Clinical trial NCT02997163
Conditions: Advanced Solid Tumors
Sponsor: Pfizer
Start date: 2017-02-21; Completion date: 2019-01-30
Enrollment: 34 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial will investigate the pharmacokinetics (PK) and safety of talazoparib in patients with advanced solid tumors and impaired renal function.

Detailed description:
At the End of the Study, patients with no clinically significant toxicities, no contraindications to continue treatment with talazoparib, and no disease progression (underlying cancer progression) may be eligible to continue talazoparib treatment in a separate open-label extension study after discussion with the Principal Investigator and obtaining Sponsor permission. Sponsor decision to allow the patient to continue dosing with talazoparib in an open-label extension study will be based on potential overall benefit-risk, patient acceptance and other relevant criteria.

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: Talazoparib
Intervention descriptions: intervention 1: Daily oral doses of talazoparib 0.5 mg

Protocol documents:
Prot_000.pdf: 
MDV3800-01/
 Protocol Version 2.0 Final 31-Aug-2018 
 
 
 
Page 1 
 
               
 
 
A wholly-owned subsidiary of Pfizer Inc. 
 
 
525 Market Street, San Francisco, CA 94105 
 
 
A Phase I Open-Label Pharmacokinetics and Safety Study of 
Talazoparib (MDV3800) in Patients With Advanced Solid Tumors and 
Normal or Varying Degrees of Renal Impairment 
 
 
MEDIVATION PROTOCOL: MDV3800-01 
PFIZER PROTOCOL: C3441001 
 
 
 
 
 
Pfizer Medical Monitor 
 MD  
 
 
 
      Protocol Version / Date  
            2.0 / Final 31-Aug-2018 
           Phase 
I 
Test Compound 
Talazoparib (PF-06944076; formerly known as MDV3800 or BMN673) 
Indication 
Advanced solid tumors  
Sponsor  
Medivation, Inc. 
EUDRACT # 
2016-002536-33 
IND # 
 
 
 
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MDV3800-01/C3441001/
 Protocol v. 2.0 – Rationale for Amendment 
Version 2.0 of the protocol is an amendment applicable to all sites and performed in order to clarify 
protocol language and to include new pharmacokinetic data for talazoparib.  
Additionally, some administrative changes have been included regarding the Pfizer and 
 teams.  
The MDV3800-01/C3441001/
 protocol was amended as follows: 
 
Document 
Version Date 
Summary of changes 
Protocol version 2.0 
31 Aug 2018 
x INVESTIGATORS: update of the  number of sites based on 
the current active sites. 
x 
 AND PFIZER TEAM: administrative changes in teams 
conformation and signature page. 
x LIST 
OF 
ABBREVIATIONS: 
inclusion 
of 
additional 
abbreviations. 
x PROTOCOL SYNOPSIS: update of sections Study Duration, 
Participating 
Investigational 
sites, 
Background 
andRrationale, definition of Evaluability, Eligibility criteria, 
PK assessments and Statistical methods. 
x SECTION 2. BACKGROUND AND RATIONALE: update of 
language as per the most recent version of Talazoparib IB. 
x SECTION 4. STUDY DESIGN: revision of language for 
clarification. 
x SECTION 5. PATIENT SELECTION: revision of wording to 
include updated talazoparib wash out period in females 
and males. 
x SECTION 6. STUDY TREATMENT: update of language for 
clarification. 
x TABLE 6. INSTRUCTIONS FOR USE OF CONCOMITANT 
THERAPIES: addition of medications previously included in 
Section 6.2 Potential Interactions between Talazoparib 
and Concomitant Medications in this table.  
x TABLE 7. SCHEDULE OF VISITS AND ASSESSMENTS: 
revision of language for clarification. 
x SECTION 8. AE REPORTING: update of language for 
clarification and addition of section “Medication Error”. 
x TABLE 9. AE REPORTING REQUIREMENTS: update of 
language for clarification. 
x TABLE 
11. 
MEDICATION 
ERROR 
REPORTING 
REQUIREMENTS: update of language for clarification. 
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x SECTION 9. STATISTICAL CONSIDERATIONS: revision of 
Population for Analyses. 
x SECTION 10. ADMINISTRATIVE, ETHICAL AND 
REGULATORY STANDARDS: revision of the section eData 
Protection”. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................................................. 11 
PROTOCOL SYNOPSIS .................................................................................................................................. 15 
1. 
BACKGROUND AND RATIONALE ......................................................................................................... 27 
1.1. 
Investigational Medicinal Product Overview .............................................................................. 27 
1.1.1. 
Background ......................................................................................................................... 27 
1.1.2. 
Clinical Study Findings with Talazoparib ............................................................................. 27 
1.1.3. 
Pharmacokinetics of Talazoparib ........................................................................................ 28 
1.2. 
Study Rationale ........................................................................................................................... 29 
1.2.1. 
Rationale for Conducting the Study .................................................................................... 29 
1.2.2. 
Rationale for Regimen and Dose Selection ......................................................................... 30 
2. 
OBJECTIVES ......................................................................................................................................... 30 
2.1. 
Primary Objective........................................................................................................................ 30 
2.2. 
Secondary Objective ................................................................................................................... 30 
3. 
STUDY DESIGN..................................................................................................................................... 30 
4. 
PATIENT SELECTION ............................................................................................................................ 33 
4.1. 
Inclusion Criteria ......................................................................................................................... 33 
4.2. 
Exclusion Criteria ......................................................................................................................... 35 
5. 
STUDY TREATMENT ............................................................................................................................. 37 
5.1. 
Study Treatment Identification ................................................................................................... 37 
5.2. 
Investigational Product Information and Management ............................................................. 37 
5.2.1. 
Packaging and Labelling ...................................................................................................... 37 
5.2.2. 
Storage and Dispensation ................................................................................................... 37 
5.2.3. 
Accountability, Return and Destruction.............................................................................. 37 
5.3. 
Study Treatment Administration ................................................................................................ 38 
5.3.1. 
Dosage and Administration ................................................................................................. 38 
5.3.2. 
Treatment Compliance ....................................................................................................... 39 
5.3.3. 
Treatment Duration ............................................................................................................ 39 
5.4. 
Treatment Schedule Adjustment and Adverse Event Management .......................................... 39 
5.4.1. 
General Rules ...................................................................................................................... 39 
5.4.2. 
Dose Modification Due to Adverse Events ......................................................................... 40 
5.4.2.1. 
Assessment of Abnormal Non Liver Tests ................................................................... 40 
5.4.2.2. 
Assessment of Abnormal Liver Tests .......................................................................... 41 
5.5. 
Study Treatment Discontinuation ............................................................................................... 45 
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6. 
CONCOMITANT TREATMENT AND PROCEDURES ............................................................................... 45 
6.1. 
Allowed Concomitant Treatments .............................................................................................. 45 
6.2. 
Concomitant Medication for Treatment of Renal Impairment .................................................. 46 
6.3. 
Prohibited Treatments ................................................................................................................ 46 
6.4. 
Palliative Radiotherapy ............................................................................................................... 48 
6.5. 
Contraception/Reproductive Consideration ............................................................................... 48 
6.5.1. 
Females ............................................................................................................................... 48 
6.5.2. 
Males ................................................................................................................................... 49 
7. 
STUDY VISITS AND ASSESSMENTS ....................................................................................................... 49 
7.1. 
Patient Inclusion ......................................................................................................................... 49 
7.1.1. 
Informed Consent ............................................................................................................... 49 
7.1.2. 
Patient Enrollment .............................................................................................................. 50 
7.2. 
Schedule of Visits and Assessments ............................................................................................ 50 
7.3. 
Study Visits .................................................................................................................................. 54 
7.3.1. 
Screening Period ................................................................................................................. 54 
7.3.2. 
Enrollment Period ............................................................................................................... 54 
7.3.3. 
Treatment Period ................................................................................................................ 55 
7.3.4. 
Safety Follow Up Visit (End of Study Visit) .......................................................................... 55 
7.3.5. 
Follow-Up ............................................................................................................................ 55 
7.4. 
Description of Study Assessments .............................................................................................. 55 
7.4.1. 
Demographics and Medical History .................................................................................... 55 
7.4.2. 
Physical Examination and Vital Signs .................................................................................. 55 
7.4.3. 
ECG ...................................................................................................................................... 55 
7.4.4. 
ECOG Performance Status .................................................................................................. 56 
7.4.5. 
Laboratory Safety Assessments .......................................................................................... 56 
7.4.6. 
Efficacy Assessments ........................................................................................................... 56 
7.4.7. 
PK Assessments ................................................................................................................... 56 
7.4.7.1. 
Blood PK samples ........................................................................................................ 57 
7.4.7.2. 
Urine PK samples ........................................................................................................ 57 
7.4.7.3. 
Blood samples for plasma protein binding evaluation ............................................... 57 
7.5. 
Permanent Patient Discontinuation ........................................................................................... 60 
8. 
ADVERSE EVENT REPORTING .............................................................................................................. 60 
8.1. 
Requirements .............................................................................................................................. 60 
8.1.1. 
Additional Details On Recording Adverse Events on the CRF ............................................. 62 
8.1.2. 
Eliciting Adverse Event Information .................................................................................... 62 
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8.1.3. 
Withdrawal From the Study Due to Adverse Events (see sections 5.5 and 7.5)................. 62 
8.1.4. 
Time Period for Collecting AE/ Information ........................................................................ 62 
8.1.4.1. 
Reporting SAEs to Pfizer Safety ................................................................................... 63 
8.1.4.2. 
Recording Non-serious AEs and SAEs on the CRF ....................................................... 63 
8.1.5. 
Causality Assessment .......................................................................................................... 64 
8.1.6. 
Sponsor’s Reporting Requirements to Regulatory Authorities .......................................... 64 
8.2. 
Definitions ................................................................................................................................... 64 
8.2.1. 
Adverse Events .................................................................................................................... 64 
8.2.2. 
Adverse Event of Special Interest (AESI) ............................................................................. 65 
8.2.3. 
Abnormal Test Findings....................................................................................................... 65 
8.2.4. 
Serious Adverse Events ....................................................................................................... 65 
8.2.5. 
Hospitalization .................................................................................................................... 66 
8.3. 
Severity Assessment ................................................................................................................... 67 
8.4. 
Special Situations ........................................................................................................................ 67 
8.4.1. 
Potential Cases of Drug-Induced Liver Injury ...................................................................... 67 
8.4.2. 
Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure ....................................................................................................................... 69 
8.4.2.1. 
Exposure During Pregnancy ........................................................................................ 69 
8.4.2.2. 
Exposure During Breastfeeding................................................................................... 70 
8.4.2.3. 
Occupational Exposure ............................................................................................... 70 
8.4.3. 
Medication Errors ............................................................................................................... 71 
9. 
STATISTICAL CONSIDERATIONS ........................................................................................................... 71 
9.1. 
Populations for Analyses ............................................................................................................. 72 
9.2. 
Demographics and Screening Characteristics ............................................................................. 72 
9.3. 
Protocol Treatment ..................................................................................................................... 72 
9.4. 
Safety Endpoints ......................................................................................................................... 72 
9.5. 
Pharmacokinetics Endpoints ....................................................................................................... 72 
9.6. 
Efficacy Endpoints ....................................................................................................................... 74 
9.7. 
Sample Size ................................................................................................................................. 74 
10. 
ADMINISTRATIVE, ETHICAL AND REGULATORY STANDARDS ......................................................... 75 
10.1. 
Study Committee .................................................................................................................... 75 
10.2. 
Ethical Conduct of the Study ................................................................................................... 75 
10.3. 
Institutional Review Board (IRB) ............................................................................................. 75 
10.4. 
Compliance with the Protocol and Protocol Amendments .................................................... 75 
10.5. 
Monitoring, Auditing and Inspecting ...................................................................................... 76 
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10.6. 
Recording, Processing and Retention of Data ........................................................................ 76 
10.7. 
Data Protection ....................................................................................................................... 77 
10.8. 
Withdrawal of Informed Consent for Submitted PK Samples ................................................ 77 
10.9. 
Insurance of Liabilities ............................................................................................................ 77 
10.10. 
Use of Information and Publication ........................................................................................ 77 
11. 
REFERENCES .................................................................................................................................... 79 
12. 
APPENDICES .................................................................................................................................... 81 
APPENDIX 1: Eastern Cooperative Oncology Group Performance Status Scale ......................................... 81 
 
LIST OF TABLES 
Table 1: AE grading for toxicities when the AE term is not listed in NCI CTCAE ......................................... 39 
Table 2: Talazoparib Treatment Adjustment for Non Liver Test Abnormalities ......................................... 41 
Table 3: Criteria for Temporary Withholding Talazoparib in Association with Liver Test Abnormalities... 42 
Table 4: Investigations of Alternative Causes for Abnormal Liver Tests..................................................... 43 
Table 5: Monitoring of Liver Tests for Potential Drug-Induced Liver Injury ............................................... 44 
Table 6: Instructions for Use of Concomitant Therapies ............................................................................ 47 
Table 7: Schedule of Visits and Assessments .............................................................................................. 51 
Table 8: Samples for PK assessment ........................................................................................................... 58 
Table 9: Adverse Events Reporting Requirements ..................................................................................... 61 
Table 10: Active Collection Period .............................................................................................................. 62 
Table 11: Medication Errors Reporting Requirements ............................................................................... 71 
 
LIST OF FIGURES 
Figure 1: Study Schema ............................................................................................................................... 33 
 
 
  
 
 
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INVESTIGATORS 
9 sites will participate in the trial. The list of Investigators participating in the study will be maintained in 
 Clinical Trial Management System.  
 
 
 
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PROTOCOL SIGNATURE PAGE – Sponsor 
 
This Clinical Study Protocol has been reviewed and approved by the Sponsor representatives listed 
below. Any modification of the Clinical Study Protocol must be agreed upon by the Sponsor and the 
Investigator and must be documented in writing. 
 PhD 
  
Date: 
………………………………………. 
, MD 
, Safety Risk Lead 
Date: 
………………………………………. 
 
Date: 
………………………………………. 
, MD 
, Clinical Development  
 
Date: 
………………………………………. 
, MS 
, Regulatory Affairs 
Date: 
………………………………………. 
31 Aug 2018
12:50:000-0400
31 Aug 2018
16:26:045-0400
31 Aug 2018
16:48:027-0400
31 Aug 2018
17:49:046-0400
31 Aug 2018
20:37:037-0400
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LIST OF ABBREVIATIONS 
 
 
AE 
Adverse Event 
Ae% 
Percent of dose excreted in urine as unchanged drug 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase / GPT 
AML 
Acute Myeloid Leukemia 
ANA 
Antinuclear Antibody 
ANC 
Absolute Neutrophil Count 
aPTT/PTT 
(Activated) Partial Thromboplastin Time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Transaminase / SGOT 
AUC 
Area under the plasma concentration-time curve 
AUC0-24 
Area Under the concentration time curve from 0 to 24 hours 
AUC0-24,u 
Unbound AUC0-24 
BCRP 
Breast cancer resistance protein 
BRCA 
Breast cancer susceptibility gene 
BUN 
Blood Urea Nitrogen 
CLCR 
Creatinine Clearance 
CL/F 
Apparent Oral Clearance 
CLu/F 
Unbound CL/F 
Cmax 
Maximum observed plasma concentration 
Cmax,u 
Unbound Cmax 
Ctrough 
Plasma trough (pre-dose) concentration 
CLCR 
Creatinine Clearance 
CLr 
Renal Clearance 
CPK 
Creatinine Phosphokinase 
CRA 
Clinical Research Associate 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CYP450 
Cytochrome P450 
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D1 
Day 1 
DILI 
Drug Induced Liver Injury 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EDP 
Exposure During Pregnancy 
eGFR 
Estimated Glomerular Filtration Rate 
EOS 
End of Study 
FDA 
Food and Drug Administration 
Fu 
Fraction of unbound drug in plasma 
Gamma GT 
Gamma-glutamyl transferase or gamma-glutamyl transpeptidase 
GCP 
Good Clinical Practices 
G-CSF/GM-
CSF 
Granulocyte/Granulocyte-macrophage colony stimulating factor 
GFR 
Glomerular Filtration Rate 
GI 
Gastrointestinal 
GGT 
Gamma glutamyl transferase 
h 
Hour 
HBsAg 
Hepatitis B surface Antigen  
HDPE 
High Density Polyethylene 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator Brochure 
ICH 
International Conference for Harmonization 
IMP 
Investigational medicinal product 
INR/PT 
International Normalized Ratio / Prothrombin time 
IRB 
Institutional Review Board 
IU 
International Unit 
IV 
Intravenous 
kg 
kilogram 
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L 
Liter 
LC-MS/MS 
Liquid Chromatography with Tandem Mass Spectrometry 
LDH 
Lactate dehydrogenase 
MAD 
Maximum Administered  Dose 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDS 
Myelodysplastic syndrome 
mg 
Milligram 
mL 
Milliliter 
MTD 
Maximum Tolerated Dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NCI ODWG 
National Cancer Institute Organ Dysfunction Working Group 
PARP 
Poly(ADP-ribose) polymerase 
P-gp 
P-glycoprotein 
PICF 
Patient Informed Consent Form 
PK 
Pharmacokinetics 
PR 
Partial Response 
PS 
Performance status 
QD 
quaque die/every day 
SAE 
Serious Adverse Event 
SCLC 
Small Cell Lung Cancer 
Scr, std 
Standardized Serum Creatinine 
SFU 
Safety Follow Up 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Total Bilirubin 
t1/2 
Terminal half-life 
Tmax 
Time to Cmax 
 
 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper Limit of Normal 
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US 
United States 
Vz/F 
Apparent volume of distribution  
WBC 
White Blood Cells 
WoCP 
Women of Childbearing Potential  
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PROTOCOL SYNOPSIS 
Protocol Title 
A Phase I Open-Label Pharmacokinetics and Safety Study of Talazoparib 
(MDV3800) in Patients With Advanced Solid Tumors and Normal or 
Varying Degrees of Renal Impairment 
Protocol # 
MDV3800-01/
/C3441001 
Indication 
Advanced solid tumors 
Study Duration 
x Accrual: approximately 18-24 months 
x Treatment: 1 cycle defined as 22 calendar days of daily oral intake 
of talazoparib (counted from day 1) regardless of any treatment 
hold. 
Sponsor  
Medivation, Inc.   
Participating 
Investigator 
Sites 
9 sites  
Background and Rationale 
Talazoparib (PF-06944076; formerly known as BMN 673 or MDV3800) is a 
potent, orally bioavailable, small molecule poly(ADP-ribose) polymerase 
(PARP) inhibitor being developed for the treatment of a variety of human 
cancers both as single agent and in combination with other agents. PARP 
represents a family of at least 17 enzymes that transfer ADP-ribose 
groups to target proteins to regulate various cellular processes including 
deoxyribonucleic acid (DNA) repair. Among them, PARP1 and PARP2 play 
important roles in DNA repair. 
PARP inhibitors exert cytotoxic effects by 2 mechanisms:   
(1) inhibition of PARP1 and PARP2 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 
transcription.  
The single dose pharmacokinetic (PK) of talazoparib has been evaluated in 
a total of 5 clinical studies, of which 4 were conducted in cancer patients 
(Studies PRP-001, PRP-002, MDV3800-03, and MDV3800-14) and 1 in 
healthy subjects (Study 673-103). 
After administration of a single 1 mg dose of talazoparib capsules to 
cancer patients, the median time to reach maximum plasma 
concentration (Tmax) was ranging from 1.0 to 2.0 hours across studies. The 
geometric mean Cmax ranged from 4.35 to 8.79 ng/mL and the geometric 
mean area under concentration-time curve from time 0 to infinity (AUCinf) 
ranged from 116 to 196 ng•h/mL. Talazoparib was eliminated slowly with 
a mean terminal half-life (t½) of 89.8 hours. The talazoparib geometric 
mean apparent volume of distribution (Vz/F) values estimated ranged 
from 447 to 847 L, which is significantly greater than total body water (42 
L), indicating that talazoparib extensively distributes to peripheral tissues. 
The geometric mean apparent oral clearance (CL/F) values estimated for 
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talazoparib ranged from 5.12 to 7.71 L/hour (h). The geometric mean 
renal clearance (CLr) ranged from 2.76 to 3.44 L/h, indicating that urinary 
excretion was a major route of elimination for talazoparib. The PK of 
talazoparib was comparable between patients with cancer and healthy 
subjects. 
The PK of talazoparib following multiple oral daily doses was evaluated in 
a total of 5 studies in patients with cancer (Studies PRP-001, PRP-002, 
673-201, 673-301, and MDV3800-14) (Studies 673-201 and 673-301 only 
included sparse sampling). Following repeated 1 mg QD dosing to steady 
state, talazoparib was rapidly absorbed with a median Tmax ranging from 
approximately 1.0 to 2.0 h across studies. Talazoparib was eliminated 
slowly, with a geometric mean CL/F ranging from 4.80 to 5.53 L/h. The 
geometric mean CLr was 3.34 L/h and 3.32 L/h in Studies PRP-001 and 
PRP-002, respectively. The talazoparib geometric mean Cmax values ranged 
from 11.4 to 19.1 ng/mL and the geometric mean area under the 
concentration-time curve for a dosing interval (AUCW) values ranged from 
126 to 208 ng•h/mL. The talazoparib geometric mean steady-state pre 
dose plasma concentration (Ctrough) values ranged from 2.99 to 4.95 
ng/mL. 
Following repeated oral dosing, there was a dose proportional increase in 
the exposure of talazoparib (both Cmax and AUC0-24) across the dose 
range of 0.025 to 2 mg and the median talazoparib accumulation ratio 
(Rac) ranged from 2.23 to 12.3. Based on the multiple dosing data and 
consistent with its observed t½ of 89.8 h, talazoparib plasma 
concentrations reached steady state around 3 weeks after repeated daily 
dosing. 
The effect of food on the talazoparib plasma PK following administration 
of a single 0.5 mg dose of talazoparib oral capsule formulation in 18 
healthy subjects (Study 673-103). Food intake (a high-fat, high-calorie 
meal) had no impact on the AUC while reduced the Cmax by 46%. 
Consistent with findings from the food effect study, population PK 
analysis using data from Studies 673-301, 673-201, PRP-001, and PRP-002 
showed food intake decreased absorption rate but had no impact on the 
extent of the absorption. The reduction in the rate of absorption with 
food is not expected to be clinically relevant as efficacy is generally driven 
by total exposure.  Therefore, talazoparib can be taken without regard of 
food. 
Following oral administration of a single 1 mg dose of 14C-talazoparib to 
female patients with advanced solid tumors (Study MDV3800-03), a mean 
of 68.7% and 19.7% of the total administered radioactive dose was 
recovered in urine and feces, respectively. Excretion of unchanged 
talazoparib in urine was the major route of elimination accounting for 
54.6% of the administered dose, while unchanged talazoparib recovered 
in the feces accounted for 13.6%. No major circulating metabolites were 
identified in plasma, and talazoparib was the only circulating drug-derived 
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entity identified in plasma. No metabolites that individually represented 
more than 10% of the administered dose were recovered in the urine or 
feces. The identified metabolic pathways of talazoparib in humans 
include: 1) mono-oxidation; 2) dehydrogenation; 3) cysteine conjugation 
of mono-desfluoro-talazoparib; and 4) glucuronide conjugation. 
A population PK analysis for talazoparib was conducted to assess the 
impact of renal impairment on the CL/F using renal function as a 
categorical covariate defined by the baseline CLCR. The results of this 
analysis indicated that talazoparib CL/F was reduced by 14.4% and 37.1% 
in patients with mild renal impairment (CLCR, 60-89 mL/min) and 
moderate renal impairment (30 mL/min ч CLCR <60 mL/min), 
respectively, compared to that of patients with normal renal function 
(CLCR t90 mL/min). Due to limited number of severe renal impairment 
patients (CLCR <30 mL/min), the impact of severe renal impairment on 
talazoparib CL/F cannot be concluded. Therefore, based on this data, 
patients with moderate or severe renal impairment (CLCR < 60 mL/min) 
may be at risk of higher exposure to talazoparib. 
There is no study prospectively designed with the objective of assessing 
the potential effect of renal impairment on human PK of talazoparib, as 
most clinical studies exclude patients with renal impairment and 
especially those with severe dysfunction. 
The study will be carried out in patients with advanced solid tumors and 
with normal, mild, moderate or severe renal function as classified by 
estimated glomerular filtration rate (eGFR) according to the 2006 
Modification of Diet in Renal Disease (MDRD) study equation [available 
via www.mdrd.com].  
This study will contribute to understand the PK of talazoparib in patients 
with varying degrees of renal impairment and to better understand the 
exposure profiles in this patient population. Based on the results of this 
study, talazoparib dosing recommendations for patients with impaired 
renal function may be provided to future treating clinicians and potential 
exposure-dependent adverse events (e.g. myelosuppression) may be 
minimized. 
The dose selected in this study is 0.5 mg/day which is considered a safe 
dose as it is 50% lower than the Maximum Tolerated Dose (MTD) 
established in patients with solid tumors in phase 1 study at 1 mg/day. 
Talazoparib has also shown clinical activities at this dose level in a phase 1 
study; however efficacy is not being explored in this study. Additionally, 
the expected exposures increase in moderate and severe renal impaired 
patients should not exceed the exposure of maximum administered dose 
(MAD) of 2 mg/day experienced in the Phase 1 studies. Talazoparib will be 
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given daily for 22 calendar days in order to assess the safety and 
pharmacokinetics of talazoparib at the steady state. 
Objectives  
Primary objective:  
To investigate the effect of mild, moderate and severe renal impairment 
on the PK of talazoparib following daily oral dosing of talazoparib for 22 
calendar days in patients with advanced solid tumors. 
Secondary objectives: 
To evaluate the safety and tolerability of talazoparib in patients with 
advanced solid tumors and with normal, mild, moderate or severe renal 
impairment.  
Study Design 
This is an open-label, non-randomized, multi-center, phase 1 trial to 
investigate the PK and the safety of talazoparib in patients with advanced 
solid tumors and impaired renal function. 
Safety and PK data from patients with mild, moderate and severe renal 
impairment as classified using the MDRD study formula per FDA guidance, 
will be compared with a control group consisting of patients with normal 
renal function.  
The 4-variable 2006 MDRD equation, expressed as a single equation, is as 
follows:  
eGFR (mL/min/1.73 m
2
) = 175 x (Scr, std)
-1.154 
x (Age)
-0.203 
x (0.742 if female) x 
(1.212 if African American) 
 (where Scr, std = standardized serum Creatinine (mg/dL); age = years) 
Patients will be enrolled in parallel and will be assigned to one of four 
groups based on their renal function.  
Renal function defining each group according to the MDRD formula as 
follows: 
x Group 
A 
(control, 
normal 
renal 
function): 
eGFR 
ш 
90 
mL/min/1.73m2.  
x Group B (mild renal impairment): eGFR ш 60 and ч 89 
mL/min/1.73m2. 
x Group C (moderate renal impairment): eGFR ш30 and ч 59 
mL/min/1.73m2. 
x Group D (severe renal impairment): eGFR ш15 and ч 29 
mL/min/1.73m2, not on dialysis.  
In each group, 6 PK evaluable patients will be treated with daily oral doses 
of talazoparib 0.5 mg for 22 calendar days, regardless of any treatment 
hold. 
If enrollment in the group of patients with severe renal dysfunction 
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(Group D) is halted due to unacceptable toxicity, 2 additional evaluable 
patients will be enrolled in each of Groups A, B and C (total of 8 evaluable 
patients each). Therefore, a total of at least 24 patients will be enrolled in 
the study. 
Patients will be considered evaluable for PK analysis (PK evaluable) if they 
are eligible and have: 
x Completed 22 calendar days of treatment with talazoparib counted 
from Day 1, regardless of any treatment hold and missed 
ч 5 consecutive doses of  talazoparib, 
x Received at least 10 consecutive days of 0.5 mg talazoparib daily 
dose without dosing interruption prior to Day 22 PK sample 
collection, 
x Completed at least 85% of total plasma PK samples collection, 
x Not vomited talazoparib dose on Day 1 and Day 22 of the PK 
samples collection. 
Patients who discontinue the study prior to completion of Day 23 
assessments and/or who do not meet the above mentioned criteria may 
be replaced according to Sponsor´s judgment. 
On Day 1 and Day 22, serial PK plasma samples up to 24 hours post-dose 
will be collected for talazoparib concentration measurement.  
Note: 24h post-dose on Day 1 corresponds to the pre-dose of Day 2; 24h 
post-dose on Day 22 corresponds to Day 23. 
One PK blood sample will also be collected at the Safety Follow up Visit 
(End of Study Visit), if the study treatment discontinues earlier than 
planned.  
Additionally, trough (pre-dose) samples will be collected on Day 8 and Day 
15.  
Blood samples for plasma protein binding evaluation will be collected 2 h 
post-dose on Day 1 and Day 22.  
All voided urine will be collected after dosing on Day 1 and Day 22 
between the intervals of 0-12h and 12-24h. Pre-dose urine samples for PK 
analyses will be collected as a single void at pre-dose on Day 1.  
Patients with no clinically significant toxicities, no contraindications to 
continue treatment with talazoparib and no disease progression 
(underlying cancer progression) may be eligible to continue talazoparib 
treatment on a separate open-label extension study after discussion with 
the Principal Investigator and obtaining Sponsor permission. Sponsor 
decision to allow the patient to continue dosing with talazoparib in an 
open-label extension study will be based on potential overall benefit-risk, 
patient acceptance to be enrolled in the open-label extension study and 
other relevant criteria. 
Population 
Inclusion Criteria 
Each patient must meet all the following criteria to be considered as 
eligible to participate in this study: 
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1. Signed and dated informed consent form (by the patient or a 
legally acceptable representative as per the local regulations) 
obtained prior to initiation of any study-specific procedure and 
treatment. 
2. Female or male of at least 18 years of age. 
3. Histologically or cytologically confirmed advanced solid tumor 
with no available standard approved treatment options in the 
opinion of the Investigator (i.e. patients who received and failed 
approved standard therapy or with no effective approved 
standard therapy available). 
4. Eastern Cooperative Oncology Group (ECOG) Performance status 
(PS) ч 2.   
5. Expected life expectancy of ш 3 months. 
6. Able to swallow the study drug (no contra indication to oral 
agents). 
7. Renal function at screening and enrollment as defined by the 
MDRD equation (available via www.mdrd.com): 
x Control, normal renal function (Group A): eGFR ш 90 
mL/min/1.73m2.  
x Mild renal impairment (Group B): eGFR ш 60 and ч 89 
mL/min/1.73m2. 
x Moderate renal impairment (Group C): eGFR ш30 and ч 59 
mL/min/1.73m2. 
x Severe renal impairment (Group D): eGFR ш 15 and ч 29 
mL/min/1.73m2, not on dialysis.  
Each patient’s renal function classification for the study will be 
based on the assessment made at enrollment, if screening 
classification is different.  
8. Patient has had no clinically significant change in renal status 
within 3 months prior to screening, according to Investigator’s 
review of clinical patient records.  
9. Patient has no unstable renal function, defined as a change in 
eGFR (calculated with the MDRD equation) of > 25% for patients 
with mild and moderate renal impaired or as a change in eGFR > 
30% for patients with severe renal impaired, from screening to 
enrollment. 
10. If taking concurrent medications for treatment of renal 
impairment, patient has been on a stable dose of all indicated 
medication(s) for at least 1 month prior to Day -1 (patient 
enrollment) and is expected to continue to remain stable during 
the study.  
11. Patient is not currently on hemodialysis and/or peritoneal dialysis 
for 
management 
of 
chronic 
kidney 
disease 
or 
acute 
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failure/conditions. 
12. Adequate other organ function at screening and enrollment as 
defined by the following criteria: 
x Hematology (blood samples collected after ш 14 days without 
growth factor support, erythropoiesis-stimulating agents or 
transfusion):  
- Absolute Neutrophils Count (ANC) ш 1.5 x 109/L. 
- Platelets ш 100 x 109/L. 
- Hemoglobin ш 9 g/dL.   
x Liver function: 
- Total serum bilirubin ч 1.5 x ULN (or ч 3 times ULN for 
patients with documented Gilbert’s syndrome or for whom 
indirect bilirubin concentrations suggest an extra-hepatic 
source of elevation). 
- Aspartate 
aminotransferase 
(AST) 
or 
alanine 
aminotransferase (ALT) 
ч 2.5×ULN OR ч 5×ULN for 
patients with liver metastases. 
13. Female patients of childbearing potential: 
a. Must have a negative serum pregnancy test at screening,  
b. Must agree to use a highly effective birth control method from 
the time of the first dose of study drug through 7 months after 
the last dose of study drug, defined as:  
- Established use of an oral, intravaginal, or transdermal 
combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation. 
- Established use of an oral, injectable, or implantable 
progestogen-only hormonal contraception associated with 
inhibition of ovulation. 
- Bilateral tubal ligation ш 6 months before enrollment 
- Placement of an intrauterine device or intrauterine 
hormone-releasing system. 
- Sexual partner(s) vasectomized for ш 6 months before 
enrollment. 
- Sexual abstinence when in relation to the preferred and 
usual lifestyle of the patient. 
And  
c. Must agree to not donate eggs from the time of first 
talazoparib administration until at least 7 months thereafter. 
EŽƚĞ͗&ĞŵĂůĞƉĂƚŝĞŶƚƐŶŽƚŽĨĐŚŝůĚďĞĂƌŝŶŐƉŽƚĞŶƚŝĂůŝŶĐůƵĚĞƚŚŽƐĞ
ǁŚŽ ĂƌĞ ƐƵƌŐŝĐĂůůǇ ƐƚĞƌŝůĞ ;ďŝůĂƚĞƌĂů ƐĂůƉŝŶŐĞĐƚŽŵǇ͕ ďŝůĂƚĞƌĂů
ŽŽƉŚŽƌĞĐƚŽŵǇ͕ Žƌ ŚǇƐƚĞƌĞĐƚŽŵǇ ǁŝƚŚ ĚŽĐƵŵĞŶƚĂƚŝŽŶ ŽĨ ƚŚĞ
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ƉƌŽĐĞĚƵƌĞͿŽƌǁŚŽĂƌĞƉŽƐƚͲŵĞŶŽƉĂƵƐĂů͕ĚĞĨŝŶĞĚĂƐ͗
- шϱϱǇĞĂƌƐŽĨĂŐĞǁŝƚŚŶŽƐƉŽŶƚĂŶĞŽƵƐŵĞŶƐĞƐĨŽƌшϭϮŵŽŶƚŚƐ
ďĞĨŽƌĞĞŶƌŽůůŵĞŶƚ͘
- фϱϱǇĞĂƌƐŽĨĂŐĞǁŝƚŚŶŽƐƉŽŶƚĂŶĞŽƵƐŵĞŶƐĞƐĨŽƌшϭϮŵŽŶƚŚƐ
ďĞĨŽƌĞ
ĞŶƌŽůůŵĞŶƚ
ĂŶĚ
ǁŝƚŚ
ĂƉŽƐƚŵĞŶŽƉĂƵƐĂů
ĨŽůůŝĐůĞͲƐƚŝŵƵůĂƚŝŶŐ ŚŽƌŵŽŶĞ ;&^,Ϳ ĐŽŶĐĞŶƚƌĂƚŝŽŶ хϯϬ/hͬ> ;Žƌ
ŵĞĞƚŝŶŐ ĐƌŝƚĞƌŝĂ ĨŽƌ ƉŽƐƚͲŵĞŶŽƉĂƵƐĂů ƐƚĂƚƵƐ ďǇ ƚŚĞ ůŽĐĂů
ůĂďŽƌĂƚŽƌǇ͘
14.  Male patients: 
a. Must agree to use a condom when having sex with a pregnant 
woman or with a non-pregnant female partner of childbearing 
potential, from 21 days before the first dose of study drug 
through 4 months after last dose of study drug.  
And 
b. Must agree to not donate sperm from the time of first 
talazoparib administration until at least 4 months thereafter. 
15. Female patients must not be breastfeeding at screening nor 
during the study participation until 7 months after the last dose of 
study drug. 
16. Willingness and ability to comply with scheduled visits, treatment 
plan, laboratory tests, and other trial procedures. 
Exclusion criteria 
Patients meeting at least one of the following criterion will not be eligible 
to participate in this study: 
1. Treatment within 14 days or five half lives prior to enrollment 
with 
any 
type 
of 
systemic 
anticancer-therapy 
or 
any 
investigational drug, whichever is longer. 
2. Have not recovered (recovery is defined as CTCAE grade ч 1) from 
the acute toxicities of previous anticancer standard or 
investigational therapy, except treatment-related alopecia or 
laboratory 
abnormalities 
otherwise 
meeting 
eligibility 
requirements.   
3. Major surgery within 28 days prior to enrollment. 
4. Serious accompanying cardiac disorder including the following:   
x Myocardial infarction or symptomatic documented cardiac 
ischemia within 3 months prior to enrollment. 
x Heart failure New York Heart Association class III or IV at 
screening.     
x Clinically significant cardiac arrhythmias if not adequately 
treated or controlled (i.e. by medication, or pacemaker).   
x History of second-degree Mobitz II or third degree heart 
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block unless a permanent pacemaker is in place.     
x Hypotension as indicated by systolic blood pressure < 86 mm 
Hg at screening and at enrollment (day-1). A second 
measurement is allowed after hydration with oral fluids if 
systolic blood pressure < 80 mmHg. 
x Bradycardia as indicated by a heart rate of < 45 beats per 
minute on the screening electrocardiogram (ECG).   
x Poorly controlled hypertension as indicated by systolic blood 
pressure > 175 mm Hg or diastolic blood pressure > 105 mm 
Hg at screening.  May be repeated in 15 minutes. 
x Screening QTcF ш 450 msec in males or ш 480 msec in 
females. 
5. Active known or suspected brain metastasis or active 
leptomeningeal disease undergoing or requiring treatment.  
(asymptomatic brain metastases not currently undergoing 
treatment are allowed) 
6. Symptomatic or impending spinal cord compression or cauda 
equina syndrome.   
7. Has undergone a liver transplant, kidney transplant or 
nephrectomy. 
8. Prior allergic reaction or severe intolerance (meeting the criteria 
for a serious adverse event, a grade 3 or 4 AE, or permanent 
treatment discontinuation) to a PARP inhibitor. 
9. Known myelodysplastic syndrome.  
10. Seropositive for human immunodeficiency virus (HIV). 
11. Any serious or unstable medical condition that interferes with 
ability to tolerate treatment or assessments associated with the 
protocol.   
12. Gastrointestinal disorder affecting absorption.  
13. Known or suspected hypersensitivity to any of the talazoparib 
capsule components.   
14. Use of P-gp inhibitor (amiodarone, atorvastatin, azithromycin, 
carvedilol, clarithromycin, cobicistat, conivaptan, darunavir, 
diltiazem, 
diosmin, 
dronedarone, 
eliglustat, 
erythromycin, 
felodipine, flibanserin, fluvoxamine, indinavir, itraconazole, 
ketoconazole, 
lapatinib, 
lopinavir, 
piperine, 
propafenone, 
quercetin, quinidine, ranolazine, ritonavir, saquinavir, schisandra 
chinensis extract, telaprevir, tipranavir,  valspodar and verapamil), 
P-gp inducer (avasimibe, carbamazepine, phenytoin, rifampin, 
and St. John’s wort), or inhibitor of BCRP (curcumin, cyclosporine, 
elacridar [GF120918], and eltrombopag) within 7 days or 5 half 
lives which ever is longer prior to Day 1. 
15. Any condition or reason that interferes with ability to participate 
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in the study, tolerate treatment or assessments associated with 
the protocol, causes undue risk, or complicates the interpretation 
of safety data, in the opinion of the Investigator or Medical 
Monitor (e.g. encephalopathy, psychiatric disorders, non-
compliance, excessive alcohol consumption, intake of drugs of 
abuse unless these drugs are medically indicated [e.g. opiates for 
pain relief]). 
Study Treatment 
Talazoparib, chemical name (8S,9R) 5-fluoro-8-(4-fluorophenyl-2,7,8,9-
tetrahydro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-3H-pyrido[4,3,2 
de]phthalazin-3-one 
(provided 
as 
the 
4-methylbenzenesulfonate 
[tosylate] salt).  
Talazoparib will be administered as 0.5 mg orally once daily for 22 days 
(Day 1 to Day 22).   
Efficacy Assessments 
Not applicable. Efficacy will not be evaluated in the study. 
Note: Screening tumor assessments will be obtained in the event that 
patients choose to continue talazoparib treatment on a separate open 
label extension protocol. 
Safety Assessments 
Safety assessments and tolerability of talazoparib will be monitored 
through the evaluation of adverse events (severity according to NCI-
CTCAE 
version 
4.03), 
clinical 
laboratory 
tests, 
vital 
signs, 
electrocardiograms (ECGs), ECOG and physical examinations at screening 
during the 22 days of duration of the study treatment until 30 days after 
the last study drug administration or before initiation of a new 
anticancer therapy (standard or investigational treatment) or the first 
day of the extension protocol whichever occurs first.   
All assessments will be scheduled as indicated in the Schedule of Visits 
and Assessments.  
PK Assessments 
Blood samples for PK: 
Plasma samples will be collected at predetermined time point. 
x Day 1 and Day 22: 
- Pre-dose:  
 
On Day 1: within 60 minutes prior to dose. 
 
On Day 22: 24h ±60 minutes from the previous dose (Day 21), 
but within 60 minutes prior to the next dose.  
- 0.5, 1, 2, 4, 6 h , between 8 and 12 h, and 24 h post-dose (i.e. total 
of 7 time points). 
Note: 24h post-dose on Day 1 corresponds to the pre-dose of Day 2; 24h 
post-dose on Day 22 corresponds to the sample on Day 23.  
Samples up to 60 minutes post-dose will be obtained with a window of ±3 
minutes. From after 60 minutes until 12 h post-dose, samples will be 
obtained with time margins of ±10 minutes. Thereafter, samples should 
be obtained within ±60 minutes of the scheduled time points.  
PK blood samples will be collected at the Safety Follow up Visit (End of 
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Study visit) if study treatment discontinues earlier than planned. 
x Day 8 and Day 15: pre-dose samples only will be collected 24 h±60 
minutes from the previous dose, but within 60 minutes before the 
next dose on the day of sample collection. 
Blood samples for plasma protein binding evaluation: 
Blood samples for plasma protein binding evaluation will be collected at 
2h post-dose on Day 1 and Day 22. Samples will be obtained with a time 
margin of ±10 minutes. 
Urine Samples for PK:  
Urine samples will be collected at the following predetermined time 
points on Day 1 and Day 22:  
x Single void at pre-dose on Day 1.  
x Urine voided after talazoparib dosing on Day 1 and Day 22 at 0-12 h 
and 12-24 h. A ±60 minute time window applies to the start and end 
times of urine collection intervals. 
Statistical Methods  
Population for Analysis:  
The safety population is defined as all patients who received any amount 
of talazoparib. 
The PK concentration population is defined as all eligible patients enrolled 
and treated who have at least 1 reportable plasma talazoparib 
concentration. 
The PK parameter analysis population is defined as all evaluable patients 
enrolled and treated who have at least 1 of the talazoparib PK parameters 
of primary endpoints interest. 
 
Sample size:  
6 PK evaluable patients will be enrolled per group. If enrollment in the 
group of patients with severe renal impairment (group D) is halted due to 
unacceptable toxicity, 2 additional evaluable patients will be enrolled in 
each Groups A, B and C (total of 8 evaluable patients each). Therefore, a 
total of at least 24 patients will be enrolled in the study. Patients who 
discontinue the study prior to completion of Day 23 assessment and/or 
who do not meet the PK evaluability criteria may be replaced if needed 
upon agreement of the Sponsor.   
 
Statistical Methods: 
x Safety Analysis: All safety analyses will be performed using the safety 
population. 
The number and percentage of patients with adverse events will be 
presented by MedDRA system organ class and preferred term, 
relationship to study treatment, severity, seriousness, and outcome 
(i.e., leading to permanent treatment discontinuation).   
Treatment-emergent safety data will be collected from Day 1 (the first 
dose of study drug) through 30 days after the last dose of study drug or 
before initiation of new anticancer therapy (standard or investigational 
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treatment) or the first day of extension protocol, whichever occurs 
first.   
Laboratory values will be classified by severity using the NCI CTCAE.  
Laboratory shift tables of baseline results to each subsequent visit will 
be produced as appropriate. Change from baseline in laboratory values 
will be tabulated and summarized graphically. 
x Efficacy Analysis: No efficacy analysis is planned in this study, although 
baseline tumor assessments will be obtained in the event that patients 
choose to continue talazoparib treatment in a separate open-label 
extension study. 
 
PK Analysis: The PK parameters will be determined from the talazoparib 
concentration-time data.  PK parameters (AUC0-24, Cmax, AUC0-24,u, Cmax,u, 
Ctrough, Tmax, Fu, Rac, Ae%, and CLr ) will be calculated by non-
compartmental analysis using WinNonlin or another appropriate 
software. Additional PK parameters will be estimateded/calculated as 
applicable. PK parameters AUC0-24, Cmax, Cmax,u, and AUC0-24,u on Days 1 and 
22 will be natural log-transformed and analyzed using an analysis of 
variance (ANOVA) model with group as a fixed effect to compare each 
renal impairment group (mild, moderate or severe; Test) with the normal 
renal function group (Reference). Additionally, weight and age will be 
considered as covariates (at the significance level of 0.05). Estimates of 
the adjusted mean differences (Test - Reference) and corresponding 90% 
confidence intervals (CIs) for each comparison will be obtained from the 
model. The adjusted mean differences and 90% CIs for the differences will 
be exponentiated to provide estimates of the ratio of adjusted geometric 
means (Test/Reference) and 90% CIs for the ratios on the untransformed 
scale.  
Relationship between renal functional measures (e.g. eGFR) and selected 
PK parameters may be explored graphically, as appropriate. A regression 
line and 90% confidence region for the PK parameters and renal function 
will be included if appropriate. Vertical lines for the renal function group 
cut-off values will also be presented on the plots. Different symbols will 
be used to identify subjects from different renal function groups.  
Linear regression will be used to analyze the potential relationship 
between selected PK parameters and renal function. Estimates of the 
slope and, intercept, together with their precision (90% CI), and the 
coefficient of determination will be obtained from the model. 
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1. BACKGROUND AND RATIONALE 
1.1. 
Investigational Medicinal Product Overview 
1.1.1. 
Background 
Talazoparib (PF-06944076; formerly 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 both as single agent and in combination with other 
agents. PARP represents a family of at least 17 enzymes that transfer ADP-ribose groups to target 
proteins to regulate various cellular processes including deoxyribonucleic acid (DNA) repair.  Among 
them, PARP1 and PARP2 play important roles in DNA repair.1 
PARP Inhibitors exert cytotoxic effects by 2 mechanisms: (1) inhibition of PARP1 and PARP2 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 transcription.2  
DNA instability is an important characteristic of many tumor types; often times a consequence of 
defects in DNA repair.3 Although a single DNA repair pathway defect may not be lethal to the cell, the 
combination of 2 pathway defects may be lethal. This process is termed synthetic lethality.4 PARP 
inhibitors induce synthetic lethality in tumor cells bearing mutations and/or deletions in genes involved 
in homologous recombination or other DNA repair pathways, including BRCA1, BRCA2, FANCA, PTEN, 
RAD51, MLH1, MSH2, ATM, MRE11, and PALB2.5–12  
Inhibition of PARP catalytic activity contributes to the process of synthetic lethality, as it 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. 
The antitumor properties of talazoparib have been demonstrated in nonclinical studies.7, 13 Talazoparib 
is more potent at inducing single-agent synthetic lethality of BRCA1- and BRCA2-deficient tumor cells in 
vitro than any other PARP inhibitors reported to date. Talazoparib inhibited growth of MX-1 human 
breast cancer cells (BRCA1-deficient) and Capan-1 human pancreatic cancer cells (BRCA2-deficient), with 
half- maximal inhibitory concentration (IC50) values of 0.3 nM and 5.0 nM, respectively.7 
Consistent with its antitumor effects in vitro, talazoparib demonstrated antitumor activity in xenograft 
tumor models in mice. Clinical development of talazoparib is ongoing in various solid tumors as 
monotherapy at the recommended dose of 1mg/day and in combination with other agents. 
1.1.2. 
Clinical Study Findings with Talazoparib 
As of 31 Juanuary 2018, approximately 659 patients and 18 healthy volunteers have received 
talazoparib at doses up to 2 mg/day in company-sponsored studies in hematologic malignancies and 
solid tumors.  
A phase 1 study in patients with advanced or recurrent solid tumors defined the maximum tolerated 
dose (MTD) of talazoparib as 1 mg/day. Data from this study demonstrated objective responses and/or 
clinical benefit in patients with breast, ovarian/peritoneal, and pancreatic cancer; small-cell lung cancer 
(SCLC); and Ewing sarcoma. A phase 2 and a phase 3 study evaluating single-agent talazoparib in 
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patients with locally advanced or metastatic breast cancer with deleterious germline BRCA mutations 
are ongoing.  
The adverse events (AEs) associated with talazoparib are generally identifiable through routine 
laboratory and clinical monitoring and may be managed by dose reduction or interruption. The most 
common AEs reported in patients treated with talazoparib as a single agent or in combination are 
myelosuppression (anemia, neutropenia, thrombocytopenia), gastrointestinal (GI) toxicity (nausea, 
vomiting, diarrhea), and fatigue. The most common AEs with a severity grade ш 3 as per the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
were 
myelosuppression.  
1.1.3. 
Pharmacokinetics of Talazoparib 
The single dose pharmacokinetic (PK) of talazoparib have been evaluated in a total of 5 clinical studies, 
of which 4 were conducted in cancer patients (Studies PRP-001, PRP-002, MDV3800-03, and MDV3800-
14) and 1 in healthy subjects (Study 673-103). 
After administration of a single 1 mg dose of talazoparib capsules to cancer patients, the median time to 
reach maximum plasma concentration (Tmax) was ranging from 1.0 to 2.0 hours (h) across studies. The 
geometric mean Cmax ranged from 4.35 to 8.79 ng/mL and the geometric mean area under 
concentration-time curve from time 0 to infinity (AUCinf) ranged from 116 to 196 ng•h/mL. Talazoparib 
was eliminated slowly with a mean t½ of 89.8 h. The talazoparib geometric mean apparent volume of 
distribution (Vz/F) values estimated ranged from 447 to 847 L, which is significantly greater than total 
body water (42 L), indicating that talazoparib extensively distributes to peripheral tissues. The geometric 
mean apparent oral clearance (CL/F) values estimated for talazoparib ranged from 5.12 to 7.71 L/h. The 
geometric mean renal clearance (CLr) ranged from 2.76 to 3.44 L/h indicating that urinary excretion was 
a major route of elimination for talazoparib. The PK of talazoparib was comparable between patients 
with cancer and healthy subjects. 
The PK of talazoparib following multiple oral daily doses was evaluated in a total of 5 studies in patients 
with cancer (Studies PRP-001, PRP-002, 673-201, 673-301, and MDV3800-14) (Studies 673-201 and 673-
301 only included sparse sampling). Following repeated 1 mg QD dosing to steady state, talazoparib was 
rapidly absorbed with a median Tmax ranging from approximately 1.0 to 2.0 h across studies. 
Talazoparib was eliminated slowly, with a geometric mean CL/F ranging from 4.80 to 5.53 L/h. The 
geometric mean CLr was 3.34 L/h and 3.32 L/h in Studies PRP-001 and PRP-002, respectively. The 
talazoparib geometric mean Cmax values ranged from 11.4 to 19.1 ng/mL and the geometric mean area 
under the concentration-time curve for a dosing interval (AUCW) values ranged from 126 to 208 
ng•h/mL. The talazoparib geometric mean steady-state pre dose plasma concentration (Ctrough) values 
ranged from 2.99 to 4.95 ng/mL. 
Following repeated oral dosing, there was a dose proportional increase in the exposure of talazoparib 
(both Cmax and AUC0-24) across the dose range of 0.025 to 2 mg and the median talazoparib 
accumulation ratio (Rac) ranged from 2.23 to 12.3. Based on the multiple dosing data and consistent 
with its observed t½ of 89.8 h, talazoparib plasma concentrations reached steady state around 3 weeks 
after repeated daily dosing. 
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The effect of food on the talazoparib plasma PK following administration of a single 0.5 mg dose of 
talazoparib oral capsule formulation in 18 healthy subjects (Study 673-103). Food intake (a high-fat, 
high-calorie meal) had no impact on the AUC while reduced the Cmax by 46%. Consistent with findings 
from the food effect study, population PK analysis using data from Studies 673-301, 673-201, PRP-001, 
and PRP-002 showed food intake decreased absorption rate but had no impact on the extent of the 
absorption.  The reduction in the rate of absorption with food is not expected to be clinically relevant as 
efficacy is generally driven by total exposure.  Therefore, talazoparib can be taken without regard of 
food. 
Following oral administration of a single 1 mg dose of 14C-talazoparib to female patients with advanced 
solid tumors (Study MDV3800-03), a mean of 68.7% and 19.7% of the total administered radioactive 
dose was recovered in urine and feces, respectively.  Excretion of unchanged talazoparib in urine was 
the major route of elimination accounting for 54.6% of the administered dose, while unchanged 
talazoparib recovered in the feces accounted for 13.6%. No major circulating metabolites were 
identified in plasma, and talazoparib was the only circulating drug-derived entity identified in plasma.  
No metabolites that individually represented more than 10% of the administered dose were recovered 
in the urine or feces. The identified metabolic pathways of talazoparib in humans include: 1) mono-
oxidation; 2) dehydrogenation; 3) cysteine conjugation of mono-desfluoro-talazoparib; and 4) 
glucuronide conjugation. 
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 or drug transporter inhibition-based drug-drug interactions 
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 or decrease when co-administered with P-gp or BCRP inhibitors or inducers, respectively. 
Additional information on the chemistry, pharmacology, toxicology, preclinical findings, and clinical 
experience to date may be found in the talazoparib Investigator’s Brochure (IB). 
1.2. 
Study Rationale 
1.2.1. 
Rationale for Conducting the Study 
Based on the available data, talazoparib appears to predominantly be excreted via the renal route. A 
population PK analysis for talazoparib was conducted to assess the impact of renal impairment on the 
CL/F using renal function as a categorical covariate defined by the baseline CLCR. The results of this 
analysis indicated that talazoparib CL/F was reduced by 14.4% and 37.1% in patients with mild renal 
impairment (CLCR, 60-89 mL/min) and moderate renal impairment (30 mL/min ч CLCR <60 mL/min), 
respectively, compared to that of patients with normal renal function (CLCR t90 mL/min). Due to limited 
number of severe renal impairment patients (CLCR <30 mL/min), the impact of severe renal impairment 
on talazoparib CL/F cannot be concluded. Therefore, based on this data, patients with moderate or 
severe renal impairment (CLCR < 60 mL/min) may be at risk of higher exposure to talazoparib. 
There is no study prospectively designed with the objective of assessing the potential effect of renal 
impairment on human PK of talazoparib as most clinical studies exclude patients with renal impairment, 
and especially those with severe dysfunction. This study is designed to provide PK data following daily 
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administration of talazoparib in cancer patients with varying degrees of renal impairment. The study will 
be carried out in patients with advanced solid tumors with normal renal function and with mild, 
moderate and severe renal impairment classified by eGFR according to the 2006 Modification of Diet in 
Renal Disease (MDRD) study equation [available via www.mdrd.com] 14.  
This study will contribute to understand the PK of talazoparib in patients with varying degrees of renal 
impairment and to better understand the exposure profiles in this patient population. Based on the 
results of this study, talazoparib dosing recommendations for patients with impaired renal function may 
be provided to future treating clinicians and potential exposure-dependent adverse events (e.g. 
myelosuppression) may be minimized. 
1.2.2. 
Rationale for Regimen and Dose Selection 
In previous clinical trials, talazoparib was given as a single dose or as daily multiple doses in patients 
with various solid tumors and hematological malignancies in doses ranging from 0.025 to 2 mg/day 
given orally. The established recommended dose is 1 mg/day p.o. and at this dose, the mean t½ was 89.8 
hours. With daily administrations at this dose, it took approximately 3 weeks to reach the steady state. 
Based on this, a single dose study in cancer patients is not appropriate as at least a 2 to 3 week washout 
period would be required to be able to evaluate key PK parameters. In this study, talazoparib will be 
given daily for 22 calendar days to assess the pharmacokinetics and safety of talazoparib at steady state.  
The dose selected in this study is 0.5 mg daily, which is considered safe as it is 50% lower than the MTD 
established in patients with solid tumors in phase 1 study at 1 mg/day. Talazoparib has also shown 
clinical activity at the dose to be used in the study in a Phase 1 trial; however efficacy is not being 
explored in this study; only pharmacokinetics is being evaluated. Additionally, the expected exposures 
increase in moderate and severe renal impaired patients should not exceed the exposure of Maximum 
Administered Dose (MAD) of 2 mg/day experienced in the Phase I studies. 
2. OBJECTIVES 
2.1. 
Primary Objective 
To investigate the effect of mild, moderate and severe renal impairment on the PK of talazoparib 
following daily oral dosing of talazoparib for 22 calendar days in patient with advanced solid tumors.    
2.2. 
Secondary Objective 
To evaluate the safety and tolerability of talazoparib in patients with advanced tumors and with normal, 
mild, moderate or severe renal impairment. 
3. STUDY DESIGN 
This is an open-label, non-randomized, multi-center, phase 1 trial to investigate the PK and the safety of 
talazoparib in patients with various advanced solid tumors and impaired renal function. 
Safety and PK data from patients with mild, moderate and severe renal impairment as classified using 
the MDRD study formula per FDA guidance will be compared with a control group consisting of patients 
with normal renal function.  
The 4 variable 2006 MDRD formula, expressed as a single equation, is as follows:  
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eGFR (mL/min/1.73 m
2
) = 175 x (Scr, std)
-1.154 
x (Age)
-0.203 
x (0.742 if female) x (1.212 if African American) 
(where Scr, std = standardized serum Creatinine (mg/dL); age = years) 
Patients will be enrolled in parallel and assigned to one of four groups based on their renal function. 
Renal function defining each group according to the MDRD formula is as follows: 
x Group A (control, normal renal function): eGFR ш 90 mL/min/1.73m2.  
x Group B (mild renal impairment): eGFR ш 60 and ч 89 mL/min/1.73m2. 
x Group C (moderate renal impairment): eGFR ш30 and ч 59 mL/min/1.73m2. 
x Group D (severe renal impairment): eGFR ш15 and ч29 mL/min/1.73m2, not on dialysis.  
In each group, 6 PK evaluable patients will be enrolled. If enrollment in the group of patients with 
severe renal dysfunction (Group D) is halted due to unacceptable toxicity, 2 additional PK evaluable 
patients will be enrolled in each of Groups A, B and C (total of 8 PK evaluable patients each). 
Therefore, a total of at least 24 patients will be enrolled in the study from 9 sites.  
All patients will be treated with oral talazoparib given on a daily basis at a dose of 0.5 mg over 22 
calendar days (from Day 1 to Day 22 defined as 1 cycle of treatment) regardless of any study treatment 
hold. Talazoparib administration within this study will be discontinued after 22 days of starting study 
treatment. 
Note: At the End of Study, patients with no clinically significant toxicities, no contraindications to 
continue treatment with talazoparib, and no disease progression (underlying cancer progression) may be 
eligible to continue talazoparib treatment in a separate open-label extension study after discussion with 
the Principal Investigator and obtaining Sponsor permission. Sponsor decision to allow the patient to 
continue dosing with talazoparib in an open-label extension study will be based on potential overall 
benefit-risk, patient acceptance and other relevant criteria. 
Study periods include: 
x Screening 
x Enrollment (D-1) 
x A 22 calendar day treatment period 
x A Safety follow up visit (also considered as the End of Study visit) 
Serial PK plasma samples will be collected at predetermined times on Day 1 and Day 22 up to 24 h post-
dose (Day 23) for talazoparib concentration measurement. Additionally though (pre-dose) samples will 
be collected on Day 8 and Day 15.  
One PK blood sample will also be collected at the Safety Follow up Visit if the study treatment 
discontinues earlier than planned. Blood samples for plasma protein binding evaluation will be collected 
on Day 1 and Day 22 (2h post dose). Urine samples for PK analyses will be collected as a single void at 
pre-dose on Day 1 and all urine voided after talazoparib dosing on Days 1 and 22 between the intervals 
of 0-12 h and 12-24 h. 
Patients will be considered evaluable for PK analysis (PK evaluable) if they are eligible and have: 
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x Completed 22 calendar days of treatment with talazoparib counted from Day 1, regardless of any 
treatment hold and missed ч5 consecutive doses of talazoparib 
x Received at least 10 consecutive days of 0.5 mg talazoparib daily dose without dosing interruption 
prior to Day 22 PK sample collection 
x Completed at least 85% of total plasma PK samples collection  
x Not vomited talazoparib dose on Day 1 and Day 22 of the PK samples collection. 
 
Patients who discontinue the study before the completion of the Day 23 assessments and/or who do not 
meet the above mentioned criteria may be replaced according to the Sponsor’s judgment. 
 
 
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Figure 1: Study Schema 
 
 
4. PATIENT SELECTION 
Patients can be enrolled in the study only if the eligibility criteria are met. This study can fulfill its 
objectives only if appropriate patients are enrolled. Patients who fail to meet ш 1 inclusion criterion or 
fulfill at least one exclusion criteria cannot be enrolled in the study. The sponsor 
 will not grant 
any eligibility waivers.   
If a patient that does not meet the eligibility criteria is incorrectly enrolled, the Investigator should 
immediately inform the 
 Medical Monitor. The decision about the continuation or discontinuation 
of these patients on the study will be based on medical judgment, treatment benefit and safety risks for 
the patient. 
4.1. 
Inclusion Criteria 
Each patient must meet all the following criteria to be considered as eligible to participate in this study: 
1. Signed and dated informed consent form (by the patient or a legally acceptable representative 
as per the local regulations) obtained prior to initiation of any study-specific procedure and 
treatment. 
2. Female or male of at least 18 years of age. 
3. Histologically or cytologically confirmed advanced solid tumor with no available standard 
approved treatment options in the opinion of the Investigator (i.e. patients who received and 
failed standard approved therapy or with no effective standard approved therapy available). 
4. Eastern Cooperative Oncology Group (ECOG) Performance status (PS) ч 2.   
5. Expected life expectancy of ш 3 months.   
6. Able to swallow the study drug (no contra indication to oral agents).   
7. Renal function at screening and enrollment as defined by the MDRD equation (available via 
www.mdrd.com): 
x Control, normal renal function (Group A): eGFR ш 90 mL/min/1.73m2.  
x Mild renal impairment (Group B): eGFR ш 60 and ч 89 mL/min/1.73m2. 
x Moderate renal impairment (Group C): eGFR ш30 and ч 59 mL/min/1.73m2. 
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x Severe renal impairment (Group D): eGFR ш 15 and ч 29 mL/min/1.73m2, not on dialysis.  
Each patient’s renal function classification for the study will be based on the assessment made 
at enrollment, if screening classification is different.  
8. Patient has no clinically significant change in renal status within 3 months prior to enrollment, 
according to Investigator’s judgment.  
9. Patient has no unstable renal function, defined as a change in eGFR (calculated with the MDRD 
equation) of > 25% for patients with mild and moderate renal impaired or as a change in eGFR > 
30% for patients with severe renal impaired, from screening to enrollment. 
10. If taking concurrent medications for treatment of renal impairment, patient has been on a 
stable dose of all indicated medication(s) for at least 1 month prior to Day -1 and is expected to 
continue to remain stable during the study.  
11. Patient is not currently on hemodialysis and/or peritoneal dialysis for management of chronic 
kidney disease or acute failure/conditions. 
12. Adequate other organ function at screening and enrollment as defined by the following criteria: 
x Hematology (blood samples collected after ш 14 days without growth factor support, 
erythropoiesis-stimulating agents or transfusion):  
- 
Absolute Neutrophils Count (ANC) t 1.5 × 109/L. 
- 
Platelets t 100 × 109/L. 
- 
Hemoglobin ш 9 g/dL.   
x Liver function: 
- 
Total serum bilirubin d 1.5 × ULN (or d 3 times ULN for patients with documented 
Gilbert’s syndrome or for whom indirect bilirubin concentrations suggest an 
extrahepatic source of elevation). 
- 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ч 2.5 × ULN 
OR ч 5 × ULN for patients with liver metastases. 
13. Female patients of childbearing potential: 
a. Must have a negative serum pregnancy test at screening,  
b. Must agree to use a highly effective birth control method from the time of the first 
talazoparib administration until at least 7 months thereafter, defined as:  
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- 
Established use of an oral, intravaginal, or transdermal combined (estrogen and 
progestogen containing) hormonal contraception associated with inhibition of 
ovulation. 
- 
Established use of an oral, injectable, or implantable progestogen-only hormonal 
contraception associated with inhibition of ovulation. 
- 
Bilateral tubal ligation ш 6 months before enrollment. 
- 
Placement of an intrauterine device or intrauterine hormone-releasing system. 
- 
Sexual partner(s) vasectomized for ш 6 months before enrollment. 
- 
Sexual abstinence when in relation to the preferred and usual lifestyle of the 
patient. 
And  
c. Must agree to not donate eggs from the time of first talazoparib administration until at 
least 7 months thereafter. 
Note: Female patients not of childbearing potential include those who are surgically 
sterile (bilateral salpingectomy, bilateral oophorectomy, or hysterectomy with 
documentation of the procedure) or who are post-menopausal, defined as: 
- 
ш 55 years of age with no spontaneous menses for ш 12 months before enrollment. 
- 
< 55 years of age with no spontaneous menses for ш 12 months before enrollment 
and with a postmenopausal follicle-stimulating hormone (FSH) concentration 
> 30 IU/L (or meeting criteria for post-menopausal status by the local laboratory). 
14.  Male patients: 
- 
Must agree to use a condom when having sex with a pregnant woman or with a non-
pregnant female partner of childbearing potential, from 21 days before the first dose of 
study drug through 4 months after last dose of study drug.  
And 
- 
Must agree to not donate sperm from the time of first talazoparib administration until 
at least 4 months hereafter. 
15. Female patients must not be breastfeeding at screening nor during the study participation until 
7 months after the last dose of study drug. 
16. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and 
other trial procedures. 
4.2. 
Exclusion Criteria 
Patients meeting at least one of the following criteria will not be eligible to participate in this study: 
1. Treatment within 14 days or five half lives prior to enrollment with any type of systemic 
anticancer-therapy or any investigational drug whichever is longer. 
2. Have not recovered (recovery is defined as CTCAE grade ч 1) from the acute toxicities of 
previous anticancer standard or investigational therapy, except treatment-related alopecia or 
laboratory abnormalities otherwise meeting eligibility requirements.   
3. Major surgery within 28 days prior to enrollment. 
4. Serious accompanying cardiac disorder including the following:   
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x Myocardial infarction or symptomatic documented cardiac ischemia within 3 months prior 
to enrollment. 
x Heart failure New York Heart Association class III or IV at screening.     
x Clinically significant cardiac arrhythmias if not adequately treated or controlled (i.e. by 
medication, or pacemaker).   
x History of second-degree Mobitz II or third degree heart block unless a permanent 
pacemaker is in place.     
x Hypotension as indicated by systolic blood pressure < 86 mm Hg at screening and at 
enrollment (Day-1). A second measurement is allowed after hydration with oral fluids if 
systolic blood pressure < 80 mmHg. 
x Bradycardia as indicated by a heart rate of < 45 beats per minute on the screening 
electrocardiogram (ECG).   
x Poorly controlled hypertension as indicated by systolic blood pressure > 175 mm Hg or 
diastolic blood pressure > 105 mm Hg at screening.  May be repeated in 15 minutes. 
x Screening QTcF ш 450 msec in males or ш 480 msec in females. 
5. Active known or suspected brain metastasis or active leptomeningeal disease undergoing or 
requiring treatment (asymptomatic brain metastases not currently undergoing treatment are 
allowed).   
6. Symptomatic or impending spinal cord compression or cauda equina syndrome.   
7. Has undergone a liver transplant, kidney transplant or nephrectomy. 
8. Prior allergic reaction or severe intolerance (meeting the criteria for a serious adverse event, a 
grade 3 or 4 AE, or permanent treatment discontinuation) to a PARP inhibitor. 
9. Known myelodysplastic syndrome.  
10. Seropositive for human immunodeficiency virus (HIV). 
11. Any serious or unstable medical condition that interferes with ability to tolerate treatment or 
assessments associated with the protocol.   
12. Gastrointestinal disorder affecting absorption.  
13. Known or suspected hypersensitivity to any of the talazoparib capsule components.   
14. Use of a P-gp inhibitor (amiodarone, atorvastatin, azithromycin, carvedilol, clarithromycin, 
cobicistat, conivaptan, darunavir, diltiazem, diosmin, dronedarone, eliglustat, erythromycin, 
felodipine, flibanserin, fluvoxamine, indinavir, itraconazole, ketoconazole, lapatinib, lopinavir, 
piperine, propafenone, quercetin, quinidine, ranolazine, ritonavir, saquinavir, schisandra 
chinensis extract, telaprevir, tipranavir, valspodar and verapamil), P-gp inducer (avasimibe, 
carbamazepine, phenytoin, rifampin, and St. John’s wort), or inhibitor of BCRP (curcumin, 
cyclosporine, elacridar [GF120918], and eltrombopag) within 7 days or 5 half lives which ever is 
longer prior to Day 1.   
15. Any condition or reason that interferes with ability to participate in the study, tolerate 
treatment or assessments associated with the protocol, causes undue risk, or complicates the 
interpretation of safety data, in the opinion of the Investigator or Medical Monitor (e.g. 
encephalopathy, psychiatric disorders, non-compliance, excessive alcohol consumption, intake 
of drugs of abuse unless these drugs are medically indicated [e.g. opiates for pain relief]). 
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5. STUDY TREATMENT 
5.1. 
Study Treatment Identification 
Talazoparib is the only study treatment in the study and is considered an Investigational Medicinal 
Product (IMP). Talazoparib has the chemical name 
 
 
 
 
 The drug substance is a
 
 The drug product consists of the drug substance 
formulated with a pharmaceutically suitable excipient filled into hydroxymethylpropylcellulose capsules. 
For the purpose of this trial, the Single Reference Document to be used for talazoparib is the IB.  
5.2. 
Investigational Product Information and Management 
5.2.1. 
Packaging and Labelling 
The drug product will be provided as powder-filled, hard gelatin opaque white capsules containing 
talazoparib at the strength of 0.25 mg calculated as the free-base equivalent. Capsules will be provided 
free of charge by the Sponsor.  
The capsules will be supplied in 30-count induction-sealed high density polyethylene (HDPE) bottles with 
child-resistant caps. 
At minimum, each label typically provides the study protocol number, contents, and directions for use, 
storage directions, clinical trial statement, Sponsor name, batch/lot number, and product retest or 
expiration date. 
5.2.2. 
Storage and Dispensation 
At the site, talazoparib must be kept in the original container and stored safely and properly in 
accordance with the study drug label.    
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
Talazoparib is considered a cytotoxic and clastogenic agent; precautions regarding appropriate secure 
storage and handling must be used by healthcare professionals, including personal protective clothing, 
disposable gloves, and equipment. Patients should be advised that oral anticancer agents are toxic 
substances and that caregivers (other than the patient) should always use gloves when handling the 
capsules.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the site. 
5.2.3. 
Accountability, Return and Destruction 
The Investigator is responsible for keeping accurate records of the clinical supplies received from the 
Sponsor or designee, the amount administered or dispensed to and returned by the patients, and the 
amount remaining at the conclusion of the trial. 
Patients must return all unused medication and empty containers to the Investigator.  
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The Investigator or designee must retain all unused or expired study supplies in a secure location 
(separately from medication that needs to be dispensed) for accountability and reconciliation by the 
Clinical Research Associate (CRA). 
Unused study drug will be destroyed on site, per the site’s standard operating procedures, ideally after 
the Sponsor or designee has granted approval for drug destruction and the CRA has accounted for all 
study drugs in a formal reconciliation process.  
If a site is unable to destroy study drug, the site can return unused study drug to a central location for 
drug destruction upon agreement with the Sponsor or designee.  
To ensure adequate records, dispensations, accountability, return / destruction of talazoparib capsules 
will be documented in a timely manner. Appropriate documents (Drug accountability/destruction log or 
similar) for this purpose will be provided. 
5.3. 
Study Treatment Administration 
5.3.1. 
Dosage and Administration 
The patient should start the study treatment within 3 calendar days after being enrolled in the study. As 
much as possible, study treatment should start on a weekday that allows D8, D15 and D22-23 visits to 
fall on a weekday. 
All patients enrolled will receive oral talazoparib given on a daily basis at a dose of 0.5 mg (2 capsules of 
0.25 mg) over 22 calendar days (from Day 1 to Day 22). 
At Day 1, all patients should be given with one bottle containing 30 capsules of talazoparib 0.25 mg. A 
resupply with a 2nd bottle containing 30 capsules of talazoparib 0.25 mg will occur at D15 for the 
remaining dosing period (D15-D22).   
Talazoparib should be taken at approximately the same time each day in the morning. The patients can 
self-administer talazoparib at home except on Days 1, 2, 8, 15 and 22. Patients should not take the study 
drug at home on Days 1, 2, 8, 15 and 22. On those days patients should be instructed to come into the 
clinic before taking his or her dose of talazoparib and these doses will be administered in the clinic by 
study staff after completing pre-dose visit assessments. If patient takes the study treatment at home on 
Day 22 before arriving at the clinic, the patient should be asked to visit the site again on Day 23 to take 
the study treatment at the clinic. All the study assessments (including PK sampling) initially planned on 
Day 22 should be collected on Day 23 instead. 
On Days 1 and 22 PK sampling days, talazoparib will be swallowed whole, under fasting conditions. 
Fasting is defined as after an overnight fast of at least 6 hours with no food allowed for at least 4 hours 
post-dose. Water is allowed as desired. On the other days, talazoparib can be given with or without 
food.  
If a patient vomits a dose, the patient should not take a second dose that calendar day. The patient 
should resume daily dosing the following day. If a patient misses a dose, he/she should take the dose as 
soon as possible, but not when more than 12 hours after the missed scheduled dose. If the dose is 
missed greater than 12 hours, the missed dose should be skipped and the patient should take the next 
dose when scheduled. 
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If a capsule is broken or damaged, the capsule should not be used, and brought back to the site for 
accountability and disposal. 
5.3.2. 
Treatment Compliance 
Patients will be instructed to bring all used and unused study drug containers and their completed study 
drug diary to all clinic visits (Day 8, Day 15 and Day 22) in order to assess the treatment compliance. Site 
staff will perform accountability of the returned drug and will assess compliance of the patient. Site staff 
must ensure that the patient clearly understands the directions for self-medication and follows the 
schedule adequately. 
5.3.3. 
Treatment Duration 
The patients will be treated only during 1 cycle, defined as a 22 calendar days counted from Day 1, 
regardless of any treatment hold.  
If Day 22 coincides with a non-working day (e.g. weekend, holiday) it is acceptable to administer study 
treatment for more than 22 calendar days up until the closest upcoming weekday, up to a maximum of 
25 days of treatment. 
Patients with no clinically significant toxicities, no contraindications to continue treatment with 
talazoparib and no disease progression (underlying cancer progression) may be eligible to continue 
talazoparib treatment on a separate open-label extension study after discussion with the Principal 
Investigator and obtaining Sponsor permission. Sponsor decision to allow the patient to continue dosing 
with talazoparib in an open-label extension study will be based on potential overall benefit-risk, patient 
acceptance to be enrolled in the open-label extension study and other relevant criteria. 
5.4. 
Treatment Schedule Adjustment and Adverse Event Management 
5.4.1. 
General Rules 
Regular assessment and monitoring of AEs is required throughout study treatment period and until the 
Safety Follow up visit, i.e. 30 days after the last dose of study drug or before initiation of a new 
anticancer therapy (standard or investigational treatment) or the first day of the extension protocol 
whichever occurs first. 
Toxicity will be assessed utilizing the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) v4.03. For adverse event terms not specifically listed in the NCI CTCAE, the 
investigator should report the adverse event using the criteria in Table 1 to assess severity. 
Table 1: AE grading for toxicities when the AE term is not listed in NCI CTCAE 
Grade 
Description 
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
2 
Moderate: minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (e.g. preparing meals, shopping for 
groceries or clothes). 
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3 
Severe: medically significant but not immediately life-threatening, 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL (e.g. bathing, dressing and undressing, feeding oneself). 
4 
Life threatening or debilitating consequences, urgent intervention indicated. 
5 
Death related to AE. 
 
Patients will be instructed to notify their study Investigator immediately for any and all toxicities. 
Assessment of causality (chronology, confounding factors, concomitant medications, diagnostic tests, 
and previous experience with the study treatment) should be conducted by the Investigator prior to 
dose modification and/or delay whenever possible. As a general approach, it is suggested that all AEs be 
managed with supportive care at the earliest signs of toxicity and before delaying/reducing study drug, 
when possible and if clinically appropriate.  
5.4.2. 
Dose Modification Due to Adverse Events 
5.4.2.1. 
Assessment of Abnormal Non Liver Tests 
 
Study treatment dose modifications due to adverse events with the exception of liver tests 
abnormalities are described in Table 2. 
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Table 2: Talazoparib Treatment Adjustment for Non Liver Test Abnormalities 
Non Liver Test Abnormalities 
Grade 1 or 2 
No requirement for dose interruption or dose reduction.   
Selected grade 3 or 4 hematological toxicity 
Anemia  
(hemoglobin 
< 8.0 g/dL) 
Hold study treatment and monitor weekly until hemoglobin returns to baseline or 
better. Implement supportive care per local guidelines.   
Study treatment should be reduced by 1 dose level to 0.25 mg/day. 
If Day 22 is reached without recovery, discontinue study treatment and refer to a 
hematologist for evaluation, including assessment for possible MDS/AML. 
Neutropenia  
(ANC < 1000/ђL) 
Hold study treatment and monitor weekly until ANC ш 1500/ђL.  Implement supportive 
care per local guidelines. Resume study treatment based on the following recovery 
times: 
9 ч 1 week:  No change.   
9 >1 week:  Reduce study drug treatment by 1 dose level to 0.25 mg/day. 
If Day 22 is reached without recovery, discontinue study treatment and refer to a 
hematologist for evaluation, including assessment for possible MDS/AML. 
Thrombocytopenia 
(platelets 
< 50,000/ђL) 
Hold study treatment until platelets ш 75,000/ђL. Implement supportive care per local 
guidelines. Resume study drug treatment based on the following recovery times: 
9 ч 1 week:  No change. 
9 >1 week:  Reduce study treatment by 1 dose level to 0.25 mg/day. 
If Day 22 is reached without recovery, discontinue study treatment and refer to a 
hematologist for evaluation, including assessment for possible MDS/AML. 
Grade 3 and 4  non hematological toxicity 
Other grade 3 or 4 
events, except 
abnormal liver tests[1] 
x For clinically important grade 3 or 4 laboratory abnormalities, study treatment 
may be held. Resume study treatment when the laboratory abnormality 
resolves to grade ч 2 (baseline grade for creatinine increases).   
x For clinically significant grade 3 or 4 adverse events, hold study treatment until 
the adverse event resolves to grade ч 2.  Resume study treatment at the same 
dose or reduce by 1 dose level to 0.25 mg/day if the event resolves or improves 
within 22 days of holding study drug treatment, and can be monitored if it 
recurs.   
Implement supportive care per local guidelines.   
Contact medical monitor to discuss potential dose modification.   
Study treatment should be permanently discontinued for unresolved grade 3 or 4 
toxicity per investigator decision that continued study drug treatment is not in the 
patient’s best interest.   
Note: Dose modifications for liver abnormalities are presented in Table 3.  
 
5.4.2.2. 
Assessment of Abnormal Liver Tests 
Patients who develop abnormal liver tests (AST, ALT, total bilirubin), abnormal international normalized 
ratio (INR) values, or signs or symptoms of hepatitis during the study treatment period may meet the 
criteria for temporarily withholding or permanently discontinuing study drug as specified in US FDA 
Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation (2009). Patients who 
meet criteria for permanent discontinuation or temporary withholding of study treatment or who do 
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not meet the criteria but who have abnormal liver tests are to be followed up according to the 
recommendations in this section. 
 
Criteria for temporary withholding Talazoparib in Association With Liver Test 
5.4.2.2.1.
Abnormalities  
Study treatment should be withheld for any liver test abnormality listed in Table 3. 
Table 3: Criteria for Temporary Withholding Talazoparib in Association with Liver Test 
Abnormalities 
Baseline AST or ALT Value 
Elevation 
ч 3 × ULN 
> 5 × ULN (ALT or AST ш 3 × ULN with the presence of signs and 
symptoms consistent with acute hepatitis and/or eosinophilia (ш 500 
eosinophils/ʅL)) 
> 3 × ULN 
> 8 × ULN 
Baseline Total Bilirubin Value 
Elevation 
ч 1.5 × ULN 
> 3 × ULN (> 5 × ULN in patients with baseline total bilirubin value of 
> 1.5 × ULN and ч 3 × ULN (patients with Gilbert syndrome or for 
whom indirect bilirubin concentration suggest an extra-hepatic 
source of elevation) 
Note: For re-challenge, dose modification may be required per Table 2.  
Study treatment should be withheld pending investigation of alternative causes of liver injury (Table 4). 
When withholding study treatment, follow-up should continue for possible drug-induced liver injury 
until the liver test abnormalities resolve to baseline grade. Rechallenge may be considered if an 
alternative cause for the abnormal liver tests (ALT, AST, total bilirubin) is discovered and the laboratory 
abnormalities resolve to normal or baseline values. 
 
 
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Table 4: Investigations of Alternative Causes for Abnormal Liver Tests 
Recommended tests: 
x Complete blood count with differential to assess for eosinophilia  
x Serum total immunoglobulin IgG, antinuclear antibody (ANA), antismooth muscle antibody, liver kidney 
microsomal antibody 1 (LKM1), and liver cytosol type 1 antibodies (L-C-1) to assess for autoimmune 
hepatitis  
x Serum acetaminophen (paracetamol) concentration 
Obtain a more detailed history: 
x Prior and concurrent diseases or illness  
x Exposure to environmental and/or industrial chemical agents  
x Symptoms (if applicable) including right upper quadrant pain, hypersensitivity-type reactions, fatigue, 
nausea, vomiting, and fever  
x Prior and concurrent use of alcohol, recreational drugs, and special diets  
x Concomitant use of medications (including nonprescription medicines and herbal and dietary 
supplements), plants, and mushrooms  
x Obtain viral serologies for hepatitis A, B, C, and E (D if positive for hepatitis B), cytomegalovirus, 
Epstein-Barr virus, herpes simplex virus  
Recommended tests as clinically indicated: 
x Echocardiogram (ECHO)  
x Serum and urine copper and serum ceruloplasmin  
x Iron studies (serum iron and ferritin) and transferrin saturation  
x Serology for celiac disease  
x Serum alpha-1 antitrypsin  
x Creatine phosphokinase (CPK), haptoglobin, lactate dehydrogenase (LDH), and peripheral blood smear  
x Appropriate liver imaging  
x Hepatology consult (liver biopsy may be considered in consultation with a hepatologist) 
 
The investigator and the Sponsor should discuss and agree with any decision to re-challenge. Following 
re-challenge, patients should be closely monitored for signs and symptoms of hepatitis and/or abnormal 
liver test results. If signs or symptoms recur with re-challenge, study drug should be permanently 
discontinued. Re-challenge should never occur if the criteria for permanent discontinuation are clearly 
met. 
 
Criteria for Permanent Discontinuation of Talazoparib in Association With Liver Test 
5.4.2.2.2.
Abnormalities  
Talazoparib should be discontinued permanently if ALL of the following 4 criteria are met (i.e. potential 
severe drug-induced liver injury/Hy’s law case):  
1. AST or ALT increases to ш 3 times ULN (> 5 times ULN if baseline ALT/AST is > 3 times ULN)  
2. Total bilirubin increases to > 2 times ULN or INR > 1.5  
3. Alkaline phosphatase value does not reach 2 times ULN (note: in the presence of elevated 
alkaline phosphatase associated with bone metastases, gamma glutamyl transferase (GGT) 
should be tested and the results should be within the reference range)  
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4. No alternative cause explains the combination of the above laboratory abnormalities; important 
alternative causes include, but are not limited to the following:  
x Hepatobiliary tract disease  
x Viral hepatitis (e.g. hepatitis A/B/C/D/E, Epstein-Barr virus, cytomegalovirus, herpes 
simplex virus, varicella, toxoplasmosis, and parvovirus)  
x Congestive heart failure, hypotension, or any cause of hypoxia to the liver causing 
ischemia  
x Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants, and mushrooms  
x Alcoholic hepatitis  
x Nonalcoholic steatohepatitis (NASH)  
x Autoimmune hepatitis  
x Wilson disease and hemochromatosis  
x Alpha-1 antitrypsin deficiency  
If an alternative cause for hepatotoxicity is identified or less stringent conditions developed than those 
noted above, then it should be determined (based on the patient population and/or severity of the 
hepatotoxicity or event) whether talazoparib should be withheld or permanently discontinued as 
appropriate for the safety of the patient. When talazoparib is temporarily withheld or permanently 
discontinued due to a potential drug-induced liver injury, a period of close observation is to commence 
until the liver test abnormalities return to baseline or normal values. The evaluations listed in Table 5 
should be performed.  
Table 5: Monitoring of Liver Tests for Potential Drug-Induced Liver Injury 
Results 
Frequency of Repeating Liver (AST, ALT, 
Biliubin (total and direct)) and INR tests 
After the initial liver abnormality 
Within 24 hours 
If AST or ALT ш 3 x ULN (> 5 x ULN if 
baseline ALT/AST is 3 x ULN) and total 
bilirubin > 2 or INR > 1.5 
Every 24 hours until laboratory 
abnormalities improve 
If AST or ALT ш 3 x ULN (>5 x ULN if 
baseline ALT/AST is 3 x ULN) and total 
bilirubin or INR are normal 
Every 48 to 72 hours until laboratory 
abnormalities improve 
If the liver test abnormalities improve 
AND the patient is asymptomatic  
Frequency may decrease 
 
As drug-induced liver injury is a diagnosis of exclusion, it is important to initiate investigation of 
alternative causes for abnormal liver tests, which may include consultation with a hepatologist. 
Guidance for such cases is provided in section 8.4.1 Potential Cases of Drug-Induced Liver Injury.  
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5.5. 
Study Treatment Discontinuation 
By default, patients are treated for 22 calendar days counted from day 1, regardless of any treatment 
hold. The Investigator will discontinue study treatment before Day 22 if any of the following conditions 
are met: 
x Patient’s decision to withdraw study treatment 
x Intercurrent illness or a change in patient´s condition or unacceptable toxicity that warrants study 
treatment discontinuation according to Investigator judgment 
x Any event, condition, criterion which would warrant treatment discontinuation according to 
section 5.4 
x Need for additional local and/or systemic non-protocol anticancer therapy or patient receives 
non-protocol anticancer therapy at any time during the study treatment.  
x Progressive Disease 
x Lost to follow up 
x Death 
x Pregnancy 
x Investigator’s decision 
x Medical Monitor’s decision 
x Sponsor’s discontinuation of the study 
Permanent treatment discontinuation is defined as permanent cessation of study drug administration.  
After permanent treatment discontinuation, a Safety Follow up Visit (End of Study visit) will be 
performed. The Safety Follow up Visit corresponds to the end of study participation.  
6. CONCOMITANT TREATMENT AND PROCEDURES 
Concomitant therapy includes any medication (e.g. prescription drugs, over-the-counter drugs, 
herbal/homeopathic remedies, nutritional supplements, etc.) used by a patient from 28 days prior to 
enrollment until 30 days after the last dose of study drug or the first day of extension study whichever 
occurs first. Any concomitant medication during the study will be recorded on the eCRF. 
In the event of an emergency, any needed medications (even if prohibited per section 6.3) may be 
prescribed as required, but the 
 Medical Monitor or designee must be notified of the use of any 
prohibited medication immediately thereafter.  
The following sections and Table 6 provide a list of allowed and prohibited medications and instructions 
on their use. 
6.1. 
Allowed Concomitant Treatments 
The Investigator may prescribe concomitant medications during the study as clinically indicated; as long 
as the prescribed medication is not prohibited by the protocol (refer to section 6.3). Allowed 
medications include (but are not limited to): 
x Anti-emetics, such as dexamethasone, metoclopramide, ondansetron, aprepitant, etc.; anti-
diarrheals, such as loperamide hydrochloride; appetite stimulants such as megestrol acetate.  
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x Supportive medications may be provided prophylactically or therapeutically at the Investigator’s 
discretion, with the exception of that colony stimulating factor (G-CSF or GM-CSF) and 
erythropoiesis-stimulating agents that are only allowed in the rescue setting (not for primary or 
secondary prophylaxis). Erythropoietin is allowed if the patient is chronically receiving this drug. 
x Bisphosphonates and the monoclonal antibody denosumab are also permitted for treatment, or 
prophylaxis, of bone metastases as per local standards of care.  
6.2. 
Concomitant Medication for Treatment of Renal Impairment 
If the patient is taking concurrent medications for treatment of renal impairment, to be eligible he/she 
must meet inclusion criterion 10. Also, concurrent medication used for the management of renal 
impairment will not be taken for at least 4 hours before and 2 hours after talazoparib dosing. During 
that period, the patient should not take these medications. 
6.3. 
Prohibited Treatments 
Patients are prohibited from receiving the following therapies from the time of patient informed 
consent form (PICF) until the Safety Follow up Visit (End of Study visit): 
x Investigational agents other than talazoparib; 
x Any additional investigational or commercial anticancer agents, such as chemotherapy, 
immunotherapy, targeted therapy, biological response modifiers, endocrine therapy, etc. even 
when used for non-cancer indications; and, 
x Live bacterial and virus vaccines. 
x Use of inhibitors or inducers of P-gp and inhibitors of BCRP (see Table 6). 
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Table 6: Instructions for Use of Concomitant Therapies 
Use Category 
Medication or Treatment 
Comment on Use 
Allowed 
Antiemetics (i.e., prochlorperazine, 
dexamethasone, metoclopramide, 
ondansetron, aprepitant) 
Not applicable 
 
Antidiarrheals (i.e., loperamide 
hydrochloride) 
Not applicable 
 
Appetite stimulants (i.e., megestrol acetate) 
Not applicable 
 
Anticoagulants 
Not applicable 
 
Bisphosphonates or other antiresorptives 
such as denosumab for bone disease 
Not applicable 
 
Corticosteroids 
Not applicable 
 
Pain medications, antidepressants, 
cardiovascular and other medications to treat 
other medical conditions with the exception 
of the medications noted in section 6.3 
Not applicable 
Antibiotics 
Not applicable 
Granulocyte-colony stimulating factor, 
erythropoietin 
Use per American Society of Clinical 
Oncology (ASCO) guidelines 
(Smith et al, 2015b), but should not 
be used prophylactically.   
Palliative radiation therapy only for local pain 
control, and only if in the opinion of the 
treating Investigator the patient does not 
have progressive disease. 
Precaution:  the combination of 
radiation therapy and talazoparib has 
not been studied.   
Prohibited 
Any standard or investigational antineoplastic 
systemic therapy (including but not limited to 
PARP inhibitor, chemotherapy, targeted 
therapy, biologics, immunotherapy, 
endocrine therapy, etc.)  
Within 4 weeks before enrollment 
through the Safety Follow up. 
Other investigational agent (i.e., biologic, 
vaccine, or other agents not approved for 
marketing) 
Within 4 weeks before enrollment 
through the safety Follow up. 
Live bacterial and virus vaccines 
Any time between Day-1 and safety 
follow-up.   
P-gp inhibitors (amiodarone, atorvastatin, 
azithromycin, carvedilol, clarithromycin, 
cobicistat, conivaptan, darunavir, diltiazem, 
diosmin, dronedarone, eliglustat, 
erythromycin, felodipine, flibanserin, 
fluvoxamine, indinavir, itraconazole, 
ketoconozole, lapatinib, lopinavir, piperine, 
propafenone, quercetin, quinidine, 
ranolazine, ritonavir, saquinavir, schisandra 
chinensis extract, telaprevir, tipranavir, 
valspodar, and verapamil) 
Within 7 days or 5 half lives which 
ever is longer prior to Day 1 through 
Safety Follow up. 
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Use Category 
Medication or Treatment 
Comment on Use 
P-gp inducers (avasimibe, carbamazepine, 
phenytoin, rifampin, and St. John’s wort) 
Within 7 days or 5 half lives which 
ever is longer prior to Day 1 through 
Safety Follow up. 
BCRP inhibitors (curcumin, cyclosporine, 
elacridar [GF120918], and eltrombopag) 
Within 7 days or 5 half lives which 
ever is longer prior to Day 1 through 
Safety Follow up. 
6.4. 
Palliative Radiotherapy 
Patients may receive palliative radiotherapy before discontinuing study treatment. However, the effect 
of talazoparib with radiation has not been evaluated. 
6.5. 
Contraception/Reproductive Consideration 
Refer to section 8.4.2.1Error! Reference source not found. for details regarding the reporting 
procedures to follow in the event of pregnancy. Instructions regarding sperm or egg donation and 
breastfeeding are provided in the inclusion/exclusion criteria (section 4). 
6.5.1. 
Females 
Women of childbearing potential must have a negative pregnancy test (tested locally) at screening 
(serum pregnancy test), on Day -1 and at the Safety Follow up (urine or serum pregnancy test) and must 
avoid pregnancy during the study.  
Urine pregnancy tests must have a limit of detection of 25 IU/L (or equivalent units) for human chorionic 
gonadotropin.  If a pregnancy test is positive, study treatment will be discontinued.    
In addition, women of childbearing potential must agree to use a highly effective birth control method 
from the time of first talazoparib administration through 7 months after the last dose of talazoparib. A 
highly effective contraceptive method is defined as: 
x Established use of an oral, intravaginal, or transdermal combined (estrogen and progestogen 
containing) hormonal contraception associated with inhibition of ovulation 
x Established use of an oral, injectable, or implantable progestogen-only hormonal contraception 
associated with inhibition of ovulation 
x Placement of an intrauterine device or intrauterine hormone-releasing system 
x Bilateral tubal ligation for ш 6 months before enrollment 
x Sexual partner(s) vasectomized for ш 6 months before enrollment 
x Sexual abstinence when in relation to the preferred and usual lifestyle of the patient. 
Note: Female patients not of childbearing potential include those who are surgically sterile (bilateral 
salpingectomy, bilateral oophorectomy, or hysterectomy with documentation of the procedure) or who 
are post-menopausal, defined as: 
- ш 55 years of age with no spontaneous menses for ш 12 months before enrollment. 
- < 55 years of age with no spontaneous menses for ш 12 months before enrollment and with 
a postmenopausal follicle-stimulating hormone (FSH) concentration > 30 IU/L (or meeting criteria 
for post-menopausal status by the local laboratory. 
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6.5.2. 
Males 
Male patients must agree to use a condom when having sex with a pregnant woman or with a non-
pregnant woman of childbearing potential, from 21 days before the first dose of study drug through 4 
months after last dose of study drug.  
7. STUDY VISITS AND ASSESSMENTS 
7.1. 
Patient Inclusion  
7.1.1. 
Informed Consent 
In compliance with the Declaration of Helsinki, ICH E6 (Section 4.8), US 21 CFR §50 and other applicable 
local regulations, a properly written and executed (PICF will be obtained for each patient prior to 
entering the patient into the study. 
Prior to any study-specific screening evaluation, the patient or legally acceptable representative (if 
applicable per local regulation) will be informed of the nature of the study and will be given pertinent 
information as to the intended purpose, possible benefits, and possible adverse experiences. A legally 
acceptable representative is an individual or other body authorized under applicable law to consent, on 
behalf of a prospective patient, to the patient’s participation in the study. 
An approved PICF will then be read and signed by the patient (or legally acceptable representative if 
applicable) and, when required, a witness, and the Investigator or a person designated by the 
Investigator, as per local regulations. The patient will be provided with a copy of the signed PICF. 
The patient may withdraw from the study at any time without prejudicing future medical treatment. In 
any case, the withdrawal should be clearly documented in the medical charts of the patient.   
If a potential patient or legally acceptable representative is illiterate or visually impaired, the 
Investigator must provide an impartial witness to read the PICF to the patient and must allow for 
questions. Thereafter, both the patient or legally acceptable representative and the witness must sign 
the PICF to attest that informed consent was freely given and understood. The PICF will include a 
statement by which the patient allows the Sponsor’s duly authorized personnel, the Ethics Committee 
(IRB), and the regulatory authorities to have direct access to its data that will be processed according to 
the confidentiality regulations.  
If important new information becomes available that may be relevant to the patient’s consent and 
willingness to continue participation in the study, the PICF will be revised and submitted to IRB for 
approval/favorable opinion. The new information will be then discussed with the patient in a timely 
manner and if he/she agrees to continue participation in the study, the revised PICF will be signed and 
dated and the patient will receive a copy. 
In line with each country’s applicable regulations, the source should also support the documentation of 
the consent process, for each patient. 
Note: If the patient continues the treatment in the context of the extension study (separate protocol), a 
new PICF will be obtained. 
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7.1.2. 
Patient Enrollment  
Details on the process to be followed to enroll the patient in the study can be found in the Registration 
Eligibility Review and Enrollment Instruction Manual provided to each site. 
Patients will be enrolled in one of the four groups based on their renal function, according to section 
4.1.  
Study treatment should be started within 3 calendar days after enrollment. 
7.2. 
Schedule of Visits and Assessments 
Prior to undergoing any study specific procedures not considered standard practice by the institution, 
patients must read and sign the PICF. Adherence to the schedule of visits and assessments is required 
and visits should be planned accordingly.  
All study visits and procedures are detailed in the Schedule of Visits and Assessments table presented in 
this section. All study procedures and assessment should be performed irrespective of any treatment 
hold. 
In the event assessments are planned for the same scheme time, the order of the assessments should 
be arranged in such a way that PK blood sampling will be done after the ECG and vital signs recordings 
have been conducted, with blood sampling exactly on time. The description of the study assessments is 
in section 7.4. 
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Table 7: Schedule of Visits and Assessments 
 
Pre-
screening 
Screening  
Enrollment 
 
Treatment period: Cycle 01 only 
 
 
Safety Follow up 
Visit (=End of 
Study Visit) (17) 
Study Day 
 
-28 to -2 
(1) 
D-1 
D1 = 
First 
Study 
Drug 
Intake 
(5) 
D2 
D3-
7 
D8 
D9-
D14 
D15 
D16-
D20 
D21 
D22 
D23 
 
Window 
 
 
 
Within  3 
calendar 
days 
post D-1 
 
+/-3 
day
s 
+/-3 
days 
+/-3 
days 
+/-3 
days 
+/-3 
days 
+/-3 
days 
+/-3 
days 
 
-3/+10days 
Informed consent signature  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, medical, surgical, disease 
history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Central review of the eligibility criteria 
(
 and enrollment   
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination (6) 
 
X 
X (3) 
 
 
 
X 
 
X 
 
 
X 
 
X 
ECOG Performance Status 
 
X 
X (3) 
 
 
 
 
 
 
 
 
 
 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
X (3) 
 
 
 
X 
 
X 
 
 
X 
 
X 
Temperature 
 
X 
X (3) 
 
 
 
 
 
 
 
 
 
 
X 
Respiratory Rate 
 
X 
X (3) 
 
 
 
X 
 
X 
 
 
X 
 
X 
12-Lead Electrocardiogram  
 
X 
 
X (2) 
 
 
 
 
 
 
 
X (2) 
 
X 
Supine Heart Rate and Blood Pressure 
 
X 
X (3) 
 
 
 
X 
 
X 
 
 
X 
 
X 
Adverse Event Review 
 
X  
(SAE) 
X  
(SAE) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior 
and 
Concomitant 
medication  
Review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Talazoparib administration 
 
 
 
X (4) 
X 
X 
X (4) 
X 
X (4) 
X 
X 
X (4) 
 
 
Talazoparib compliance 
 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
Serology for HIV 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test assessed locally  
(7) 
 
X 
X  
 
 
 
 
 
 
 
 
 
 
X 
C
CI
C
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Pre-
screening 
Screening  
Enrollment 
 
Treatment period: Cycle 01 only 
 
 
Safety Follow up 
Visit (=End of 
Study Visit) (17) 
Study Day 
 
-28 to -2 
(1) 
D-1 
D1 = 
First 
Study 
Drug 
Intake 
(5) 
D2 
D3-
7 
D8 
D9-
D14 
D15 
D16-
D20 
D21 
D22 
D23 
 
Window 
 
 
 
Within  3 
calendar 
days 
post D-1 
 
+/-3 
day
s 
+/-3 
days 
+/-3 
days 
+/-3 
days 
+/-3 
days 
+/-3 
days 
+/-3 
days 
 
-3/+10days 
Follicle-stimulating hormone  (8) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistry (9) 
 
X 
X (3) 
 
 
 
X 
 
X 
 
 
X 
 
X 
eGFR calculation according to MDRD 
equation  
 
X 
X(3) 
 
 
 
 
 
 
 
 
 
 
 
Hematology (10) 
 
X 
X (3) 
 
 
 
X 
 
X 
 
 
X 
 
X 
Coagulation/urinalysis (11) 
 
X 
X (3) 
 
 
 
 
 
 
 
 
 
 
X 
Tumor assessments  (12) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for PK (13) 
 
 
 
X  
X  
 
X   
 
X  
 
 
X  
X  
X (1 sample only in 
case of early study 
treatment 
discontinuation) 
Blood sample for protein binding analysis 
(14) 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Urine sample for PK (15) 
 
 
 
X 
X 
 
 
 
 
 
 
X 
X 
 
Blood sample for banking (17) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
1: If a transient but clinically significant clinical or laboratory abnormality is seen just prior to enrollment, that the screening period may be extended up to 7 days and if the repeat assessments 
(e.g. on the Day -1) labs are acceptable/meeting the inclusion criteria, then the patient may be included. 
2: Triplicate ECGs (approximately 1-2 minutes apart) assessed locally will be collected at pre-dose and 2 hour post-dose on Day 1 and Day 22. ECG should be done prior to PK drawn with a window 
of ±10 min. 
3: These tests must be done at screening and at enrollment. For patients where enrollment visit is done within 3 days of the screening tests, tests at enrollment can be omitted unless clinically 
indicated to repeat them. 
4: On the days of ambulatory visits, talazoparib will not be taken at home and will be withheld until after the PK sample is collected. 
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5: The patient should start the study treatment within 3 calendar days after enrollment. 
6: Assess systems (eg, general appearance, head, eyes, ears, nose, mouth, skin, heart, lung, lymph nodes, gastrointestinal, genitourinary, neurologic, and skeletal) per standard of care at the study 
site or as clinically indicated by symptoms. 
7: For women of childbearing potential only: must have a negative pregnancy test at screening (serum), on day – 1 and at the Safety FU (urine or serum). Urine pregnancy tests must have a limit of 
detection of 25 IU/L (or equivalent units) for human chorionic gonadotropin.  Discontinue study treatment if a pregnancy test is positive.    
8: Collect only for females with no spontaneous menses for ш 12 months, who are ч 55 years old, and who do not have documented surgical sterilization. 
9: Serum chemistry includes: Albumin, Alkaline phosphatase, ALT, AST, Total Bilirubin (TB), Bicarbonate, Blood Urea Nitrogen (BUN) (urea), calcium, creatinine, chloride, Gamma GT,  glucose, LDH, 
sodium, phosphate, potassium, total protein, Uric Acid, FSH (for women at screening only and if applicable). 
Blood samples for blood chemistry can be drawn within 72 hours prior to dosing. 
10: Hematology includes: Erythrocytes, Hematocrit, Hemoglobin, White Blood Cell (WBC), Absolute Neutrophil Count (ANC), Lymphocytes, Platelets. 
Blood samples for hematology assessments can be drawn within 72 hours prior to dosing. 
11: Coagulation includes: PT or INR, aPTT/PTT.  
Urinalysis (dipstick) includes: pH, specific gravity, protein, glucose, ketones, bilirubin, blood, leukocyte esterase. Microscopy is required if dipstick results for blood and leukocyte esterase are 
positive; Day -1 screening coagulation and urinalysis samples can be taken within 72 hours prior to dosing. 
12: Tumor assessment: Initial Tumor imaging must be performed within 28 days prior to enrollment. Scans and other imaging as part of the standard of care for the concerned solid tumor should be 
performed. 
13: Serial plasma PK analysis will be collected at predetermined times on Day 1 and Day 22. Blood samples for PK bioanalysis will be drawn at the following selected time-points during Day 1 and 
Day 22: pre-dose On day 1 (within 60 minutes prior to dose) and on Day 22 (24 h± 60 minutes from the previous dose (Day21) but within 60 minutes prior to next dose) and then at 0.5, 1, 2, 4, 6, 8-
12, and 24 h post-dose. Post-dose samples up to 60 minutes post-dose will be obtained within a window of ± 3 minutes. From after 60 minutes until 12 h post-dose, samples will be obtained with 
time margins of ±10 minutes. Thereafter, samples should be obtained within ±60 minutes of the scheduled time points. 
Note: 24h post-dose on Day 1 corresponds to the pre-dose on Day 2 and 24h post-dose on Day 22 corresponds to the sample on Day 23.   
Additionally pre-dose samples on Day 8 and Day 15 will be collected 24 h ± 60 minutes from the previous dose but within 60 minutes before the next dose on the day of sample collection.  
14: Blood samples for plasma protein binding evaluation will be collected at 2 hours post-dose on Day 1 and Day 22. Samples will be obtained with a time window of ±10 minutes. 
15: Urine samples for PK analyses will be collected as a single void at pre-dose on Day 1. All urine voided after talazoparib dosing on Day 1 and Day 22 will be collected at the intervals of 0-12 h and 
12-24 h. The ± 60 minute time window also applies to the start and end times of urine collection intervals. 
16: 30 days (-3/+10 days) after the last study drug administration or before initiation of a new anti-cancer therapy (standard or investigational). For patients who enroll and continued talazoparib a 
separate open label extension protocol within 30 days after the last dose of talazoparib the safety follow up will be omitted.  
17: Collect blood sample to be stored for reflex testing for HBV (HBsAg, anti-HBc) and HCV (HCV Ab, reflex testing for HCV RNA if positive).   
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7.3. 
Study Visits 
7.3.1. 
Screening Period 
The screening period starts with the signature of the PICF and ends when the patient is enrolled. 
Assessments should be done during the screening period according to the Schedule of Visits and 
Assessments in section 7.2. All procedures and assessments must be completed within 28 days before 
enrollment except as noted. 
7.3.2. 
Enrollment Period 
Day -1 corresponds to the day of the enrollment of the patient in the study. Tests mandated at 
enrollment according to 
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Table 7 need to be repeated even if done at screening, unless otherwise specified. 
7.3.3. 
Treatment Period  
Study treatment should begin within 3 calendar days of enrollment. Day 1 is the first day the patient 
receives study treatment.  
Study visits during the treatment period will be done according to the Schedule of Visits and 
Assessments in section 7.2.  
7.3.4. 
Safety Follow Up Visit (End of Study Visit)  
The Safety Follow up visit (also called End of Study visit) must be scheduled approximately 30 days 
(window -3/+10 days) after the last study drug administration or before initiation of any new anti-cancer 
therapy, whichever occurs first. The Safety Follow up Visit corresponds to the end of study participation. 
The primary purpose of this visit is to follow up on any AE ongoing at the time of treatment 
discontinuation, and to assess any new AEs that may have occurred since treatment discontinuation. 
For eligible patients who are enrolled and continued talazoparib in a separate open label extension 
protocol within 30 days after the last dose of talazoparib, the safety follow up visit will be omitted.  
7.3.5. 
Follow-Up  
No follow up visit is planned in the context of this study.  
Patients may be eligible to continue talazoparib treatment on a separate open-label extension study 
(refer to section 5.3.3). 
7.4. 
Description of Study Assessments 
7.4.1. 
Demographics and Medical History 
The Investigator will collect and report in the eCRF demographics and complete history of malignant and 
clinically-significant non-malignant diseases including known hypersensitivity reactions. 
7.4.2. 
Physical Examination and Vital Signs 
Physical examination and vital signs collection includes: 
x An examination of major body systems 
x Height and weight  
x Temperature  
x Respiratory Rate 
x Supine Heart Rate 
x Blood Pressure 
7.4.3. 
ECG 
Refer to the Schedule of Visits and Assessments in section 7.2. 
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7.4.4. 
ECOG Performance Status 
Assessment of ECOG PS (Appendix 1) is required to assess patient´s functional status for study eligibility 
purposes and will be performed throughout the study according to the Schedule of Visits and 
Assessments (section 7.2). 
7.4.5. 
Laboratory Safety Assessments 
The following laboratory safety assessments will be done at screening, enrollment, during the study 
treatment phase, and at the Safety Follow up Visit (also called End of study visit) according to the 
Schedule of Visits and Assessments in section 7.2.  
x Hematology: Erythrocytes, Hematocrit, Hemoglobin, White Blood Cell (WBC), Absolute Neutrophil 
Count (ANC), Lymphocytes, Platelets. 
x Serum chemistry: Albumin, Alkaline phosphatase, ALT, AST, Total Bilirubin, Bicarbonate, Blood 
Urea Nitrogen (BUN) (urea), calcium, chloride, creatinine, gamma GT, glucose, LDH, sodium, 
phosphate, potassium, total protein, Uric Acid, FSH (for women at screening only and if 
applicable).  
x Calculation of eGFR according to MDRD equation at screening and at Day -1. 
x Coagulation tests: INR or PT and aPTT/PTT (at baseline and then only if clinically indicated) 
x Urinalysis (dipstick): pH, specific gravity, protein, glucose, ketones, bilirubin, blood, leukocyte 
esterase. Microscopy is required if dipstick results for blood and leukocyte esterase are positive. 
x Serum pregnancy test: only in women of childbearing potential at screening 
x Serum or urine pregnancy test at enrollment (Day -1), at the Safety Follow up visit and when 
clinically indicated. 
x Serology for HIV (only at screening) 
x Blood sample for banking to be stored for reflex testing for HBV (HBsAg, anti-HBc) and HCV 
(HCV Ab, reflex testing for HCV RNA if positive).   
For information on the assessment and collection of AEs refer to section 8 and to the Schedule of Visits 
and Assessments in section 7.2. 
7.4.6. 
Efficacy Assessments 
No efficacy analysis is planned in this study, although screening tumor assessments will be obtained in 
the event that eligible patients choose to continue talazoparib treatment in the separate open-label 
extension study. 
7.4.7. 
PK Assessments 
Procedures for sample collection, labeling, storage and shipment of PK samples will be described in the 
study Laboratory Manual. The exact times of each PK sample collection will be recorded in the eCRF. PK 
samples will be analyzed for talazoparib concentration using a validated LC-MS/MS method. 
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7.4.7.1. 
Blood PK samples  
Blood samples for PK analyses will be drawn at the following selected time-points: 
x Day 1 and Day 22: 
o Pre-dose: 
 On Day 1: within 60 minutes prior to dose 
 On Day 22: 24h ± 60 minutes from the previous dose (Day 21) but within 60 minutes 
prior to the next dose 
o Post dose: 0.5, 1, 2, 4, 6 h, between 8 and 12 h, and 24 h after taking talazoparib. Post-
dose samples up to 60 minutes post-dose will be obtained with a window of ± 3 minutes. 
From after 60 minutes until 12 hours post-dose, samples will be obtained with time 
margins of ± 10 minutes. Thereafter, samples should be obtained within ± 60 minutes of 
the scheduled time points. 
Note: the 24h post -dose sample on Day 1 corresponds to the pre-dose sample on Day 2 and the 
24h post-dose sample on Day 22 corresponds to the sample on Day 23. 
x Day 8 and Day 15: Pre-dose samples will be collected 24h ± 60 minutes from the previous dose 
but within 60 minutes before the next dose on the day of sample collection. 
Note: One PK Blood sample will also be collected at the safety follow up if the study treatment 
discontinues earlier than planned. 
7.4.7.2. 
Urine PK samples 
Urine samples for PK analyses will be collected as follows: 
x As a single void at pre-dose on Day 1 
x All urine voided after talazoparib dosing on Day 1 and Day 22 will be collected between the 
intervals of 0-12 h and 12-24 h. A ± 60 minute time window applies to the start and end times of 
urine collection intervals. 
7.4.7.3. 
Blood samples for plasma protein binding evaluation 
Blood samples for plasma protein binding evaluation will be collected at 2h post-dose on Day 1 and Day 
22. A ± 10 minute window will apply. 
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Table 8: Samples for PK assessment 
PK 
SAMPLES 
Day1 
 
Day 1/ 
Day 2 
D8 
D15 
D22 
D22/ 
D23 
Pre-
Dose 
Post-Dose 
Post-
dose 
Day 1 
= Pre-
Dose 
Day 2 
Pre-
dose 
Pre-
dose 
Pre-
Dose 
Post-Dose 
Post-
dose  
Blood 
sample 
for PK  
x 
x 
x 
x 
x 
x 
x 
x 
X 
X 
x 
x 
x 
x 
x 
x 
x 
x 
Window 
 
withi
n 60 
min 
0.5  
(+/- 3 
min) 
1h  
(+/- 3 
min) 
2h  
(+/- 
10 
min) 
4h  
(+/- 
10 
min) 
6h  
(+/- 
10 
min) 
8-12h 
(+/- 10 
min) 
24h 
 (+/- 
60 
min) 
within 
60 
min(1) 
within 
60 
min(1) 
withi
n 60 
min(1
) 
0.5  
(+/- 3 
min) 
1h 
(+/
- 3 
mi
n) 
2h  
(+/- 
10 
min) 
4h  
(+/- 
10 
min) 
6h 
 (+/- 
10 
min) 
8-12h 
(+/- 
10 
min) 
24h  
(+/- 60 
min) 
Blood 
sample 
for 
protein 
binding 
analysis 
 
 
 
X 
(+/- 
10 
min) 
 
 
 
 
 
 
 
 
 
X 
(+/- 
10 
min) 
 
 
 
 
Urine 
sample 
for PK  
x 
x 
x 
 
 
 
x 
x 
Window 
within 
2 h 
0-12 hour  (+/- 60 min 
12-24 hour (+/- 60 min) 
 
 
 
0-12 hour  (+/- 60 
min) 
12-24 hour (+/- 60 min 
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(1) Pre-dose samples on Day 8, Day 15, and Day 22 will be collected 24h ± 60 minutes from the previous dose but within 60 minutes before the next dose on the day of sample 
collection. 
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7.5. 
Permanent Patient Discontinuation 
The Investigator has the right to withdraw a patient from the study at any time. In addition, patients 
have the right to withdraw from the study at any time for any reason. 
Permanent treatment discontinuation is defined as permanent cessation of study drug administration. 
After permanent discontinuation, a Safety Follow Up Visit (End of Study Visit) will be performed.   
The Safety Follow Up Visit corresponds to the End of Study participation.  
Should a patient decide to withdraw consent, all efforts will be made to complete and report the 
observations as thoroughly as possible. The Investigator should contact the patient by telephone or 
through a visit to establish as completely as possible the reason for the withdrawal. A complete final 
evaluation at the time of the patient’s withdrawal should be made with an explanation of why the 
patient is withdrawing from the study. Withdrawal should be documented on the initial PICF, and must 
be dated and signed by the patient and by the Investigator 
In the case a patient does not show up for study visits, site staff should make reasonable contact 
attempts before declaring the patient as lost to follow-up. These attempts need to be documented in 
the medical records.  
8. ADVERSE EVENT REPORTING 
8.1. 
Requirements 
Table 9 below summarizes the requirements for recording safety events on the CRF and for reporting 
safety events on the 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.  
 
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Table 9: Adverse Events Reporting Requirements 
Safety Event 
Recorded on the CRF 
Reported 
on 
the 
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 or suspected causal relationship to the 
investigational product(s) will be reported as described in the following paragraphs. 
Events listed in Table 9 above that require reporting to Pfizer Safety on the 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 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 SAE 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 section 8.2.4 
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 SAE Report Form; additional source 
documents (eg, medical records, CRF, laboratory data) are to be sent to Pfizer Safety ONLY upon 
request. 
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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 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 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 sections 5.5 and 7.5) 
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.  
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 SAE Report Form, in accordance with section 8.1 above. 
8.1.4. 
Time Period for Collecting AE/ Information 
The time period for actively eliciting and collecting AEs and SAEs (“active collection period”) for each 
patient will be as per the Table below: 
Table 10: Active Collection Period 
Study Period 
SAEs (including AESI) 
AEs 
From the time the 
patient signs the PICF 
Yes 
No 
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From first dose of study 
drug until the Safety 
Follow up Visit (30 days 
after the last dose of 
study drug) or before 
initiation of any new 
anticancer therapy or 
enrollment into the 
talazoparib open-label 
extension study. 
Yes 
Yes 
After the Safety Follow 
up Visit 
(End of Study Visit) 
If assessed as related to the 
study drug by the 
Investigator. 
No 
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 
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 anticancer 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 anticancer 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. 
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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 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 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:  
x Abnormal test findings; 
x Clinically significant signs and symptoms; 
x Changes in physical examination findings; 
x Hypersensitivity; 
x Drug abuse; 
x Drug dependency. 
Additionally, AEs may include signs and symptoms resulting from: 
x Drug overdose; 
x Drug withdrawal; 
x Drug misuse;  
x Drug interactions; 
x Extravasation; 
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x Exposure during pregnancy (EDP); 
x Exposure via breastfeeding; 
x Medication error; 
x Occupational exposure. 
Worsening of signs and symptoms of the malignancy under study should be recorded as an AE 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. 
Adverse Event of Special Interest (AESI) 
AESIs include a diagnosis of MDS or AML (consistent with events observed with talazoparib) and 
abnormal liver test results.   
Liver test abnormalities that require reporting are the following: 
x 
AST or ALT ш 3 times ULN (> 5 × ULN if baseline ALT/AST is > 3 × ULN) and total bilirubin > 
2 times ULN or INR > 1.5 
x 
AST or ALT ш 3 times ULN with signs and symptoms consistent with hepatitis and/or 
eosinophilia (ш 500 eosinophils/ђL) 
Tissue samples and any other supporting data used to enable the diagnosis of MDS or AML should be 
submitted for central review if requested. 
AESIs must be transmitted to Pfizer Safety Unit by completing a SAE form. 
8.2.3. 
Abnormal Test Findings 
Abnormal objective test findings should be recorded as AEs when any of the following conditions are 
met:  
x 
Test result is associated with accompanying symptoms; 
x 
Test result requires additional diagnostic testing or medical/surgical intervention;  
x 
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, 
x 
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. 
8.2.4. 
Serious Adverse Events 
A serious adverse event is any untoward medical occurrence at any dose that: 
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x 
Results in death; 
x 
Is life-threatening (immediate risk of death); 
x 
Requires inpatient hospitalization or prolongation of existing hospitalization; 
x 
Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions); and, 
x 
Results in congenital anomaly/birth defect. 
Or that is considered to be: 
x 
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 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; development of 
drug dependency or drug abuse; or the diagnosis o fa second primary malignancy. 
x 
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.  
x 
Hospitalization due to signs and symptoms of disease progression should not be reported as an 
SAE.  
x 
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 section 8.3). 
8.2.5. 
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 (e.g. 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: 
x 
Rehabilitation facilities; 
x 
Hospice facilities; 
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x 
Respite care (eg, caregiver relief); 
x 
Skilled nursing facilities; 
x 
Nursing homes; 
x 
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:  
x 
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); 
x 
Social admission (eg, patient has no place to sleep); 
x 
Administrative admission (eg, for yearly physical examination); 
x 
Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol); 
x 
Optional admission not associated with a precipitating clinical AE (eg, for elective cosmetic 
surgery); 
x 
Hospitalization for observation without a medical AE; 
x 
Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient; and, 
x 
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. 
8.3. 
Severity Assessment 
The intensity of AEs will be classified and recorded according to the NCI CTCAE (v4.03) in the CRF or 
according to the grading defined in section 5.4.1 if the AE is not specifically listed in NCI CTCAE. 
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 
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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 times the upper limit of normal (× ULN) should be monitored more 
frequently to determine if they are an “adaptor” or are “susceptible.” 
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TB) elevations (> 2 × ULN) by several days or weeks. The 
increase in TB typically occurs while AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TB 
values will be elevated within the same lab sample). In rare instances, by the time TB 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 TB 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: 
x 
Patients with AST/ALT and TB baseline values within the normal range who subsequently 
present with AST or ALT values > 3 × ULN and a TB value > 2 × ULN with no evidence of 
hemolysis and an alkaline phosphatase value < 2 × ULN or not available; 
x 
For patients with baseline AST or ALT or TB 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: 
o Pre-existing 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). 
o Pre-existing values of TB above the normal range: TB 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 TB 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 hfrom awareness of the abnormal results.  This evaluation should include laboratory tests, detailed 
history, and physical assessment.   
In addition to repeating measurements of AST, ALT and TB, 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 
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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 (e.g., biliary tract) may be warranted.  
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and TB elevation 
defined above should be considered potential DILI (Hy’s law) cases if no other reason for the 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.  
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 h of investigator awareness. 
8.4.2.1. 
Exposure During Pregnancy 
For both unapproved/unlicensed products and for marketed products, an exposure during pregnancy 
(EDP) occurs if: 
x 
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; 
x 
An example of environmental exposure would be a case involving direct contact with a Pfizer 
product in a pregnant woman (e.g., a nurse reports that she is pregnant and has been exposed 
to chemotherapeutic products). 
x 
A male has been exposed (e.g., 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 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 (e.g., 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 hof awareness of the exposure.  The 
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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). 
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:  
x 
Spontaneous abortion includes miscarriage and missed abortion; 
x 
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 h of the investigator’s awareness, using the SAE Report Form. 
An exposure during breastfeeding report is not created when a Pfizer drug specifically approved for use 
in breastfeeding women (e.g., 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. 
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An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s awareness, 
using the 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 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. 
Table 11: Medication Errors Reporting Requirements 
Safety Event 
Recorded on the CRF 
Reported 
on 
the 
SAE 
Report 
Form 
to 
Pfizer 
Safety Within 24 Hours of 
Awareness 
Medication error 
All (regardless of whether associated 
with an AE) 
Only if associated with an 
SAE 
 
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: 
x 
Medication errors involving patient exposure to the investigational product; 
x 
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 SAE Report Form only 
when associated with an SAE. 
There is no specific treatment in the event of talazoparib overdose, and symptoms of overdose are not 
established. In the event of overdose, treatment with talazoparib should be stopped, and physicians 
should consider gastric decontamination, follow general supportive measures and treat 
symptomatically. 
 
9. STATISTICAL CONSIDERATIONS 
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9.1. 
Populations for Analyses 
All safety analyses will be performed using the safety population defined as all patients who received 
any amount of talazoparib. 
The PK concentration population is defined as all eligible patients enrolled and treated who have at least 
1 plasma talazoparib concentration. 
The PK parameter analysis population is defined as all evaluable patients enrolled and treated who have 
at least 1 of the talazoparib PK parameters of primary interest. 
9.2. 
Demographics and Screening Characteristics 
Demographics and screening characteristics data will be listed and summarized by each group. 
9.3. 
Protocol Treatment 
Duration of treatment, duration of exposure, cumulative dose and relative dose intensity will be 
summarized by renal impairment group using the safety population.  
9.4. 
Safety Endpoints 
The assessment of safety will be made on the safety population and will be based on summaries of AEs, 
physical examinations (including weight), vital signs, electrocardiograms (ECGs), laboratory evaluations 
and ECOG performance status.  
The latest version of the Medical Dictionary for Regulatory Activities (MedDRA) will be used to code all 
AEs to a preferred term and system organ class. 
The number and percentage of patients with adverse events will be presented by MedDRA’s System 
Organ Class (SOC) and Preferred Term (PT), relationship to study treatment, severity, seriousness and 
action taken (e.g., leading to permanent treatment discontinuation).  
Detailed listings for all AEs will also be provided. 
Laboratory parameters, graded according to the NCI CTCAE v4.03, will be summarized at screening, 
along visits and at the safety follow up visit. Tables of shifts in toxicity will also be provided. 
9.5. 
Pharmacokinetics Endpoints 
Actual PK sampling times and doses will be used for PK parameters calculations. 
The following PK parameters will be calculated by non-compartmental analysis using WinNonlin or 
another appropriate software.  
x 
AUC0-24: area under the concentration time curve from 0 to 24 hours 
x 
Cmax: maximum observed plasma  concentration  
x 
AUC0-24,u: unbound AUC0-24 
x 
Cmax,u: unbound Cmax  
x 
Ctrough: pre-dose plasma drug concentration  
x 
Tmax: time of Cmax estimated directly from the experimental data 
x 
oral unbound CL/FFu: fraction of unbound drug  
x 
Rac: accumulation ratio 
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x 
Ae%: Percentage of dose excreted in urine as unchanged drug  
x 
CLr: renal clearance  
Additional PK parameters will be calculated as applicable.  
The concentration-times data of talazoparib in plasma will be separately tabulated. 
The following statistics will be calculated for each of the sampling points: arithmetic mean, standard 
deviation and coefficient of variation (CV), geometric mean, geometric CV, minimum, median, maximum 
value and the number of measurements. Concentrations below LLOQ will be set to zero when 
calculating descriptive statistics. Means at any time will only be reported if the mean ш LLOQ; for mean < 
LLOQ, “missing” is reported in the tables.  
The PK characteristics of Tmax and Rac will be described utilizing minimum, maximum and median. All PK 
parameters except Tmax  and Rac will be expressed as individual data as well as arithmetic mean, standard 
deviation and coefficient of variation (CV), geometric mean, geometric CV, minimum, median, maximum 
value and the number of measurements. 
PK parameters AUC0-24, Cmax, Cmax,u, and AUC0-24,u on Days 1 and 22 will be natural log-transformed and 
analyzed using an analysis of variance (ANOVA) model with group as a fixed effect to compare each 
renal impairment group (mild, moderate or severe; Test) with the normal renal function group 
(Reference). Additionally, weight and age will be considered as covaraites (at the significance level of 
0.05). Estimates of the adjusted mean differences (Test - Reference) and corresponding 90% CIs for each 
comparison will be obtained from the model. The adjusted mean differences and the 90% CIs for the 
differences will be exponentiated to provide estimates of the ratio of adjusted geometric means 
(Test/Reference) and 90% CIs for the ratios on the untransformed scale.  
Relationship between renal functional measures (e.g. eGFR) and selected PK parameters may be 
explored graphically as appropriate. A regression line and 90% confidence region for the PK parameters 
and renal function will be included if appropriate. Vertical lines for the renal function group cut-off 
values will also be presented on the plots. Different symbols will be used to identify subjects from 
different renal function groups. 
Linear regression will be used to analyze the potential relationship between selected PK parameters and 
renal function.  Estimates of the slope and, intercept, together with their precision (90% CI), and the 
coefficient of determination will be obtained from the model. 
The PK parameters of talazoparib will be summarized descriptively by renal function group and Day.  
Boxplots of mean, median and individual subject parameters will be made across all the groups for 
AUC0-24, and Cmax by Day.  Concentrations will be listed and summarized descriptively by PK sampling 
time and group.  Summary profiles (means and medians) of the concentration- time data will be 
presented with all renal function groups plotted across different groups by Day. Individual subject 
concentration time profiles will be also presented.  For summary statistics and summary plots by 
sampling time, the nominal PK sampling time will be used, for individual subject plots by time, the actual 
PK sampling time will be used. 
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9.6. 
Efficacy Endpoints 
No efficacy analysis is planned in this study. 
9.7. 
Sample Size  
Patients are assigned to one of four groups, based on renal function.  
The study will enroll at least 6 PK evaluable patients with advanced solid tumors per group so at least 24 
patients will be enrolled.  
If enrollment for severe renal impairment group is halted due to unacceptable toxicity profile, 2 
additional evaluable patients will be enrolled in each of Groups A, B and C (total of 8 PK evaluable 
patients each).  
Patients will be considered PK evaluable if they are eligible and have: 
x Completed 22 calendar days of treatment with talazoparib counted from day 1, regardless of any 
treatment hold and miss ч 5 consecutive doses of talazoparib, 
x Received at least 10 consecutive days of 0.5 mg talazoparib daily dose without dosing interruption 
prior to Day 22 PK sample collection, 
x Completed at least 85% of total plasma PK samples collection, 
x Not vomited talazoparib dose on Day 1 and Day 22 of the PK samples collection. 
 
Patients who discontinue the study before the completion of the Day 23 (i.e., 24 h of Day 22) 
assessment and/or who do not meet the above mentioned criteria may be replaced according to 
Sponsor´s judgment. 
 
 
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10. ADMINISTRATIVE, ETHICAL AND REGULATORY STANDARDS 
10.1. Study Committee 
No study committees are planned for this study.   
10.2. Ethical Conduct of the Study 
This clinical study was designed and shall be implemented and reported in accordance with the protocol, 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations 
(including European Directives 2001/20/EC and 2005/28/EC and the US Code of Federal Regulations Title 
21), and with the ethical principles laid down in the Declaration of Helsinki. This study will be conducted 
under ethical, scientific and medical standards that protect the rights of participants which include 
informed consent, independent review, and post-study medical care.  
10.3. Institutional Review Board (IRB)  
Each participating institution must provide the review and approval of this protocol, the associated 
informed consent documents and any recruitment material to an appropriate Institutional Review Board 
(IRB). The IRB decision concerning the conduct of the study will be made in writing and kept with the 
Investigator study file. A copy of this decision will also be provided to 
 
Particular attention is drawn to the FDA's requirements for IRBs. By signing the "Statement of 
Investigator" form (Form FDA 1572), the Investigator provides 
 with the necessary assurance that 
an IRB is responsible for the initial/continuing review and subsequent approval of the proposed clinical 
study in accordance with these regulations when applicable. 
In compliance with the applicable country regulations, the Investigator is responsible for keeping the IRB 
informed of the progress with study renewal at least once a year, or more frequently, as required by the 
IRB. The Investigator must also report any SAE, life-threatening problems or deaths to the IRB as per 
institutional guidelines and inform the Sponsor according to GCP and applicable local regulations. The 
IRB must be informed by the Investigator of the termination of the study. 
10.4. Compliance with the Protocol and Protocol Amendments 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the Investigator contact 
 or its agents, to request approval of a protocol 
deviation, as no such authorized deviations are permitted.  
When a deviation occurs in an emergency situation, such as when a departure from the protocol is 
required to protect the life or physical well-being of a participant, 
 and the reviewing IRB must be 
notified as soon as possible after the emergency situation occurred (ICH E6 GCP 4.5.2 and 21 CFR part 
312.66 ).  
A planned deviation from the protocol that is non-emergent and represents a major change in the 
protocol as approved by the IRB must be considered an amendment and treated as such. Even if the 
Investigator feels a protocol deviation would improve the conduct of the study this must be considered 
a protocol amendment, and unless such an amendment is agreed upon by 
/the Sponsor and 
subsequently approved by the Health Authorities and IRB, it cannot be implemented. All significant 
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protocol deviations will be recorded and reported in the Clinical Study Report (CSR). Any modifications 
to the protocol which may impact the conduct of the study, potential benefit of the patient or may 
affect patient safety, including changes of study objectives, study design, patient population, sample 
sizes, study procedures, or significant administrative aspects will require a formal amendment to the 
protocol.  As previously stated, only amendments that are required to eliminate an immediate hazard to 
patients for patient safety can be implemented prior to the IRB approval. Notwithstanding the need for 
approval of formal protocol amendments, the Investigator is expected to take any immediate action 
required for the safety of any patient included in this study, even if this action represents a deviation 
from the protocol. 
10.5. Monitoring, Auditing and Inspecting 
To ensure compliance with current local regulations and the ICH guidelines, data generated by this study 
must be available for monitoring, audit or inspection upon request by representatives of the national 
and local health authorities, 
/the Sponsor and duly authorized representatives of any entity 
providing support for this study. On site, they will notably review for AEs and study records and directly 
compare them with source documents, review regulatory documents, discuss the conduct of the study 
with the Investigator, verify study drug accountability and confirm that the facilities remain acceptable. 
10.6. Recording, Processing and Retention of Data 
The investigator is responsible for the preparation and maintenance of adequate case histories designed 
to record all observations and other relevant data. All patient data reported in the eCRF must be derived 
from source documents and as such be consistent with the source documents, or the discrepancies must 
be explained. 
Data will be entered and collected via an electronic data capture system (EDC) using eCRFs. EDC is a 
validated system designed for entry of data in compliance with U.S. Food and Drug Administration (FDA) 
regulations for electronic records (21 CFR Part 11). Study site staff will receive training and have access 
to a manual for appropriate eCRF completion. All eCRFs should be completed by designated, trained site 
staff. eCRFs should be reviewed and electronically signed and dated by the Investigator or authorized 
designee. Only identified and trained users may view the data as their actions will become part of the 
audit trail. 
While study sites will be responsible for data entry, 
 will be responsible for data management of 
this study, including quality checks. 
The eCRF must be completed shortly after the patient’s visit. All requested information must be entered 
on the eCRF. If an item is not available or is not applicable, it must be documented as such. The 
completed eCRF must be promptly reviewed and approved by the Investigator or authorized designee. 
In the event of discrepant data, 
 will request data clarification from the sites. The sites will resolve 
the discrepancy electronically in the EDC system. eCRF and data clarification documentation will be 
maintained in the EDC system’s audit trail. 
At the end of the study, the investigator will receive patient data, for their site, in a readable format on 
CD, DVD, or other similar storage format that must be kept with the study records. Acknowledgement of 
receipt of the storage disc or similar storage format is required. 
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The investigator will retain copies of study documentation for a period of at least 15 years from study 
completion. Additional considerations must be made about complying with applicable local laws, 
guidelines, etc. 
10.7. Data Protection 
Patient confidentiality is strictly held in trust by the participating Investigators, their staff, 
 the 
Sponsor or affiliates. This confidentiality is extended to cover testing of biological samples and genetic 
tests in addition to the clinical information relating to participating patients. 
Patient and investigator personal data which may be included in the study database shall be treated in 
compliance with all applicable laws and regulations. When archiving or processing personal data, 
 
and the Sponsor shall take all appropriate measures to safeguard and prevent access to this data by any 
unauthorized third party. The confidentiality of participating patients will be respected with strict 
adherence to professional standards and applicable privacy rules (i.e., Health Insurance Portability and 
Accountability Act [HIPPA] Privacy Rule). 
The study protocol, documentation, data and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized third 
party without prior written approval by 
 or the Sponsor. 
The 
 Medical Monitor or other authorized representatives (
/the Sponsor/Regulatory 
Authorities/Ethics Committees) may inspect all documents and records required to be maintained by 
the investigator, including but not limited to, medical records (office, clinic or hospital) and pharmacy 
records for the patients in this study.  The site will permit access to such records. 
10.8. Withdrawal of Informed Consent for Submitted PK Samples 
If a patient withdraws his/her consent, the Investigator has the responsibility to notify 
 
immediately. 
 will ensure that the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed/destroyed/repatriated and the actions 
are documented and returned to the study site. 
10.9. Insurance of Liabilities 
If required, the Investigator may forward to the IRB a copy of the insurance document required by 
 
in order to cover his/her liabilities, and those of any other participating parties. 
10.10. Use of Information and Publication 
All information concerning the study drug or in connection with this study, supplied by 
/the 
Sponsor and/or by any other party collaborating with 
/the Sponsor within this study, and not 
previously published, is considered confidential and proprietary information. This information includes, 
but is not limited to, the Investigator's Brochure, clinical protocol, workbooks (if applicable), case report 
forms, assay methods, technical methodology, and other technical and scientific data. This confidential 
information shall remain the sole property of the Sponsor and shall not be disclosed to others without 
prior written consent from 
 the Sponsor. Information shall not be used except in the 
performance of this study. 
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Page 78 
To allow for the use of the information derived from this clinical study and to insure compliance to 
current regulations, the Investigator is obliged to provide 
/the Sponsor with complete test results 
and all data developed in this study. No publication, abstract or presentation of the study will be made 
without the approval of the Sponsor. 
/the Sponsor will review the manuscript to prevent forfeiture 
of patent rights to data not in the public domain. Prior to publication, the authorship list will be agreed 
upon by 
/the Sponsor. For the purpose of the efficacy and safety analyses, the names on the author 
list will be given according to the participation in the concept of the study design as well as accrual input 
(number of eligible patients accrued) by the Investigators at each center. The maximum number of 
authors will be determined by the publication policy established by the targeted journal. Abstracts and 
publications will be submitted to the authors and to the Sponsor at least 30 days prior to the expected 
date of submission to the intended publisher. 
 
 
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Page 79 
11. REFERENCES 
1. Schreiber V, Dantzer F, Ame J-C, et al: Poly(ADP-ribose): novel functions for an old molecule. Nat Rev 
Mol Cell Biol 7:517–528, 2006 
2. Murai J, Huang SN, Das BB, et al: Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res 
72:5588–5599, 2012 
3. Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 144:646–674, 2011 
4. Ashworth A: A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the 
treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol Off J Am Soc Clin Oncol 
26:3785–3790, 2008 
5. Mateo J, Carreira S, Sandhu S, et al: DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N 
Engl J Med 373:1697–1708, 2015 
6. Swisher E, Brenton J, Kaufmann S, et al: 215 Updated clinical and preliminary correlative results of 
ARIEL2, a Phase 2 study to identify ovarian cancer patients likely to respond to rucaparib. Eur J Cancer 
50:73, 2014 
7. Shen Y, Rehman FL, Feng Y, et al: BMN 673, a novel and highly potent PARP1/2 inhibitor for the 
treatment of human cancers with DNA repair deficiency. Clin Cancer Res Off J Am Assoc Cancer Res 
19:5003–5015, 2013 
8. Williamson CT, Muzik H, Turhan AG, et al: ATM deficiency sensitizes mantle cell lymphoma cells to 
poly(ADP-ribose) polymerase-1 inhibitors. Mol Cancer Ther 9:347–357, 2010 
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9. Preclinical testing of the PARP inhibitor ABT-888 in microsatellite instable colorectal cancer. [Internet]. 
J Clin Oncol [cited 2016 May 24] Available from: http://meetinglibrary.asco.org/content/32465-65 
10. Mendes-Pereira AM, Martin SA, Brough R, et al: Synthetic lethal targeting of PTEN mutant cells with 
PARP inhibitors. EMBO Mol Med 1:315–322, 2009 
11. Bryant HE, Schultz N, Thomas HD, et al: Specific killing of BRCA2-deficient tumours with inhibitors of 
poly(ADP-ribose) polymerase. Nature 434:913–917, 2005 
12. Farmer H, McCabe N, Lord CJ, et al: Targeting the DNA repair defect in BRCA mutant cells as a 
therapeutic strategy. Nature 434:917–921, 2005 
13. Murai J, Huang S-YN, Renaud A, et al: Stereospecific PARP trapping by BMN 673 and comparison 
with olaparib and rucaparib. Mol Cancer Ther 13:433–443, 2014 
14. Levey AS, Coresh J, Greene T, et al: Using standardized serum creatinine values in the modification of 
diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 145:247–
254, 2006 
 
 
 
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12. APPENDICES 
APPENDIX 1: Eastern Cooperative Oncology Group Performance Status Scale 
 
Grade 
 
Description 
 
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 and sedentary nature, e.g., light housework, 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 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 
 
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