily in 28-day cycles.  
3.1.2. Criteria for Dose Escalation (Dose Escalation part only)
A modified 3+3 dose escalation scheme will be used.
Two dose levels (0.75 mg/day and 1.0 mg/day) will be evaluated in the dose escalation part.  
Up to 3 patients in a cohort may be enrolled simultaneously; occasionally, due to 
logistical/clinical reasons, more than 3 but no more than 9 patients may be enrolled at each 
dose level.  Initially, 3 patients will receive 0.75 mg/day.  If no DLT is observed in the initial 
3 patients at 0.75 mg/day, the next dose level at 1.0 mg/day will be opened.  If a DLT is 
observed in 1 or 2 of the initial 3 dosed patients, 3 additional patients up to a total of 6 
patients will be enrolled and receive 0.75 mg/day.  If 1 of 6 patients experience a DLT at 
0.75 mg/day, the dose will be escalated to 1.0 mg/day.  In case 2 of 6 dosed patients 
experience a DLT, 3 additional patients up to a total of 9 patients will be enrolled and receive
0.75 mg/day if deemed necessary in the opinion of the sponsor and the investigators.  For the 
case where 2 of 6 dosed patients experience a DLT but additional 3 patients will not be 
enrolled, RP2D will not be determined in the current study design.  Dose escalation will 
complete if a DLT is observed in 2 of 9 patients and the RP2D will be declared at 0.75 
mg/day.  If 3 patients experience a DLT, no further patients will be dosed at that dose or 
higher.
Following dose escalation, 3 patients will receive 1.0 mg/day.  If a DLT is observed in >1 of 
the initial 3 dosed patients, 0.75 mg/day may be evaluated and the above dose escalation 


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schema will be followed.  If a DLT is observed in 1 of initial 3 patients at 1.0 mg, 3 
additional patients up to a total of 6 patients will be enrolled and receive 1.0 mg/day.  In case
a DLT is observed in 2 of 6 dosed patients, 3 additional patients up to a total of 9 patients 
will be enrolled and receive 1.0 mg/day if deemed necessary in the opinion of the sponsor 
and the investigators. Dose escalation will complete if a DLT is observed in 1 of 6 patients 
or in 2 of 9 patients and the RP2D will be declared at 1.0 mg/day.  If a DLT is observed in >2
of 9 (or 2 of 6 if 3 additional patients will not be enrolled) patients, the RP2D may be 
declared at 0.75 mg/day if 6 patients are evaluated with 1 DLT at 0.75 mg/day, or 
additional patients will be enrolled at 0.75 mg/day to declare the RP2D.
Patients not meeting the criteria for inclusion in the Per Protocol Analysis set outlined in the 
Analysis Sets section 9.1 (ie, not evaluable for assessment of DLT) will be replaced.  The 
safety information obtained from the patients who exclude from the Per Protocol Analysis set 
may be used for determination of dose escalation.
Subsequent dose levels may not be used (except within a patient, see below) until all patients 
entered at the current dose level have been dosed and observed for at least one complete 
cycle, and the number of DLTs among those patients in their first cycle has been determined.  
Intrapatient dose escalation may be permitted in the C3441030 study.  A patient may have 
his/her dose-escalated to the next highest dose level if all of the following conditions are 
satisfied: 

Cycle 1 was completed without any DLT;

His/her maximum talazoparib-related toxicity during prior cycles of therapy was 
Grade 2;

Minimum 3 patients at the highest dose level have completed Cycle 1 with 
talazoparib without having DLT or 1 out of 6 or 2 out of 9; 

The decision to increase the dose has been approved by discussion with both the 
investigator and the sponsor.  A patient whose dose has been escalated will not 
contribute to the assessment of the number of DLTs at the escalated dose level.
3.2. DLT Definition (Dose Escalation part only)
Severity of AEs will be graded according to CTCAE version 4.03.  For the purpose of dose 
escalation, any of the following AEs occurring in the first cycle of treatment including the 
PK lead-in period which are attributable to talazoparib will be classified as DLTs:
Hematologic:

Grade 4 neutropenia lasting >7 days;


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
Febrile neutropenia (defined as absolute neutrophil count (ANC) <1000/mm3 with a 
single temperature of >38.3 C or a sustained temperature of 38C for more than 1 
hour);

Grade 3 neutropenic infection (defined as ANC < 1000/mm3 or <1.0 x 109/L and 
Grade >3 infection);

Grade 3 thrombocytopenia associated with Grade 2 hemorrhage or requiring 
transfusion;

Grade 4 thrombocytopenia;

Grade 4 anemia;

Grade 3 anemia requiring transfusion;

If daily dosing is interrupted for 7 or more total days in the first cycle for Grade 3 
neutropenia or Grade 3 thrombocytopenia.
Non-hematologic:
Any Grade 3 AE, except:

Non-clinically significant Grade 3 laboratory abnormalities;

Non-hematologic Grade 3 AE deemed not clinically significant;

Grade 3 nausea, vomiting and diarrhea that responds to medical intervention within 
72 hours;

Grade 3 fatigue that improves to Grade 2 within 7 days;
Liver toxicity:

Alanine or aspartate aminotransferase (ALT or AST) > 5×upper limit of normal 
(ULN) (a lower threshold should be considered if the ALT/AST abnormalities are 
accompanied with symptoms and signs of hepatitis) AND 2×increases above the 
baseline values;

ALT/AST 3×ULN concurrent with total bilirubin (TBili) >2×ULN;

TBili >5×ULN.
General toxicity:

Failure to deliver 75% of doses due to toxicities attributable to talazoparib.


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4. PATIENT ELIGIBILITY CRITERIA
The C3441030 study can fulfill its objectives only if appropriate patients are enrolled.  The 
following eligibility criteria are designed to select patients for whom participation in the 
study is considered appropriate.  All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular patient is suitable for this 
protocol.
4.1. Dose Escalation part
4.1.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the 
study:  
1. Histological or cytological diagnosis of locally advanced or metastatic solid tumor 
that is resistant to standard therapy or for which no standard therapy is available.  
2. Females and/or male patients age 20 years.  
3. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.  
4. Adequate Bone Marrow Function, including:
a.
ANC 1,500/mm3 or 1.5×109/L without the use of growth factor;
b. Platelets 100,000/mm3 or 100×109/L without the use of platelet transfusions or 
growth factors;
c.
Hemoglobin 9 g/dL , with last transfusion at least 14 days prior to the first dose 
of study treatment.
5. Adequate Renal Function, including:
a.
Estimated creatinine clearance 45 mL/min as calculated using the method 
standard for the institution.  
6. Adequate Liver Function, including:
a.
Serum TBili 1.5×ULN unless the patient has documented Gilbert syndrome 
(3×ULN for Gilbert syndrome);
b. AST and ALT 2.5×ULN (5.0×ULN if there is liver involvement by the tumor); 
c.
Alkaline phosphatase 2.5×ULN (5×ULN in case of bone metastasis).  
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8. Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade 1 
except for AEs not constituting a safety risk by investigator judgment.
9. Serum or urine pregnancy test (for females of childbearing potential) negative at 
screening.
Female patients of nonchildbearing potential must meet at least 1 of the following 
criteria:

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum follicle-stimulating hormone (FSH) level 
confirming the postmenopausal state;

Have undergone a documented hysterectomy and/or bilateral oophorectomy; 

Have medically confirmed ovarian failure.  
All other female patients (including female patients with tubal ligations) are 
considered to be of childbearing potential.  
10. Evidence of a personally signed and dated informed consent document (ICD)
indicating that the patient  has been informed of all pertinent aspects of the study.  
11. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other procedures.  
4.1.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Patients with known symptomatic brain metastases requiring steroids.  Patients with 
previously diagnosed brain metastases are eligible if they have completed their 
treatment and have recovered from the acute effects of radiation therapy or surgery 
prior to study entry, have discontinued corticosteroid treatment for these metastases 
for at least 4 weeks and are neurologically stable.
2. Major surgery within 4 weeks prior to the first dose of study treatment.
3. Radiation therapy within 4 weeks prior to the first dose of study treatment.  Palliative 
radiotherapy for the treatment of painful bony lesions within 2 weeks prior to the first 
dose of study treatment.
4. Any anti-tumor systemic cytotoxic therapies within 4 weeks prior to the first dose of 
study treatment (6 weeks for nitrosoureas or mitomycin-C), treatment with immune 
modulators (including, but not limited to, corticosteroids (at a prednisone-equivalent 


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dose of > 10 mg/day), cyclosporine and tacrolimus; locally active treatments such as 
Beconase are allowed) within 4 weeks prior to the first dose of study treatment.
5. Previous high-dose chemotherapy requiring stem cell rescue.
6. Prior irradiation to >25% of the bone marrow (see Appendix 2 Bone Marrow Reserve 
in Adults).
7. Active and clinically significant bacterial, fungal, or viral infection, including 
hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency 
virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
8. Myocardial infarction within 6 months before starting therapy, symptomatic 
congestive heart failure (New York Heart Association class III or IV), unstable 
angina, or unstable cardiac arrhythmia requiring medication.  Stable cardiac 
arrhythmia (e.g.  chronic atrial fibrillation controlled by medication) can be eligible.  
9. Hypertension that cannot be controlled by medications (>150/100 mmHg despite 
optimal medical therapy).
10. Participation in other studies involving investigational drug(s) within 4 weeks prior to 
the first dose of study treatment.  
11. Known or suspected hypersensitivity to active ingredient/excipients.  
12. Other acute or chronic medical or psychiatric condition, including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into the
study.
13. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
patients who are Pfizer employees, including their family members, directly involved
in the conduct of the study.
14. Fertile male patients and female patients of childbearing potential who are unwilling 
or unable to use 2 highly effective methods of contraception as outlined in this 
protocol for the duration of the study and for 6 months (180 days) in male patients 
and 7 months in female patients after the last dose of investigational product.
15. Breastfeeding at screening or at any time during study participation.
16. Current use of a strong P-gp inhibitor (e.g.  dronedarone, quinidine, ranolazine,
verapamil, itraconazole, ketoconazole), strong P-gp inducer (eg, rifampin, tipranavir, 
ritonavir), or strong inhibitor of BCRP within 1 week or 5 half lives which ever is 


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longer prior to the first dose of study treatment.
Patients on verapamil are excluded from the study unless the patient and investigator 
agree to switch to an alternative, allowed antihypertensive.  Any such switch must 
begin at least 7 days before the first dose of study treatment and additional blood 
pressure monitoring will be performed as considered medically necessary by the 
investigator to monitor blood pressure control.  
4.2. Expansion part
4.2.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the 
study:  
1. Histologically or cytologically confirmed carcinoma of the breast.
2. Locally advanced breast cancer that is not amenable to curative radiation or surgery 
and/or metastatic disease.
3. Documentation of a deleterious, suspected deleterious, or pathogenic germline 
BRCA1 or BRCA2 mutation by Myriad Genetics’ BRACAnalysis CDx test.
4. No more than 3 prior chemotherapy-inclusive regimens for locally advanced or 
metastatic disease (no limit on prior hormonal therapies or targeted anti-cancer 
therapies which mechanistic targets are rapamycin [mTOR] or CDK4/6 inhibitors, 
immuno-oncology agents, tyrosine kinase inhibitors, or monoclonal antibodies 
against CTLA4 or VEGF).
5. Prior treatment with a taxane and/or anthracycline in the neoadjuvant, adjuvant, 
locally advanced, or metastatic setting unless medically contraindicated.
6. Female and/or male patients age 20 years.
7. Have measurable lesion by the RECIST v.1.1.
8. ECOG Performance Status ≤2.
9. Adequate organ function as defined below:
o
Serum AST and ALT ≤2.5 × ULN; if liver function abnormalities are due to 
hepatic metastasis, then AST and ALT ≤5 × ULN;
o
Total serum bilirubin ≤1.5 × ULN (≤3 × ULN for Gilbert’s syndrome);
o
Alkaline phosphatase 2.5 x ULN (5 x ULN in case of bone metastasis);
o
Estimated creatinine clearance 30 mL/min as calculated using the method 
standard for the institution;


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o
Hemoglobin ≥9.0 g/dL with last transfusion at least 14 days prior to the first dose 
of study treatment;
o
ANC ≥1500/mm3 or 1.5 x 109/L without the use of growth factor;
o
Platelet count ≥100,000/mm3 or 100 x 109/L without the use of platlet 
transfusions or growth factor.
10. Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade 1 
except for AEs not constituting a safety risk by investigator judgment.
11. Able to take oral medications.
12. Serum or urine pregnancy test (for females of childbearing potential) negative at 
screening.
Female patients of nonchildbearing potential must meet at least 1 of the following 
criteria:

Achieved postmenopausal status, defined as follows: cessation of regular 
menses for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum FSH level confirming the 
postmenopausal state;

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure.
All other female patients (including female patients with tubal ligations) are 
considered to be of childbearing potential.
13. Evidence of a personally signed and dated ICD indicating that the patient  has been 
informed of all pertinent aspects of the study.  
14. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other procedures.
4.2.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. First-line locally advanced or metastatic breast cancer with no prior neoadjuvant and 
adjuvant chemotherapy unless the investigator determined that treatment with a 
PARP inhibitor such as talazoparib would be in the best interest of the patient.  Note 
that recurrence within 6 months since the last neoadjuvant or adjuvant treatment can 
be considered as first-line therapy.
2. Prior treatment with a PARP inhibitor (not including iniparib).


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3. Objective disease progression while receiving platinum chemotherapy administered 
for locally advanced or metastatic disease; patients who received platinum in the 
adjuvant or neoadjuvant setting were eligible; however, patients may not have 
relapsed within 6 months of the last dose of prior platinum therapy; patients who 
received low-dose platinum therapy administered in combination with radiation 
therapy were allowed.
4. Cytotoxic chemotherapy, radiation therapy, antihormonal therapy or other targeted 
anticancer therapy within 14 days before starting study treatment.
5. HER2 positive breast cancer.
6. Active inflammatory breast cancer (classified as T4d by TNM classification).
7. Central nervous system (CNS) metastases except adequately treated brain metastases 
documented by baseline CT or MRI scan that had not progressed since previous scans 
and that did not require corticosteroids (prednisone 5 mg/day or equivalent was 
allowed) for management of CNS symptoms.  Patients with leptomeningeal 
carcinomatosis are excluded.
8. Diagnosis of any other malignancy within 5 years prior to study registration, except 
for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of 
the cervix.
9. Active and clinically significant bacterial, fungal, or viral infection, including HBV, 
HCV, known HIV or AIDS-related illness.
10. Participation in other studies involving investigational drug(s) within 14 days before 
starting study treatment.
11. Major surgery within 14 days before starting study treatment.  
12. Myocardial infarction within 6 months before starting study treatment, symptomatic 
congestive heart failure (New York Heart Association class III or IV), unstable 
angina, or unstable cardiac arrhythmia requiring medication.  Stable cardiac 
arrhythmia (e.g.  chronic atrial fibrillation controlled by medication) can be eligible.
13. Current or anticipated use within 7 days prior to the first dose of study treatment, or 
anticipated use during the study of strong P-gp inhibitors.  For a list of strong P-gp 
inhibitors, refer to section Section 5.7.
14. Fertile male patients and female patients of childbearing potential who are unwilling 
or unable to use 2 highly effective methods of contraception as outlined in this 
protocol for the duration of the study and for at least 6 months (180 days) in male 
patients and 7 months in female patients after the last dose of investigational product.  
15. Breastfeeding at screening or at any time during study participation (patients who are 
planning to interrupt breastfeeding are not eligible).
16. Previous high-dose chemotherapy requiring stem cell rescue.
17. Prior irradiation to >25% of the bone marrow (see Appendix 2 Bone Marrow Reserve 
in Adults).


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18. Hypertension that cannot be controlled by medications (>150/100 mmHg despite 
optimal medical therapy).
19. Other acute or chronic medical or psychiatric condition, including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study.
20. Known or suspected hypersensitivity to active ingredient/excipients.
21. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
patients who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
4.3. Lifestyle Requirements
In this study, fertile male patients and female patients who are of childbearing potential, as 
applicable to the study will receive talazoparib, which has been associated with suspected 
teratogenicity/fetotoxicity.  Patients who are, in the opinion of the investigator, sexually 
active and at risk for pregnancy with their partner(s) must agree to use 2 methods of highly 
effective contraception throughout the study and for at least 6 months (180 days) in male 
patients and 7 months in female patients after the last dose of talazoparib.  The investigator 
or his or her designee, in consultation with the patient, will confirm that the patient has 
selected 2 appropriate methods of contraception for the individual patient from the list of 
permitted contraception methods (see below) and will confirm that the patient has been 
instructed in their consistent and correct use.  At time points indicated in the schedule of 
activities, the investigator or designee will inform the patient of the need to use 2 highly 
effective methods of contraception consistently and correctly and document the conversation, 
and the patient’s affirmation, in the patient’s chart.  In addition, the investigator or designee 
will instruct the patient to call immediately if 1 or both of the selected contraception methods 
is discontinued or if pregnancy is known or suspected in the patient or partner.  
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the patient or 
male patient’s female partner plans to remain on the same treatment throughout the 
entire study and has been using that hormonal contraceptive for an adequate period of 
time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).


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3. Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository).  For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate.
4. Male sterilization with absence of sperm in the postvasectomy ejaculate.  
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
Male patients must refrain from donating sperm throughout the study and for at least 6 
months (180 days) in male patient after the last dose of talazoparib.
4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation.  
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational product identifiers, patient study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study.  The contact number can also be used by investigator staff 
if they are seeking advice on medical questions or problems; however, it should be used only 
in the event that the established communication pathways between the investigator site and 
the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).
For this study, the investigational product(s) is talazoparib.
5.1. Allocation to Treatment
Dose level allocation for the patients in dose escalation part was performed by the sponsor 
after patients have given their written informed consent and have completed the necessary 
baseline assessments.  


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In all study parts, the site staff will fax or e-mail a complete Registration Form to the 
designated sponsor study team member or designee.  The sponsor will assign a patient 
identification number and supply this number to the site.  The patient identification number 
will be used on all study-related documentation at the site.
No patient shall receive talazoparib until the investigator or designee has received the 
following information in writing from the sponsor:

Confirmation of the patient’s enrollment;

Specification of the dose level for the patient (the dose escalation part only) and; 

Permission to proceed with dosing the patient.  
The sponsor or designee will notify the other sites of the inclusion of a new patient, and will 
inform study sites about the next possible enrollment date.
5.2. Patient Compliance
Patients will be required to return all unused study treatment at the beginning of each cycle.  
The number of capsules returned by the patient will be counted, documented, and recorded.
A patient diary will be provided to the patients to aid in patient compliance with the dosing 
instructions.  The diary will be maintained by the patient to include missed or changed 
talazoparib doses.  Patients will be required to return all bottles of talazoparib every cycle.  
The number of talazoparib capsules remaining will be documented and recorded at each 
cycle.  The patient diary may also be used to support this part of the talazoparib  
accountability process.  
5.3. Investigational Product Supplies 
5.3.1. Dosage Form(s) and Packaging
Talazoparib will be provided as capsules for oral administration.  The 0.25 mg capsules will 
be supplied in separate bottles (or blister cards, as appropriate) and labeled according to local 
regulatory requirements.  For the expansion part, 1.0 mg capsule will also be supplied as a 
starting dose; 0.25 mg capsule should only be used for patients who require dose reduction.
5.3.2. Preparation and Dispensing
The study treatment should be dispensed at each visit per the schedule of treatment.  A 
qualified staff member will dispense the investigational product in the bottles (or blister 
cards, as appropriate) provided, in quantities appropriate for the study visit schedule or 
requirements of dose reduction.  The patient/caregiver should be instructed to maintain the 
product in the bottle (or blister cards, as appropriate) provided throughout the course of 
dosing, keep the investigational product away from children, and return the bottle (or blister 
cards, as appropriate) to the site at the next study visit.  


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5.4. Administration
Talazoparib will be administered on a continuous basis.  Talazoparib may be taken with or 
without food.  Before serial PK sampling (ie, on Cycle 1 Day -7 and Cycle 1 Day 22), 
talazoparib will be administered with plenty of water on an empty stomach ie, patients should 
refrain from food and beverages (except for water) for at least 6 hours before and 1 hour after 
dosing.
A cycle is defined as the time from Day 1 dose to the next Day 1 dose.  If there are no 
treatment delays, a cycle will be 28 days.  
Patients will swallow the investigational product whole, and will not manipulate or chew the 
investigational product prior to swallowing.  Patients should be instructed to take their 
medication at approximately the same time each day and to not take more than the prescribed 
dose at any time.  If a patient misses a day of treatment, he/she must be instructed not to 
“make it up” but to resume subsequent doses the next day as prescribed.  If a patient vomits 
any time after taking a dose, he/she must be instructed not to “make it up” but to resume 
subsequent doses the next day as prescribed.  If a patient inadvertently takes 1 extra dose 
during a day, the patient should not take the next dose of talazoparib.  
5.4.1. Recommended Dose Modifications
Every effort should be made to administer investigational product on the planned dose and 
schedule.
In the event of significant toxicity, dosing may be delayed and/or reduced as described 
below.  In the event of multiple toxicities, dose modification should be based on the worst 
toxicity observed.  Patients are to be instructed to notify investigators at the first occurrence 
of any adverse symptom.
Dose modifications may occur in one of three ways:

Within a cycle: dosing interruption until adequate recovery and dose reduction, if 
required, during a given treatment cycle; 

Between cycles: next cycle administration may be delayed due to persisting toxicity 
when a new cycle is due to start;

In the next cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle.  
5.4.2. Dosing Interruptions
Appropriate follow-up assessments should be done until adequate recovery occurs as 
assessed by the investigator.  Criteria required before treatment can resume are described in 
the Dose Delays section.


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Doses may be held as needed until toxicity resolution.  Depending on when the adverse event 
resolved, a treatment interruption may lead to the patient missing all subsequent planned 
doses within that same cycle or even to delay the initiation of the subsequent cycle.  
If the adverse event that led to the treatment interruption recovers within the same cycle, then 
re-dosing in that cycle is allowed.  Doses omitted for toxicity are not replaced within the 
same cycle.  The need for a dose reduction at the time of treatment resumption should be 
based on the criteria defined in the Dose Reductions section, unless expressly agreed 
otherwise following discussion between the investigator and the sponsor.  If a dose reduction 
is applied in the same cycle, the patient will need to return to the clinic to receive new drug 
supply.
In the event of a treatment interruption for reasons other than treatment-related toxicity (eg, 
elective surgery) lasting >2 weeks, treatment resumption will be decided in consultation with 
the sponsor.
5.4.3. Dose Delays
This section provides general instructions in case of dose delays.  Refer to the Dose 
Reductions section for adverse events requiring dose reduction at the time of treatment 
resumption.
In the dose escalation part, re-treatment following treatment interruption for treatment-related 
toxicity or at the start of any new cycle may not occur until all of the following parameters 
have been met:

ANC 1,000/mm3

Platelets count 75,000/mm3

Nonhematologic toxicities have returned to baseline or Grade 1 severity (or, at the 
investigator’s discretion, Grade 2 if not considered a safety risk for the patient).
If a treatment delay results from worsening of hematologic or biochemical parameters, the 
frequency of relevant blood tests should be increased as clinically indicated.
If these conditions are met within 4 weeks of treatment interruption or cycle delay, 
talazoparib may be resumed.  If these conditions are not met, treatment resumption must be 
delayed up to a maximum of 4 weeks.  If patients require discontinuation of talazoparib for 
more than 28 days at any time during the study, then study treatment should be permanently 
discontinued, unless the investigator’s benefit/risk assessment suggests otherwise after 
discussion with the Sponsor’s medical monitor (See Schedule of Activities, [Dose Escalation 
Part] footnote e).  
If a treatment interruption continues beyond Day 28 of the current cycle, then the day when 
treatment is restarted will be counted as Day 1 of the next cycle.  


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5.4.4. Dose Reductions
Following dosing interruption or cycle delay due to toxicity, the talazoparib dose may need 
to be reduced when treatment is resumed.
No specific dose adjustments are recommended for Grade 1/2 treatment-related toxicity other 
than renal impairment.  However, investigators should always manage their patients 
according to their medical judgment based on the particular clinical circumstances.  In 
patients with moderate renal impairment (creatinine clearance 30-59 mL/min), the starting 
dose will be reduced 1 dose level (Table 1).
Dose reduction of talazoparib by 1 and, if needed, 2 dose levels (Table 1) will be allowed 
depending on the type and severity of toxicity encountered.  Patients requiring more than 2 
(for 0.75 mg dose level; the dose escalation part only) or 3 (for 1.0 mg dose level) dose 
reductions will be discontinued from the treatment and entered into the follow-up phase, 
unless otherwise agreed between the investigator and the sponsor.  All dose 
modifications/adjustments must be clearly documented in the patient's source notes and case 
report form (CRF).  
Once a dose has been reduced for a given patient, all subsequent cycles should be 
administered at that dose level, unless further dose reduction is required.  
Table 1.
Available Dose Levels 
Dose Level
Initial dose of 0.75 mg 
(Dose Escalation part only)
Initial dose of 1.0 mg
Starting
0.75 mg/day
1.0 mg/day
-1
0.5 mg/day
0.75 mg/day
-2
0.25 mg/day*
0.5 mg/day
-3
NA
0.25 mg/day*
* talazoparib dose de-escalation below 0.25 mg/day is not allowed.
In the dose escalation part, patients experiencing a DLT during Cycle 1 may resume dosing 
at the next lower dose level (if applicable) once adequate recovery (to baseline or Grade ≤1) 
is achieved.  No dose reductions are planned for patients experiencing toxicities other than 
those listed as DLTs.  However, patients experiencing recurrent and intolerable Grade 2 
toxicity may resume dosing at the next lower dose level once recovery to Grade 1 or 
baseline is achieved.  
Recommended dose reductions are described in Table 2.


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Table 2.
Dose Modifications for Investigational Product-Related Toxicity (Dose 
Escalation part only)
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Anemia 
(hemoglobin < 8.0 
g/dL) 
Continue at the 
same dose level.
Withhold dose and monitor weekly until hemoglobin returns to 
baseline grade.  Implement supportive care per local guidelines.  
Talazoparib may be reduced by 1 dose level.
If anemia persists for > 4 weeks without recovery to baseline 
grade, discontinue talazoparib and refer to a hematologist for 
evaluation, including assessment for possible myelodysplastic 
syndrome or acute myeloid leukemia.  
Neutropenia (ANC 
< 1000/μL) 
Continue at the 
same dose level.
Withhold dose and monitor weekly until ANC ≥ 1500/μL.  
Implement supportive care per local guidelines.  Resume 
talazoparib based on the following recovery times: 

≤ 1 week: The same dose level.  

>1 week: Reduce talazoparib by 1 dose level.  
If neutropenia persists for > 4 weeks without recovery to ≥ 
1500/μL, discontinue talazoparib and refer to a hematologist for 
evaluation, including assessment for possible myelodysplastic 
syndrome or acute myeloid leukemia.  
Thrombocytopenia 
(platelets 
< 50,000/μL) 
Continue at the 
same dose level.
Withhold dose until platelets ≥ 75,000/μL.  Implement supportive 
care per local guidelines.  Resume talazoparib based on the 
following recovery times: 

≤ 1 week: The same dose level.  

>1 week: Reduce talazoparib by 1 dose level.  
If thrombocytopenia persists for > 4 weeks without recovery to ≥ 
75,000/μL, discontinue talazoparib and refer to a hematologist for 
evaluation, including assessment for possible myelodysplastic 
syndrome or acute myeloid leukemia.  
Nonhematologic lab 
abnormality, except 
liver function tests
Continue at the 
same dose level.
Withhold dose until toxicity is 
Grade ≤ 2 (or has returned to 
baseline for creatinine 
increases), then resume 
talazoparib at the same dose 
or reduce by 1 dose level.  
Implement supportive care 
per local guidelines.  Contact
the sponsor to discuss 
potential dose modification.  
Permanently discontinue if
lasting >4 weeks, but
treatment may be resumed at 
a 1 dose level reduction if 
clear clinical benefit is 
observed, after discussion 
with the sponsor.  
Withhold dose until toxicity is 
Grade ≤ 2 (or has returned to 
baseline for creatinine increases), 
then resume talazoparib at a 1 
dose level reduction.  Implement 
supportive care per local 
guidelines.  Contact the sponsor to 
discuss potential dose 
modification.  
Permanently discontinue if lasting 
>1 week, but treatment may be 
resumed at a 1 dose level 
reduction if clear clinical benefit 
is observed, after discussion with
the sponsor.  
Permanently discontinue for 
recurrence.


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Table 2.
Dose Modifications for Investigational Product-Related Toxicity (Dose 
Escalation part only)
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Abnormal liver 
function tests
Continue at the 
same dose level.
Withhold dose as specified in Table 4 until toxicity is Grade ≤1 or 
has returned to baseline grade.  The investigator and the sponsor 
should discuss and agree with any decision to rechallenge.  
Following rechallenge, patients should be closely monitored for 
signs and symptoms of hepatitis and/or abnormal liver test results.
Guidelines for follow-up for possible drug-induced liver injury are 
provided in Section 8.4.1.  Rechallenge should not occur when the 
liver test abnormalities are accompanied with signs or symptoms 
consistent with hepatitis or meet severe drug-induced liver injury.  
Nonlaboratory 
(other toxicities 
listed above)∗
Continue at the 
same dose level.
Withhold dose until toxicity is Grade ≤ 1 or has returned to 
baseline, then resume talazoparib at the same dose or reduce by 1 
dose level.  Implement supportive care per local guidelines.  
Contact the sponsor to discuss potential dose modification.  
Permanently discontinue if lasting longer than 4 weeks, but
treatment may be resumed at a 1 dose level reduction if clear 
clinical benefit is observed, after discussion with the sponsor.  
∗Talazoparib dose re-escalation may be allowed after the reduced dose is tolerated without recurrence of 
toxicities, and after discussion with the medical monitor.  
Table 3.
Dose Modification of Talazoparib Due to Adverse Events (Expansion part 
only)
Toxicity
Management of Adverse Events
Grade 1 or 2
No requirement for dose interruption or dose reduction.  
Grade 3 or 4 Anemia 
(hemoglobin <8.0 g/dL)
Hold talazoparib and implement supportive care per local guidelines.  
Monitor weekly until hemoglobin returns to ≥9 g/dL or better, then resume 
talazoparib at a reduced dose level.
If anemia persists for >8 weeks without recovery to at least 9.0 g/dL despite 
supportive care measures, discontinue talazoparib and refer to a 
hematologist for evaluation.
•
Transfusions and erythropoiesis-stimulating agents are permitted to 
support management of hematological toxicities.  (see section 5.7).
•
If 4 blood transfusions within 3 months period are required, discussion 
with medical monitor is required to continue/resume study drug.  
Grade 3 or 4 Neutropenia 
(ANC <1000/μL)
Hold talazoparib and implement supportive care per local guidelines.  
Monitor weekly until ANC ≥1500/μL, then resume talazoparib at a reduced 
dose level.
If neutropenia recurs after the dose reduction, hold talazoparib and 
implement supportive care per local guidelines.  Monitor weekly until 
ANC Ӌ1500/μL, then resume talazoparib at a further reduced dose.
If neutropenia persists for >4 weeks without recovery to ≥1500/μL at any 
dose level despite supportive care measures, discontinue talazoparib and 
refer to a hematologist for evaluation.
•
G-CSF and GM-CSF may be used at investigators discretion for the 
supportive treatment of neutropenia (see Section 5.7).


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Table 3.
Dose Modification of Talazoparib Due to Adverse Events (Expansion part 
only)
Toxicity
Management of Adverse Events
Grade 3 or 4 
Thrombocytopenia (platelets 
<50,000/µL)
Hold talazoparib and implement supportive care per local guidelines.  
Monitor weekly until platelets 50,000/µL, then resume talazoparib at a 
reduced dose.  
If thrombocytopenia (<50,000/µL) recurs after one dose reduction, hold 
talazoparib and implement supportive care per local guidelines.  Monitor 
weekly until platelets 75,000/µL, then resume talazoparib at a further 
reduced dose.
If thrombocytopenia persists for >4 weeks without recovery to 75,000/µL 
despite supportive care measures, discontinue talazoparib and refer to a 
hematologist for evaluation.
Nonhematologic laboratory 
Grade 3 events, except 
abnormal liver tests
Hold talazoparib as follows:
For Grade 3 laboratory abnormalities, hold talazoparib until the laboratory 
abnormality resolves to Grade 2 (to baseline grade for creatinine 
increases).  Resume talazoparib at the same dose or reduce by 1 dose level.  
For Grade 4 laboratory abnormalities, hold talazoparib until the laboratory 
abnormality resolves to Grade 2 (to baseline grade for creatinine 
increases).  Resume talazoparib at a 1 dose level reduction.  
Implement supportive care per local guidelines.  
Contact medical monitor to discuss potential dose modification.  
Talazoparib must be permanently discontinued for unresolved Grade 3 
toxicity lasting longer than 14 days or for Grade 4 toxicity lasting longer 
than 3 days.  Treatment may be resumed at a 1 dose level reduction if clear 
clinical benefit is observed, after discussion with the sponsor.
Grade 3 abnormal liver tests
Hold talazoparib for liver test abnormalities as specified in Table 4.  
Guidelines for follow-up for possible drug-induced liver injury after the 
liver test abnormalities resolve to baseline grade are provided in Section 
8.4.1.  Rechallenge should not occur when the liver test abnormalities are 
accompanied with signs or symptoms consistent with hepatitis or meet 
severe drug-induced liver injury.
Nonlaboratory Grade 3 
events determined to be 
clinically significant
Hold talazoparib as follows:
For Grade 3 adverse events, hold talazoparib until the adverse event 
resolves to Grade 1 or baseline.  Resume talazoparib at the same dose or 
reduce by 1 dose level.  
For Grade 4 adverse events, hold talazoparib until the adverse event 
resolves to Grade 1 or baseline.  Resume talazoparib at a reduced dose 
level.  
Abbreviations: ANC=absolute neutrophil count; G-CSF=granulocyte colony-stimulating factor;
GM-CSF=granulocyte-macrophage colony-stimulating factor.


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Table 4.
Criteria for Temporary Withholding of Study Drug in Association With 
Liver Test Abnormalities
Baseline AST or ALT Value 
Elevation 
≤3×ULN 
>5×ULN (ALT or AST ≥3×ULN with the presence of signs 
and symptoms consistent with acute hepatitis and/or 
eosinophilia [≥500 eosinophils/μL]) 
>3×ULN and ≤5×ULN 
>8×ULN 
Baseline Total Bilirubin Value 
Elevation 
≤1.5×ULN 
>3×ULN 
>1.5×ULN and ≤3×ULN 
(Patients with Gilbert syndrome or for whom 
indirect bilirubin concentrations suggest an 
extrahepatic source of elevation) 
>5×ULN 
Abbreviations: ALT= alanine aminotransferase; AST= aspartate aminotransferase; ULN= upper limit of 
normal.
5.5. Investigational Product Storage 
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels.  
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label.  
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all nonworking days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order.
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer.
Once an excursion is identified, the investigational product must be quarantined and not used 
until the Pfizer provides permission to use the investigational product.  It will not be 


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considered a protocol deviation if Pfizer approves the use of the investigational product after 
the temperature excursion.  Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation.  
Specific details regarding information the site should report for each excursion will be 
provided to the site.  
Site staff will instruct patients on the proper storage requirements for take home 
investigational products.  
5.6. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.
All bottles of study drug and unused study drugs must be returned to the investigator by the 
patient at the beginning of each cycle and at the end of the trial.
5.6.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational
product (eg, at the site).  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.7. Concomitant Treatment(s)
Concomitant treatment considered necessary for the patient’s well-being may be given at 
discretion of the treating physician.
All concomitant treatments, blood products, as well as nondrug interventions received by 
patients from screening until the end of study visit will be recorded on the CRF.  All 
concomitant treatments must be approved by the sponsor prior to the first dose of study 
treatment.
Guidelines for concomitant use of talazoparib with P-gp inhibitors are as follows: 
Strong P-gp inhibitors that result in ≥2-fold increase in the exposure of an in vivo probe P-gp 
substrate according to the University of Washington Drug-Drug Interaction database 
(https://www.druginteractioninfo.org/) are prohibited: amiodarone, carvedilol, 
clarithromycin, cobicistat, darunavir, dronedarone, erythromycin, indinavir, itraconazole, 
ketoconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir, 
telaprevir, tipranavir, valspodar, and verapamil.
Caution and monitoring for potential increased adverse reactions should be used upon 
concomitant use of the following transporter inhibitors with talazoparib: atorvastatin, 


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azithromycin, conivaptan, curcumin, cyclosporine, diltiazem, diosmin, eliglustat, elacridar 
(GF120918), eltrombopag, felodipine, flibanserin, fluvoxamine, piperine, quercetin, and 
schisandra chinensis extract.  
The list of strong P-gp inhibitors and transporter inhibitors to be used with caution will be 
updated annually and reflected in the Investigator Brochure.
5.7.1. Other Anti-tumor/Anti-cancer or Experimental Drugs
No additional anti-tumor treatment will be permitted while patients are receiving study 
treatment.  Additionally, the concurrent use of select vitamins or herbal supplements is not 
permitted.
Palliative radiotherapy on study is permitted for the treatment of painful bony lesions 
provided that the lesions were known at the time of study entry and the investigator clearly 
indicates that the need for palliative radiotherapy is not indicative of disease progression,
after discussion with the Sponsor’s medical monitor.  In view of the current lack of data 
about the interaction of talazoparib with radiotherapy, talazoparib treatment should be 
interrupted during palliative radiotherapy, stopping 10 days before and resuming treatment 
after recovery from acute radiation toxicities to baseline.
5.7.2. Supportive Care 
Palliative and supportive care for disease related symptoms may be administered at the 
investigator’s discretion and according to any available American Society of Clinical 
Oncology (ASCO) guidelines.  
5.7.3. Hematopoietic Growth Factors
In the dose escalation part, primary prophylactic use of granulocyte-colony stimulating 
factors is not permitted during Cycle 1.  They may be used to treat treatment emergent 
neutropenia as indicated by the current American Society of Clinical Oncology guidelines34.  
Refer to the local guideline for the indication and/or administration method of granulocyte 
colony-stimulating factors (G-CSFs).
5.7.4. Anti-Diarrheal, Anti-Emetic Therapy 
In the dose escalation part, primary prophylaxis of diarrhea, nausea and vomiting is not
permitted in the first cycle.  Primary prophylaxis in subsequent cycles is at the investigator’s 
discretion.  The choice of the prophylactic drug as well as the duration of treatment is up to 
the investigator with sponsor approval assuming there is no known or expected drug-drug 
interaction and assuming the drug is not included in the Concomitant Treatment(s) section.
5.7.5. Anti-Inflammatory Therapy
Anti-inflammatory or narcotic analgesic may be offered as needed assuming there is no 
known or expected drug-drug interaction and assuming the drug is not included in the 
Concomitant Treatment(s) section.  


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5.7.6. Corticosteroids 
Chronic systemic corticosteroid use for palliative or supportive purposes is not permitted.  
Acute emergency administration, topical applications, inhaled sprays, eye drops, or local 
injections of corticosteroids are allowed.
5.7.7. Surgery 
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and talazoparib required to minimize the risk of 
impaired wound healing and bleeding has not been determined.  Stopping talazoparib is 
recommended at least 10 days prior to surgery.  Postoperatively, the decision to reinitiate 
talazoparib treatment should be based on a clinical assessment of satisfactory wound healing 
and recovery from surgery.  
6. STUDY PROCEDURES 
6.1. Screening
For screening procedures see the Schedule of Activities and Assessments sections.  Dose 
level allocation in the dose escalation part was performed by the sponsor.  After patients have 
given their written informed consent and have completed the necessary baseline assessments, 
the site staff will fax or e-mail a complete Registration Form to the designated sponsor study 
team member or designee.  
In the expansion part, all patients must have test results of BRACAnalysis CDx indicating 
deleterious, suspected deleterious, or pathogenic germline BRCA1 or BRCA2 mutations 
before study treatment.  This test will be done as early as possible during the screening 
period (or outside of 28-days Screening period if patients provide informed concent 
document (ICD) for BRCA1/2 mutation testing).  For patients who already received results 
from a BRACAnalysis CDx test in 2017 or later, repeat testing is not required but the report 
must be submitted to Sponsor for approval.  
6.2. Study Period
For the treatment period procedures and blood sampling point for PK, see the Schedule of 
Activities and Assessments sections.  
In the dose escalation part, a PK lead-in was undertaken 7 days before Cycle 1 Day 1 to 
characterize the PK profile.  During PK lead-in, Cycle 1 or after completion of Cycle 1, the 
investigator documented if DLT was observed in each patient.  Refer to the Study Manual for 
details of DLT documentation.  
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6.3. Follow-up 
For follow-up procedures see the Schedule of Activities and Assessments sections.
In the expansion part, long-term follow-up begins after the last dose and can be conducted by 
telephone unless follow-up of unresolved AE is required.  Survival status and post study 
therapy can be obtained by any means including telephone, during a visit, chart review, or 
contact with someone who is knowledgeable of the patient’s status (eg, relative, friend, 
referring healthcare provider).  
6.4. Patient Withdrawal 
Withdrawal of consent:
Patients who request to discontinue receipt of study treatment will remain in the study and 
must continue to be followed for protocol specified follow-up procedures.  The only 
exception to this is when a patient specifically withdraws consent for any further contact with 
him or her or persons previously authorized by the patient to provide this information.  
Patients should notify the investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible.  The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of investigational product or also from study procedures and/or posttreatment 
study follow-up, and entered on the appropriate CRF page.  In the event that vital status 
(whether the patient is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.
Lost to follow-up:
All reasonable efforts must be made to locate patients to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the patient as noted above.  Lost 
to follow-up is defined by the inability to reach the patient after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the patient to 1 registered mail 
letter.  All attempts should be documented in the patient’s medical records.  If it is 
determined that the patient has died, the site will use locally permissible methods to obtain 
the date and cause of death.  If the investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the patient’s informed consent, 
then the investigator may use a sponsor-retained third-party representative to assist site staff 
with obtaining the patient’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study.  The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information.  If, after all attempts, the patient remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the patient’s medical records.
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 


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Withdrawal From the Study Due to Adverse Events (see also the Patient Withdrawal section)
or behavioral reasons, or the inability of the patient to comply with the protocol-required 
schedule of study visits or procedures at a given investigator site.  
Reasons for withdrawal of study treatment may include:

Objective disease progression; 

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity;

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Patient refused further treatment;

Study terminated by sponsor;

Death.
Reasons for withdrawal from study follow-up may include:

Completed study follow-up;

Study terminated by sponsor;

Lost to follow-up;

Refused further follow-up;

Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the patient return all unused investigational 
product(s), request that the patient return for a final visit, if applicable, and follow up with 
the patient regarding any unresolved AEs.
If the patient refuses further visits, no further study-specific evaluations should be performed 
and no additional data should be collected.  The sponsor may retain and continue to use any 
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7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, shipment 
instructions and contact information will be provided to the investigator site prior to initiation 
of the study.
7.1. Safety Assessment
Safety assessments will include collection of AEs, serious adverse events (SAEs), vital signs 
and physical examination, electrocardiogram (ECG [12-lead]), laboratory assessments, 
including pregnancy tests and verification of concomitant treatments.
7.1.1. Pregnancy Testing
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, will be performed on 2 occasions prior to starting 
administration of study treatment-once at the start of screening and once at the baseline visit
(immediately before starting the investigational product).  Following a negative pregnancy 
test result at screening, appropriate contraception must be commenced and a second negative 
pregnancy test result will be required at the baseline visit before the patient may receive the 
investigational product.  Pregnancy tests will be repeated at every treatment cycle during the 
active treatment period, at the end of study treatment, and additionally whenever 1 menstrual 
cycle is missed or when potential pregnancy is otherwise suspected.  Additional pregnancy 
tests may also be undertaken if requested by institutional review boards (IRBs)/ethics 
committees (ECs) or if required by local regulations.  In the case of a positive confirmed 
pregnancy, the patient will be withdrawn from administration of investigational product and 
from the study.
7.1.2. Adverse Events
Assessment of adverse events will include the type, incidence, severity (graded by the NCI 
CTCAE version 4.03) timing, seriousness, and relatedness.
7.1.3. Laboratory Safety Assessment
Hematology and blood chemistry will be drawn at the time points described in the schedule 
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Table 5.
Safety Laboratory Tests
Hematology
Chemistry
Urinalysis
Virus Test
Pregnancy Test
Hemoglobin
ALT
Urine dipstick for urine 
protein: If positive collect 
24 hr and microscopic 
(Reflex Testing) is 
preferable but urine 
protein/creatine ratio is 
also acceptable in 
agreement with the 
sponsor
HBV
For female 
patients of 
childbearing 
potential, serum 
or urine
Platelets
AST
HCV
White blood cell
(WBC)
Alk Phos
HIV
Neutrophils %
Sodium
Lymphocytes %
Potassium
Monocytes %
Magnesium
Eosinophils %
Chloride
Basophils %
Total calcium
Red blood cell 
(RBC)
Total bilirubin*
Hematocrit
Blood urea nitrogen
(BUN) or Urea
Creatinine
Uric Acid
Glucose (nonfasted**)
Albumin
Phosphoros or 
Phosphate
Total protein
CO2 (Dose Escalation 
part only)
* For potential Hy's Law cases, in addition to repeating AST and ALT, laboratory tests should include albumin, 
creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time 
(PT)/international normalized ratio (INR), alkaline phosphatase, total bile acids and acetaminophen drug and/or 
protein adduct levels.  
** Blood sample might be drawn under fasting conditions on Cycle 1 Day -7 and Cycle 1 Day 22 for the dose 
escalation part to avoid potential interaction of food on PK assessment although nonfasted sampling is required 
for Glucose.
7.1.4. Vital Signs and Physical Examination
Patients will have a physical examination to include weight, vital signs (blood pressure (BP) 
and pulse rate recorded in sitting position), assessment of ECOG performance status and 
height; height will be measured at baseline only.  
7.1.5. (12-Lead) Electrocardiogram
Electrocardiogram (ECG): A single 12-lead (with a 10-second rhythm strip) tracing will be 
used.  It is preferable that the machine used has a capacity to calculate the standard intervals 
automatically.  If the QTcF is prolonged (>500 msec, ie, CTCAE Grade 3), 3 consecutive 
ECGs will be performed at approximately 2 minutes apart to determine the mean QTcF 
interval to confirm presence of QTc prolongation, then the ECGs should be re-evaluated by a 
qualified person at the site for confirmation as soon as the finding is made, including 
verification that the machine reading is accurate.  If manual reading verifies a QTcF of > 500
msec, immediate correction for reversible causes (including electrolyte abnormalities, 
hypoxia and concomitant medications for drugs with the potential to prolong the QTcF 


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interval) should be performed.  In addition, repeat ECGs should be immediately performed 
hourly for at least 3 hours until the QTcF interval falls below 500 msec.  If QTcF interval 
reverts to less than 500 msec, and in the judgment of the investigator(s) and sponsor is 
determined to be due to cause(s) other than investigational product, treatment may be 
continued with regular ECG monitoring.  If in that timeframe the QTcF intervals rise above 
500 msec the investigational product will be held until the QTcF interval decreases to 500
msec.  Patients will then restart the investigational product at the next lowest dose level.  If 
the QTcF interval has still not decreased to <500 msec after 2 weeks, or if at any time a 
patient has a QTcF interval >515 msec or becomes symptomatic, the patient will be removed 
from the study.  Additional triplicate and/or a single ECG(s) may be performed as clinically 
indicated.  
Prior to concluding that an episode of prolongation of the QTcF interval is due to 
investigational product, thorough consideration should be given to potential precipitating 
factors (eg, change in patient clinical condition, effect of concurrent medication, electrolyte 
disturbance) and possible evaluation by specialist.
If a patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, 
or stroke), an ECG should be obtained at the time of the event.  
When matched with PK sampling, the ECG must be carried out before each PK sample 
drawing such that the PK sample is collected at the nominal time (ie, the timing of the PK 
collections over rides the timing of the ECG collections).  
7.2. Pharmacokinetics Assessments
7.2.1. Plasma for PK analysis of talazoparib 
Blood samples (approximately 3 mL) to provide a minimum of approximately 1 mL of 
plasma for PK analysis will be collected into appropriately labeled tubes containing 
tripotassium ethylenediaminetetraacetic acid (K3EDTA) as outlined in the SCHEDULE OF 
ACTIVITIES section of the protocol.  The PK sampling schedule may be modified based on 
emerging PK data.  
In addition to samples collected at the scheduled times, an additional blood sample should be 
collected from patients experiencing unexpected and/or serious AEs.  In case of QTc values 
>500 msec, a blood sample for PK analysis should be collected.  The date and time of blood 
sample collection and of last dosing prior to PK collection documented on the CRF.  
Where noted in the schedule of activities, blood samples for talazoparib concentrations will 
be collected at approximately the same time as other assessments such as pharmacodynamics 
(PD) samples and ECGs (first ECG then PK collection), etc., wherever possible.  
All efforts will be made to obtain the PK samples at the scheduled nominal time relative to 
dosing.  However, the exact time of the sample collection will always be noted on the CRF.  
If a scheduled blood sample collection cannot be completed for any reason, the missed 
sample time may be re-scheduled with agreement of the clinical investigator, patient, and 
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With regard to serial PK sampling in lead in phase and on Cycle 1 days 22-23 of the dose 
escalation part, samples obtained within 10% of the nominal time (eg, within 6 minutes of a 
60-minute sample) from dosing will not be captured as a protocol deviation, as long as the 
exact time of the sample collection is noted on the source document and data collection tool 
(eg, CRF).
For the expansion part, pre-dose samples obtained within 10% of the nominal time AND 
collected prior to administration of talazoparib on that day (for pre-dose PK samples) will be 
considered protocol compliant.  Patients must be instructed to withhold their daily dose of 
study drugs on PK sampling days until the pre-dose PK sample collection has been 
completed.  The actual time of the sample collection and the most recent dosing time before 
and after each collection will be recorded on the CRF.  The date of missing dose should also 
be recorded in the CRF.
PK samples will be assayed for talazoparib using a validated analytical method in 
compliance with Pfizer standard operating procedures (SOPs).  
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity.  Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.  
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.  Any deviation from the specified sample handling 
procedure resulting in compromised sample integrity will be considered a protocol deviation.
As part of understanding the PK of the investigational product, samples may be used for 
metabolite identification and/or evaluation of the bioanalytical method, 
 
  These data will not be included in the Clinical Study Report 
(CSR).
7.3. Tumor Response Assessments
Tumor assessments will include all known or suspected disease sites.  Imaging includes
chest, abdomen and pelvis computed tomography (CT) or magnetic resonance imaging 
(MRI) scans.  The same imaging technique used to characterize each identified and reported 
lesion at baseline will be employed in the following tumor assessments.
Requirement for brain CT or MRI
In the dose escalation part, brain CT or MRI scan for patients with known or suspected brain 
metastases and bone scan and/or bone x-rays for patients with known or suspected bone 
metastases are also included  Baseline CNS imaging is not required with the exception of 
symptomatic patients to rule out CNS metastases.  
In the expansion part, a brain MRI or CT is to be performed at Screening to evaluate patients 
for presence/absence of brain metastases.  Newly diagnosed CNS metastases at Screening 
makes a patient ineligible until such time as it can be adequately treated, at which point the 
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patient may be re-screened.  If adequately treated metastatic disease to the brain is present at 
Screening, an MRI or CT will be performed during the study as clinically indicated.  Bone 
scan will be performed at Screening.  If metastatic disease to the bone is present at Screening, 
a bone scan will be performed every 12 weeks (±7 days) for the initial 24 weeks and every 16 
weeks (±7 days) thereafter, and as clinically indicated.  
Assessment for anti-tumor activity
Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
baseline, during treatment as specified in the schedule of activities, whenever disease 
progression is suspected (eg, symptomatic deterioration), at the time of withdrawal from 
treatment (if not done in the previous 6 weeks) and at the time of clinical suspicion of disease 
progression.
Assessment of response will be made using RECIST version 1.1 (see Appendix 3.).  
In the expansion part, CR and PR is confirmed by a second image at least 4 weeks from the 
initial imaging showing response.  In addition, BICR will be conducted.  All radiographical 
images for tumor assessment have to be submitted for review.  Once study endpoints are 
summarized and it is notified by Sponsor, tumor assessment including brain and bone scan 
can be done per local standard practice and the requirement of imaging submission is no 
longer applicable.
All patients’ files and radiologic images must be available for source verification and for 
potential peer review.  
7.4. Assessment of germline BRCA mutations for eligibility (Expansion part only)
Patients enrolling in the expansion part are required to have deleterious, suspected 
deleterious, or pathogenic germline BRCA1 or BRCA2 mutations, identified by 
BRACAnalysis CDx test.  Testing may be performed during the screening period (or outside 
of the 28-days Screening period for patients who provide their consent for BRCA testing).  
Results from the BRACAnalysis CDx test may either be obtained through study sponsored 
central laboratory testing or from results of previously performed BRACAnalysis CDx 
testing, with Sponsor pre approval.  Instructions for submission of blood sample for 
BRACAnalysis CDx will be provided in the Study Manual.
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8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; (2) 
non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure.  
Safety Event
Recorded on the CRF
Reported on the CT 
SAE Report Form to 
Pfizer Safety Within 
24 Hours of Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product under 
study during pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during 
pregnancy, exposure via 
breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
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event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
patient death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details On Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study patient.  In addition, each study patient will be questioned about the 
occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Patient 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF.  


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When a patient withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each patient begins from the time the patient provides informed consent, which 
is obtained before the patient’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days after the last administration of the investigational product.
For patients who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a patient during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a patient after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow-up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
If a patient begins a new anti-cancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
If a patient begins a new anti-cancer therapy, the recording period for non-serious AEs ends 
at the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 


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an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records.  
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study patient administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;


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
Medication error;

Occupational exposure.
Worsening of signs and symptoms of the malignancy under study should be recorded as AEs 
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 


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result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the active collection 
period.  Hospitalization due to signs and symptoms of disease progression should not be 
reported as an SAE.  If the malignancy has a fatal outcome during the study or within the 
active collection period, then the event leading to death must be recorded as an AE on the 
CRF, and as an SAE with Common Terminology Criteria for Adverse Events (CTCAE) 
Grade 5 (see the Severity Assessment section).
A serious injury that can cause a serious deterioration in state of health can include:

A life-threatening illness, even if temporary in nature;

A permanent impairment of a body function or permanent damage to a body 
structure; 

A condition necessitating medical or surgical intervention to prevent the above 
2 bulleted items;

Examples: clinically relevant increase in the duration of a surgical procedure; a 
condition that requires hospitalization or significant prolongation of existing 
hospitalization;

Any indirect harm as a consequence of an incorrect diagnostic or in vitro diagnostic 
device test results when used within the manufacturer’s instructions for use;

Fetal distress, fetal death, or any congenital abnormality or birth defects.
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;


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
Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.


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8.3. Severity Assessment
GRADE
Clinical Description of Severity
0 
No change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the patient’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some patients, transaminase elevations are a harbinger of a more 
serious potential outcome.  These patients fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Patients who experience a transaminase elevation above 3× ULN should be 
monitored more frequently to determine if they are an “adaptor” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations (>2 ×
ULN) by several days or weeks.  The increase in TBili typically occurs while AST/ALT 
is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be elevated within 
the same lab sample).  In rare instances, by the time TBili elevations are detected, AST/ALT 
values might have decreased.  This occurrence is still regarded as a potential DILI.  
Therefore, abnormal elevations in either AST OR ALT in addition to TBili that meet the 
criteria outlined below are considered potential DILI (assessed per Hy’s law criteria) cases 
and should always be considered important medical events, even before all other possible 
causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the patient’s 
individual baseline values and underlying conditions.  Patients who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:


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
Patients with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For patients with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.  
The patient should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered.  
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted.  
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no other 
reason for the liver function test (LFT) abnormalities has yet been found.  Such potential DILI 
(Hy’s law) cases are to be reported as SAEs, irrespective of availability of all the results of 
the investigations performed to determine etiology of the LFT abnormalities.  


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A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.2. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.2.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an EDP occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a patient or patient’s partner becomes or is found to be pregnant during the patient’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a patient 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).


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If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.  
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the patient with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
patient was given the Pregnant Partner Release of Information Form to provide to his partner.
8.4.2.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.2.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a patient enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.3. Medication Errors
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.


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Safety Event
Recorded on the CRF
Reported on the CT 
SAE Report Form to 
Pfizer Safety Within 
24 Hours of Awareness
Medication errors
All (regardless of whether 
associated with an AE)
Only if associated with 
an SAE
8.4.3.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong patient, or at the wrong time, or at the wrong dosage strength.  
Medication errors include:

Medication errors involving patient exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.  
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1. Analysis Sets 
Analysis sets will be defined separately for each study part; the Dose Escalation part and the 
Expansion part.


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1. Safety analysis set
The safety analysis set includes all enrolled patients who receive at least one dose of 
study treatment.
2. Full analysis set
The full analysis set includes all enrolled patients who receive at least one dose of 
study treatment.  By definition, it is identical to the full safety analysis set defined 
above.
3. Per-protocol analysis set (evaluable for RP2D in the Dose Escalation part only)
The per-protocol analysis set includes all enrolled patients who receive at least one 
dose of study treatment and who do not have major treatment deviations during the
first cycle.  Patients with major treatment deviations in the first cycle are not 
evaluable for the RP2D assessment and will be replaced as needed to permit RP2D
estimation.  Major treatment deviations include:

Administration of less than 75% of the planned first cycle dose of talazoparib 
(provided that it is not due to toxicity attributable to talazoparib)

Administration of more than 125% of the planned first cycle dose of talazoparib
4. PK analysis sets
The PK parameter analysis population is defined as all enrolled patients treated who 
have sufficient information to estimate at least 1 of the PK parameters of interest.
The PK concentration population is defined as all enrolled patients who are treated 
and have at least 1 analyte concentration.
9.2. Statistical Methods and Properties
All analyses will be separately conducted for each study part.
In the Dose Escalation part, the following table shows the probability of escalating to the 
next dose level for a range of underlying true DLT rates.  For example, for a DLT that occurs 
in 10% of patients, there is a greater than 90% probability of escalating.  Conversely, for a 
DLT that occurs with a rate of 70%, the probability of escalating is 3%.  It is assumed that 
dose escalation occurs with either 0/3 or 1/6 patients with DLTs.
Table 6.
Probability of Escalating Dose
True underlying DLT rate
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of escalating dose
0.91
0.71
0.49
0.31
0.17
0.08
0.03
0.009
0.001


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The estimated RP2D is the highest tested dose level with DLT rate less than 33% in at least 6
DLT-evaluable patients.
9.3. Sample Size Determination
Dose Escalation part
According to the modified 3+3 design, the number of patients to be enrolled in the study will 
depend upon the observed safety profile, which will determine the number of patients at each 
dose level and the number of dose levels explored.  It is envisaged that maximum sample size 
would be 18 patients.
Expansion part
Assuming confirmed talazoparib ORR 50% and null proportion 18.4% based on the results of 
EMBRACA (Section 1.2.3), 17 patients are needed to preserve 80% probability of the lower 
limit of two-sided 90% CI of the comfirmed ORR exceeding the null proportion of 18.4%.
Although there are no formal statistical decision rules, if the lower limit of the two-sided 
90% CI of confirmed ORR exceeds 18.4%, it is considered that talazoparib shows clinical 
meaningful antitumor activity in Japanese patients with gBRCAm locally 
advanced/metastatic breast cancer.
9.4. Efficacy Analysis
Summaries and analyses of efficacy endpoints will include all patients in the Full analysis 
set.  
9.4.1. Analysis of Primary and Secondary Efficacy Endpoints
All analyses for primary and secondary endpoints based on radiological (and photographical 
where applicable) assessments of tumor burden (ie.  OR, DC, DoR, PFS) will be performed 
according to derived Investigator assessment and independent radiology assessment (the 
expansion part only).
The primary endpoint in the expansion part is the confirmed ORR assessed using RECIST 
version 1.1 by Investigator Assessment.  For the primary analysis, the number, percent and 
exact two-sided 90% CI will be calculated.
Analyses of the other binary secondary endpoints (e.g.  ORR in dose escalation part, ORR 
assessed by BICR and Disease Control rate (DCR) in the expantion part) will be performed 
using the same statistical methods as the primary analysis. DCR at 16 and 24 weeks will be 
provided.
Time-to-event endpoints (e.g.  TTR, PFS, DoR and OS) will be descriptively summarized 
using the Kaplan-Meier method and displayed graphically if appropriate.  The 25th, 50th, and 
75th percentiles of each endpoint and the 1-year probability of OS will be provided with two-
sided 90% CI.


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Tumor responseses assessed using RECIST version 1.1 response criteria in Appendix 3, will 
be presented in the form of patient data listings that include, but are not limited to, tumor 
type, starting dose, tumor response at each visit, and best overall response.  In addition, 
progression date, death date, date of first response and last tumor assessment date will be 
listed.
TTR, PFS, DoR and OS will be presented in listings.
Objective Response (OR) 
OR is defined as a CR or PR according to the RECIST version 1.1 recorded from first dose 
of study treatment until disease progression, start of subsequent anti-cancer therapy or death 
due to any cause.  
Disease Control (DC) 
DC is defined as CR, PR or SD according to the RECIST version 1.1 recorded in the time 
period between first dose of study treatment and disease progression or death to any cause.
Time to Tumor Response (TTR)
For patients with an OR (PR or CR), TTR is defined as the time from the first dose date to 
date of first documentation of OR.
Progression Free Survival (PFS)
PFS is defined as the time from the first dose date to date of first documentation of 
progression disease (PD) or death due to any cause.
Censoring: Patients without an event or with an event more than 16 weeks after the last 
adequate tumor assessment will be censored on the date of the last adequate tumor 
assessment that documented no progression.  In addition, if a new anti-cancer therapy is 
started prior to an event, the patient will be censored on the date of the last adequate tumor 
assessment that documented no progression prior to the start of the new anti-cancer therapy.
Duration of Response (DoR)
For patients with an objective response, DoR is the time from first documentation of PR or 
CR to date of first documentation of PD or death due to any cause.
Censoring:  Same as censoring for the definition of PFS.
Overall Survival (OS)
OS is defined as the time from the first dose date to date of death due to any cause.
Censoring:  Patients last known to be alive are censored at date of last contact.


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9.5. Analysis of Pharmacokinetics and Pharmacodynamics 
9.5.1. Analysis of Pharmacokinetics 
9.5.1.1. Single-Dose and Steady-State Talazoparib Pharmacokinetic Analysis
Dose Escalation part
Plasma PK parameters including the maximum concentration (Cmax), time to maximum 
plasma concentration (Tmax), area under the plasma concentration versus time curve (AUClast, 
AUCτ) and the lowest concentration observed during the dosing interval (Cmin) for 
talazoparib will be estimated using noncompartmental analysis.  If data permit or if 
considered appropriate, area under the plasma concentration versus time curve from time 0 
extrapolated to infinity (AUCinf), terminal phase half-life (t½), apparent oral clearance 
(CL/F), apparent volume of distribution (Vz/F), accumulation ratio (Rac) and linearity ratio 
(Rss) will be also estimated.  The single-dose in lead in phase and steady-state PK parameters 
on Day 22 in Cycle 1 will be summarized descriptively (n, mean, standard deviation, 
coefficient of variation (CV), median, minimum, maximum, geometric mean and its 
associated CV) by dose, cycle and day.
For talazoparib concentrations, concentrations will be summarized descriptively (n, mean, 
standard deviation, CV, median, minimum, maximum, geometric mean and its associated 
CV) by dose, cycle, day and nominal time.  Individual patient, median and mean profiles of 
the concentration-time data will be plotted by dose, cycle and day (single dose and steady 
state) using nominal times.  Individual, median and mean profiles will be presented on both 
linear-linear and log-linear scales.
Dose normalized AUCinf (AUCτ at steady state), AUClast, Cmax and Cmin (only at steady state)
will be plotted against dose (using a logarithmic scale) by cycle and day.  These plots will 
include individual patient values and the geometric means for each dose.  These plots will be 
used to help understand the relationship between the PK parameters and dose.
The observed accumulation ratio and the linearity ratio will be summarized descriptively.  
Trough concentrations will be plotted for each dose using a box-whisker plot by cycle and 
day within cycle
All the concentration data will be listed but the concentrations deviated more than 20% from 
the planned time will not be included in summarization.
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Expansion part
Trough concentrations will be summarized descriptively (n, mean, standard deviation, CV, 
median, minimum, maximum, geometric mean and its associated CV) by cycle and day.  
Trough concentrations will be plotted for each dose using a box whisker plot by cycle and 
day.  The pre-dose sample should be collected 24 hours ±10% (2 hours and 24 minutes) after 
the previous day’s dose and no more than 5 minutes (0.083 hours) after the administration of 
the dose on the day of PK sample collection.
9.5.2. Population Pharmacokinetic Analysis or Pharmacokinetic/Pharmacodynamic 
(PK/PD) Modeling
PK and PD data from this study may be analyzed using modeling approaches and may also 
be pooled with data from other studies to investigate any association between talazoparib 
exposure 
or significant safety and/or efficacy endpoints.  The results of these 
analyses, if performed, may be reported separately.
9.6. Safety Analysis
Summaries and analyses of safety parameters will include all patients in the Safety Analysis 
Set.  Baseline value will be defined as the value prior to dosing (either screening or lead-in 
visit, whichever is closer to the first dose).
9.6.1. Analysis of DLT (the Primary Endpoint for the dose escalation part)
DLT is the primary endpoint of the dose escalation part of the study.  The occurrence of 
DLTs observed in the dosing cohorts is used to estimate the RP2D as described in the Study 
Design section.  Adverse Events constituting DLTs will be listed per dose level.
9.6.2. Analysis of Secondary Safety Endpoints
Adverse Events
AEs will graded by the investigator according to the CTCAE version 4.03 and coded using 
the Medical Dictionary for Regulatory Activities (MedDRA).  The focus of AE summaries 
will be on Treatment Emergent Adverse Events, those with initial onset or increasing in 
severity after the first dose of study treatment.  The number and percentage of patients who 
experienced any AE, SAE, treatment related AE, and treatment related SAE will be
summarized according to worst toxicity grades.
Laboratory Test Abnormalities
The number and percentage of patients who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each laboratory assay.  Shift 
tables will be provided to examine the distribution of laboratory toxicities.
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal, or not done.  
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9.6.3. Electrocardiogram
The analysis of ECG results will be based on patients in the safety analysis set with baseline 
and on-treatment ECG data.
Any data obtained from ECGs repeated for safety reasons after the nominal time-points will 
not be averaged along with the preceding measurements.  Interval measurements from 
repeated ECGs will be included in the outlier analysis (categorical analysis) as individual 
values obtained at unscheduled time points.
QT intervals will be corrected for heart rate (HR) (QTc) using Fridericia’s and Bazett’s 
correction factors.  Data will be summarized and listed for RR, PR, QRS, QT, QTc, QTcF 
and QTcB by starting dose.  Descriptive statistics (n, mean, median, standard deviation, 
minimum, and maximum) will be used to summarize the absolute intervals and changes from 
baseline intervals after treatment by starting dose and time point.  For each patient and by 
starting dose, the maximum change from baseline will be calculated as well as the maximum 
increase from baseline interval across time-points.  Categorical analysis will be conducted for 
the maximum increase from baseline intervals.  Shift tables will be provided for baseline vs 
worst on treatment corrected QT (one or more correction methods will be used) using 
maximum CTCAE Grade.
9.7. Interim Analysis
No formal interim analysis will be conducted for this study.  As this is an open-label study, 
the sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating dose-escalation decisions, facilitating PK/PD 
modeling, supporting clinical development and/or due to regulatory requests.  In addition, in 
the expansion part, the unblinded reviews may be performed after at least 8 evaluable 
patients are followed for 12 weeks for the purpose of approaching regulatory authorities to
discuss earlier application for approval if promising efficacy is observed (Table 7).  The 
number of promising confirmed objective responders are based on the Bayesian posterior 
criterion;
Criterion: Posterior Probability (True ORR >18.4% Observed Responders) >99%.
Table 7.
Number of Confirmed Objective Responders for Unblinded Reviews
Number of Evaluable Patients
Confirmed Objective Responders (CR+PR)
by Investigator and BICR assessment a
8 to 9
5
10 to 13
6
14 to 16
7
Abbreviations: BICR = blinded independent central review; CR = complete response; PR = partial response.
a.  Minimum number of responders to be met the criterion based on the posterior Beta distribution.  Prior 
distribution is Beta (½, ½) as non-informative prior.
9.8. Data Monitoring Committee 
This study will not use a data monitoring committee (DMC).


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10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the patient's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
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In most cases, the source documents are the hospital or the physician's chart.  In these cases, 
data collected on the CRFs must match the data in those charts.  
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to ICH guidelines, according to local regulations, or 
as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.  
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 


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Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.  
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law.
When study data are compiled for transfer to Pfizer and other authorized parties, patient 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study patients.  The investigator 
site will maintain a confidential list of patients who participated in the study, linking each 
patient’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with applicable privacy laws.
The informed consent documents and any patient recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any patient 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC 
before use, and available for inspection.
The investigator must ensure that each study patient, is fully informed about the nature and 
objectives of the study and possible risks associated with participation.  
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient before any study-specific activity is performed.  In the dose 
escalation part, before starting the treatment on Cycle 2 Day 1, the investigator to obtain an 
additional consent from a patient to continue the study treatment beyond Cycle 1.  The 
investigator will retain the original of each patient's signed consent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
End of trial is defined as last patient last visit (LPLV).


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14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
talazoparib at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating patients and the hospital pharmacy 
(if applicable) within 4 weeks.  As directed by Pfizer, all study materials must be collected 
and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.  
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final patient was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.


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www.pfizer.com
Pfizer posts Public Disclosure Synopses (CSR synopses in which any data that could be used 
to identify individual patients has been removed) on www.pfizer.com for Pfizer-sponsored 
interventional studies at the same time the US Basic Results document is posted to 
www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues.


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Appendix 1.  Abbreviations
The following is a list of abbreviations that may be used in the protocol.  
Abbreviation
Term
ADP
adenosine diphosphate
ADR
adverse drug reaction
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the curve
AUCinf
area under the plasma concentration-time curve from zero to 
infinity
AUClast
area under the plasma concentration-time curve from zero to 
time of last measurable concentration
AUCτ
area under the plasma concentration-time curve for a dosing 
interval
BBS
Biospecimen Banking System
BCRP
breast cancer resistance protein
BER
base excision repair
BICR
blinded independent central review
BP
blood pressure
BRCA
breast cancer susceptibility gene
BUN
blood urea nitrogen
C
cycle
Cmax
maximum concentration
Cmin
lowest concentration
C1D1
cycle 1 day 1
CI
confidence interval
CK
creatine kinase
CL/F
apparent oral clearance
CNS
central nervous system
CR
complete response
CRF
case report form
CSA
clinical study agreement
CSR
clinical study report
CT
computed tomography
CT
clinical trial
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
DC
disease control
CCI


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DCR
disease control rate
DDI
drug-drug interaction
DDR
deoxyribonucleic acid damage response
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DoR
duration of response
EC
ethics committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
exposure during pregnancy
EDTA
edetic acid (ethylenediaminetetraacetic acid)
eg
for example
etc
‘and other things’ or ‘and so forth’
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
gBRCAm
germline breast cancer susceptibility gene mutation
GCP
Good Clinical Practice
G-CSFs
granulocyte colony-stimulating factors
GGT
gamma-glutamyl transferase
GI
gastrointestinal
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
HR
heart rate
HRD
homologous recombination deficiency
ICD
informed consent document
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ID
identification
ie
that is
IND
investigational new drug application
INR
international normalized ratio
IRB
institutional review board
ITT
intent-to-treat
IUD
intrauterine device
K2EDTA
dipotassium ethylenediaminetetraacetic acid
K3EDTA
tripotassium ethylenediaminetetraacetic acid
LFT
liver function test
LPLV
last patient last visit


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MD
multiple dose
MedDRA
Medical Dictionary for Regulatory Activities
MHLW
Ministry of Health, Labour and Welfare
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
N/A
not applicable
NAD
nicotinamide adenine dinucleotide
NCI 
National Cancer Institute 
OR
objective response
ORR
objective response rate
OS
overall survival
PARP
poly(ADP-ribose) polymerase
PCD
primary completion date
PCT
physician’s choice treatment
PD
pharmacodynamics
PD
progression disease
PFS
progression-free survival
P-gp
P-glycoprotein
PgR
progesterone receptor
PI
principal investigator
PK
pharmacokinetics
PR
partial response
PS
performance status
PT
prothrombin time
QD
quaque die
QT
time between the start of the Q wave and the end of the T wave
Rac
accumulation ratio
Rss
linearity ratio
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
RR
response rate
SAE
serious adverse event
SAP
statistical analysis plan
SCLC
small cell lung cancer
SD
stable disease
SD
single dose
SOP
standard operating procedure
SRSD
single reference safety document
t½
terminal phase half-life
TBili
total bilirubin
Tmax
time to maximum concentration
TNBC
triple negative breast cancer
TNM
tumor, node, metastasis


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TTR
time to tumor response
ULN
upper limit of normal
US
United States
Vz/F
apparent volume distribution, estimated from terminal phase, 
for extravascular dosing
WBC
white blood cell 


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Appendix 2.  Bone Marrow Reserve in Adults 
Adapted from R.E.  ELLIS: The Distribution of Active Bone Marrow in the Adult, Phy.  Med.  
Biol.  5, 255-258, 1961
Marrow Distribution of the Adult
SITE
MARROW
wt.  (g)
FRACTION 
RED 
MARROW
AGE 40
RED 
MARROW
wt.  (g)
AGE 40
% TOTAL
RED MARROW
CRANIUM
Head :
136.6
AND
Cranium
165.8
0.75
124.3
13.1
13.1
MANDIBLE
Mandible
16.4
0.75
12.3
Upper Limb Girdle :
86.7
HUMERI,
SCAPULAE,
2 Humerus, 
head & neck
26.5
0.75
20.0
8.3
8.3
CLAVICLES
2 Scapulae 
67.4
0.75
50.5
2 Clavicles
21.6
0.75
16.2
Sternum
39.0
0.6
23.4
2.3
Ribs : 
82.6
1 pair
10.2
All 0.4
4.1
2 
12.6
5.0
3
16.0
6.4
STERNUM
4
18.6
7.4
AND
5
23.8
9.5
7.9
10.2
RIBS
6
23.6
9.4
7
25.0
10.0
8
24.0
9.6
9
21.2
8.5
10
16.0
6.4
11
11.2
4.5
12
4.6
1.8
Sacrum 
194.0
0.75
145.6
13.9
PELVIC 
BONES
2 os coxae
310.6
0.75
233.0
22.3
36.2
FEMUR
2 Femoral head 
and neck
53.0
0.75
40.0
3.8


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Marrow Distribution of the Adult (cont’d)
SITE
MARROW
wt.  (g)
FRACTION RED 
MARROW
AGE 40
RED 
MARROW
wt.  (g)
AGE 40
% TOTAL
RED MARROW
Vertebrae
(Cervical):
35.8
1
6.6
All 0.75
5.0
2
8.4
6.3
3
5.4
4.1
3.4
4
5.7
4.3
5
5.8
4.4
6
7.0
5.3
7
8.5
6.4
Vertebrae
(Thoracic):
147.9
1 pair
10.8
All 0.75
8.1
2
11.7
8.8
3
11.4
8.5
4
12.2
9.1
VERTEBRAE
5
13.4
10.1
14.1
28.4
6
15.3
11.5
7
16.1
12.1
8
18.5
13.9
9
19.7
14.8
10
21.2
15.9
11
21.7
16.3
12
25.0
18.8
Vertebrae
(Lumbar) :
114.1
1 pair
27.8
All 0.75
20.8
2
29.1
21.8
10.9
3
31.8
23.8
4
32.1
24.1
5
31.4
23.6
TOTAL
1497.7
1045.7
100.0
100.0


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Appendix 3.  RECIST (Response Evaluation Criteria In Solid Tumors) version 1.1 
Guidelines
Adapted from E.A.  Eisenhauer, et al: New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1).  European Journal of Cancer 45 (2009) 228–247.  
CATEGORIZING LESION AT BASELINE
MEASURABLE LESIONS

Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter twice the slice thickness and at least 10 mm or greater  
when assessed by CT or MRI (slice thickness 5-8 mm).

Lesions with longest diameter at least 20 mm when assessed by Chest X-ray.  

Superficial lesions with longest diameter 10 mm or greater when assessed by caliper.  

Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE:  THE SHORTEST AXIS IS USED AS THE DIAMETER FOR MALIGNANT 
LYMPH NODES, LONGEST AXIS FOR ALL OTHER MEASURABLE LESIONS.  
NON-MEASURABLE DISEASE 
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.

Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline.  

Previous local treatment: A previously irradiated lesion (or lesion patiented to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment.
NORMAL SITES

Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non-target disease.  Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above.  If non-cystic lesions are also present, these are preferred as target 
lesions.

Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease.


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RECORDING TUMOR ASSESSMENTS 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate.  
TARGET LESIONS
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study.  

If two target lesions coalesce the measurement of the coalesced mass is used.  If a 
large target lesion splits, the sum of the parts is used.

Measurements for target lesions that become small should continue to be recorded.  If 
a target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be 
recorded.
NOTE: WHEN NODAL LESIONS DECREASE TO <10 MM (NORMAL), THE 
ACTUAL MEASUREMENT SHOULD STILL BE RECORDED.
NON-TARGET DISEASE 
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT 
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a 
single item on the case report form (e.g., ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’).
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION.
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are indeterminate.  
TARGET DISEASE

Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis 
<10 mm).  All target lesions must be assessed.

Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measurable lesions.  The short diameter is used in the 


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sum for target nodes, while the longest diameter is used in the sum for all other target 
lesions.  All target lesions must be assessed.  

Stable: Does not qualify for CR, PR or Progression.  All target lesions must be 
assessed.  Stable can follow PR only in the rare case that the sum increases by less 
than 20% from the nadir, but enough that a previously documented 30% decrease no 
longer holds.  

Objective Progression (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease in 
the sum is observed during therapy), with a minimum absolute increase of 5 mm.  

Indeterminate.  Progression has not been documented, and 
one or more target measurable lesions have not been assessed; 
or assessment methods used were inconsistent with those used at baseline;
or one or more target lesions cannot be measured accurately (e.g., poorly visible 
unless due to being too small to measure);
or one or more target lesions were excised or irradiated and have not reappeared or 
increased.  
NON-TARGET DISEASE

CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels.  All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits.  

PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare.  

Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at 
baseline.
NEW LESIONS 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
SUPPLEMENTAL INVESTIGATIONS

If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with 
biopsy or fine needle aspirate.  If no disease is identified, objective status is CR.


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
If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status.  
SUBJECTIVE PROGRESSION
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment.  
Table 1.  Objective Response Status at Each Evaluation
Target Lesions
Non-target Disease
New Lesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Indeterminate or 
Missing 
No
PR
PR
Non-CR/Non-PD, 
Indeterminate, or 
Missing
No
PR
SD
Non-CR/Non-PD, 
Indeterminate, or 
Missing
No
Stable
Indeterminate or 
Missing
Non-PD
No
Indeterminate
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Table 2.  Objective Response Status at each Evaluation for Patients with Non-Target 
Disease Only
Non-target Disease
New Lesions
Objective status
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Indeterminate
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes
PD


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Determination of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest sum 
on study).  In the expansion part, for CR and PR, the patient’s best response assignment will 
depend on the achievement of both measurement and confirmation criteria.  CR and PR is 
confirmed by a second image at least 4 weeks from the initial imaging showing response.  In 
the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval of 6 weeks.  


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Appendix 4.  ECOG Performance Status*
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair.
5
Dead.
*As published in Am J Clin Oncol 5:649-655, 1982.

SAP_001.pdf: 
Protocol C3441030 (PF-06944076, Talazoparib) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
Protocol C3441030
A PHASE 1 STUDY OF THE SAFETY, PHARMACOKINETICS AND 
ANTI-TUMOR ACTIVITY OF TALAZOPARIB, POLY (ADP-RIBOSE) 
POLYMERASE (PARP) INHIBITOR, IN JAPANESE PATIENTS WITH 
ADVANCED SOLID TUMORS
Statistical Analysis Plan 
(SAP)
Version:
2
Date:
15 APR 2021


Protocol C3441030 (PF-06944076, Talazoparib) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
APPENDICES ...........................................................................................................................5
1. VERSION HISTORY............................................................................................................6
2. INTRODUCTION .................................................................................................................6
2.1. Study Objectives, Endpoints, and Estimands............................................................7
2.1.1. Primary Estimand .........................................................................................9
2.1.2. Secondary Estimand ...................................................................................10
2.1.3. Additional Estimand...................................................................................10
2.2. Study Design ...........................................................................................................10
2.2.1. Starting Dose ..............................................................................................11
2.2.2. Criteria for Dose Escalation (Dose Escalation part only)...........................11
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................12
3.1. Primary Endpoint(s) ................................................................................................12
3.1.1. DLT Definition (Dose Escalation part only) ..............................................12
3.2. Secondary Endpoint(s) ............................................................................................13
3.2.1. Safety Endpoints.........................................................................................13
3.2.2. Pharmacokinetic Endpoints ........................................................................13
3.2.3. Efficacy Endpoints......................................................................................15
3.2.3.1. Tumor Assessment ....................................................................15
3.2.3.2. Best Overall Response (Confirmed Response) .........................19
3.2.3.3. Best Overall Response (Unconfirmed Response) .....................20
3.2.3.4. Percent Change from Baseline in Sum of Diameters for 
Target Lesions ...................................................................................21
3.2.3.5. Progression Free Survival (PFS)...............................................21
3.2.3.6. Duration of Response (DoR).....................................................23
3.2.3.7. Overall Survival (OS)................................................................23
3.2.3.8. Time to Response (TTR)...........................................................24
3.4. Baseline Variables...................................................................................................24
3.5. Safety Endpoints .....................................................................................................24
3.5.1. Adverse Events...........................................................................................24
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3.5.2. Laboratory Data..........................................................................................25
3.5.3. Vital Signs ..................................................................................................26
3.5.4. Electrocardiograms.....................................................................................26
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................27
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................28
5.1. Hypotheses and Decision Rules ..............................................................................28
5.2. General Methods .....................................................................................................28
5.2.1. Analyses for Binary Endpoints...................................................................28
5.2.2. Analyses for Continuous Endpoints ...........................................................28
5.2.3. Analyses for Categorical Endpoints ...........................................................29
5.2.4. Analyses for Time-to-Event Endpoints ......................................................29
5.3. Methods to Manage Missing Data ..........................................................................29
5.3.1. Efficacy and Safety Endpoints....................................................................29
5.3.2. Pharmacokinetic Endpoints ........................................................................31
6. ANALYSES AND SUMMARIES ......................................................................................32
6.1. Primary Endpoint(s) ................................................................................................32
6.1.1. First-cycle Dose-Limiting Toxicities (DLTs) in Dose Escalation part ......32
6.1.1.1. Main Analysis ...........................................................................32
6.1.1.2. Sensitivity/Supplementary Analyses.........................................32
6.1.2. Confirmed objective response (OR) as assessed using RECIST 
version 1.1 by Investigator Assessment in Expansion part..............................32
6.1.2.1. Main Analysis ...........................................................................32
6.1.2.2. Sensitivity/Supplementary Analyses.........................................33
6.2. Secondary Endpoint(s) ............................................................................................33
6.2.1. Pharmacokinetic Endpoints ........................................................................33
6.2.1.1. Single-Dose and Steady-State Talazoparib 
Pharmacokinetic Analysis .................................................................33
6.2.1.2. Population Pharmacokinetic Analysis or 
Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling..................34
6.2.2. Efficacy Endpoints......................................................................................34
6.2.2.1. Objective Response...................................................................34
6.2.2.2. Time to Response (TTR)...........................................................35
6.2.2.3. Duration of Response (DoR).....................................................36


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6.2.2.4. Progression Free Survival (PFS)...............................................36
6.2.2.5. Overall Survival (OS)................................................................36
6.4. Subset Analyses.......................................................................................................37
6.5. Baseline and Other Summaries and Analyses.........................................................37
6.5.1. Baseline Summaries....................................................................................37
6.5.2. Study Conduct and Participant Disposition................................................38
6.5.3. Study Treatment Exposure .........................................................................39
6.5.4. Concomitant Medications and Nondrug Treatments..................................39
6.6. Safety Summaries and Analyses .............................................................................39
6.6.1. Adverse Events ...........................................................................................39
6.6.2. Laboratory Data..........................................................................................41
6.6.2.1. Parameters with NCI CTCAE Grades Available ......................41
6.6.2.2. Laboratory Assessment by Visit ...............................................42
6.6.2.3. Assessment of Possible Drug-Induced Liver Injury (DILI)......42
6.6.2.4. Clinically Significant Abnormalities.........................................42
6.6.3. Vital Signs ..................................................................................................42
6.6.4. Electrocardiograms.....................................................................................42
6.6.5. Physical Examination .................................................................................43
6.6.6. ECOG Performance Status .........................................................................43
7. INTERIM ANALYSES.......................................................................................................43
7.1. Introduction .............................................................................................................43
7.2. Interim Analyses and Summaries............................................................................43
8. REFERENCES ....................................................................................................................44
9. APPENDICES .....................................................................................................................45
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................6
Table 2.
Pharmacokinetic Parameters of Talazoparib Single Dose........................14
Table 3.
Pharmacokinetic Parameters of Talazoparib Multiple Dose ....................14
Table 4.
Objective Response Status at Each Assessment for Patients with 
Target Lesions at Baseline........................................................................18
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Table 5.
Objective Response Status at Each Assessment for Patients with 
Non-target Lesions Only at Baseline........................................................19
Table 6.
PFS Outcome and Event Dates.................................................................22
Table 7.
PFS Censoring Reasons and Hierarchy....................................................22
Table 8.
Vital Signs Abnormal Categories (Position: Sitting)................................42
Table 9.
Electrocardiograms Abnormal Categories (Unit: msec)...........................43
APPENDICES
Appendix 1. Data Derivation Details.......................................................................................45
Appendix 1.1. Definition and Use of Visit Windows in Reporting.........................................45
Appendix 1.2. Date of Last Contact.........................................................................................48


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PFIZER CONFIDENTIAL 
Page 6
1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated
Protocol 
Amendment
Rationale
Specific Changes
1
27 DEC 2018
1
12 SEP 2017
N/A
N/A
2
15 APR 2021
2
28 FEB 2019
The expansion part 
was added to 
evaluate the
efficacy, the safety 
and PK at RP2D of 
single agent 
talazoparib in 
Japanese patients 
with gBRCA
mutated 
advanced/metastati
c breast cancer.
Most of the sections were updated and modified to 
reflect the addition of the expansion part.
•
Introduction
•
Study Objectives, Endpoints, and Estimands
•
Study Design
•
Endpoint and Baseline Variables
•
Primary Endpoint(s)
•
Secondary Endpoint(s)
•
Baseline Variables
•
Safety Endpoint
•
Analysis Sets
•
General Methodology and Conventions
•
Hypotheses and Decision Rules
•
General Methods
•
Methods to Manage Missing Data
•
Analyses and Summaries
•
Primary Endpoint(s)
•
Secondary Endpoint(s)
•
Baseline and Other Summaries and Analyses
•
Safety Summaries and Analyses
•
Appendices
In addition, administrative changes were made
throughout the SAP associated with the protocol 
amendment.
2. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C3441030.  This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment.
Talazoparib (PF-06944076 also known as MDV3800 or BMN 673) is a potent, orally 
bioavailable, small molecule PARP inhibitor in development for the treatment of a variety of 
human cancers.  Talazoparib is cytotoxic to human cancer cell lines harboring gene 
mutations that compromise DNA repair, an effect referred to as synthetic lethality.
C
C
C
C


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Page 7
As there was no clinical experience with talazoparib in Japanese patients at the time of study 
initiation, the current Phase 1 study was initially designed to evaluate the safety, tolerability, 
preliminary efficacy, and pharmacokinetic (PK) profile of talazoparib as a single agent in 
Japanese patients with advanced solid tumors. This part is called the dose escalation part.
In the global phase 1 (PRP-001), the MTD and recommended Phase 2 dose (RP2D) as a 
single-agent was investigated using dose escalation scheme starting from 0.025 mg/day up to 
1.1 mg/day. Total of 3 Dose-Limiting Toxicities (DLTs) in Cycle 1 were observed at dose 
level of 0.9 mg/day (n=1, Grade 3 thrombocytepenia) and 1.1 mg/day (n=2, Grade 3 and 4 
thrombocytopenia) when administered continuously with the cycle length of 28 days. The 
MTD/RP2D was determined as 1.0 mg/day. Based on these results, the starting dose selected 
in this study is 0.75 mg/day where no DLT was observed and one level lower than the 
MTD/RP2D. Talazoparib will be administered once daily in continuous dosing regimen with 
the treatment cycle of 28 days.
The dose escalation part of the C3441030 study applied modified 3+3 dose escalation 
scheme to identify the RP2D in Japanese patients. The dose was escalated to the next dose 
level (1.0 mg/day) according to the pre-defined dose escalation scheme and based on the 
incidence of DLTs at the intial dose level (0.75 mg/day). However, the highest dose used in 
the study was 1.0 mg/day. The dose over the MTD determined in Study PRP-001 was be 
explored. The study also includes Lead-in PK period. A single dose of talazoparib was
administered 7 days prior to Cycle1 Day1 and multiple PK samples were collected.
As of 24 January 2019, a total of 9 patients were enrolled in the dose escalation part of the 
C3441030 study.  DLT were not reported in any patients receiving 0.75 mg/day (n=3) or
1.0 mg/day (n=6).  Therefore, the RP2D of single-agent talazoparib was determined to be 
1.0 mg/day in Japanese patients with advanced solid tumors.  Overall the safety profile in the 
dose escalation part was similar to the adverse events (AEs) observed in global studies of 
talazoparib.  Most common AEs of single-agent talazoparib in Japanese patients were 
hematological toxicities and hepatotoxicities.  Based on the preliminary PK analysis results 
(n=3 each in 0.75 and 1.0 mg/day), the PK profile of single-agent talazoparib in Japanese 
patients was comparable with that in Western population.  These data also supported RP2D 
in Japanese patients.
Following on the encouraging results of EMBRACA and determination of RP2D in Japanese 
patients, the C3441030 study was expanded to further evaluate efficacy, safety and PK at 
RP2D in Japanese patients with gBRCAm HER2-negative locally advanced or metastatic 
breast cancer in protocol amendment 2.
2.1. Study Objectives, Endpoints, and Estimands
Study Objectives and Endpoints for Dose 
Escalation 
part 
(Solid 
Tumor)Primary 
Objective(s): 
Primary Endpoint(s): 


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• To assess safety and tolerability at increasing dose 
levels of talazoparib in successive cohorts of patients 
with solid tumors in order to select the RP2D in 
Japanese.
• First-cycle DLTs.
Secondary Objective(s): 
Secondary Endpoint(s): 
• To evaluate the overall safety profile. 
• Adverse Events as characterized by type, frequency, 
severity (as graded by NCI CTCAE version 4.03), timing, 
seriousness, and relationship to talazoparib.
• Laboratory abnormalities as characterized by type, 
frequency, severity (as graded by NCI CTCAE version
4.03),  and timing.
• Vital Signs. 
• To characterize the single and steady-state 
pharmacokinetics (PK) of single-agent talazoparib
• Pharmacokinetic parameters of talazoparib: 
• Single Dose (SD) - Cmax, Tmax, AUClast, AUCτ, CL/F, 
and Vz/F and t1/2, and AUCinf as data permit.  
• Multiple Dose (MD) (assuming steady state is 
achieved) - Css,max, Tss,max, Cmin, AUCss,τ, CL/F, Rac 
(AUCss,τ /AUCsd,τ) and Rss (AUCss,τ /AUCsd,inf) as data 
permit.
• To assess preliminary evidence of anti-tumor activity 
of single agent talazoparib.
• Objective response (OR), as assessed using the Response 
Evaluation Criteria in Solid Tumors (RECIST) version 
1.1
• Time-to-event endpoints: eg, DoR and PFS if applicable
Study Objectives and Endpoints for Expansion part (gBRCAm breast cancer)
Primary Objective(s): 
Primary Endpoint(s): 
• To evaluate the anti-tumor activity of single agent 
talazoparib in Japanese patients with gBRCAm HER2-
negative locally advanced or metastatic breast cancer.
• Confirmed objective response (OR) as assessed using 
RECIST version 1.1 by Investigator Assessment.
Secondary Objective(s): 
Secondary Endpoint(s): 
• To further evaluate anti-tumor activity.
• OR as assessed using RECIST version 1.1 by Blinded 
Independent Central Review (BICR).
• Disease Control defined as patients with a confirmed 
complete response (CR), confirmed partial response (PR) 
and stable disease (SD) at 16 and 24 weeks.
• Time to event endpoints: Time-to-tumor response (TTR), 
CCI


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DoR, PFS, and OS.
• To evaluate the overall safety profile of talazoparib.
• AEs including laboratory abnormalities as characterized 
by type, frequency, severity (as graded by the NCI 
CTCAE, version 4.03), timing, seriousness, and 
relationship to talazoparib.
• To characterize the PK of single-agent talazoparib.
• Trough concentrations of talazoparib.
2.1.1. Primary Estimand
The primary estimand of this study is a composite estimand (accounting for both treatment 
adherence and response), defined according to the primary objective and in alignment with 
the primary endpoint.  It includes the following 4 attributes:
Dose Escalation part
•
Population: Japanese patients with advanced solid tumors, as defined by the inclusion 
and exclusion criteria, and who do not have major treatment deviations during the first 
cycle. One of the non-negligible major treatment deviations is low adherence defined as
less than 75% of the planned first cycle dose of study treatment due to toxicity that is not
attributable to study treatment.  The details of analysis set, Per Protocol, is defined in 
Section 4.
•
Variable: Binomial DLT occurrence within the first cycle.  The DLTs are defined in
Section 3.1.1.
•
Intercurrent event(s): The intercurrent event is captured through the variable definition.
•
Population-level summary:  Percentage of patients who experienced DLT within the first 
cycle.
Expansion part
•
Population: Japanese patients with gBRCAm HER2-negative locally advanced or 
metastatic breast cancer, as defined by the inclusion and exclusion criteria, and who 
received at least 1 dose of study drug without regard to tolerability or duration of 
treatment.  The details of analysis set, Full analysis set, is defined in Section 4.
CCI


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
Variable: Confirmed objective response defined as CR or PR according to RECIST v1.1 
based on investigator assessment.

Intercurrent event(s): The intercurrent event is captured through the variable definition.

Population-level summary:  Percentage of patients who experienced confirmed objective 
response.
2.1.2. Secondary Estimand
Not applicable
2.1.3. Additional Estimand
Not applicable
2.2. Study Design
This is a Phase 1 study which consists of 2 parts; Dose Escalation part and Expansion part.
The dose escalation part is open label and evaluates safety, preliminary efficacy and PK of 
single agent talazoparib in sequential cohorts of adult patients with advanced solid tumors 
who are resistant to standard therapy or for whom no standard therapy is available.  
Successive cohorts of patients received escalating doses of talazoparib on an outpatient basis 
starting from 0.75 mg/day.  This part evaluated 2 dose levels; 0.75 mg and 1.0 mg.  To 
understand the single dose safety and single dose PK assessments of talazoparib, a lead-in 
period preceding the continuous daily doses have been included in the dose escalation part.  
In the 7-day lead in period, a single lead in dose was given on Day -7.  No talazoparib was 
administered during the interval between the lead-in single dose and Day 1 of the first cycle.  
Study treatment is given as on outpatient basis, however a patient is required to stay 
overnight at the study site during any intensive PK collection period (i.e. Day -7 and Day 22 
in Cycle 1).
In the dose escalation part, a total of 9 patients were enrolled. No DLTs were observed in any 
patients receiving 0.75 mg/day (n=3) or 1.0 mg/day (n=6). Therefore enrollment was
completed for dose escalation part.
Protocol amendment 2 includes the addition of an expansion part. The expansion part is an 
open-label, multicenter, efficacy, safety and PK study of single-agent talazoparib at RP2D
determined in the dose escalation part in adult patients with locally advanced or metastatic 
breast cancer who have deleterious or suspected deleterious germline BRCA1 or BRCA2
mutations. The patients in the expansion part will receive 1.0 mg/day of talazoparib which 
was RP2D identified in the dose escalation part of the C3441030 study. The expansion part
will include Blinded Independent Central Review (BICR) assessment for the efficacy 
evaluation. All radiographic images taken during the study must be available and be 
submitted for central review.


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In the expansion part, a minimum of 17 patients will be enrolled evaluable for the primary 
endpoint.
In all study parts, treatment with talazoparib will continue until either disease progression, 
unacceptable toxicity or withdrawal of consent.
2.2.1. Starting Dose
The starting dose was 0.75 mg given once daily in 28-day cycles in dose escalation part.
The starting dose in expansion part will be 1.0 mg/day. In patients with moderate renal 
impairment (creatinine clearance 30-59 mL/min), the starting dose will be reduced 1 dose 
level.
2.2.2. Criteria for Dose Escalation (Dose Escalation part only)
A modified 3+3 dose escalation scheme will be used.
Two dose levels (0.75 mg/day and 1.0 mg/day) will be evaluated in the dose escalation part.  
Up to 3 patients in a cohort may be enrolled simultaneously; occasionally, due to 
logistical/clinical reasons, more than 3 but no more than 9 patients may be enrolled at each 
dose level. Initially, 3 patients will receive 0.75 mg/day.  If no DLT is observed in the initial 
3 patients at 0.75 mg/day, the next dose level at 1.0 mg/day will be opened.  If a DLT is 
observed in 1 or 2 of the initial 3 dosed patients, 3 additional patients up to a total of 6 
patients will be enrolled and receive 0.75 mg/day.  If 1 of 6 patients experience a DLT at 
0.75 mg/day, the dose will be escalated to 1.0 mg/day.  In case 2 of 6 dosed patients 
experience a DLT, 3 additional patients up to a total of 9 patients will be enrolled and receive 
0.75 mg/day if deemed necessary in the opinion of the sponsor and the investigators.  For the 
case where 2 of 6 dosed patients experience a DLT but additional 3 patients will not be 
enrolled, RP2D will not be determined in the current study design.  Dose escalation will 
complete if a DLT is observed in 2 of 9 patients and the RP2D will be declared at 0.75 
mg/day. If ≥3 patients experience a DLT, no further patients will be dosed at that dose or 
higher.
Following dose escalation, 3 patients will receive 1.0 mg/day.  If a DLT is observed in >1 of 
the initial 3 dosed patients, 0.75 mg/day may be evaluated and the above dose escalation 
schema will be followed.  If a DLT is observed in ≤1 of initial 3 patients at 1.0 mg, 3 
additional patients up to a total of 6 patients will be enrolled and receive 1.0 mg/day.  In case 
a DLT is observed in 2 of 6 dosed patients, 3 additional patients up to a total of 9 patients 
will be enrolled and receive 1.0 mg/day if deemed necessary in the opinion of the sponsor 
and the investigators.  Dose escalation will complete if a DLT is observed in ≤1 of 6 patients 
or in 2 of 9 patients and the RP2D will be declared at 1.0 mg/day.  If a DLT is observed in >2 
of 9 (or 2 of 6 if 3 additional patients will not be enrolled) patients, the RP2D may be 
declared at 0.75 mg/day if 6 patients are evaluated with ≤1 DLT at 0.75 mg/day, or additional 
patients will be enrolled at 0.75 mg/day to declare the RP2D.
Patients not meeting the criteria for inclusion in the Per Protocol Analysis set defined in 
Section 4 (i.e., not evaluable for assessment of DLT) will be replaced.  The safety 


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information obtained from the patients who are excluded from the Per Protocol Analysis set 
may be used for determination of dose escalation.
Subsequent dose levels may not be used (except within a patient, see below) until all patients 
entered at the current dose level have been dosed and observed for at least one complete 
cycle, and the number of DLTs among those patients in their first cycle has been determined.
Intrapatient dose escalation may be permitted in the C3441030 study.  A patient may have 
his/her dose-escalated to the next highest dose level if all of the following conditions are 
satisfied: 

Cycle 1 was completed without any DLT;

His/her maximum talazoparib-related toxicity during prior cycles of therapy was 
Grade ≤2;

Minimum 3 patients at the highest dose level have completed Cycle 1 with talazoparib
without having DLT or 1 out of 6 or 2 out of 9; 

The decision to increase the dose has been approved by discussion with both the 
investigator and the sponsor.  A patient whose dose has been escalated will not contribute 
to the assessment of the number of DLTs at the escalated dose level.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
The primary endpoint of dose escalation part is the first-cycle DLTs as defined in Section 
3.1.1. The primary endpoint of expansin part is confirmed OR as assessed using RECIST 
version 1.1 by Investigator Assessment as defined in Section 3.2.3.
3.1.1. DLT Definition (Dose Escalation part only)
Severity of AEs will be graded according to CTCAE version 4.03.  For the purpose of dose 
escalation, any of the following AEs occurring in the first cycle of treatment including the 
PK lead-in period which are attributable to talazoparib will be classified as DLTs:
Hematologic:

Grade 4 neutropenia lasting >7 days;

Febrile neutropenia (defined as absolute neutrophil count (ANC) <1000/mm3 with a 
single temperature of >38.3 C or a sustained temperature of ≥38C for more than 1 
hour);

Grade ≥3 neutropenic infection (defined as ANC < 1000/mm3 or <1.0 x 109/L and 
Grade >3 infection);


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
Grade ≥3 thrombocytopenia associated with ≥Grade 2 hemorrhage or requiring 
transfusion;

Grade 4 thrombocytopenia;

Grade 4 anemia;

Grade 3 anemia requiring transfusion;

If daily dosing is interrupted for 7 or more total days in the first cycle for Grade 3 
neutropenia or Grade 3 thrombocytopenia.
Non-hematologic:
Any Grade ≥3 AE, except:

Non-clinically significant Grade ≥3 laboratory abnormalities;

Non-hematologic Grade ≥3 AE deemed not clinically significant;

Grade ≥3 nausea, vomiting and diarrhea that responds to medical intervention within 
72 hours;

Grade ≥3 fatigue that improves to Grade ≤2 within 7 days;
Liver toxicity:

Alanine or aspartate aminotransferase (ALT or AST) > 5×upper limit of normal 
(ULN) (a lower threshold should be considered if the ALT/AST abnormalities are 
accompanied with symptoms and signs of hepatitis) AND 2×increases above the 
baseline values;

ALT/AST ≥3×ULN concurrent with total bilirubin (TBili) >2×ULN;

TBili >5×ULN.
General toxicity:

Failure to deliver 75% of doses due to toxicities attributable to talazoparib.
3.2. Secondary Endpoint(s)
3.2.1. Safety Endpoints
Secondary safety endpoints are described in Section 3.5.
3.2.2. Pharmacokinetic Endpoints

PK parameters of talazoparib single dose if data permit (Table 2).


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Table 2.
Pharmacokinetic Parameters of Talazoparib Single Dose
Parameter
Definition
Method of Determination
Cmax
Maximum observed plasma concentration
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as 
time of first occurrence
AUClast
Area under the plasma concentration-time profile 
from time zero to the time of the last quantifiable 
concentration (Clast)
Linear/Log trapezoidal method
AUC
Area under the plasma concentration-time profile 
from time zero to time tau (τ), where τ = 24 hours for 
QD dosing
Linear/Log trapezoidal method
CL/Fa
Apparent clearance
Dose / AUCinf
Vz/Fa
Apparent volume of distribution
Dose / (AUCinf ·kel)
where kel is the terminal phase 
rate constant calculated by a linear 
regression of the log-linear 
concentration-time curve.  Only 
those data points judged to 
describe the terminal log-linear 
decline were used in the 
regression.
t½a
Terminal half-life
Loge(2)/kel,
AUCinfa
Area under the plasma concentration-time profile 
from time zero extrapolated to infinity
AUClast + (Clast*/ kel), where Clast*
is the estimated concentration at 
the time of the last quantifiable 
concentration.
AUCinf(dn)a
Dose normalized AUCinf
AUCinf / Dose
AUClast(dn)
Dose normalized AUClast
AUClast / Dose
Cmax(dn)
Dose normalized Cmax
Cmax / Dose
a If data permit

PK parameters of talazoparib multiple dose assuming that steady state is achieved if data 
permit (Table 3).
Table 3.
Pharmacokinetic Parameters of Talazoparib Multiple Dose
Parameter
Definition
Method of Determination
Css,max
Maximum observed plasma concentration (at steady 
state)
Observed directly from data
Cmin
Predose concentration during multiple dosing
Observed directly from data
Tss,max
Time for Cmax (at steady state)
Observed directly from data as 
time of first occurrence
AUCss,
Area under the plasma concentration-time profile 
from time zero to time tau (τ), where τ = 24 hours for 
QD dosing (at steady state)
Linear/Log trapezoidal method
CL/Fss
Apparent clearance (at steady state)
Dose / AUCss,
Rac
Accumulation Ratio
AUCss,/AUCsd,
Rssa
Linearity Ratio
AUCss,/AUCsd,inf
AUC(dn)
Dose normalized AUC
AUC/ Dose


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Table 3.
Pharmacokinetic Parameters of Talazoparib Multiple Dose
Parameter
Definition
Method of Determination
AUClast(dn)
Dose normalized AUClast
AUClast / Dose
Cmax(dn)
Dose normalized Cmax
Css,max / Dose
Cmin(dn)
Dose normalized Cmin
Cmin / Dose
a If data permit
3.2.3. Efficacy Endpoints
3.2.3.1. Tumor Assessment
Objective response status will be assessed by investigators at each assessment and recorded 
on the CRF using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
defined by Eisenhauer et al (2009)1.
3.2.3.1.1. Categorizing Lesion at Baseline
Measurable Lesions

Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm).

Lesions with longest diameter at least 20 mm when assessed by Chest X-ray.

Superficial lesions with longest diameter 10 mm or greater when assessed by caliper.

Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE:  The shortest axis is used as the diameter for malignant lymph nodes, longest axis for 
all other measurable lesions.
Non-measurable Lesions
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as 
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.

Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of measurability 
at baseline.

Previous local treatment:  A previously irradiated lesion (or lesion patiented to other local 
treatment) is non-measurable unless it has progressed since completion of treatment.


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Normal Sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should not 
be recorded either as target or non-target disease.  Cystic lesions thought to represent 
cystic metastases can be measurable lesions, if they meet the specific definition above.  If 
non-cystic lesions are also present, these are preferred as target lesions.

Normal nodes:  Nodes with short axis <10 mm are considered normal and should not be 
recorded or followed either as measurable or non-measurable disease.
Recording Tumor Assessments
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate.
Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study.

If two target lesions coalesce the measurement of the coalesced mass is used.  If a large 
target lesion splits, the sum of the parts is used.

Measurements for target lesions that become small should continue to be recorded.  If a 
target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be recorded.
NOTE:  When nodal lesions decrease to <10 mm (normal), the actual measurement should 
still be recorded.
Non-target Lesions
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT 
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a 
single item on the case report form (e.g., ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’).


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3.2.3.1.2. Objective Response Status at Each Assessment
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made, the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are indeterminate.
Target Lesions

Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis <10 
mm).  All target lesions must be assessed.

Partial Response (PR): Greater than or equal to 30% decrease under baseline of the sum 
of diameters of all target measurable lesions.  The short diameter is used in the sum for 
target nodes, while the longest diameter is used in the sum for all other target lesions.  All 
target lesions must be assessed.

Stable Disease (SD): Does not qualify for CR, PR or Progression.  All target lesions must 
be assessed.  Stable can follow PR only in the rare case that the sum increases by less 
than 20% from the nadir, but enough that a previously documented 30% decrease no 
longer holds.

Progressive Disease (PD): 20% increase in the sum of diameters of target measurable 
lesions above the smallest sum observed (over baseline if no decrease in the sum is 
observed during therapy), with a minimum absolute increase of 5 mm.  

Indeterminate: Progression has not been documented, and
one or more target measurable lesions have not been assessed;
or assessment methods used were inconsistent with those used at baseline;
or one or more target lesions cannot be measured accurately (e.g., poorly visible unless
    due to being too small to measure);
or one or more target lesions were excised or irradiated and have not reappeared or
    increased.
Non-target Lesions

CR: Disappearance of all non-target lesions and normalization of tumor marker levels. 
All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level above 
the normal limits. 

PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor burden 
must increase sufficiently to merit discontinuation of therapy.  In the presence of SD or 
PR in target disease, progression due to unequivocal increase in non-target disease should 
be rare.


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
Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at baseline.
New Lesions
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations

If CR determination depends on a residual lesion that decreased in size but did not
disappear completely, it is recommended the residual lesion be investigated with biopsy 
or fine needle aspirate.  If no disease is identified, objective status is CR.

If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status.
Subjective Progression
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment.
Objective Response Status
Assessment is based on the target and non-target lesions response as described in Table 4 and 
Table 5.
Table 4.
Objective Response Status at Each Assessment for Patients with Target 
Lesions at Baseline
Target Lesions
Non-target Lesions
New Lesions
Objective Status
CR
CR
No
CR
CR
Non-CR/Non-PD or 
Indeterminate
No
PR
PR
Non-PD* or 
Indeterminate
No
PR
SD
Non-PD* or 
Indeterminate
No
SD
Indeterminate
Non-PD*
No
Indeterminate
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD


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Table 4.
Objective Response Status at Each Assessment for Patients with Target 
Lesions at Baseline
Target Lesions
Non-target Lesions
New Lesions
Objective Status
Any
Any
Yes**
PD
*   Non-PD includes CR and Non-CR/Non-PD
** New lesions must be unequivocal
Table 5.
Objective Response Status at Each Assessment for Patients with Non-
target Lesions Only at Baseline
Non-target Lesions
New Lesions
Objective Status
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Indeterminate
No
Indeterminate
PD
Yes or No
PD
Any
Yes*
PD
* New lesions must be unequivocal
Date of Response
If there are multiple scan dates associated with a tumor evaluation, i.e., radiological 
assessments occur over a series of days rather than the same day, the earliest scan date 
associated with the evaluation will be used as the date of the assessment.
Time to Response (TTR)
For patients with an Objective Response (PR or CR), TTR is defined as the time from the 
first dose date to date of first documentation of Objective Response.
3.2.3.2. Best Overall Response (Confirmed Response)
The best overall response is the best response recorded from start date until disease 
progression or start of new anti-cancer therapy. The best overall response will be 
programmatically derived based on the investigator assessments of objective response status.
CR:  Two objective statuses of CR a minimum of four weeks apart documented before 
progression and start of new anti-cancer therapy.
PR:  Two objective statuses of PR or better (PR followed by PR or PR followed by CR) a 
minimum of four weeks apart documented before progression and start of new anti-cancer 
therapy, but not qualifying as CR.  Sequences of PR–SD–PR are considered PRs as long as 
the two PR responses are observed at a minimum of 4 weeks apart.
SD: At least one objective status of stable or better documented at least 6 weeks after start 
date and before progression and the start of new anti-cancer therapy but not qualifying as CR 
or PR.


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PD:  Progression documented within 16 weeks after start date and not qualifying as CR, PR 
or SD.
Not Evaluable (NE):  All other cases.  Note that reasons for NE will be summarized and the 
following reasons could be used:

Early death (Note: death prior to 6 weeks after start date)

No post-baseline assessments

All post-baseline assessments have overall response Indeterminate

New anti-cancer therapy started before first post-baseline assessment

SD too early (<6 weeks after start date)

PD too late (>16 weeks after start date)
Special and rare cases where BOR is NE due to both early SD and late PD will be classified 
as ‘SD too early’.
An objective status of PR or SD cannot follow one of CR.  SD can follow PR only in the rare 
case that tumor increases by less than 20% from the nadir, but enough that a previously 
documented 30% decrease from baseline no longer holds.  If this occurs the sequence PR–
SD–PR is considered a confirmed PR.  A sequence of PR–SD–SD–PD would be a best 
response of SD if the window for SD definition has been met.
The overall response rate (ORR) is defined as the percentage of patients with a best overall 
response of CR or PR.
The disease control rate (DCR) is defined as the percentage of patients with a best overall 
response of CR, PR, SD or Non-CR/Non-PD.
3.2.3.3. Best Overall Response (Unconfirmed Response)
Unconfirmed CR (uCR):  One objective status of CR documented before progression or start 
of new anti-cancer therapy.
Unconfirmed PR (uPR):  One objective status of PR documented before progression and start 
of new anti-cancer therapy, but not qualifying as uCR.
SD: At least one objective status of SD or better documented at least 6 weeks after start date 
and before progression and the start of new anti-cancer therapy but not qualifying as uCR or 
uPR.
PD:  Progression documented within 16 weeks after start date and not qualifying as uCR, 
uPR or SD.


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Not Evaluable (NE):  All other cases.  Note that reasons for NE will be summarized and the 
following reasons could be used: 

Early death (Note: death prior to 6 weeks after start date)

No post-baseline assessments

All post-baseline assessments have overall response Indeterminate

New anti-cancer therapy started before first post-baseline assessment

SD too early (<6 weeks after start date)

PD too late (>16 weeks after start date)
Special and rare cases where BOR is NE due to both early SD and late PD will be classified 
as ‘SD too early’.
An objective status of PR or SD cannot follow one of CR.  SD can follow PR only in the rare 
case that tumor increases by less than 20% from the nadir, but enough that a previously 
documented 30% decrease from baseline no longer holds.
The unconfirmed overall response rate (uORR) is defined as the percentage of patients with a 
best overall response of uCR or uPR.
The unconfirmed disease control rate (uDCR) is defined as the percentage of patients with a 
best overall response of uCR, uPR, SD or Non-CR/Non-PD.
3.2.3.4. Percent Change from Baseline in Sum of Diameters for Target Lesions
Percent change from baseline in sum of diameters for target lesions at each assessment based 
on investigator assessment will be derived.  Within all post-baseline assessements, the best 
(reduced) percent change from baseline in sum of diameters for target lesions will also be 
derived.
3.2.3.5. Progression Free Survival (PFS)
PFS is defined as the time from the first dose date to date of first documentation of PD or 
death due to any cause.
PD or death within 16 weeks of the last adequate tumor assessment or within 16 weeks after 
the start date will be counted as an event according to the tumor assessment date or date of 
death, as appropriate.
Censoring: Patients without an event or with an event more than 16 weeks after the last 
adequate tumor assessment will be censored on the date of the last adequate tumor 
assessment that documented no progression.  In addition, if a new anti-cancer therapy is 


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started prior to an event, the patient will be censored on the date of the last adequate tumor 
assessment that documented no progression prior to the start of the new anti-cancer therapy.
An adequate post-baseline assessment is defined as an assessment where a response of CR, 
PR, SD, Non-CR/Non-PD, or PD can be determined.  Time points where the response is 
Indeterminate or no assessment was performed will not be used for determining the 
censoring date.
Patients with no baseline tumor assessment (including patients with an inadequate baseline 
assessment) or with no adequate post-baseline tumor assessments within 16 weeks after the 
start date will be censored on the start date, unless the patient dies within 16 weeks of the 
start date,  in which case, death will be an event on date of death.
Events and censoring rules are summarized in Table 6.
Table 6.
PFS Outcome and Event Dates
Situation
Date of Progression/Censoring
Outcome
No adequate baseline assessment
Start date a
Censored a
PD or death ≤16 weeks after last 
adequate tumor assessment or ≤16 
weeks after start date
Date of PD or death
Event
PD or death >16 weeks after the last 
adequate tumor assessment b
Date of last adequate tumor 
assessment b documenting no PD 
prior to new anti-cancer therapy 
or missed assessments
Censored
No PD
New anti-cancer therapy given
a. If the patient dies ≤16 weeks after start date, the death is an event with date on death date.
b. If there are no adequate post-baseline assessments prior to the PD or death, then the time without adequate 
assessment should be measured from the start date; if the criteria were met the censoring will be on the 
start date.
Reasons for censoring should be summarized according to the categories in Table 7
following the hierarchy shown.
Table 7.
PFS Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
No adequate baseline assessment
No adequate baseline 
assessment
2
Start of new anti-cancer therapy before event.
Start of new anti-cancer 
therapy
3
Event more than 8 weeks from last adequate 
post-baseline tumor assessment/start date
Event after missing 
assessments a
4
No event and [withdrawal of consent date ≥ 
start date OR End of study (EOS) = Subject 
refused further follow-up]
Withdrawal of consent
5
No event and lost to follow-up in any 
Lost to follow-up


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Table 7.
PFS Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
disposition page 
6
No event and [EOS present OR disposition 
page for any EPOCH after screening says 
patient will not continue into any subsequent 
phase of the study] and no adequate post-
baseline tumor assessment
No adequate post-baseline 
tumor assessment
7
No event and none of the conditions in the 
prior hierarchy are met
Ongoing without an event
a.
more than 16 weeks after last adequate tumor assessment.
3.2.3.6. Duration of Response (DoR)
For patients with an objective response, DoR is the time from first documentation of PR or 
CR to date of first documentation of PD or death due to any cause.
Censoring:  Same as censoring for the definition of PFS.
3.2.3.7. Overall Survival (OS)
OS is defined as the time from the first dose date to date of death due to any cause.  
Censoring:  Patients last known to be alive are censored at date of last contact.  
The date of last contact will be derived for patients not known to have died at the analysis 
data cutoff date using the latest complete date (non-imputed) among the following:

All patient assessment dates (e.g., blood draws [laboratory, PK], vital signs, performance 
status, ECG, tumor assessments, concomitant radiation, surgery)  

Start and end dates of follow-up anti-cancer therapies 

AE start and end dates

Last date of contact where “Subject Remains in Follow-up” collected on the “Survival 
Follow-up” eCRF (do not use date of survival follow-up assessment unless status is alive)

Study drug start and end dates

Randomization date

Date of discontinuation on disposition eCRF pages (do not use if reason for 
discontinuation is lost to follow-up or death).


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3.2.3.8. Time to Response (TTR)
For patients with an OR (PR or CR), TTR is defined as the time from the first dose date to 
date of first documentation of OR in expansion part.
3.4. Baseline Variables
Baseline value will be defined as the value prior to dosing study treatment (either screening 
or lead-in visit, whichever is closer to the first dose).
Baseline characteristics including demographics, physical measurements, disease history and 
prior anti-cancer therapies described in Section 6.5.1 will be summarized according to Pfizer 
Safety Rulebook2.
3.5. Safety Endpoints
Safety endpoints will be summarized according to Pfizer Safety Rulebook2.
3.5.1. Adverse Events
An AE is considered treatment emergent relative to a given treatment if:
•
the event occurs for the first time during the effective duration of treatment and was not 
seen prior to the start of treatment, or
•
the event was seen prior to the start of treatment but increased in severity during 
treatment.
The treatment-emergent period is defined as the period of time from the date and time of the 
first dose of study drug through 30 days after the last dose (permanent discontinuation of 
study drug) or the day before initiation of a new antineoplastic therapy, whichever occurs 
first. The treatment-emergent period will be used in the summaries of treatment-emergent 
adverse events (TEAEs).
Assessment of AEs will include the type, incidence, severity (graded by investigators
according to the NCI CTCAE version 4.03), timing, seriousness, and relatedness.  AEs will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  Clustered 
MedDRA preferred term might be defined by the study team in Pfizer and documented
separately from this analysis plan.
CCI


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3.5.2. Laboratory Data
Laboratory abnormalities will be characterized by type, frequency and severity (graded by 
the NCI CTCAE, version 4.03), and timing.
Non-numerical qualifiers (with the exception of fasting flags) will not be taken into 
consideration in the derivation of NCI CTCAE criteria (e.g. hypokalemia Grade 1 and Grade 
2 are only distinguished by a non-numerical qualifier and therefore Grade 1 will not be 
derived).
Abnormalities classified according to NCI CTCAE will be described using the worst grade. 
For those parameters which are graded with two toxicities such as potassium 
(hypokalemia/hyperkalemia), the toxicities will be summarized separately. Low direction 
toxicity (e.g. hypokalemia) grades at baseline and post baseline will be set to 0 when the 
variables are derived for summarizing high direction toxicity (e.g. hyperkalemia), and vice 
versa.
For white blood cell (WBC) differential counts (total neutrophil [including bands], 
lymphocyte, monocyte, eosinophil, and basophil counts), the absolute value will be used 
when reported.  When only percentages are available (this is mainly important for neutrophils 
and lymphocytes, because the NCI CTCAE grading is based on the absolute counts), the 
absolute value is derived as follows:
Derived differential absolute count = (WBC count) × (Differential %value / 100)
If the range for the differential absolute count is not available (only range for value in % is 
available) then Grade 1 will be attributed to as follows: 

Lymphocyte count decreased

Derived absolute count does not meet Grade 2-4 criteria, and

% value < % LLN value, and

Derived absolute count  ≥800/mm3

Neutrophil count decreased

Derived absolute count does not meet Grade 2-4 criteria, and

% value < % LLN value, and

Derived absolute count  ≥1500/mm3
For calcium, NCI CTCAE grading is based on Corrected Calcium and Ionized Calcium 
(CALCIO). Corrected Calcium is calculated from Albumin and Calcium as follows


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
Corrected Calcium (mmol/L) = measured total Calcium (mmol/L) + 0.02 (40 – serum 
Albumin [g/L])
Clinically significant abnormalities will be identified by a comparison against prespecified
percentage of the normal range (e.g. >20% above the Upper Limit of Normal or >10% below 
the Lower Limit of Normal). Different laboratory tests will look for abnormalities above the 
upper normal range, or below the lower normal range, or both.
3.5.3. Vital Signs
Patients will have assessments to include weight, height, blood pressure (BP) and pulse rate,
and Eastern Cooperative Oncology Group (ECOG) performance status.  BP and pulse rate to 
be recorded in sitting position.  Height will be measured at baseline only (screening visit).
Body Mass Index (BMI) will be derived if weight and height are collected as:
2
2
)
100
/)
(
(
)
(
)
/
(
cm
Height
kg
Weight
m
kg
BMI

3.5.4. Electrocardiograms
A single 12-lead electrocardiogram (ECG) will be performed.  QT intervals will be corrected 
for heart rate (HR) (QTc) using Fridericia’s and Bazett’s correction factors:

Fridericia’s correction: 
3
/
60 HR
QT
QTcF 

Bazett’s correction: 
HR
QT
QTcB
/
60

If HR are not collected, HR will be derived by RR interval as;
HR = (60 / RR) × 1000
where HR in beats per minute (bpm) and RR interval in milli-seconds.  Then QTcF and 
QTcB will be derived using RR interval.

Fridericia’s correction: 
3
1000
/
RR
QT
QTcF 

Bazett’s correction: 
1000
/
RR
QT
QTcB 
If the QTcF is prolonged (>500 msec, i.e., CTCAE Grade ≥3), 3 consective ECGs will be 
performed approximately 2 minutes apart to determine mean QTcF interval to confirm 
presence of QTc prolongation and the ECGs should be re-evaluated by a qualified person at 
the institution for confirmation.  Additional ECGs may be performed as clinically indicated.


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The following ECG tests will be observed or derived.  Although there are observed and 
derived QTcF values, derived QTcF will be primarily used for analysis.

Observed ECG tests through eCRF

RR interval

PR interval

QRS interval

QT interval

QTc interval

QTcF interval

Derived ECG tests

QTcF interval

QTcB interval
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to releasing the database and classifications will 
be documented per standard operating procedures.
Population
Description
Enrolled
All participants who sign the informed consent document.
Full
All participants assigned to study treatment and who take at least 1 dose 
of study treatment.
Per Protocol
Per Protocol Analysis Set (PPAS) will be evaluable for RP2D and a 
subset of the Full Analysis Set (FAS) in dose escalation part only.  This 
set will exclude patients with major treatment deviations in the first 
cycle; who are not evaluable for the RP2D assessment and will be 
replaced as needed to permit RP2D estimation.  Major treatment 
deviations include:

Administration of less than 75% of the planned first cycle dose of 
talazoparib (provided that it is not due to toxicity attributable to 
talazoparib)

Administration of more than 125% of the planned first cycle dose of 
talazoparib


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Population
Description
Safety
All participants assigned to study treatment and who take at least 1 dose 
of study treatment.
Pharmacokinetic
Parameter
All enrolled participants treated who have sufficient information to 
estimate at least 1 of the pharmacokinetic parameters of interest in dose 
escalation part only.
Pharmacokinetic
Concentration
All enrolled participants who are treated and have at least 1 analyte 
concentration.
5. GENERAL METHODOLOGY AND CONVENTIONS
Primary completion date (PCD) will be the date of 24 weeks after Last Subject First Dose
(LSFD). Primary analysis up to PCD will follow the official primary database release. Final 
analysis will follow the official final database release.
5.1. Hypotheses and Decision Rules
There is no formal hypothesis testing planned for this study. In the dose escalation part, the
objective is to determine  RP2D.  The estimated RP2D will be the highest tested dose level 
with DLT rate less than 33% in at least 6 DLT-evaluable patients in the Per Protocol 
Analysis Set.  In the expansion part, the objective is to estimate ORR. If the lower limit of 
the two-sided 90% CI of confirmed ORR exceeds 18.4%, observed ORR in physician’s 
choice therapy (PCT) arm in EMBRACA study, it is considered that talazoparib shows 
clinical meaningful antitumor activity in Japanese patients with gBRCAm locally 
advanced/metastatic breast cancer.
5.2. General Methods
Unless otherwise specified, analyses and summaries will be presented by starting dose
groups and total group as follows. Total group will not be presented if there is only one 
starting dose group.

Talazoparib 0.75 mg/day

Talazoparib 1.0 mg/day

Total
5.2.1. Analyses for Binary Endpoints
The number and percent will be presented.  Unless otherwise specified, the 95% confidence 
interval (CI) for the percent will also be presented when applicable. The CI will be obtained 
using exact method (Clopper-Pearson method) based on binomial distribution.
5.2.2. Analyses for Continuous Endpoints
Appropriate descriptive statistics will be presented depending on the distribution.  In general, 
the number, mean, standard deviation will be presented.  Other descriptive statistics [e.g.


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minimum, 1st , 2nd and 3rd quartiles, maximum, standard error of the mean, coefficient of 
variation (CV), geometric mean and geometric CV] will also be presented when appropriate.
5.2.3. Analyses for Categorical Endpoints
The number and percent of each category will be presented.
5.2.4. Analyses for Time-to-Event Endpoints
Time-to-event endpoints will be descriptively summarized using the Kaplan-Meier method 
and estimated survival curves will be displayed graphically when appropriate.  Graphs will 
describe the number of participants at risk over time.  The median, quartiles, and 
probabilities of an event at particular points in time will be estimated by the Kaplan-Meier 
method.  Confidence intervals for medians and quartiles are based on the Brookmeyer-
Crowley method.  Confidence intervals for the estimated probability of an event at a 
particular time point will be generated using the Greenwood formula.
5.3. Methods to Manage Missing Data
5.3.1. Efficacy and Safety Endpoints
In general, missing values will not be imputed for efficacy and safety endpoints except for 
impuations according to standard algorithms2 or imputations provided below.
Missing or partial dates will be imputed when date is required for a calculation of duration.
Missing or Partial Death Dates
If there is a record for death, but the date is missing or is partial, it will be imputed based on 
the last contact date defined in Appendix 1.2.

If the entire date is missing, the death date will be imputed as the day after the date of last 
contact.

If the day or both day and month is missing, the death date will be imputed to the 
maximum of the full (non-imputed) day after the date of last contact and the following: 

1st day of the month and year of death, if day of death is missing OR

January 1st of the year of death, if both the day and month of death are missing.
Date of Last Dose of Study Drug
No imputation will be done for first dose date.  Date of last dose of study drug, if unknown or 
partially unknown, will be imputed as follows:

If the last date of study drug is completely missing and there is no Disposition CRF page 
and no death date, the patient will be considered to be ongoing and use the cutoff date for 
the analysis as the last dosing date.


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
If the last date of study drug is completely or partially missing and there is EITHER an 
Disposition (End of Treatment) CRF page OR a death date available (within the data 
cutoff date), then impute this date as the last dose date:

= 31DECYYYY, if only Year is available and Year < Year of min (Disposition date, 
death date) 

= Last day of the month, if both Year and Month are available and Year = Year of 
min (Disposition date, death date) and Month < Month of min (Disposition date, 
death date)

= min (Disposition date, death date), for all other cases.
Date of Start of New Anti-cancer Therapy
Incomplete dates for start date of new anti-cancer therapy will be imputed as follows and will 
be used for determining censoring dates for efficacy analyses.

The end date of new anti-cancer therapy will be included in the imputations for start date 
of new anti-cancer therapy.  If the end date of new anti-cancer therapy is

completely missing then it will be ignored in the imputations below

partially missing with only year (YYYY) available then the imputations below will 
consider 31DECYYYY as the end date of the new anti-cancer therapy

partially missing with only month and year  available then the imputations below will 
consider the last day of the month for MMMYYYY as the end date of the new anti-
cancer therapy

For patients who have not discontinued study treatment at the analysis cutoff date, last 
dose of study treatment is set to the analysis cutoff date is the imputations below

If the start date of new anti-cancer therapy is completely or partially missing then the 
imputed start date of new anti-cancer therapy is:

= 31DECYYYY, if only Year is available and Year < Year of min [max(PD date + 1, 
last dose of study treatment + 1), end date of new anti-cancer therapy]

= Last day of the month, if both Year and Month are available and

Year = Year of min [max(PD date + 1, last dose of study treatment + 1), end date 
of new anti-cancer therapy]

Month < Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]


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
= min [max(PD date + 1, last dose of study treatment + 1), end date of new anti-
cancer therapy], for all other cases.
Other Missing or Partial Dates
In compliance with the Pfizer Safety Rulebook2, imputation methods generally apply to 
partial dates as follows:

If the day of the month is missing for a start date used in a calculation, the 1st of the 
month will be used to replace the missing date.

If both the day and month are missing, the first day of the year is used.

For stop dates, the last day of the month, or last day of the year is used if the day or day 
and month are missing, respectively.
These rules are used unless the calculations result in negative time durations (e.g., date of 
resolution cannot be prior to date of onset). In these case, the resolution and onset dates will 
be the same and the duration will be set to 1 day.
5.3.2. Pharmacokinetic Endpoints
Concentrations Below the Limit of Quantification
In all data presentations (except listings), concentrations below the limit of quantification
(BLQ) will be set to zero. In listings BLQ values will be reported as “<LLQ”, where LLQ
will be replaced with the value for the lower limit of quantification.
Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set
concentrations to missing if one of the following cases is true:
1. A concentration has been collected as ND (i.e., not done) or NS (i.e., no sample);
2. A deviation in sampling time is of sufficient concern (>10% of the nominal time) or a 
concentration has been flagged anomalous by the pharmacokineticist.
Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a patient’s concentration data due to insufficient
sampling, the parameter will be coded as NC (i.e., not calculated). If PK parameter cannot 
be derived from a patient’s concentration data due to discontinuation of treatment, the 
parameter will be coded as NS (i.e., no sample).
In summary tables, statistics will be calculated by setting NC and NS values to missing; and
statistics will be presented for a particular treatment with ≥3 evaluable measurements. For
statistical analyses (i.e., analysis of variance), PK parameters coded as NC will also be set to


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missing; and analyses will not be performed for a particular parameter if more than 50% of
the data are NC.
If an individual patient has a known biased estimate of a PK parameter (due for example to
an unexpected event such as vomiting before all the compound is adequately absorbed in the
body), this will be footnoted in summary tables and will not be included in the calculation of
summary statistics or statistical analyses.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
6.1.1. First-cycle Dose-Limiting Toxicities (DLTs) in Dose Escalation part
6.1.1.1. Main Analysis

Estimand strategy: Composite (Section 2.1.1).

Analysis set: Per Protocol (Section 4).

Analysis methodology:  The number and percentage of patients who experienced DLTs 
listed in Section 3.1.1 will be presented by each dose group and total group.

Intercurrent events and missing data:  The intercurrent event is captured through the 
DLTs definition (Section 2.1.1).  Missing data is not expected.

DLTs recorded on the CRF and adverse events constituting DLTs will be listed.
6.1.1.2. Sensitivity/Supplementary Analyses
Since there are no statistical assuptions and missing data is not expected, no sensitivity and
supplementary analysis will be conducted.
6.1.2. Confirmed objective response (OR) as assessed using RECIST version 1.1 by 
Investigator Assessment in Expansion part
6.1.2.1. Main Analysis

Estimand strategy: Composite (Section 2.1.1).

Analysis set: Full Analysis Set (Section 4).

Analysis methodology:  The number, percentage and exact two-sided 90% CI of patients 
who experienced confirmed objective response as assessed using RECIST version 1.1 by 
Investigator Assessment.

Intercurrent events and missing data:  The intercurrent event is captured through the the 
variable definition (Section 3.2.3). Missing data is not expected.


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6.1.2.2. Sensitivity/Supplementary Analyses
Since there are no statistical assuptions and missing data is not expected, no sensitivity and
supplementary analysis will be conducted.
6.2. Secondary Endpoint(s)
Analyses and summaries for secondary safety endpoints are described in Section 6.6.
6.2.1. Pharmacokinetic Endpoints
6.2.1.1. Single-Dose and Steady-State Talazoparib Pharmacokinetic Analysis
Plasma PK parameters and concentrations of talazoparib will be analyzed on PK Parameter
Analysis Set and PK Concentration Analysis Set, respectively (Section 4).  Missing data will 
be treated as described in Section 5.3.2.
Dose Escalation part
Plasma PK parameters including the maximum concentration (Cmax), time to maximum 
plasma concentration (Tmax), area under the plasma concentration versus time curve (AUClast, 
AUC) and the lowest concentration observed during the dosing interval (Cmin) for 
talazoparib will be estimated using noncompartmental analysis.  If data permit or if 
considered appropriate, area under the plasma concentration versus time curve from time 0 
extrapolated to infinity (AUCinf), terminal phase half-life (t½), apparent oral clearance 
(CL/F), apparent volume of distribution (Vz/F), accumulation ratio (Rac) and linearity ratio 
(Rss) will be also estimated. The single-dose in lead in phase and steady-state PK parameters 
on Day 22 in Cycle 1 will be summarized descriptively (n, arithmetic mean, standard 
deviation (SD), coefficient of variation (CV), median, minimum, maximum, geometric mean 
and its associated CV for PK parameters except Tmax and t1/2, n, median, minimum, 
maximum for Tmax, n, arithmetic mean, SD, CV, median, minimum, maximum for t½) by 
dose, cycle and day.
Supporting data from the estimation of t½ and AUCinf will be listed by analyte where
applicable: terminal phase rate constant (kel); goodness of fit statistic from the log-linear
regression (r2); the percent of AUCinf based on extrapolation (AUCextrap%); and the first, last, 
and number of time points used in the estimation of kel. This data may be included in the 
clinical study report.
For talazoparib concentrations, concentrations will be summarized descriptively (n, mean, 
standard deviation, CV, median, minimum, maximum, geometric mean and its associated 
CV) by dose, cycle, day and nominal time.  Individual patient, median and mean profiles of 
the concentration-time data will be plotted by dose, cycle and day (single dose and steady 
state) using nominal times.  Individual, median and mean profiles will be presented on both 
linear-linear and log-linear scales.
Dose normalized AUCinf (AUCat steady state), AUClast, Cmax and Cmin (only at steady state)
will be plotted against dose by cycle and day.  These plots will include individual patient 


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values and the geometric means for each dose.  These plots will be used to help understand 
the relationship between the PK parameters and dose.
The observed accumulation ratio and the linearity ratio will be summarized descriptively.
Trough concentrations will be plotted for each dose using a box-whisker plot by cycle and 
day within cycle.
All the concentration data will be listed but the concentrations deviated more than 10% from 
the planned time will not be included in summarization.
Expansion part
Trough concentrations (Ctrough) at steady-state will be summarized descriptively (n, arithmetic 
mean, SD, CV, median, minimum, maximum, geometric mean and its associated CV) by 
cycle and day (if the data permits, by each dose). Ctrough at steady-state will be plotted for 
each dose using a box whisker plot by cycle and day. Individual mean Ctrough values of all 
cycles will be calculated, and then the geometric mean and geometric %CV will be provided.
Ctrough at steady-state is defined as the pre-dose concentration that meets the following dose-
compliant acceptance criteria:
•
Patient must have received 7 consecutive days at the same dose of talazoparib once daily 
prior to the pre-dose PK sampling.
•
PK samples must have been collected 24 hours ±10% after the dose administered the day 
prior to the pre-dose PK sampling.
6.2.1.2. Population Pharmacokinetic Analysis or Pharmacokinetic/Pharmacodynamic 
(PK/PD) Modeling
PK and PD data from this study may be analyzed using modeling approaches and may also 
be pooled with data from other studies to investigate any association between talazoparib 
exposure 
 or significant safety and/or efficacy endpoints.  The results of these 
analyses, if performed, may be reported separately.
6.2.2. Efficacy Endpoints
6.2.2.1. Objective Response
Objective responses will be analyzed on the Full Analysis Set (Section 4).
Dose Escalation part
The number and percent of the each unconfirmed best overall response and each reason for 
NE will be presented.  The number, percent and its exact 95% CI of the unconfirmed overall 
response and unconfirmed disease control will be presented, respectively.
CCI


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The best percent change from baseline in sum of diameters for target lesions based on
investigator assessment will be plotted in bar chart sorted in descending order from positive
(increased) to negative (decreased).
All tumor measurements and assessments based on investigator assessment will be presented 
in the form of patient data listings that include, but are not limited to, evaluation date, lesion 
type, lesion number, disease site, lesion site, lesion assessment and procedure.
All objective tumor assessments based on investigator assessment will be presented in the 
form of patient data listings that include, but are not limited to, evaluation date, response 
parameter (e.g. sum of diameters for target, target response, non-target response, new lesion 
progression, overall response and best overall response) and assessment result.
All derived tumor assessments and responses based on investigator assessment will be listed.
Expansion part
The number and percent of the each confirmed and unconfirmed best overall response and 
each reason for NE based on investigator assessment and BICR assessment will be presented, 
respectively. The number, percent and its exact 90% CI of the confirmed and unconfirmed 
overall response and confirmed and unconfirmed disease control (overall, at 16 weeks and 24 
weeks) will be presented, respectively.  
The best percent change from baseline in sum of diameters for target lesions based on
investigator assessment and BICR assessment will be plotted in bar chart sorted in 
descending order from positive (increased) to negative (decreased), respectively.
All tumor measurements and assessments based on investigator assessment and BICR 
assessment will be presented in the form of patient data listings that include, but are not 
limited to, evaluation date, lesion type, lesion number, disease site, lesion site, lesion 
assessment and procedure.
All objective tumor assessments based on investigator assessment and BICR assessment will 
be presented in the form of patient data listings that include, but are not limited to, evaluation 
date, response parameter (e.g. sum of diameters for target, target response, non-target 
response, new lesion progression, overall response and best overall response) and assessment 
result.
All derived tumor assessments and responses based on investigator assessment and BICR 
assessment will be listed.
6.2.2.2. Time to Response (TTR)
TTR based on investigator assessment and BICR assessment will be analyzed on the patients
with confirmed CR or PR in the Full Analysis Set (Section 4) in expansion part.  


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6.2.2.3. Duration of Response (DoR)
DoR based on investigator assessment and BICR assessment (expansion part only) will be 
analyzed on the patients with unconfirmed CR or PR (dose escalation part) and confirmed 
CR or PR (expansion part) in the Full Analysis Set (Section 4).  The number and percent of 
event (PD or death) and censord will be presented.  The probability of being event-free at 3, 
6, 9 and 12 months will be presented with its 95% CI.  The estimated survival curves will be 
displayed graphically using Kaplan-Meier method.
Time to response and DoR based on investigator assessment and BICR assessment 
(expansion part only) will be presented in the form of patient data listings that include, but 
are not limited to, first dose date, date of first response, time to response, date of event or 
censoring, time to event or censoring, event type/censor and reason for censoring.
6.2.2.4. Progression Free Survival (PFS)
PFS based on investigator assessment and BICR assessment (expansion part only) will be 
analyzed on the Full Analysis Set (Section 4).  The number and percent of event (PD or 
death) and censord will be presented.  The probability of being event-free at 6, 12 and 18
months will be presented with its 95% CI.  The estimated survival curves will be displayed 
graphically using Kaplan-Meier method.
PFS based on investigator assessment and BICR assessment (expansion part only) will be 
presented in the form of patient data listings that include, but are not limited to, first dose 
date, date of event or censoring, time to event or censoring, event type/censor and reason for 
censoring.
6.2.2.5. Overall Survival (OS)
OS will be analyzed on the Full Analysis Set (Section 4) in expansion part. The number and 
percent of event (death) and censord will be presented.  The probability of being event-free at 
12 months will be presented with its 90% CI. The estimated survival curves will be displayed 
graphically using Kaplan-Meier method.
OS will be presented in the form of patient data listings that include, but are not limited to, 
start date, date of event or censoring, time to event or censoring, event type/censor and 
reason for censoring.
CCI


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6.4. Subset Analyses
None
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
Following data will be summarized and listed on the Full Analysis Set (Section 4).

Demographic characteristics

Age (years)

Age in adult age categories; <18, 18-44, 45-64, ≥65 years

Gender; Male, Female

Race

Ethnicity

Physical measurements

Weight (cm)

Height (kg)

BMI (kg/m2)

ECOG performace status

General medical histories (coded by MedDRA preferred term; conditions are either 
Before or Ongoing)

Disease characteristics

Primary diagnosis (coded by MedDRA preferred term)

Base of primary diagnoses

Histopathological grade; 1, 2, 3, 4, not reported (dose escalation part only)

Disease recurrence type (dose escalation part only)

Number of prior systemic medications; 0, 1, 2, 3, ≥4 regimens

Number of prior adjuvant and neo-adjuvant medications; 0, 1, 2, 3, ≥4 regimens


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
Measurable disease by investigator assessment; yes, no, no disease

Number of involved target tumor sites by investigator assessment; 1, 2, 3, ≥4 sites

Number of involved non-target tumor sites by investigator assessment; 1, 2, 3, ≥4 
sites

Time since initial diagnosis (months)

HER2 status; positive, negative (expansion part only)

BRCA status; positive (BRCA1, BRCA2), negative (expansion part only)

Prior therapies

Prior cancer therapy for primary diagnosis (coded by WHODrug preferred term)

Prior radiation therapy (coded by MedDRA preferred term)

Prior surgery (coded by MedDRA preferred term)
6.5.2. Study Conduct and Participant Disposition
Subject evaluation groups as shown below will be summarized and listed on the Enrolled 
population (Section 4).

Not screen failure but not assigned

Assigned to treatment

Treated

Not treated

Full Analysis Set

Per Protocol Analysis Set (dose escalation part only)

Safety Analysis Set

Pharmacokinetic Parameter Analysis Set (dose escalation part only)

Pharmacokinetic Concentration Analysis Set
Inclusion and exclusion criteria and patients dispositions will be summarized and listed on 
the Enrolled population (Section 4).


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6.5.3. Study Treatment Exposure
Study treatment exposure will be analyzed and listed on the Safety Analysis Set (Section 4).

Duration of treatment (days): sum of the actual dosing day

Total number of cycles started in each cohort

Number of cycles started by patients

Patients with maximum cycle started; 1, 2, 3, 4, ≥5 cycles

Patients with at least one dose interruption

Maximum dose interruption in patients with at least one dose interruption;
<1, 1 −<2, 2 −<3, ≥3 weeks

Cumulative dose (mg): sum of the actual doses received in overall cycles

Actual dose intensity (mg/day): the actual total dose divided by the actual number of days

Relative dose intensity (%): the actual dose intensity divided by the intended dose

Dose reductions due to any cause: no dose reduction; 1, 2, 3 dose level.  Dose reduction 
is defined as non-zero dose less than the planned dose.  The loweset dose level in overall 
treatment period will be summarized.  One dose level is defined as 0.25 mg/day.
6.5.4. Concomitant Medications and Nondrug Treatments
Following data will be summarized and listed on the Safety Analysis Set (Section 4).

Concomitant medications (coded by WHODrug preferred term)

Concomitant nondrug treatments / procedures (coded by MedDRA preferred term)

Follow-up cancer therapies (coded by WHODrug preferred term)

Follow-up radiation therapies (coded by MedDRA preferred term)

Follow-up surgeries (coded by MedDRA preferred term)
6.6. Safety Summaries and Analyses
All safety endpoints will be analyzed on the Safety Analysis Set (Section 4).
6.6.1. Adverse Events
The focus of AE summaries will be on Treatment Emergent Adverse Events (TEAEs) as 
defined in Section 3.5.1.


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Unless otherwise specified, AEs will be summarized by number and percentage of patients 
with the AE in the category of interest, by treatment group, primary System Organ Class
(SOC) and Preferred Term (PT).
Each patient will be counted only once within each SOC or PT. If a patient experiences more 
than one AE within a SOC or PT for the same summary period, only the AE with the 
strongest relationship or the worst grade will be included in the summaries of relationship 
and grade.
In case a patient has events with missing and non-missing grades, the maximum of the non-
missing grades will be displayed. No imputation of missing grades will be performed.
The following tables will be created by relationship (all causalities and treatment related):

The overall summary of TEAEs table will include the number and percentage of patients 
with each of the following:

Any AEs

Serious AEs

Maximum grade 3 or 4 AEs

Maximum grade 5 AEs

AEs leading to discontinuation of study

AEs leading to discontinuation of study drug and continue study

AEs leading to interruption (temporary discontinuation) of study drug

AEs leading to dose reduction of study drug

TEAEs by SOC and PT, and maximum grade

TEAEs by decreasing frequency of PT with selected cluster terms
The following individual listings will be created:

Deaths

Serious AEs

All AEs

AEs leading to discontinuation of study


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
AEs leading to discontinuation of study drug and continue study

AEs leading to interruption (temporary discontinuation) of study drug

AEs leading to dose reduction of study drug

Medication errors
6.6.2. Laboratory Data
6.6.2.1. Parameters with NCI CTCAE Grades Available
The laboratory toxicities will be tabulated using descriptive statistics (number of patients and 
percentages) during the on-treatment period. The denominator to calculate percentages for 
each laboratory parameter is the number of patients evaluable for NCI CTCAE grading (i.e.
those patients for whom a Grade 0, 1, 2, 3 or 4 can be derived).

The summary of laboratory parameters by NCI CTCAE grade table will include number 
and percentage of patients with Grade 0, 1, 2, 3, 4 and Total, laboratory abnormalities 
during the on-treatment period.

The shift table will summarize baseline NCI CTCAE grade versus the worst on-treatment 
NCI CTCAE grade. The highest NCI CTCAE grade during the on-treatment period is 
considered as the worst grade for the summary.
Individual patients laboratory data listing will also be created with NCI CTCAE grading.
The above analyses apply to hematology and chemistry evaluations which can be graded per 
NCI CTCAE:

Hematology: 
Hemoglobin, Leukocytes (white blood cell decreased), Lymphocytes (lymphocyte count 
increased/decreased), Neutrophils / Absolute Neutrophils Count (ANC) (neutrophil count 
decreased), Platelet Count (PLT) (platelet count decreased).

Serum Chemistry:
Albumin (hypoalbuminemia), Alkaline Phosphatase (alkaline phosphatase increased), 
Alanine Aminotransferase (ALT) (ALT increased), Amylase (serum amylase increased), 
Aspartate Aminotransferase (AST) (AST increased), Total Bilirubin (blood bilirubin 
increased, Cholesterol (cholesterol high), Creatinine (creatinine increased), Creatine 
Kinase 
(CPK
increased), 
Potassium 
(hypokalemia/ 
hyperkalemia), 
Sodium 
(hyponatremia/ 
hypernatremia), 
Magnesium 
(hypomagnesemia/hypermagnesemia), 
Calcium (hypocalcemia/ hypercalcemia), Glucose (hypoglycemia/hyperglycemia), 
Gamma Glutamyl Transferase (GGT) (GGT increased), Lipase (lipase increased), 
Phosphates (hypophosphatemia), Triglycerides (hypertriglyceridemia).


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6.6.2.2. Laboratory Assessment by Visit
Logitudinal absolute values and change from baseline values will be summarized and plotted 
in line graph with mean and 95% CI by visit in the following laboratory tests:

Hematology:  Hemoglobin, Leukocytes, Neutrophils and Platelets

Chemistry:  ALT, AST and Creatinine
6.6.2.3. Assessment of Possible Drug-Induced Liver Injury (DILI)
ALT, AST and total bilirubin (TBILI) during the on-treatment period are used to assess 
possible DILI. Multiples of upper limit of normal will be derived for each record.  Maximum 
multiples of ALT or AST versus TBILI will be plotted in scatter plot as known the evaluation 
of Drug-Induced Serious Hepatotoxicity (eDISH) plot.
6.6.2.4. Clinically Significant Abnormalities
The most abnormal values that met clinically significant abnormality criteria for each test
will be listed by subject.
6.6.3. Vital Signs
For each vital sign assessment, actual and change from baseline values will be summarized 
by visit.  The number and percentage of patients with vital sign values in specific categories
(e.g., parameter measurements above or below a certain critical value) will be summarized
(Table 8).
Table 8.
Vital Signs Abnormal Categories (Position: Sitting)
Parameter (Unit)
Criteria
Systolic Blood Pressur (mmHg)
Value <90
Change ≥30 increase
Change ≥30 decrease
Diastolic Blood Pressure (mmHg)
Value <50
Change ≥20 increase
Change ≥20 decrease
Pulse Rate (beats/minite)
Value <40
Value >120
All vital sign values described above will be listed.
6.6.4. Electrocardiograms
ECG measurements collected at nominal time-points will be used for the statistical analysis 
by visit.  Any data obtained from ECGs repeated for safety reasons after the nominal 
time-points will not be averaged along with the preceding measurements.  Interval 
measurements (e.g., triplicate measurements) from repeated ECGs will be included in the 
outlier analysis (categorical analysis) and shift table analysis of notable QTc parameters as 
individual values obtained at unscheduled time points.


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Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) will be 
used to summarize the absolute values, changes from baseline and maximum change from 
baseline values by visit.  Categorical analysis will be conducted for the individual values and 
maximum increase from baselin values, respectively (Table 9).
Table 9.
Electrocardiograms Abnormal Categories (Unit: msec)
Parameter
Criteria
Parameter
Criteria
PR interval
Value ≥300
QT interval
Value ≥500
%Change ≥25/50% a
QTc/QTcB/QTcF 
450≤Value <480
QRS interval
Value ≥200 (<18 Years)
interval
480≤Value <500
Value ≥140 (18-44 Years)
Value ≥500
Value ≥140 (45-64 Years)
30≤Change <60
Value ≥140 (≥65 Years)
Change ≥60
%Change ≥25/50% (<18 Years) b
%Change ≥50% (18-44 Years)
%Change ≥50% (45-64 Years)
%Change ≥50% (≥65 Years)
a.  Patients with Baseline value >200 or Baseline value ≤200, respectively
b.  Patients with Baseline value ≥100 or Baseline value <100, respectively
Shift tables will be provided for baseline versus worst on-treatment QTc resutls (i.e., QTc, 
QTcF and QTcB) using maximum NCI CTCAE grade.
All ECG interval values (observed and derived) and qualitative ECG abnormalities will be 
listed.
6.6.5. Physical Examination
The findings in physical examination at screening visit will be listed by body system.  Also 
post-baseline physical examination date will be listed.
6.6.6. ECOG Performance Status
The ECOG performance status shift from baseline to highest score during the on-treatment 
period will be summarized. ECOG performance status with shift from ECOG=0 or 1 to 
ECOG 2 or higher will also be presented in a data listing.
7. INTERIM ANALYSES
7.1. Introduction
There are no planned interim analyses.  As this is an open-label to the investigators, patients 
and the Pfizer study team and uncontrolled study, interim analyses may be performed for 
study monitoring for internal decision making, application for approval or due to regulatory 
requests.  There will be no need for unblinding and there are no issues of protecting the type 
1 error rate.
7.2. Interim Analyses and Summaries
Not applicable


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8. REFERENCES
1.
Eisenhauer E, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J,
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R,
Lacombe D, Verweij J. New response evaluation criteria in solid tumors: Revised
RECIST guideline version 1.1. Eur J Can 2009; 45:228-47.
C
C
C
C


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9. APPENDICES
Appendix 1. Data Derivation Details
Appendix 1.1. Definition and Use of Visit Windows in Reporting
Visit windows will be used for any variables (e.g. laboratory tests, vital signs, ECGs) except 
PK measurements that display by visit (dose escalation part only).  In general, Baseline visit 
will be displayed.  Screening and Lead-in visits will be displayed, if appropriate.
Visit Label
Target Day
Definition
[Day window]
Dose Escalation part
Screening
Study Day -1
≤28 days prior to Lead-in
[Study Day -28 to -1]
Lead-in
Study Day 1
Dosing day in Lead-in
[Study Day 1]
Baseline
Study Day 1
Dosing start day in Study (i.e. Lead-in)
[Study Day -28 to 1]
Cycle 1 Day 1
Cycle Day 1
Dosing start day in Cycle 1
[Cycle Day -1 to 1]
Cycle 1 Day 8
Cycle Day 8
[Cycle Day 7 to 9]
Cycle 1 Day 15
Cycle Day 15
[Cycle Day 14 to 16]
Cycle 1 Day 22
Cycle Day 22
[Cycle Day 21 to 23]
Cycle 2 Day 1
Cycle Day 1
Dosing start day in Cycle 2
[Cycle Day 1 to 3]
Cycle ≥3 Day 1
Cycle Day 1
Dosing start day in Cycle ≥3
[Cycle Day -2 to 3]
EoT
Not Applicable
End of Treatment
Expansion part
Screening
Study Day -1
≤28 days prior to Lead-in
[Study Day -28 to -1]
Baseline
Study Day 1
Dosing start day in Study
[Study Day -28 to 1]
Cycle 1 Day 1
Cycle Day 1
Dosing start day in Cycle 1
[Cycle Day -3 to 1]
Cycle 1 Day 15
Cycle Day 15
[Cycle Day 12 to 18]
Cycle 2 Day 1
Cycle Day 1
Dosing start day in Cycle 2
[Cycle Day -3 to 1]
Cycle 2 Day 15
Cycle Day 15
[Cycle Day 12 to 18]
Cycle ≥3 Day 1
Cycle Day 1
Dosing start day in Cycle ≥3
[Cycle Day -3 to 1]


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Visit Label
Target Day
Definition
[Day window]
EoT
Not Applicable
End of Treatment
NOTE:  If two or more visits fall into the same window, keep the one closest to the Target Day.  If 
two visits are equal distant from the Target Day in absolute value, the later visit should be used.


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Visit windows will be used for PK measurements in dose escalation part.
Period
Visit Label
Time Post Dose
Definition
[Hour window]
Single Dose
Lead-in Day -7
0 Hour
Predose
[No allowance]
Lead-in Day -7
0.5 Hour
[within 10% of the 
nominal time (e.g., within 
6 minutes of a 60-minute 
sample)]
Lead-in Day -7
0.75 Hour
Lead-in Day -7
1 Hour
Lead-in Day -7
2 Hours
Lead-in Day -7
3 Hours
Lead-in Day -7
4 Hours
Lead-in Day -7
6 Hours
Lead-in Day -7
8 Hours
Lead-in Day -7
10 Hours
Lead-in Day -6
24 Hours
Lead-in Day -5
48 Hours
Lead-in Day -4
72 Hours
Lead-in Day -3
96 Hours
Cycle 1 Day 1
168 Hours
Cycle 1 Day 15
0 Hour
Predose
[No allowance]
Multiple Dose
Cycle 1 Day 22
0 Hour
Predose
[No allowance]
Cycle 1 Day 22
0.5 Hour
[within 10% of the 
nominal time (e.g., within 
6 minutes of a 60-minute 
sample)]
Cycle 1 Day 22
0.75 Hour
Cycle 1 Day 22
1 Hour
Cycle 1 Day 22
2 Hours
Cycle 1 Day 22
3 Hours
Cycle 1 Day 22
4 Hours
Cycle 1 Day 22
6 Hours
Cycle 1 Day 22
8 Hours
Cycle 1 Day 22
10 Hours
Cycle 1 Day 23
24 Hours
Cycle 3 Day 1
0 Hour
Predose
[No allowance]
Cycle 4 Day 1
0 Hour
Predose
[No allowance]


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Appendix 1.2. Date of Last Contact
The date of last contact will be derived for patients not known to have died at the analysis 
data cutoff date using the latest complete date (non-imputed) among the following:

All patient assessment dates (e.g., blood draws [laboratory, PK], vital signs, performance 
status, electrocardiogram, tumor assessments)

Start and end dates of follow-up anti-cancer therapies including radiation and surgery

Adverse event start and end dates

Study drug start and end dates

First dose date

Date of discontinuation on disposition CRF pages (do not use if reason for 
discontinuation is lost to follow-up or death).
NOTE:

Only dates associated with patient visits or actual examinations of the patient will be 
used.  Dates associated with a technical operation unrelated to patient status (e.g., the date 
a blood sample was processed) will not be used.

Assessment dates after the cutoff date will not be applied to derive the last contact date.