Conditions: Advanced Solid Tumors
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 38
Healthy volunteers: no

Brief summary:
This is a trial to investigate the pharmacokinetics (PK) and the safety of talazoparib in patients with advanced solid tumors and impaired hepatic 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. The decision to allow the patient to continue dosing with talazoparib in an open-label extension (OLE) study will be based on potential overall benefit-risk and patient meeting eligibility criteria for OLE.

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 document:
Prot_000.pdf: 
MDV3800-02
 Protocol Version 5.0 14-Sep-2018 
 
CONFIDENTIAL 
 
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 Hepatic Impairment 
 
 
 
MEDIVATION PROTOCOL: MDV3800-02  
PFIZER PROTOCOL: C3441002 
  
 
 
 
 
Pfizer Medical Monitor 
, MD 
 
 
 
 
 
 
 
 
Protocol Version / Date  
5.0 /14-Sep-2018 
Phase 
I 
Test Compound(s) 
Talazoparib (also known as MDV3800, BMN673) 
Indication 
Advanced solid tumors  
Sponsor  
Medivation, Inc. 
EUDRACT # 
Not Applicable 
IND # 
  
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MDV3800-02/C3441002
 Protocol v. 5.0 – Rationale for Amendment 
Version 5.0 of the protocol is an amendment applicable to all sites and performed in order to clarify 
protocol language and to include updated pharmacokinetic data for talazoparib.  
Additionally, some administrative changes have been included regarding the Pfizer 
 teams.  
The MDV3800-02/C3441002
protocol was amended as follows: 
Document 
Version Date 
Summary of changes 
Protocol version 5.0 
14 Sep 2018 
x
 PFIZER TEAM: administrative changes in teams 
conformation and signature page. 
xLIST 
OF 
ABBREVIATIONS: 
inclusion 
of 
additional 
abbreviations. 
xPROTOCOL 
SYNOPSIS: 
Update 
of 
Study 
Duration, 
Background and Rationale, Study Design (definition of 
evaluability), Population (inclusion/exclusion criteria) and 
Statistical Methods.  
xSECTION 1 BACKGROUND AND RATIONALE: update of 
language as per the most recent version of Talazoparib IB. 
xSECTION 4 .PATIENT SELECTION: revision of wording to 
include updated talazoparib wash out period in females 
and males. 
xSECTION 5. STUDY TREATMENT: update of language for 
clarification. 
xTABLE 4. 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 5. SCHEDULE OF VISITS AND ASSESSMENTS:  
revision of language for clarification. 
xTABLE 7. AE REPORTING REQUIREMENTS: update of 
language for clarification. 
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 
PROTOCOL SIGNATURE PAGE – Sponsor .................................................................................................... 10 
LIST OF ABBREVIATIONS ............................................................................................................................. 11 
PROTOCOL SYNOPSIS .................................................................................................................................. 13 
1. 
BACKGROUND AND RATIONALE ......................................................................................................... 25 
1.1 
Investigational Medicinal Product Overview: Talazoparib ......................................................... 25 
1.1.1 
Background ......................................................................................................................... 25 
1.1.2 
Clinical Study Findings with Talazoparib ............................................................................. 26 
1.1.3 
Pharmacokinetics of Talazoparib ........................................................................................ 26 
1.2 
Study Rationale ........................................................................................................................... 28 
1.2.1 
Rationale for Conducting the Study .................................................................................... 28 
1.2.2 
Rationale for Regimen and Dose Selection ......................................................................... 28 
2. 
OBJECTIVES ......................................................................................................................................... 29 
2.1 
Primary Objective........................................................................................................................ 29 
2.2 
Secondary Objective ................................................................................................................... 29 
3. 
STUDY DESIGN..................................................................................................................................... 29 
4. 
PATIENT SELECTION ............................................................................................................................ 31 
4.1 
Inclusion Criteria ......................................................................................................................... 31 
4.2 
Exclusion Criteria ......................................................................................................................... 33 
5. 
STUDY TREATMENT ............................................................................................................................. 34 
5.1 
Study Treatment Identification ................................................................................................... 34 
5.2 
Investigational Product Information and Management ............................................................. 35 
5.2.1 
Packaging and Labelling ...................................................................................................... 35 
5.2.2 
Storage and Dispensation ................................................................................................... 35 
5.2.3 
Accountability, Return and Destruction.............................................................................. 35 
5.3 
Study Treatment Administration ................................................................................................ 36 
5.3.1 
Dosage and Administration ................................................................................................. 36 
5.3.2 
Pre-medication .................................................................................................................... 37 
5.3.3 
Treatment Compliance ....................................................................................................... 37 
5.3.4 
Treatment Duration ............................................................................................................ 37 
5.4 
Treatment Schedule Adjustment and Adverse Event Management .......................................... 37 
5.4.1 
General Rules ...................................................................................................................... 37 
5.4.2 
Dose Modification due to Adverse Events .......................................................................... 38 
5.4.2.1 
Talazoparib Treatment Adjustment for Non Liver Test Abnormalities ........................... 38 
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5.4.2.2 
Talazoparib Treatment Adjustment due to Liver Test Abnormalities ............................ 40 
5.5 
Study Treatment Discontinuation ............................................................................................... 40 
6. 
CONCOMITANT TREATMENT AND PROCEDURES ............................................................................... 41 
6.1 
Allowed and Prohibited Concomitant Treatments ..................................................................... 41 
6.2 
Palliative Radiotherapy ............................................................................................................... 42 
6.3 
Contraception/Reproductive Consideration ............................................................................... 43 
6.3.1 
Female Patients ................................................................................................................... 43 
6.3.2 
Male Patients ...................................................................................................................... 44 
7. 
STUDY VISITS AND ASSESSMENTS ....................................................................................................... 44 
7.1 
Patient Inclusion ......................................................................................................................... 44 
7.1.1 
Informed Consent ............................................................................................................... 44 
7.1.2 
Patient Enrollment .............................................................................................................. 45 
7.2 
Schedule of Visits and Assessments ............................................................................................ 45 
7.3 
Study Visits .................................................................................................................................. 49 
7.3.1 
Screening Period ................................................................................................................. 49 
7.3.2 
Enrollment Period ............................................................................................................... 49 
7.3.3 
Treatment Period ................................................................................................................ 49 
7.3.4 
Safety Follow Up Visit (End of Study Visit) .......................................................................... 49 
7.3.5 
Follow-up ............................................................................................................................ 49 
7.4 
Description of Study Assessments .............................................................................................. 49 
7.4.1 
Safety Assessments ............................................................................................................. 49 
7.4.1.1 
Physical Examination and Vital signs .............................................................................. 50 
7.4.1.2 
ECOG Performance Status .............................................................................................. 50 
7.4.1.3 
ECG .................................................................................................................................. 50 
7.4.1.4 
Laboratory Assessments ................................................................................................. 50 
7.4.2 
Efficacy Assessments ........................................................................................................... 51 
7.4.3 
PK Assessments ................................................................................................................... 51 
7.4.3.1 
Blood PK Samples ............................................................................................................ 51 
7.4.3.2 
Blood Samples for Plasma Protein Binding Evaluation ................................................... 52 
7.4.3.3 
Urine PK Samples ............................................................................................................ 52 
7.5 
Permanent Patient Discontinuation ........................................................................................... 54 
8. 
ADVERSE EVENT REPORTING .............................................................................................................. 54 
8.1 
Requirements .............................................................................................................................. 54 
8.1.1 
Additional Details On Recording Adverse Events on the CRF ............................................. 55 
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8.1.2 
Eliciting Adverse Event Information .................................................................................... 56 
8.1.3 
Withdrawal From the Study Due to Adverse Events .......................................................... 56 
8.1.4 
Time Period for Collecting AE/ Information ........................................................................ 56 
8.1.4.1 
Reporting SAEs to Pfizer Safety ....................................................................................... 57 
8.1.4.2 
Recording Non-serious AEs and SAEs on the CRF ........................................................... 57 
8.1.5 
Causality Assessment .......................................................................................................... 57 
8.1.6 
Sponsor’s Reporting Requirements to Regulatory Authorities .......................................... 58 
8.2 
Definitions ................................................................................................................................... 58 
8.2.1 
Adverse Events .................................................................................................................... 58 
8.2.2 
Adverse Event of Special Interest (AESI) ............................................................................. 59 
8.2.3 
Abnormal Test Findings....................................................................................................... 59 
8.2.4 
Serious Adverse Events ....................................................................................................... 59 
8.2.5 
Hospitalization .................................................................................................................... 60 
8.3 
Severity Assessment ................................................................................................................... 61 
8.4 
Special Situations ........................................................................................................................ 61 
8.4.1 
Potential Cases of Drug-Induced Liver Injury ...................................................................... 61 
8.4.2 
Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure ....................................................................................................................... 63 
8.4.2.1 
Exposure During Pregnancy ............................................................................................ 63 
8.4.2.2 
Exposure During Breastfeeding ...................................................................................... 64 
8.4.2.3 
Occupational Exposure ................................................................................................... 65 
8.4.3 
Medication Errors ............................................................................................................... 65 
9. 
STATISTICAL CONSIDERATIONS ........................................................................................................... 65 
9.1 
Populations for Analyses ............................................................................................................. 65 
9.2 
Demographics and Screening Characteristics ............................................................................. 66 
9.3 
Protocol Treatment ..................................................................................................................... 66 
9.4 
Safety Endpoints ......................................................................................................................... 66 
9.5 
Pharmacokinetics Endpoints ....................................................................................................... 66 
9.6 
Efficacy Endpoints ....................................................................................................................... 67 
9.7 
Sample Size ................................................................................................................................. 67 
10. 
ADMINISTRATIVE, ETHICAL AND REGULATORY STANDARDS ......................................................... 68 
10.1 
Study Committee ........................................................................................................................ 68 
10.2 
Ethical Conduct of the Study ....................................................................................................... 68 
10.3 
Institutional Review Board (IRB) ................................................................................................. 68 
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10.4 
Compliance with the Protocol and Protocol Amendments ........................................................ 69 
10.5 
Monitoring, Auditing and Inspecting .......................................................................................... 69 
10.6 
Recording, Processing and Retention of Data ............................................................................ 69 
10.7 
Data Protection ........................................................................................................................... 70 
10.8 
Withdrawal of Informed Consent for Submitted PK Samples .................................................... 71 
10.9 
Insurance of Liabilities ................................................................................................................ 71 
10.10 
Use of Information and Publication ........................................................................................ 71 
11. 
REFERENCES .................................................................................................................................... 72 
12. 
APPENDICES .................................................................................................................................... 74 
APPENDIX 1: Eastern Cooperative Oncology Group Performance Status Scale ......................................... 74 
 
 
 
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List of Tables 
Table 1: AE Grading for toxicities when the AE term is not listed in the NCI CTCAE v.4.03 ....................... 38 
Table 2: Talazoparib Treatment Adjustment for Non Liver Test Abnormalities ......................................... 39 
Table 3: Criteria for Permanent Discontinuation of Talazoparib in Association with Liver Test 
Abnormalities .............................................................................................................................................. 40 
Table 4: Instructions for Use of Concomitant Therapies ............................................................................ 41 
Table 5: Schedule of Visits and Assessments .............................................................................................. 46 
Table 6: PK Collection Schedule .................................................................................................................. 53 
Table 7: Adverse Events Reporting Requirements ..................................................................................... 54 
Table 8: Active Collection Period ................................................................................................................ 56 
 
List of Figures 
Figure 1: Study Schema ............................................................................................................................... 31 
 
 
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INVESTIGATORS 
 
Six (6) to twelve (12) 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 
 
Date: 
………………………………………. 
 
 MPH 
 Biostatistics 
Date: 
………………………………………. 
 
 MD  
 Clinical Development  
Date: 
………………………………………. 
 
, MS 
 Regulatory Affairs 
Date: 
………………………………………. 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
Ae% 
Percentage of dose excreted in urine as unchanged drug 
ALT 
Alanine Aminotransferase / GPT 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute Neutrophil Count 
ANOVA 
Analysis of variance 
aPTT/PTT 
(activated) Partial Thromboplastin Time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Transaminase / GOT 
AUC 
Area under the plasma concentration-time curve 
AUC0-24 
Area under the concentration time curve from 0 to 24 hours 
AUC0-24u 
Unbound AUC0-24 
AUCinf 
Area under concentration-time curve from time 0 to infinity 
AUCW 
Area under the concentration-time curve for a dosing interval 
BCRP 
Breast cancer resistance protein 
BRCA 
Breast cancer susceptibility gene 
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CK 
Creatinine kinase 
CL/F 
Apparent clearance of drug from plasma after oral administration 
CLu/F 
Apparent clearance of unbound drug from plasma after oral administration 
CLr 
Renal clearance 
Cmax 
Maximum observed plasma concentration 
Cmaxu 
unbound Cmax 
Ctrough 
Predose plasma drug concentration 
CYP450 
Cytochrome P450 
CRA 
Clinical Research Associate 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
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 
FANCA 
Fanconi Anemia Complementation Group A 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating- hormone 
fu 
Fraction of unbound drug in plasma 
GCP 
Good Clinical Practices 
GI 
Gastrointestinal 
GGT 
Gamma glutamyl transferase 
h 
Hour/hours 
HBsAg 
Hepatitis B surface Antigen  
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HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDPE 
High Density Polyethylene 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator Brochure 
ICH 
International Council for Harmonization 
IMP 
Investigational medicinal product 
INR/PT 
International Normalized Ratio / Prothrombin time 
IRB 
Institutional Review Board 
LC-MS/MS 
Liquid Chromatography with Tandem Mass Spectrometry 
LDH 
Lactate dehydrogenase 
LFT 
Liver Function Tests 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDRD 
Modification of Diet in Renal Disease 
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 
OLE 
Open-label extension 
PARP 
Poly(ADP-ribose) polymerase 
P-gp 
P-glycoprotein 
PICF 
Patient Informed Consent Form 
PK 
Pharmacokinetics 
PR 
Partial Response 
PS 
Performance status 
Rac 
Accumulation ratio 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SCLC 
Small Cell Lung Cancer 
SFU 
Safety Follow Up 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Total Bilirubin 
T1/2 
Terminal half-life 
Tmax 
Time to Cmax 
 
 
ULN 
Upper Limit of Normal 
Vz/F 
Apparent volume of distribution 
WBC 
White Blood Cells 
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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 Hepatic Impairment. 
Protocol # 
MDV3800-02
/C3441002 
Indication 
Advanced solid tumors. 
Study Duration 
Accrual: approximately 24 months. 
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 
6 to 12 sites.  
Background and Rationale 
Talazoparib (PF-06944076; formerly known as BMN 673 and 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 a 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 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 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) 
ƌĂŶŐĞĚĨƌŽŵϭϭϲƚŽϭϵϲŶŐͻŚͬŵ>͘dĂůĂǌŽƉĂƌŝďǁĂƐĞůŝŵŝŶĂƚĞĚƐůŽǁůǇǁŝƚŚ
a mean terminal half-life (T1/2) of 89.8 hs. 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/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), and 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 hs 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 AUC from 0 to 24 h 
(AUC0-24) ranged from ϭϮϲ ƚŽ ϮϬϴ ŶŐͻŚͬŵ>͘ dŚĞ ƚĂůĂǌŽƉĂƌŝď ŐĞŽŵĞƚƌŝĐ
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 T1/2 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 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 toof 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 
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feces.  
Results of a population PK analysis for talazoparib indicated that there 
was no effect of mild hepatic impairment on talazoparib exposure. 
However, talazoparib has not been studied in patients with moderate or 
severe hepatic impairment. To address these knowledge gaps, this study 
is designed to provide pharmacokinetic and safety data following daily 
administration of talazoparib in cancer patients with varying degrees of 
hepatic impairment. 
The study will be carried out in patients with advanced solid tumors with 
normal liver tests and with mild, moderate and severe hepatic 
dysfunction (per the NCI-ODWG classification). Based on the results of 
this study, talazoparib dosing recommendations for patients with 
impaired liver function may be provided to future treating clinicians. 
The dose selected in this study is 0.5 mg/per day which is considered a 
safe dose as it is lower than the Maximum Tolerated Dose (MTD) 
established in patients with normal hepatic function at 1 mg/day. 
Talazoparib has also shown clinical activities at this dose level in a phase I 
study. Talazoparib will be given for 22 calendar days in order to assess the 
safety and pharmacokinetic of talazoparib at the steady state. 
Objectives / Endpoints  
Primary Objective: 
To investigate the effect of mild, moderate or severe hepatic 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 hepatic 
impairment. 
Study Design 
This is an open-label, non-randomized, multi-center, phase I trial to 
investigate the PK and the safety of talazoparib in patients with advanced 
solid tumors and impaired hepatic function. 
PK and Safety data from patients with mild, moderate and severe hepatic 
dysfunction as classified using the National Cancer Institute Organ 
Dysfunction Working Group (NCI-ODWG) criteria for hepatic impairment 
will be compared with a control group consisting of patients with normal 
hepatic function. 
Patients will be assigned to one of four groups based on their hepatic 
function. 
Hepatic function as per the NCI-ODWG classification is defined as follows: 
-
Group A (control, normal hepatic function): Total bilirubin (TB) 
ĂŶĚĂƐƉĂƌƚĂƚĞĂŵŝŶŽƚƌĂŶƐĨĞƌĂƐĞ;^dͿчƵƉƉĞƌůŝŵŝƚŽĨŶŽƌŵĂů
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(ULN). 
-
Group B (mild hepatic dysfunctionͿ͗dчh>EĂnd AST > ULN or 
TB > 1.0 to 1.5 x ULN and any AST value. 
-
Group C (moderate hepatic dysfunction): TB > 1.5 to 3.0 x ULN 
and any AST value. 
-
Group D (severe hepatic dysfunction): TB > 3 x ULN and any AST 
value. 
Patients in Groups A, B, C and D will be enrolled in parallel.  
In each group, 6 PK evaluable patients will be treated with daily oral doses 
of talazoparib 0.5 mg for 22 calendar days irrespective of any treatment 
hold.  
If enrollment in the group of patients with severe hepatic dysfunction 
(Group D) is halted due to safety, 2 additional PK 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 PK-evaluable if they are: 
-
Eligible, 
-
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, and 
-
Received at least 10 consecutive days of 0.5 mg talazoparib daily 
dose without dosing interruption prior to Day 22 PK sample 
collection, and
-
Completed at least 85% of total plasma PK samples collection, 
and 
-
Not vomited talazoparib dose on Day 1 and the last day of dose. 
Patients who discontinue the study prior to completion of Day 23 
assessment 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 h 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 
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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 at the 
intervals of 0-12h and 12-24h. Pre-dose urine samples for PK analyses will 
be collected as a single void 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 (OLE) study. Decision to 
allow the patient to continue dosing with talazoparib in an OLE study will 
be based on potential overall benefit-risk and the patient meeting 
eligibility criteria for the OLE study. 
Population 
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). 
2. Female or male at least 18 years of age. 
3. Histologically or cytologically confirmed advanced solid tumor 
with no available standard treatment options in the opinion of 
the Investigator (i.e. patients who received and failed standard 
therapy or with no effective standard therapy available). 
4. Eastern Cooperative Oncology Group (ECOG) Performance status 
ч 2. 
5. ExpeĐƚĞĚůŝĨĞĞǆƉĞĐƚĂŶĐǇŽĨшϯmonths. 
6. Able to swallow the study drug (no contraindication to oral 
agents). 
7. Hepatic function at screening and enrollment as defined by the 
NCI-ODWG criteria: 
xNormal hepatic function (Group A): Total bilirubin (TB) and 
ĂƐƉĂƌƚĂƚĞĂŵŝŶŽƚƌĂŶƐĨĞƌĂƐĞ;^dͿчƵƉƉĞƌůŝŵŝƚŽĨŶŽƌŵĂů
(ULN) or  
xMild hepatic dysfunction (Group B): dчh>EĂŶĚ^dх
ULN or TB > 1.0 to 1.5 x ULN and any AST value or 
xModerate hepatic dysfunction (Group C): TB > 1.5 to 3.0 x 
ULN and any AST value or 
xSevere hepatic dysfunction (Group D): TB > 3 x ULN and any 
AST value. 
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Each patient’s hepatic function classification for the study will be 
based on the assessment made at enrollment, if screening 
classification is different. No distinction will be made between hepatic 
impairment due to metastases and due to other causes. 
8. Adequate other organ function at screening and enrollment as 
defined by the following criteria, at screening: 
xHematology (blood samples collected ĂĨƚĞƌш 14 days 
without growth factor support or transfusion):  
- Absolute Neutrophils Count (ANC) t 1.5 x 109/L, 
- Platelets t 50 x 109/L, 
- Hemoglobin ш 8 g/dL. 
xRenal: Ğ'&Z;ĞƐƚŝŵĂƚĞĚŐůŽŵĞƌƵůĂƌĨŝůƚƌĂƚŝŽŶƌĂƚĞͿш 55 
mL/min/1.73 m2 by MDRD equation (Modification of Diet 
in Renal Disease [available via www.mdrd.com]). 
Patients with Ğ'&Zш 55 mL/min/1.73 m2 at screening but with 
eGFR < 55 mL/min/1.73 m2 at enrollment may be included if 
the second value is within 15% of the screening eGFR. 
9. Female patients of childbearing potential:   
x
Must have a negative serum pregnancy test at screening  
x
Must agree to use a highly effective form of 
contraception from the time of the first dose of study 
drug through 7 months after the last dose of study drug, 
defined as:  
xFor patients with normal hepatic functions only: 
- 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 
xFor all patients: 
- Placement of an intrauterine device or 
intrauterine hormone releasing-system. 
- ^ĞǆƵĂůƉĂƌƚŶĞƌ;ƐͿǀĂƐĞĐƚŽŵŝǌĞĚĨŽƌш 6 months 
before enrollment. 
- ŝůĂƚĞƌĂůƚƵďĂůůŝŐĂƚŝŽŶшϲŵŽŶƚŚƐďĞĨŽƌĞ
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enrollment. 
- Sexual abstinence when in relation to the 
preferred and usual lifestyle of the patient. 
and  
x
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: 
x
ш 55 years of age with no spontaneous menses ĨŽƌш 12 
months before enrollment. 
x
< 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). 
10.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 thereafter. 
11.Female patients must not be breastfeeding at screening nor 
during the study participation until 7 months after the last dose 
of the study drug. 
12.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 (whichever is longer) 
prior to enrollment with any type of systemic anticancer-therapy 
or any investigational drug. 
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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 Mobitz II second degree or third degree heart 
block unless a permanent pacemaker is in place.  
x
Hypotension as indicated by systolic blood pressure (SBP) 
< 80 mm Hg at screening and at enrollment (day - 1). A 
second measurement is allowed after hydration with po 
fluids if SBP values < 80 mm Hg. 
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
^ĐƌĞĞŶŝŶŐYdĐ&шϰϱϬŵƐĞĐŝŶŵĂůĞƐŽƌшϰϴϬŵƐĞĐŝŶ
females. 
5. Active known or suspected brain metastasis or active 
leptomeningeal disease needing treatment (asymptomatic brain 
metastases not currently undergoing treatments (including 
corticosteroids, radiation, anticonvulsants even with prophylactic 
intent 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 (i.e. meeting the 
criteria for a serious adverse event, a grade 3 or 4 adverse event, 
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 
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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 whichever 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]). 
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 
calendar days (Day 1 to Day 22). 
-
On Days 1 and 22 PK sampling days, all patients will receive 
talazoparib under fasted conditions. Fasting is defined as after an 
overnight fast of at least 6h and no food will be allowed for at least 
4h post-dose. 
-
On the other days, talazoparib can be given with or without food. 
-
Water is allowed as desired. 
Note: 
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. 
Decision to allow the patient to continue dosing with talazoparib in an 
open-label extension (OLE) study will be based on potential overall 
benefit-risk and patient meeting eligibility criteria for OLE. 
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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 calendar 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 points. 
x
Day 1 and Day 22: 
9 Pre-dose : 

On Day 1: within 60 minutes prior to dose  

On Day 22: 24 h ± 60 minutes from the previous dose (Day 21) 
but within 60 minutes prior to next dose  
9 0.5, 1, 2, 4, 6, between 8 and 12 h, and 24 hs 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.  
One PK blood sample will also be collected at the Safety Follow up Visit 
(End of Study visit) if study treatment discontinues earlier than planned. 
x
Day 8 and Day 15: pre-dose samples 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 2h 
post-dose on Day 1 and Day 22. Samples will be obtained with a time 
margins of ±10 minutes. 
 
 
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Urine Samples for PK: 
Urine samples will be collected at the following predetermined time 
points on Day 1 and Day 22: 
x
A 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 minutes 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 who 
have at least 1 plasma talazoparib concentration. 
The PK analyses population is defined as all patients enrolled and treated 
who have at least 1 of the talazoparib PK parameters of primary interest. 
Sample size: 6 PK-evaluable patients will be enrolled per group. If 
enrollment in the group of patients with severe hepatic dysfunction 
(Group D) is halted due to safety, 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 who discontinue the study prior to completion of Day 23 
assessment and/or who do not meet the PK parameter 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 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 OLE study. 
x PK Analysis: The PK parameters will be determined from the 
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talazoparib concentration-time data. PK parameters (AUC0-24, Cmax, 
AUC0-24u, Cmaxu, Ctrough, Tmax, CL/F, CLu/F, fu, Rac, Ae%, and CLr) will be 
calculated using a non-compartmental model with WinNonlin or 
another appropriate software. Additional PK parameters will be 
calculated as applicable. 
PK parameters AUC0-24, Cmax, Cmaxu, and AUC0-24u 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 hepatic impairment group (mild, moderate or severe; Test) 
with the normal hepatic function group (Reference). Additionally, 
weight and age will be considered as a 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 
hepatic functional measures (e.g., TB and AST) and selected PK 
parameters may be explored graphically, as appropriate. 
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1. BACKGROUND AND RATIONALE 
1.1 Investigational Medicinal Product Overview: Talazoparib 
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 a 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 breast cancer susceptibility gene (BRCA)1, BRCA2, Fanconi anemia complementiation 
group (FANCA), Phosphatase and tensin homolog (PTEN), Radiation gene 51 (RAD51), MLH1 
(human mutL homolog 1), Human mutL homolog 2 (MSH2), Ataxia-Telangiectasia Mutated 
(ATM), Double-strand break repair gene MRE11 (MRE11) and PALB2-associated Cancer Risk 
(PALB2) (5;6;7;8;9;10;11;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 (13, 14). 
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 (13). 
Consistent with its antitumor effects in vitro, talazoparib demonstrated antitumor activity in 
xenograft tumor models in mice.  
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1.1.2 Clinical Study Findings with Talazoparib 
As of 31 January 2018, approximately 659 patients and 18 healthy volunteers have received 
talazoparib at doses up to 2 mg/day in company-sponsored studies in hematologic malignancies and 
solid tumors. A phase I 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 patients with locally advanced or metastatic breast cancer 
with deleterious germline BRCA mutations have demonstrated clinically meaningful objective 
response rates and significantly prolonged progression-free survival compared to physician’s choice 
treatment, respectively.  
The most common adverse events (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 
ǁŝƚŚĂƐĞǀĞƌŝƚǇŐƌĂĚĞшϯas per the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) were myelosuppression. Uncommon instances of increased Liver 
Function Tests or hepatotoxicity have been reported in trials with talazoparib (refer to 
talazoparib Investigator’s Brochure (IB)).  
The AEs associated with talazoparib are generally identifiable through routine laboratory and 
clinical monitoring and may be managed by dose reduction or interruption. Clinical development 
of talazoparib is ongoing in various solid tumors as a single agent at the recommended dose of 
1mg/day and in combination with other agents. 
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 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 (AUCinfͿƌĂŶŐĞĚĨƌŽŵϭϭϲƚŽϭϵϲŶŐͻŚͬŵ>͘
Talazoparib was eliminated slowly with a mean T1/2 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. 
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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), and 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 
ĨƌŽŵϭϮϲƚŽϮϬϴŶŐͻŚͬŵ>͘dŚĞƚĂůĂǌŽƉĂƌŝďŐĞŽŵĞƚƌŝĐŵĞĂŶƐƚĞĂĚǇ-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 T1/2 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 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 
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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 phase I, in vitro and in vivo preclinical data, talazoparib appears to be predominantly 
excreted via the renal route. Therefore, it seems that the drug is minimally metabolized in the 
liver following multiple dose intakes. Results of a population PK analysis for talazoparib indicated 
that there was no effect of mild hepatic impairment on talazoparib exposure. However, 
talazoparib has not been studied in patients with moderate or severe hepatic impairment. To 
address these knowledge gaps, this study is designed to provide pharmacokinetic and safety data 
following daily administration of talazoparib in cancer patients with varying degrees of hepatic 
impairment.  
The study will be carried out in patients with advanced solid tumors with normal liver tests and 
with mild, moderate and severe hepatic dysfunction per the National Cancer Institute Organ 
Dysfunction Working Group (NCI-ODWG) classification. Based on the results of this study, 
talazoparib dosing recommendations for patients with impaired liver function may be provided to 
future treating clinicians. 
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 T1/2 was approximately 89.8 h. With daily dose administration, 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 wash-out period would be required to be able to evaluate 
key PK parameters. 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 normal hepatic function and solid tumors in a phase I study at 1 
mg/day. Talazoparib has also shown clinical activity at this dose in a phase I study. However 
efficacy is not being explored in this study; only PK and safety are being evaluated. 
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2. OBJECTIVES 
2.1 Primary Objective 
To investigate the effect of mild, moderate or severe hepatic impairment on the PK of talazoparib 
following daily oral dosing for 22 calendar days, in patients with advanced solid tumors. 
2.2 Secondary Objective 
To evaluate the safety and tolerability of talazoparib in patients with advanced solid tumors and 
with normal, mild, moderate or severe hepatic impairment. 
3. STUDY DESIGN 
This is an open-label, non-randomized, multi-center, phase I trial to investigate the PK and the 
safety of talazoparib in patients with advanced solid tumors and impaired hepatic function. 
Safety and PK data from patients with mild, moderate and severe hepatic impairment as 
classified using the NCI-ODWG criteria for hepatic impairment will be compared with a control 
group consisting of patients with normal hepatic function.  
Patients will be assigned to one of four groups based on their hepatic function. Hepatic function 
defined for each group as per the NCI-ODWG classification is as follows: 
x Group A (control, normal hepatic function): Total bilirubin (TB) and aspartate 
ĂŵŝŶŽƚƌĂŶƐĨĞƌĂƐĞ;^dͿчƵƉƉĞƌůŝŵŝƚŽĨŶŽƌŵĂů;h>EͿ 
x Group B (mild hepatic dysfunction): dчh>EĂŶĚ^dхh>EŽƌd > 1.0 to 1.5 x ULN and 
any AST value. 
x Group C (moderate hepatic dysfunction): TB > 1.5 to 3.0 x ULN and any AST value. 
x Group D (severe hepatic dysfunction): TB > 3 x ULN and any AST value. 
Patients in Groups A, B, C and D will be enrolled in parallel. 
All patients will be treated with oral talazoparib given on a daily basis at the 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 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 
(OLE) study. The decision to allow the patient to continue dosing with talazoparib in an OLE study 
will be based on potential overall benefit-risk and patient meeting eligibility criteria for OLE. 
 
 
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Study periods include: 

Screening,  

Enrollment (D-1),  

A 22 calendar day treatment and  

A safety follow up visit (also called as the End of Study visit) which will occur approximately 
30 days (window -3/+10 days) after the last study drug administration or before initiation of 
a new anticancer therapy whichever occurs first.  
In each group, 6 PK-evaluable patients will be treated by daily oral doses of talazoparib 0.5 mg for 
22 calendar days counted from Day 1 (date of first study drug administration), irrespective of any 
treatment hold. If enrollment in the group of patients with severe hepatic dysfunction (Group D) 
is halted due to safety, 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 6 to 12 participating sites. 
Patients will be considered PK-evaluable if they meet all of the following criteria: 

Eligible, 

Completed 22 calendar days of treatment with talazoparib counted from Day 1, regardless 
of any treatment hold ĂŶĚŵŝƐƐĞƐч 5 consecutive doses of study drug,  

Received at least 10 consecutive days of 0.5 mg talazoparib daily dose without dosing 
interruption prior to Day 22 PK sample collection, 

Completed at least 85% of total plasma PK samples collection, and 

Not vomited talazoparib dose on Day 1 and the last day of dose.
Patients who discontinue the study before the completion of Day 23 assessment and/or who do not 
meet the above-mentioned criteria may be replaced, according to Sponsor´s judgment. 
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 trough 
concentration (pre-dose) samples will be collected on Day 8 and Day 15. One PK plasma sample 
will also be collected at the Safety Follow up Visit (also called the End of Study visit) if the study 
treatment discontinues earlier than planned. 
Plasma samples for plasma protein binding evaluation will be collected on Day 1 and Day 22 (2 h 
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 at the intervals of 0-12 h and 12-24 h. 
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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 all inclusion criteria 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 
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 treatment options in the opinion of the Investigator (i.e. patients who received 
and failed standard therapy or with no effective standard therapy available). 
4. Eastern ŽŽƉĞƌĂƚŝǀĞKŶĐŽůŽŐǇ'ƌŽƵƉ;K'ͿWĞƌĨŽƌŵĂŶĐĞƐƚĂƚƵƐч 2. 
5. ǆƉĞĐƚĞĚůŝĨĞĞǆƉĞĐƚĂŶĐǇŽĨш 3 months.   
6. Able to swallow the study drug (no contraindication to oral agents). 
7. Hepatic function at screening and enrollment as defined by the NCI-ODWG criteria for 
hepatic impairment: 
x Normal hepatic function (Group A): Total bilirubin (TB) and aspartate 
ĂŵŝŶŽƚƌĂŶƐĨĞƌĂƐĞ;^dͿчƵƉƉĞƌůŝŵŝƚŽĨŶŽƌŵĂů;h>EͿŽƌ 
x Mild hepatic dysfunction (Group B)͗dчh>EĂŶĚ^dхh>EŽƌd > 1.0 to 1.5 x 
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ULN and any AST value , or 
x Moderate hepatic dysfunction (Group C): TB > 1.5 to 3.0 x ULN and any AST value 
or 
x Severe hepatic dysfunction (Group D): TB > 3 x ULN and any AST value. 
Each patient’s hepatic function classification for the study will be based on the assessment 
made at enrollment, if screening classification is different. No distinction will be made 
between hepatic impairment due to metastases and due to other causes. 
8. Adequate other organ function at screening and enrollment as defined by the following 
criteria: 
x Hematology ;ďůŽŽĚƐĂŵƉůĞƐĐŽůůĞĐƚĞĚш 14 days without growth factor support or 
transfusion):  
 Absolute Neutrophils Count (ANC) t 1.5 x 109/L 
 Platelets t 50 x 109/L 
 Hemoglobin ш 8 g/dL. 
x Renal: eGFR (estimated glomerular filtration rate) ш 55 mL/min/1.73 m2 byMDRD 
equation (Modification of Diet in Renal Disease [available via www.mdrd.com]). 
WĂƚŝĞŶƚƐ ǁŝƚŚ Ğ'&Z ш 55 mL/min/1.73 m2 at screening but with eGFR < 55 
mL/min/1.73 m2 at enrollment may be included if the second value is within 15% 
of the screening eGFR. 
9. 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:  
x For patients with normal liver function : 
9 Established use of an oral, intravaginal, or transdermal combined (estrogen 
and progestogen containing) hormonal contraception associated with 
inhibition of ovulation 
9 Established use of an oral, injectable, or implantable progestogen 
only- hormonal contraception associated with inhibition of ovulation 
x For all patients: 
9 Placement 
of 
an 
intrauterine 
device 
or 
intrauterine 
hormone 
releasing-system 
9 ^ĞǆƵĂůƉĂƌƚŶĞƌ;ƐͿǀĂƐĞĐƚŽŵŝǌĞĚĨŽƌш 6 months before enrollment 
9 Bilateral tubal ligation ш 6 months before enrollment 
9 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. 
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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 ǇĞĂƌƐŽĨĂŐĞǁŝƚŚŶŽƐƉŽŶƚĂŶĞŽƵƐŵĞŶƐĞƐĨŽƌш 12 months before enrollment. 
-
< 55 ǇĞĂƌƐŽĨĂŐĞǁŝƚŚŶŽƐƉŽŶƚĂŶĞŽƵƐŵĞŶƐĞƐĨŽƌ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. 
10.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. 
11.Female patients must not be breastfeeding at screening nor during the study 
participation until 7 months after the last dose of study drug. 
12.Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, 
and other trial procedures. 
4.2 Exclusion Criteria 
1. Treatment within 14 days or five half lives prior to enrollment whichever is longer with 
any type of systemic anticancer-therapy or any investigational drug.  
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, anticoagulation or pacemaker). 
x History of Mobitz II second degree 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 
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Hg or diastolic blood pressure > 105 mm Hg at screening. May be repeated in 15 
minutes. 
x ^ĐƌĞĞŶŝŶŐYdĐ&шϰϱϬŵƐĞĐŝŶŵĂůĞƐŽƌшϰϴϬŵƐĞĐŝŶĨĞŵĂůĞƐ͘ 
5. Active known or suspected brain metastasis or active leptomeningeal disease needing 
treatment, (asymptomatic brain metastases not currently undergoing treatment 
(including radiation, corticosteroids and/or anticonvulsants, even with prophylactic 
intentare 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 whichever 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]). 
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). 
 
 
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. 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 
Investigator´s Brochure. 
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 strengths 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.  
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). 
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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 Day 8, Day 15 
and Day 22-23 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). 
On Day 1, all patients should be given 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 Day 15 for the 
remaining dosing period (Day 15-Day 22). 
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 their dose of talazoparib and these doses will be administered in 
the clinic by study staff after completing pre-dose visit assessments. If patients take 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 h with no food allowed for at least 4 h 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 more than 12 h 
after the missed scheduled dose. If greater than 12 h, 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 should be brought back to 
the site for accountability and disposal. 
5.3.2 Pre-medication 
No pre-medication is required for the intake of talazoparib. 
5.3.3 Treatment Compliance 
Patients will be instructed to bring all used and unused study drug containers and their completed 
study drug diary on 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. 
5.3.4 Treatment Duration 
The patients will be treated only for 1 cycle, defined as a total of 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 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 in a separate OLE study. The decision to allow the patient to 
continue dosing with talazoparib in the OLE study will be based on potential overall benefit-risk, 
and patient meeting eligibility criteria for OLE. 
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 (window -3/+10 days) after the last study drug administration 
or before initiation of any new anticancer therapy (standard or investigational treatment) 
whichever occurs first. 
Toxicity will be assessed utilizing the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v4.03. For AE terms not specifically listed in the NCI CTCAE, the 
Investigator should report the AE and use the criteria in Table 1 to assess severity: 
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Table 1: AE Grading for toxicities when the AE term is not listed in the NCI CTCAE v.4.03 
 
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). 
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 Talazoparib Treatment Adjustment for Non Liver Test Abnormalities 
Study treatment dose modifications due to AEs, with the exception of liver tests abnormalities, are 
described in Table 2. Talazoparib dose can not be re-escalated after it is reduced due to talazoparib-
related AEs. 
 
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Table 2: Talazoparib Treatment Adjustment for Non Liver Test Abnormalities 
Toxicity 
Talazoparib Adjustment 
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/μL) 
Hold study treatment and monitor weekly until ANC ш 1500/μL.  
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. 
Thrombocytopenia 
(platelets < 
50,000/μL) 
Hold study ƚƌĞĂƚŵĞŶƚƵŶƚŝůƉůĂƚĞůĞƚƐш50,000/μL. 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. 
Grade 3 and 4 non hematological toxicity 
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Other grade 3 or 4 
events, except 
abnormal liver tests 
x
For clinically important grade 3 laboratory abnormalities, study 
treatment may be held. Resume study treatment when the 
ůĂďŽƌĂƚŽƌǇĂďŶŽƌŵĂůŝƚǇƌĞƐŽůǀĞƐƚŽŐƌĂĚĞчϮ;ďĂƐĞůŝŶĞŐƌĂĚĞĨŽƌ
creatinine increases). For clinically important grade 4 laboratory 
abnormalities hold talazoparib until the laboratory abnormality 
ƌĞƐŽůǀĞƐƚŽ'ƌĂĚĞчϮ͘ Reduce study treatment one dose level.  
 
x
For clinically significant grade 3 or 4 AEs, hold study treatment 
until the AE resolves to grade ч 1. If the event resolves or 
improves within 22 days of holding study treatment, and can be 
monitored if it recurs, for Grade 3 AEs resume study treatment at 
the same dose or reduce by 1 dose level to 0.25 mg/day. For 
Grade 4 AEs reduce study treatment by 1 dose level to 0.25 
mg/day.  
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 
treatment is not in the patient’s best interest. 
5.4.2.2 Talazoparib Treatment Adjustment due to Liver Test Abnormalities 
Talazoparib must be discontinued for any one of the liver test abnormalities listed in the table 
below. Re-challenging is not permitted. 
Table 3: Criteria for Permanent Discontinuation of Talazoparib in Association with Liver Test 
Abnormalities 
Baseline AST or ALT Value 
Elevation 
ч ULN 
ш 3 × ULN  
> ULN 
>2 x baseline value 
Baseline Total Bilirubin Value 
Elevation 
Any 
2 x baseline value 
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: 

Patient’s decision to withdraw study treatment, 

Intercurrent illness or a change in patient´s condition or unacceptable toxicity that warrants 
study treatment discontinuation according to Investigator judgment, 
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
Any event, condition, criterion which would warrant treatment discontinuation according to 
section 5.4, 

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, 

Progressive disease, 

Lost to follow up, 

Death, 

Pregnancy, 

Investigator’s decision, 

Medical Monitor’s decision, 

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 before initiation of a new anticancer 
therapy (standard or investigational treatment) or the first day of OLE study whichever occurs first. 
Any concomitant medication reported/administered during the study will be recorded on the eCRF. 
In the event of an emergency, any needed medications (even if prohibited per section 6.1 Allowed 
and Prohibited Concomitant Treatments may be prescribed as required, but the 
 Medical 
Monitor or designee must be notified of the use of any prohibited medication immediately 
thereafter.  
6.1 Allowed and Prohibited Concomitant Treatments 
Allowed and prohibited medications are described in Table 4. 
Table 4: 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 
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Use Category 
Medication or Treatment 
Comment on Use 
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 below (i.e. 
prohibited treatment) 
Not applicable 
Antibiotics 
Not applicable 
Granulocyte-colony stimulating factor, 
erythropoietin stimulating agents 
Use per American Society of Clinical 
Oncology (ASCO) guidelines (Smith et 
al, 2015), 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 other than 
talazoparib (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 
whichever is longer prior to Day 1 
through Safety Follow up. 
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. 
6.2 Palliative Radiotherapy 
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Patients may receive palliative radiotherapy before discontinuing study treatment only for local 
pain control, and only if in the opinion of the treating Investigator the patient does not have 
progressive disease. However, the effect of talazoparib with radiation has not been evaluated. 
6.3 Contraception/Reproductive Consideration 
Refer to section 8.4.2.1 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). 
6.3.1 Female Patients 
Women of childbearing potential must have a negative pregnancy test (testing locally) at screening, 
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 
according to section 5.5. 
Women of childbearing potential must agree to use a highly effective birth control method from the 
time of first dose of study drug through 7 months after the last dose of talazoparib. A highly 
effective contraceptive method is defined as: 

For patients with normal hepatic function: 
R  Established use of an oral, intravaginal, or transdermal combined (estrogen and 
progestogen containing) hormonal contraception associated with inhibition of 
ovulation. 
R Established use of an oral, injectable, or implantable progestogen-only hormonal 
contraception associated with inhibition of ovulation. 

For all patients 
R Placement of an intrauterine device or intrauterine hormone-releasing system. 
R ŝůĂƚĞƌĂůƚƵďĂůůŝŐĂƚŝŽŶĨŽƌшϲŵŽŶƚŚƐďĞĨŽƌĞĞŶƌŽůůŵĞŶƚ. 
R Sexual partner(s) vasectomized ĨŽƌш 6 months before enrollment. 
R 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 ǇĞĂƌƐŽĨĂŐĞǁŝƚŚŶŽƐƉŽŶƚĂŶĞŽƵƐŵĞŶƐĞƐĨŽƌш 12 months before enrollment. 
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- < 55 ǇĞĂƌƐŽĨĂŐĞǁŝƚŚŶŽƐƉŽŶƚĂŶĞŽƵƐŵĞŶƐĞƐĨŽƌ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. 
6.3.2 Male Patients 
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. Contraception should be considered for a non-pregnant 
female partner of childbearing potential. 
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 CFR, 21 CFR §50 and other 
applicable local regulations, a properly written and executed patient informed consent form (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 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 
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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 OLE study, a new PICF will be 
obtained. 
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 hepatic function.  
Hepatic function as per the NCI-ODWG criteria is as follows: 
x Group A (control, normal hepatic dysfunction): Total bilirubin (TB) and aspartate 
ĂŵŝŶŽƚƌĂŶƐĨĞƌĂƐĞ;^dͿчƵƉƉĞƌůŝŵŝƚŽĨŶŽƌŵĂů;h>EͿ. 
x Group B (mild hepatic dysfunction): dчh>EĂŶĚ^dхh>Eor TB > 1.0 to 1.5 x ULN and 
any AST value. 
x Group C (moderate hepatic dysfunction): TB > 1.5 to 3.0 x ULN and any AST value. 
x Group D (severe hepatic dysfunction): TB > 3 x ULN and any AST value. 
The patient should start the study treatment within 3 calendar days after patient enrollment. 
7.2 Schedule of Visits and Assessments 
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 assessments 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 5: Schedule of Visits and Assessments 
 
Pre-
screening 
Screening  
Enrollment 
 
Treatment period: Cycle 01 only 
 
 
Safety Follow 
up Visit (=End 
of Study Visit) 
(10) 
Study Day 
 
-28 to -2 
(16) 
D-1 
D1 = 
First 
Study 
Drug 
Intake 
(12) 
D2 
D3-7 
D8 
D9-
D14 
D15 
D16-
D20 
D21 
D22 
D23 
 
Window 
 
 
 
Within 3 
calendar 
days 
post D-1 
 
+/-3 
days 
+/-3 
days 
+/-3 
days 
+/-3 
days 
+/-3 
days 
+/-3 
days 
+/-3 
days 
                                               
-3/+10 days 
Informed consent signature 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, medical, surgical, disease 
history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Child-Pugh Classification 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Central review of the eligibility criteria 
 
 and enrollment  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination  
 
X 
X (14) 
 
 
 
X 
 
X 
 
 
X 
 
X 
ECOG Performance Status 
 
X 
X (14) 
 
 
 
 
 
 
 
 
 
 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
X (14) 
 
 
 
X 
 
X 
 
 
X 
 
X 
Temperature 
 
X 
X (14) 
 
 
 
 
 
 
 
 
 
 
X 
Respiratory Rate 
 
X 
X (14) 
 
 
 
X 
 
X 
 
 
X 
 
X 
12-Lead Electrocardiogram  
 
X 
 
X (3) 
 
 
 
 
 
 
 
X (3) 
 
X 
Supine Heart Rate and Blood Pressure 
 
X 
X (14) 
 
X 
 
X 
 
X 
 
 
X 
 
X 
Adverse Event Review 
 
X  
(SAE) 
X  
(SAE) 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Prior and Concomitant Medication Review 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Talazoparib Administration 
 
 
 
X 
(15) 
X 
X 
X 
(15) 
X 
X 
(15) 
X 
X 
X 
(15) 
 
 
Talazoparib Compliance 
 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
Serology for HIV 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
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Pre-
screening 
Screening  
Enrollmen
t 
 
Treatment period: Cycle 01 only 
 
 
Safety Follow 
Up Visit (=End 
of Study Visit) 
(10) 
Study Day 
 
-28 to -2 
(16) 
D-1 
D1 = 
First 
Study 
Drug 
Intake 
(12) 
D2 
D3-7 
D8 
D9-
D14 
D15 
D16-
D20 
D21 
D22 
D23 
 
Window 
 
 
 
Within 3 
calendar  
days 
post D-1 
 
+/-3 
days 
+/-3 
days 
+/-3 
days 
+/-3 
days 
+/-3 
days 
+/-3 
days 
+/-3 
days 
+/-3 
days 
-3/+10 days 
Serum Pregnancy Test(1) 
 
X 
X (13) 
 
 
 
 
 
 
 
 
 
 
X 
Follicle-stimulating hormone (2) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry (4) 
 
X 
X (14) 
 
 
 
X 
 
X 
 
 
X 
 
X 
Hematology (5) 
 
X 
X (14) 
 
 
 
X 
 
X 
 
 
X 
 
X 
Coagulation/urinalysis (6) 
 
X 
X (14) 
 
 
 
 
 
 
 
 
 
 
X 
Tumor Assessments (11) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sample for PK (7) 
 
 
 
X  
X  
 
X   
 
X  
 
 
X  
X  
X  (only 1 
sample in case 
of early study 
treatment 
discontinuation) 
Blood Sample for Protein Binding Analysis (8) 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Urine Sample for PK (9) 
 
 
 
X 
X 
 
 
 
 
 
 
X 
X 
 
Blood Samples for Banking (17) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
1: For women of childbearing potential only: must have a negative pregnancy test (locally) 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.    
2: ŽůůĞĐƚŽŶůǇĨŽƌĨĞŵĂůĞƐǁŝƚŚŶŽƐƉŽŶƚĂŶĞŽƵƐŵĞŶƐĞƐĨŽƌш ϭϮŵŽŶƚŚƐ͕ǁŚŽĂƌĞч 55 years old, and who do not have documented surgical sterilization. 
3: Triplicate Electrocardiograms (ECGs) (approximately 1-2 minutes apart) assessed locally, will be collected at pre-dose and 2 h post-dose on Day 1 and Day 22. ECG should be done prior to 
PK draw with a window of ±10 minutes. 
4: Serum chemistry includes: albumin, alkaline phosphatase, ALT, AST, Total Bilirubin (TB), Bicarbonate, Blood Urea Nitrogen (BUN) , calcium, creatinine, chloride, Gamma GT, glucose, LDH, 
sodium, phosphate, potassium, total protein, uric acid. eGFR by MDRD is required at Screening and Day -1 only. Blood samples for blood chemistry can be drawn within 72 h prior to dosing. 
5: Hematology includes: erythrocytes, hematocrit, hemoglobin, White Blood Cell (WBC), Absolute Neutrophil Count (ANC), lymphocytes and platelets. 
Blood samples for hematology assessments can be drawn within 72 h prior to dosing. 
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6: Coagulation includes: aPTT (or TCA), pT or INR.  
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 h prior to dosing. 
7: 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 (Day 21) but within 60 minutes prior to next dose) then 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 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. 
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 D23.   
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.  
8: Blood samples for plasma protein binding evaluation will be collected at 2 h post-dose on Day 1 and Day 22. Samples will be obtained with a time window of ±10 minutes. 
9: 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. 
10: 30 days after the last study drug administration or before initiation of a new anti-cancer therapy (standard or investigational). For eligible patients who are enrolled and continue 
talazoparib in a separate OLE study within 30 days after the last dose of talazoparib, the safety follow up will be omitted.  
11: Tumor assessment: Initial Tumor imaging must be performed within 35 days prior to enrollment. Scans and other imaging as part of the standard of care for the concerned solid tumor 
should be performed. 
12: The patient should start the study treatment within 3 calendar days after enrollment. 
13: If the serum pregnancy test is performed > 7 days prior to the first study drug intake, a urine pregnancy test should be performed at the time of enrollment. 
14: 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. 
15: On the days of ambulatory visits, talazoparib will not be taken at home and will be withheld until after the pre-dose PK sample is collected. 
16: 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, the patient may be included. 
17: Collect blood sample, at screening, to be stored for reflex testing for HBV (HBsAg, anti-HBc) and HCV (HCV Ab, reflex testing for HCV RNA if positive at screening). 
 
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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 Table 5 will 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 after patient enrollment. 
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 30 days (window -
3/+10 days) after the last study drug administration or before initiation of any new anti-cancer 
therapy whichever occurs first.  
For eligible patients who are enrolled and continue talazoparib in a separate OLE study within 30 
days after the last dose of talazoparib, the safety follow up visit will be omitted. 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 
The Safety Follow Up Visit corresponds to the end of study participation. 
7.3.5 Follow-up  
No follow up visits are planned in the context of this study (patients may be eligible to continue 
talazoparib treatment on a separate OLE study, refer to section 5.3.4). 
7.4 Description of Study Assessments 
7.4.1 Safety Assessments 
The following safety assessments will be done at screening, enrollment (Day -1) and during the 
treatment period according to the Schedule of Visits and Assessments in section 7.2.  
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There is no need to repeat safety assessments at enrollment for patients whose enrollment visit is 
done within 3 days of the screening tests. In this case, tests/assessments at enrollment can be 
omitted unless clinically indicated to repeat them.  
7.4.1.1  Physical Examination and Vital signs 

Physical exam: includes an examination of major body systems and weight at screening and 
at enrollment (Day -1), at Days 8, 15 and 22 prior to dose, and at Safety Follow Up Visit. 

Temperature: at screening, at enrollment (Day -1) and at Safety Follow Up Visit. 

Respiratory Rate: at screening and at enrollment (Day -1), at Day 8, 15 and 22 prior to dose, 
and at Safety Follow Up Visit. 

Supine Heart Rate and Blood Pressure: at screening and at enrollment (Day -1), at Days 2, 8, 
15 and 22 prior to dose and at Safety Follow Up Visit. 
7.4.1.2 ECOG Performance Status 
Assessment of the ECOG Performance Status (PS) according to ECOG scale (Appendix 1) is required 
to assess patient´s functional status for study eligibility purposes and will be performed at screening 
and at enrollment (Day -1) and at Safety Follow Up Visit. 
7.4.1.3 ECG 
At screening, and at pre-dose and 2 h post-dose on Day 1 and Day 22; and at Safety Follow Up Visit. 
A time window of ±10 minutes is allowed. 
7.4.1.4 Laboratory 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.  

Hematology: Erythrocytes, Hematocrit, Hemoglobin, White Blood Cell (WBC), Absolute 
Neutrophil Count (ANC), Lymphocytes, Platelets. 

Serum chemistry: albumin, alkaline phosphatase, ALT, AST, Total Bilirubin, Bicarbonates, 
Blood Urea Nitrogen (BUN) (urea), calcium, chloride, creatinine, Gamma GT, glucose, LDH, 
sodium, phosphate, potassium, total protein, Uric Acid. eGFR by MDRD at screening and at 
enrollment (Day -1) only. 

Coagulation tests: INR or PT and aPTT/PTT only at screening, at enrollment (Day -1) and at 
the SFU visit.  

Urinalysis (dipstick): pH, specific gravity, protein, glucose, ketones, bilirubin, blood, 
leukocyte esterase only at screening, at Day -1 and at the SFU visit. Microscopy is required if 
dipstick results for blood and leukocyte esterase are positive. 

Serum pregnancy test: only in women of childbearing potential at screening.  
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
Serum or urine pregnancy test: only in women of childbearing potential at enrollment (Day -
1) at the Safety Follow Up Visit and when clinically indicated.  

Serology for HIV: at screening.  

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). This sample will be used to determine 
possible etiology of abnormal liver tests. 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. 
7.4.2 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 OLE 
study. 
7.4.3 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. Refer to Table 6 for the sample schedule. 
7.4.3.1 Blood PK Samples 
Blood samples for PK analyses will be drawn at the following selected time-points: 

Day 1 and Day 22:  
-
Pre-dose  

On Day 1 : within 60 minutes prior to dose 

On Day 22; 24 h ± 60 minutes from the previous dose (Day 21) but within 60 
minutes prior to next dose ) 
-
0.5, 1, 2, 4, 6 h, between 8 and 12 h, and 24 h post-dose. 
Post-dose 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. 
Note: 24 h post-dose on Day 1 corresponds to pre-dose on Day 2 and the 24 h post-dose 
sample on Day 22 corresponds to the sample on Day 23. 

Day 8 and Day 15: pre-dose samples 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.  
Note: One PK Blood sample will also be collected at the Safety Follow Up Visit if the study 
treatment discontinues earlier than planned. 
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7.4.3.2 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. 
7.4.3.3 Urine PK Samples 
Urine samples for PK analyses will be collected: 
-
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.  
A ±60 minutes time window applies to the start and end times of urine collection intervals. 
 
 
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Table 6: PK Collection Schedule 
 
 
Footnote 1: Pre-dose samples on Day 8, Day 15, and Day 22 will be collected 24 h ± 60 minutes from the previous dose but within 60 min before the next dose on the day of 
sample collection.
SAMPLES 
COLLECTION 
Day 1 
Day 
1/ 
Day 2 
Day 
8 
Day 
15 
Day 22 
Day 22 
/ 23 
Post-Dose 
Post 
dose 
Day 
1     = 
Pre-
Dose 
Day 
2 
Pre-
dos
e 
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 
within 
60 
min 
0.5h 
(±3 
min) 
1h 
(±3 
min) 
2h 
(±10 
min) 
4h 
(±10 
min) 
6h 
(±10 
min) 
8-12h 
(±10 
min) 
 
24h 
(±60 
min)  
within 
60min
(1) 
within 
60min(
1) 
within 
60min(
1) 
0.5h 
(±3 
min) 
1h 
(±3 
min) 
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 h (±60 min) 
12-24 h (±60 min) 
 
 
 
0-12 h (±60 min) 
12-24 h (±60 min) 
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7.5 Permanent Patient Discontinuation 
The Investigator has the right to discontinue a patient from study treatment or withdraw a patient 
from the study at any time. In addition, patients have the right to voluntarily discontinue study 
treatment or 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 complete 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 7 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. 
Table 7: Adverse Events Reporting Requirements 
Safety Event 
Recorded on the CRF 
Reported on the SAE Report 
Form to Pfizer Safety Within 
24 H 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)      
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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 7 above that require reporting to Pfizer Safety on the SAE Report Form within 
24 h 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 h 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. 
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. 
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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 Study Treatment Discontinuation and 7.5 Permanent Patient Discontinuation. 
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 8: Active Collection Period 
Study Period 
SAEs (including AESI) 
AEs 
From the time the patient signs the 
PICF 
Yes 
No 
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. 
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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. In addition, any cases of exposure in utero up to 7 months and 4 months after last 
dose of investigational agent in females and males respectively should be reported as detailed in 
section 8.4.2. 
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. 
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 
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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:  

Abnormal test findings; 

Clinically significant signs and symptoms; 

Changes in physical examination findings; 

Hypersensitivity; 

Drug abuse; 

Drug dependency. 
Additionally, AEs may include signs and symptoms resulting from: 

Drug overdose; 

Drug withdrawal; 

Drug misuse;  

Drug interactions; 

Extravasation; 

Exposure during pregnancy (EDP); 

Exposure via breastfeeding; 

Medication error; 

Occupational exposure. 
Worsening of signs and symptoms of the malignancy under study should be recorded as AEs in the 
appropriate section of the CRF. Disease progression assessed by measurement of malignant lesions 
on radiographs or other methods should not be reported as AEs. 
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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: 
-
^dŽƌ >dш ϯ ƚŝŵĞƐ h>E ;х ϱ пh>E ŝĨ ďĂƐĞůŝŶe ALT/AST is > 3 × ULN) and total 
bilirubin > 2 times ULN or INR > 1.5 
-
^dŽƌ>dшϯƚŝŵĞƐh>EǁŝƚŚƐŝŐŶƐĂŶĚƐǇŵƉƚŽŵƐĐŽŶƐŝƐƚĞŶƚǁŝƚŚŚĞƉĂƚŝƚŝƐĂŶĚͬŽƌ
ĞŽƐŝŶŽƉŚŝůŝĂ;шϱϬϬĞŽƐŝŶŽƉŚŝůƐͬђ>Ϳ 
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:  

Test result is associated with accompanying symptoms and/or 

Test result requires additional diagnostic testing or medical/surgical intervention; and/or 

Test result leads toa change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy; and/or 

Test result is considered to be an AE by the investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE. Any abnormal test result that is determined to be an error does not require 
recording as an AE. 
8.2.4 Serious Adverse Events 
A serious adverse event is any untoward medical occurrence at any dose that: 

Results in death; 

Is life-threatening (immediate risk of death); 

Requires inpatient hospitalization or prolongation of existing hospitalization; 

Results in persistent or significant disability/incapacity (substantial disruption of the ability 
to conduct normal life functions); 

Results in congenital anomaly/birth defect. 
Or that is considered to be: 
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
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 of a second primary malignancy. 

Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the active collection 
period.  

Hospitalization due to signs and symptoms of disease progression should not be reported as 
an SAE.  

If the malignancy has a fatal outcome during the study or within the active collection period, 
then the event leading to death must be recorded as an AE on the CRF, and as an SAE with 
Common Terminology Criteria for Adverse Events (CTCAE) Grade 5 (see section 8.3). 
8.2.5 Hospitalization 
Hospitalization is defined as any initial admission (even less than 24 h) in a hospital or equivalent 
healthcare facility, or any prolongation of an existing admission. Admission also includes transfer 
within the hospital to an acute/intensive care unit (eg, from the psychiatric wing to a medical floor, 
medical floor to a coronary care unit, or neurological floor to a tuberculosis unit). An emergency 
room visit does not necessarily constitute a hospitalization; however, the event leading to the 
emergency room visit is assessed for medical importance. 
Hospitalization does not include the following: 

Rehabilitation facilities; 

Hospice facilities; 

Respite care (eg, caregiver relief); 

Skilled nursing facilities; 

Nursing homes; 

Same-day surgeries (as outpatient/same-day/ambulatory procedures). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical AE is not 
in itself an SAE. Examples include:  
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
Admission for treatment of a preexisting condition not associated with the development of 
a new AE or with a worsening of the preexisting condition (eg, for workup of a persistent 
pretreatment laboratory abnormality); 

Social admission (eg, patient has no place to sleep); 

Administrative admission (eg., for yearly physical examination); 

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol); 

Optional admission not associated with a precipitating clinical AE (eg, for elective cosmetic 
surgery); 

Hospitalization for observation without a medical AE; 

Preplanned treatments or surgical procedures. These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient; 

Admission exclusively for the administration of blood products. 
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not be 
reported as SAEs. However, the medical condition for which the procedure was performed should 
be reported if it meets the definition of an SAE. For example, an acute appendicitis that begins 
during the reporting period should be reported if the SAE requirements are met, and the resulting 
appendectomy should be recorded as treatment of the AE. 
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 
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 ULN should be monitored more frequently 
to determine if they are an “adaptor” or are “susceptible.” 
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In the majority of DILI cases, elevations in AST and/or ALT precede 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 TBili 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: 

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; 

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: 
R 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). 
R 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 h from awareness of the abnormal results. This evaluation should include laboratory tests, 
detailed history, and physical assessment.   
In addition to repeating measurements of AST and 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 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 
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medications), recreational drug, supplement (herbal) use and consumption, family history, sexual 
history, travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be collected.  
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary tract) may 
be warranted.  
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 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: 

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg., because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or being 
exposed to the investigational product; 

An example of environmental exposure would be a case involving direct contact with a 
Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has been 
exposed to chemotherapeutic products). 

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed during 
his partner’s pregnancy. 
If a patient or patient’s partner becomes or is found to be pregnant during the patient’s treatment 
with the investigational product, the investigator must report this information to Pfizer Safety on 
the SAE Report Form and an EDP supplemental form, regardless of whether an SAE has occurred. In 
addition, the investigator must submit information regarding environmental exposure to a Pfizer 
product in a pregnant woman (eg, a patient reports that she is pregnant and has been exposed to a 
cytotoxic product by inhalation or spillage) to Pfizer Safety using the EDP supplemental form. This 
must be done irrespective of whether an AE has occurred and within 24 h of awareness of the 
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exposure. The information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy). 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for all EDP 
reports with an unknown outcome. The investigator will follow the pregnancy until completion (or 
until pregnancy termination) and notify Pfizer Safety of the outcome as a follow-up to the initial 
EDP supplemental form. In the case of a live birth, the structural integrity of the neonate can be 
assessed at the time of birth. In the event of a termination, the reason(s) for termination should be 
specified and, if clinically possible, the structural integrity of the terminated fetus should be 
assessed by gross visual inspection (unless pre-procedure test findings are conclusive for a 
congenital anomaly and the findings are reported). 
If the outcome of the pregnancy meets the criteria for an SAE (ie., ectopic pregnancy, spontaneous 
abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a live-born baby, a 
terminated fetus, an intrauterine fetal demise, or a neonatal death]), the investigator should follow 
the procedures for reporting SAEs. 
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows:  

Spontaneous abortion includes miscarriage and missed abortion; 

Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs when 
the investigator assesses the infant death as related or possibly related to exposure to the 
investigational product.  
Additional information regarding the EDP may be requested by the sponsor. Further follow-up of 
birth outcomes will be handled on a case-by-case basis (eg, follow-up on preterm infants to identify 
developmental delays). In the case of paternal exposure, the investigator will provide the patient 
with the Pregnant Partner Release of Information Form to deliver to his partner. The investigator 
must document in the source documents that the patient was given the Pregnant Partner Release 
of Information Form to provide to his partner. 
8.4.2.2 Exposure During Breastfeeding 
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of an 
associated SAE, to Pfizer Safety within 24 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 (eg, vitamins) is administered in accord with authorized 
use. However, if the infant experiences an SAE associated with such a drug’s administration, the SAE 
is reported together with the exposure during breastfeeding. 
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8.4.2.3 Occupational Exposure 
An occupational exposure occurs when, during the performance of job duties, a person (whether a 
healthcare professional or otherwise) gets in unplanned direct contact with the product, which may 
or may not lead to the occurrence of an AE. 
An occupational exposure is reported to Pfizer Safety within 24 h 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  
Medication errors may result from the administration or consumption of the investigational 
product by the wrong patient, or at the wrong time, or at the wrong dosage strength. 
Medication errors include: 

Medication errors involving patient exposure to the investigational product; 

Potential medication errors or uses outside of what is foreseen in the protocol that do or do 
not involve the participating patient. 
Such medication errors occurring to a study participant are to be captured on the medication error 
page of the CRF, which is a specific version of the AE page. 
In the event of medication dosing error, the sponsor should be notified immediately. 
Whether or not the medication error is accompanied by an AE, as determined by the investigator, 
the medication error is recorded on the medication error page of the CRF and, if applicable, any 
associated AE(s), serious and non-serious, are recorded on an AE page of the CRF.   
Medication errors should be reported to Pfizer Safety within 24 h 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 
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 population is defined as all eligible patients who have at least 1 plasma talazoparib 
concentration. 
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The PK analyses population is defined as all eligible patients enrolled and treated who provide 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 hepatic 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, 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. 
The following PK parameters will be calculated for the PK evaluable population using 
noncompartmental analysis in WinNonlin or another appropriate software.  

AUC0-24: area under the concentration time curve from 0 to 24 h  

Cmax: maximum observed plasma concentration 

AUC0-24u: unbound AUC0-24  

Cmaxu: unbound Cmax 

Ctrough: predose plasma drug concentration  

Tmax: time to reach Cmax  

CL/F: apparent clearance of drug from plasma after oral administration 

CLu/F: apparent clearance of unbound drug from plasma after oral administration 

fu: fraction of unbound drug 

Rac: accumulation ratio  
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
Ae%: percentage of dose excreted in urine as unchanged drug  

CLr: renal clearance  
Additional PK parameters will be calculated as applicable. The concentration-time 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 statŝƐƚŝĐƐ͘DĞĂŶƐĂƚĂŶǇƚŝŵĞǁŝůůŽŶůǇďĞƌĞƉŽƌƚĞĚŝĨƚŚĞŵĞĂŶш>>KY͖
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 CV, geometric mean, geometric CV, minimum, median, maximum value and the 
number of measurements. 
PK parameters AUC0-24, Cmax, Cmaxu, and AUC0-24u 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 hepatic impairment group (mild, moderate or severe; Test) with the normal hepatic function 
group (Reference). Additionally, weight and age will be considered as a covariates (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 hepatic functional measures (e.g., TB and AST) and selected PK parameters 
may be explored graphically as appropriate. 
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 hepatic function. The study will enroll 6 PK-
evaluable patients with advanced solid tumors per group. If enrollment for severe hepatic 
dysfunction group is halted due to safety, 2 additional evaluable patients will be enrolled in each 
Groups A, B and C (total of 8 evaluable patients each). Therefore at least 24 patients will be 
enrolled.  
Patients will be considered evaluable if they are: 
x
Eligible, 
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x
Completed 22 calendar days (counted from Day 1) of treatment with talazoparib regardless 
of any treatment hold ĂŶĚŵŝƐƐĞƐч 5 consecutive doses of study drug, and  
x
Received at least 10 consecutive days of 0.5 mg talazoparib daily dose without dosing 
interruption prior to Day 22 PK sample collection, and 
x
Completed at least 85% of total plasma PK samples, and 
x
Not vomited talazoparib dose on Day 1 and the last day of dose. 
Patients who discontinue the study before the completion of the Day 23 (i.e., 24 h of Day 22) 
assessment and/or do not meet the above-mentioned criteria may be replaced if needed according 
to Sponsor´s judgment. 
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, applicable local 
regulations (including the US Code of Federal Regulations title 21), the Council for International 
Organizations of Medical Sciences (CIOMS), and 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 
. 
Particular attention is drawn to the FDA's requirements for IRBs under 21 CFR Part 56. 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 
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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 GCP 4.5.2 and 21 CFR 
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 protocol deviations will be recorded and reported in the Clinical Study Report (CSR). 
This includes any modifications to the protocol which may have an impact on 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 
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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 CRFs. 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 CRF completion. All CRFs should be completed by 
designated, trained site staff. CRFs 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 CRF must be completed shortly after the patient’s visit. All requested information must be 
entered on the CRF. 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. CRF 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. 
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 (e.g., Health Insurance 
Portability and Accountability Act [HIPPA] Privacy Rule). 
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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 (
 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 the 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 
 
 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 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. 
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 
 or 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. 
 or 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 
 or 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 
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to the authors and to the Sponsor at least 30 days prior to the expected date of submission to the 
intended publisher. 
11.REFERENCES 
1. Schreiber V, Dantzer F, Amé JC, de Murcia G. Poly(ADP-ribose): novel functions for an old 
molecule. Nat Rev Mol Cell Biol. 2006 Jul;7(7):517-28. 
2. Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, et al. Trapping of PARP1 and 
PARP2 by clinical PARP inhibitors. Cancer Res. 2012 Nov 1;72(21):5588-99. 
3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 
4;144(5):646-74. 
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. 2008 Aug 1;26(22):3785-90.  
5. Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-repair 
defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015 Oct 29;373(18):1697-
708. 
6. Swisher E, Brenton J, Kaufmann S, Oza A, Coleman RL, O’Malley D, et al. Updated clinical 
and preliminary correlative results of ARIEL2, a phase 2 study to identify ovarian cancer 
patients likely to respond to rucaparib [abstract]. Eur J Cancer. 2014 Nov;50(Suppl 6):215. 
7. Shen Y, Rehman FL, Feng Y, Boshuizen J, Bajrami I, Elliott R, 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. 2013 Sep 15;19(18):5003-15. 
8. Williamson CT, Muzik H, Turhan AG, Zamò A, O’Connor MJ, Bebb DG, et al. ATM deficiency 
sensitizes mantle cell lymphoma cells to poly(ADP-ribose) polymerase-1 inhibitors. Mol 
Cancer Ther. 2010 Feb;9(2):347-57. 
9. Vilar Sanchez E, Chow A, Raskin L, Iniesta MD, Mukherjee B, Gruber SB. Preclinical testing of 
the PARP inhibitor ABT-888 in microsatellite instable colorectal cancer [abstract]. J Clin 
Oncol. 2009 May 20;27(15 Suppl):11028. 
10.Mendes-Pereira AM, Martin SA, Brough R, McCarthy A, Taylor JR, Kim JS, et al. Synthetic 
lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med. 2009 Sep;1(6-
7):315-22. 
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11.Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of 
BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005 Apr 
14;434(7035):913-7. 
12.Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA 
repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005 Apr 
14;434(7035):917-21. 
13.Shen Y, Rehman FL, Feng Y, Boshuizen J, Bajrami I, Elliott R, 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. 2013 Sep 15;19(18):5003-15. 
14.Murai J, Huang SY, Renaud A, Zhang Y, Ji J, Takeda S, et al. Stereospecific PARP trapping by 
BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther. 2014a 
Feb;13(2):433-43. 
 
 
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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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SAP_001.pdf: 
Medivation, Inc.
Protocol No. MDV3800-02
Statistical Analysis Plan – Amendment 1
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PFIZER CONFIDENTIAL
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Statistical Analysis Plan
Medivation Protocol No. MDV3800-02
14 September 2018
A Phase I Open-Label Pharmacokinetics and Safety Study of Talazoparib 
(MDV3800) in Patients with Advanced Solid Tumors and Normal or 
Varying Degrees of Hepatic Impairment
Sponsor:
Medivation, Inc.
A wholly owned subsidiary of Pfizer Inc.
525 Market Street, 36th Floor
San Francisco, CA 94105, USA
Prepared by:
USA
Tel: 
Fax: 
Document status:
Amendment 1.0, SAP v 2.0
Release date: 
December 9, 2019
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Statistical Analysis Plan – Amendment 1
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Revision History
Version
Date
Author(s)
Summary of Changes/Comments
Version 
1.0
06 March 2017
 
 
 
N/A. This is the original SAP based on 
the final protocol dated August 9th, 
2016.
Version 
2.0
9 December 2019
Amended to include updates from 
Protocol Amendment (v5.0, September 
14, 2018) and add details for planned 
analysis.
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Protocol No. MDV3800-02
Statistical Analysis Plan – Amendment 1
Page 3 of 25
PFIZER CONFIDENTIAL
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. INTRODUCTION .................................................................................................................7
2. STUDY OBJECTIVES..........................................................................................................8
2.1. Primary Objective .....................................................................................................8
2.2. Secondary Objective .................................................................................................8
3. STUDY DESIGN AND METHODS ....................................................................................8
3.1. PK Evaluable Patients ...............................................................................................9
3.2. Collection of Plasma Concentration........................................................................10
3.3. Study Endpoints ......................................................................................................11
3.3.1. Pharmacokinetic Endpoints ........................................................................11
3.3.2. Safety Endpoints.........................................................................................11
3.4. Randomization ........................................................................................................11
3.5. Sample Size Justification ........................................................................................11
3.6. Data Handling .........................................................................................................12
3.6.1. Concentrations Below the Limit of Quantification ....................................12
3.6.2. Deviations, Missing Concentrations and Anomalous Values.....................12
3.6.3. Pharmacokinetic Parameters.......................................................................12
4. DATA ANALYSIS..............................................................................................................14
4.1. Analysis Populations...............................................................................................14
4.2. Study Patients..........................................................................................................14
4.3. Patient Demographics .............................................................................................15
4.4. Baseline Definition..................................................................................................15
4.5. Medical/Surgical History and Procedures/Non-Drug Therapies ............................15
4.6. Prior and Concomitant Medications........................................................................15
4.7. Treatment Compliance ............................................................................................16
4.8. Pharmacokinetic Analysis.......................................................................................16
4.8.1. Plasma and Urine Concentrations...............................................................16
4.8.2. Pharmacokinetic Parameters.......................................................................17
4.8.3. Comparative Analyses of PK Parameters...................................................18
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Statistical Analysis Plan – Amendment 1
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4.9. Efficacy Analysis ....................................................................................................19
4.10. Safety Analysis......................................................................................................19
4.10.1. Study Product Exposure/Administration..................................................19
4.10.2. Adverse Events .........................................................................................19
4.10.3. Clinical Laboratory Assessments .............................................................20
4.10.4. Vital Signs Assessments...........................................................................21
4.10.5. Resting 12-Lead ECGs .............................................................................21
4.10.6. Physical Examinations..............................................................................21
4.10.7. ECOG Performance Status .......................................................................21
4.11. Interim Analysis ....................................................................................................21
4.12. Statistical Programming and Deliverables ............................................................22
4.13. Changes to the Planned Analysis ..........................................................................22
5. REFERENCES ....................................................................................................................23
LIST OF TABLES
Table 1.
Group Assignment......................................................................................9
Table 2.
PK Parameters ..........................................................................................17
LIST OF FIGURES
Figure 1.
Study Schema ...........................................................................................10
APPENDICES
Appendix 1. Table 1.................................................................................................................24
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Statistical Analysis Plan – Amendment 1
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Glossary and Abbreviations
Abbreviation
Term
Ae0-24%
Amount of drug excreted in urine from time 0 to 24 hours expressed 
as percentage of administered dose
Ae0-24
Amount of unchanged drug excreted into urine from 0 to 24 hours
AE
Adverse Event
ALT
Alanine Aminotransferase/GPT
ANC
Absolute Neutrophil Count
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
aPTT/PTT
(Activated) Partial Thromboplastin Time
AST
Aspartate Transaminase / GOT
ATC
Anatomical Therapeutic Chemical
AUC
Area under the concentration-time curve
AUC0-24
Area under the concentration time curve from time 0 to 24 hours
AUC0-24u
Area under the free concentration time curve from 0 to 24 hours
Unbound AUC0-24
BMI
Body mass index
BQL
Below Quantification Limit
BUN
Blood Urea Nitrogen
C0-12ur
Drug concentration in urine from time 0 to 12 hours
C12-24ur
Drug concentration in urine from time 12 to 24 hours
CI
Confidence interval
CLCR
Creatinine Clearance
CL/F
Apparent Oral Clearance
CLr
Renal Clearance
CLu/F
Unbound CL/F
cm
Centimeter
Cmax
Maximum observed plasma concentration
Cmaxu
Unbound Cmax
Ctrough
Plasma trough (pre-dose) concentration
Ctotal
Total plasma concentration of drug
Cunbound
unbound concentration of drug
CV
Coefficient of variation
D1
Day 1
D2
Day 22
DNA
Deoxyribonucleic acid
ECGs
Electrocardiograms
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
eGFR
Estimated Glomerular Filtration Rate
EOS
End of Study
FDA
Food and Drug Administration
fu
Fraction of unbound drug in plasma
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Abbreviation
Term
Gamma GT
Gamma-glutamyl transferase or gamma-glutamyl transpeptidase
H or Hr.
Hour
HBsAg
Hepatitis B surface Antigen
HDPE
High Density Polyethylene
HIV
Human Immunodeficiency Virus
INR/PT
International Normalized Ratio/Prothrombin time
kg
kilogram
LDH
Lactate dehydrogenase
LLOQ
Lower limit of quantification
m2
Square meter
MAD
Maximum Administered Dose
Max
Maximum
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
min
Minute
Min
Minimum
mL
Milliliter
MDV3800
Talazoparib
MRT
Mean residence time
MTD
Maximum Tolerated Dose
n or N
Number of patients
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
ND
Not Done
NS
No Sample
PARP
Poly (ADP-ribose) polymerase
PK
Pharmacokinetic(s)
Rac
Accumulation ratio
SAEs
Serious Adverse Events
SAP
Statistical Analysis Plan
SD
Standard Deviation
SFU
Safety Follow Up
t½
Terminal half-life
TB
Total bilirubin
TEAE
Treatment Emergent Adverse Event
TLFs
Tables, Listings and Figures
Tmax
Time to Cmax
ULN
Upper limit of normal
V0-12ur
Urine volume from time zero to 12 hours
V12-24ur
Urine volume from time 12 to 24 hours
WBC
White Blood Cells
WHO
World Health Organization
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1. INTRODUCTION
Talazoparib (also known as BMN 673 and MDV3800) is a poly (ADP-ribose) polymerase 
(PARP) inhibitor being developed for the treatment of a variety of human cancers. 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 study drug, talazoparib, is a potent, orally bioavailable small molecule poly PARP 
inhibitor in development for the treatment of a variety of human cancers both as single agent 
and in combination with DNA-damaging chemotherapy.
The pharmacokinetics (PK) of talazoparib as a single agent were evaluated in 142 adult 
patients with hematologic malignancies and solid tumors at doses of 0.025 to 2 mg/day 
administered orally, as a single dose or as multiple doses. The PK was similar in patients of 
each cancer type and no differences were apparent between males and females. Oral 
absorption of talazoparib was rapid and independent of dose after administration of single or 
multiple doses. Elimination appeared to follow biphasic kinetics. At 1 mg/day, the mean 
terminal half-life (t½) was approximately 89.8 hrs. Following repeated administration at 1 
mg/day, the median talazoparib accumulation ratio (Rac) ranged from 2.23 to 12.3. Apparent 
oral clearance (CL/F) of talazoparib appeared to be dose linear. A food-effect study 
conducted at 0.5 mg/day in healthy volunteers showed that food had no clinically meaningful 
effect on the extent of absorption (AUC) of talazoparib.
PK studies have shown that overall, plasma talazoparib concentrations increase in a dose-
dependent manner. After a daily administration of talazoparib 1 mg, it took approximately 3 
weeks to reach the steady state. Based on phase 1, in vitro and in vivo preclinical data, 
talazoparib appears to predominantly excrete via the renal route. Therefore, it seems that the 
drug is minimally metabolized in the liver following multiple dose intakes. However, the 
potential effect of hepatic impairment on human PK of talazoparib is not known as most 
clinical studies exclude patients with liver impairment.
This study is designed to provide pharmacokinetic and safety data following daily 
administration of talazoparib in cancer patients with varying degrees of hepatic impairment.
The study is carried out in patients with advanced solid tumors with normal liver function
and with mild, moderate and severe hepatic dysfunction as classified using the National 
Cancer Institute Organ Dysfunction Working Group (per the NCI-ODWG) criteria. Based 
on the results of this study, talazoparib dosing recommendations for patients with impaired 
liver function may be provided to future treating clinicians.
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The dose selected in this study is 0.5 mg/day which is considered a safe dose as it is lower 
than the Maximum Tolerated Dose (MTD) established in patients with normal hepatic 
function at 1 mg/day. Talazoparib has also shown clinical efficacy at this dose level in a 
phase 1 study. Talazoparib will be given for 22 days in order to assess the safety and PK of 
talazoparib at the steady state.
This statistical analysis plan (SAP) covers the detailed procedures for performing statistical 
analyses and for producing tables, listings, and figures (TLFs) in the study.
2. STUDY OBJECTIVES
2.1. Primary Objective
•
To investigate the effect of mild, moderate or severe hepatic impairment on the 
pharmacokinetics of talazoparib following daily oral dosing of talazoparib for 
22 calendar days in patients with advanced solid tumors.  
2.2. Secondary Objective
•
To evaluate the safety and tolerability of talazoparib in patients with advanced solid 
tumors and with normal, mild, moderate or severe hepatic impairment.
3. STUDY DESIGN AND METHODS
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 hepatic 
function.
Safety and PK data from patients with mild, moderate and severe hepatic impairment as 
classified using the NCI-ODWG criteria for hepatic impairment will be compared with a 
control group consisting of patients with normal hepatic function.
Patients will be assigned to one of four groups based on their hepatic function. Hepatic 
function defined for each group as per the NCI-ODWG classification is presented in Table 1.
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Table 1.
Group Assignment
Group
Description
Patients*
A
Control, normal hepatic function: Total 
bilirubin (TB) and aspartate aminotransferase 
(AST) ≤upper limit of normal (ULN)
6 (8)
B
Mild hepatic dysfunction: TB ≤ULN and AST 
> ULN or TB >1.0 to 1.5 × ULN and any AST 
value
6 (8)
C
Moderate hepatic dysfunction: TB >1.5 to 3.0 
× ULN and any AST value
6 (8)
D
Severe hepatic dysfunction: TB >3 × ULN and 
any AST value
6 (0)
* The patient number in the parenthesis will be assigned if Group D is halted due to safety.
Study periods include:
•
Screening;
•
Enrollment (D-1);
•
A 22 day treatment period, and
•
A safety follow up visit (also called as the End of Study visit) which will occur 
approximately 30 days (window -3/+10 days) after the last study drug administration 
or before initiation of a new anticancer therapy, or enrollment into the talazoparib 
open-label extension (OLE) study, whichever occurs first.
In each group, 6 patients will be treated with a daily oral dose of talazoparib 0.5 mg for at 
least 22 calendar days counted from Day 1 (date of first study drug administration). If
treatment in the group of patients with severe hepatic dysfunction (Group D) is halted due to 
safety, 2 additional patients will be enrolled in each of Groups A, B and C (total of 8 PK 
evaluable patients in each group). Therefore, a total of at least 24 patients will be enrolled in 
the study.
3.1. PK Evaluable Patients
Patients will be considered PK Evaluable if they meet all the following criteria:
•
Completed the Day 22 visit;
•
Missed less than 5 consecutive doses;
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•
Received at least 10 consecutive days of 0.5 mg talazoparib daily dose immediately 
preceding D22 visit without dosing interruption;
•
At least 85% of total plasma PK samples collection is reported.
Patients who discontinue the study before the completion of the Day 22 assessment and/or 
who do not meet the above-mentioned criteria may be replaced if needed, upon agreement of
the Sponsor.
3.2. Collection of Plasma Concentration
Serial PK plasma samples will be collected at predetermined times on Day 1 and Day 22 up 
to 24 hours post-dose (Day 2 and Day 23, respectively) for talazoparib concentration 
measurement during which time the patients will be confined to the clinical research facility. 
Additionally, trough (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 (also called the End of 
Study 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 at the intervals of 0-12 hours and 12-
24 hours.
The study schema is shown in Figure 1.
Figure 1.
Study Schema
For a detailed description of study procedures, please refer to protocol Section 7 “STUDY 
VISITS AND ASSESSMENT.
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3.3. Study Endpoints
3.3.1. Pharmacokinetic Endpoints
Primary Endpoints
Talazoparib plasma PK parameters: AUC0-24, Cmax, AUC0-24u, and Cmaxu at steady state (on 
Day 22).
Secondary Endpoints
Plasma talazoparib: 
Single-dose parameters: AU0-24, Cmax, Tmax, fu, AUC0-24u, and Cmaxu;
Multiple-dose parameters: Ctrough, Tmax, fu, Rac, CL/F, and CLu/F.
Urine talazoparib:
Single-dose parameters: Ae0-24 and Ae0-24%;
Multiple-dose parameters: Ae0-24, Ae0-24%, and CLr.
Additional PK parameters will be calculated as applicable.
3.3.2. Safety Endpoints
Any events occurring following start of treatment or increasing in severity will be counted as 
treatment emergent.
Events that occur in a non-treatment period (for example Follow-up) will be counted as 
treatment emergent and attributed to the previous treatment taken.  The safety will be 
evaluated based on the assessments of adverse events (AEs), vital signs, 12-lead 
electrocardiograms (ECGs), laboratory assessments and Eastern Cooperative Oncology 
Group (ECOG) performance status.
3.4. Randomization 
No randomization will be conducted in the study. 
3.5. Sample Size Justification
Patients are assigned to one of four groups, based on hepatic function. The study will enroll 
6 PK evaluable patients (evaluability criteria are included in Section 3) with advanced solid 
tumors per group. If enrollment for severe hepatic dysfunction group is halted due to safety, 
2 additional evaluable patients will be enrolled in each of Groups A, B and C (total of 8 
evaluable subjects in each group). Therefore at least 24 patients will be enrolled. 
Non-evaluable patients may be replaced if needed upon agreement of the Sponsor.
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3.6. Data Handling
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied for missing values.
3.6.1. Concentrations Below the Limit of Quantification
In all data presentations (except a few specific scenarios listed below), concentrations below 
the quantification limit (BQL) will be set to zero.  In data listings, BQL values will be 
reported as “<LLQ”, where LLQ will be replaced with the value for the lower limit of 
quantification). In individual concentration vs. time plots on the semi-logarithmic scale, all 
BQL values will set to missing. 
The mean plots will match the summary table results and will not have an observation at a 
given time point if more than half of the subjects have values BQL.
BQL values will be set to zero when calculating descriptive statistics. Zero concentrations 
will be considered as missing in geometric mean calculation. For PK parameter calculations, 
BQL concentrations will be treated as zero when they occur before the first measurable
concentration; all other BQL values will be treated as missing and set to “.”
3.6.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set
concentrations to missing if one of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample);
2. A deviation in sampling time is of enough concern or a concentration has been 
flagged anomalous by the pharmacokinetics.
Note that summary statistics will not be presented at a time point if more than 50% of the 
data are missing.
3.6.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a subject’s concentration data, the parameter will 
be coded as NC (i.e., not calculated).  (Note that NC values will not be generated beyond the 
day that a subject discontinues).
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a treatment with ≥3 evaluable measurements.  For statistical analyses 
(ie, analysis of variance), PK parameters coded as NC will also be set to missing; and 
analyses will not be performed for a parameter if more than 50% of the data are NC.
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If an individual subject has a known biased estimate of a PK parameter (for example due to 
an unexpected event such as vomiting before all the compound is adequately absorbed in the 
body), this will be footnoted in summary tables and will not be included in the calculation of 
summary statistics or statistical analyses. Concentration Data for Parameter Calculations: 
The concentration data, as reported by the respective bioanalytical groups, will be used 
without rounding for all analyses.
Concentration Data Listings: For consistency in presentation of data across clinical studies, 
talazoparib concentration values reported by the respective bioanalytical groups may be 
converted to other units in the listings. In cases where concentration data may be supplied 
electronically with unrealistic precision, rounded values may be presented.  A default of 
3 significant figures is suggested, except for Tmax (2 decimal places).
Parameter Data Listings: The non-compartmental parameters should not be reported to any 
greater precision than that of the concentration data.  A default of 3 significant figures is 
preferred.  
Summary Statistics of PK data:
Parameter values (and if applicable, concentration values) should be rounded to the same 
precision used in data listings prior to any statistical analysis or descriptive summaries.  
Descriptive summaries:
•
Means, Median – 1 more significant figure than the data;
•
Tmax and any other parameters which are time parameters, median will have the same 
significant figures as the data;
•
Standard Deviation – 1 more significant figure than means;
•
CV% – whole numbers;
•
Minimum, Maximum – same significant figures as the data.
Statistical summaries of PK data: 
•
Means, Differences, CIs (non-transformed data) – 1 more significant figure than the
data;
•
Ratios, CIs (log transformed data) – 2 decimal places;
•
Individual differences, ratios and ln ratios – same significant figures as the data. 
Study Reports: 
Generally, for consistency and to simplify document QC, values presented within tables in a 
Clinical Study Report will match the data in the source tables.  
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For reporting of safety data, unless otherwise indicated, continuous variables will be 
summarized with the following descriptive statistics: n (number of observations), (arithmetic) 
mean, standard deviation (SD), minimum (min) value, median, and maximum (max) value.
4. DATA ANALYSIS
4.1. Analysis Populations
Safety Population: All patients who receive any amount of talazoparib will be included in 
the safety analyses and listings.
PK Concentration Population: All enrolled patients who receive at least 1 dose of 
talazoparib and who have at least 1 reportable talazoparib concentration. This population will 
be used for listings of talazoparib plasma and urine concentrations.
PK Parameter Analysis Population: All enrolled patients who receive at least 1 dose of 
talazoparib and who have at least 1 of the talazoparib PK parameters. This analysis
population will be used for listings of talazoparib PK parameters for Day 1 and Day 22 and 
for the Day 1 summary tables and figures for single-dose talazoparib PK parameters. 
PK Evaluable Analysis Population: All enrolled patients who meet the PK evaluability 
criteria listed in Section 3 and provide at least 1 of the talazoparib PK parameters of the 
primary interest from the Day 22 visit. This analysis population will be used for the 
summary tables and figures for multiple-dose talazoparib PK parameters. 
The frequency and percentage of patients in each population will be summarized by hepatic 
impairment group. Patients who are excluded from the analysis populations will be listed by 
hepatic impairment group and patient.
Other Analysis Population: The protein-binding analysis will include all enrolled patients 
with at least one adequate protein-binding assessment.
4.2. Study Patients
Patient Disposition
Patient disposition will be summarized by hepatic impairment group using the number of 
enrolled patients. The number and percent of patients who complete and discontinue study 
will be included in this summary. Additionally, the number and percent of patients included
in each analysis population listed in Section 4.1 will be provided. Number and percent of 
patients continuing open-label extension study will be provided as well.
Patients who fail the screening procedure and the reasons for screen failure will be listed. 
Patient disposition and completion status will be listed for all enrolled patients.
Eligibility status for the study will be listed for all enrolled patients. 
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Protocol Deviations
Protocol deviations will be identified prior to database lock and may include but are not 
limited to: significant violations of inclusion/exclusion criteria, noncompliance of the study 
treatment taken, use of prohibited medications or not following clinical trial protocol 
procedures that may affect evaluation of the PK profile.
Key protocol deviations will be listed by patient and summarized by deviation category as 
per Pfizer CT40-GSOP.1
4.3. Patient Demographics 
The demographic will consist of age, gender, race, ethnicity, height (cm), weight (kg), and 
BMI (kg/m2). Demographic data analysis will be provided for Safety Population. Individual 
demographic data will be listed by hepatic impairment group and by patient and summarized 
by hepatic impairment group.
The age is a calculated parameter. Age will be calculated using the patient’s date of birth and 
the patient’s informed consent date. 
Continuous variables (age, height, weight, BMI) will be summarized by n, mean, SD, Min, 
median, and Max. Number of patients and percentages will be used to describe categorical 
(discrete) variables (gender, race and ethnicity). 
4.4. Baseline Definition
For laboratory and vital signs parameters, baseline is defined as the last value measured prior 
to the first dose of study drug.
For ECGs, baseline is defined as the average value of triplicate ECGs at pre-dose on Day 1.
Change from Baseline is defined as [Post-baseline Value – Baseline Value].
4.5. Medical/Surgical History and Procedures/Non-Drug Therapies
The presence/absence of any current medical condition and/or other significant medical 
history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 
21.1. 
Initial Diagnosis/cancer history and Medical/surgical history collected at the screening will 
be summarized by hepatic impairment group and will be listed by patient. Prior surgery and 
radiation therapy for cancer, and other procedures will be listed by patient.
4.6. Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization 
(WHO) Drug Enhanced Dictionary (September 2015 or later). Prior medications (including 
prior systemic anti-cancer therapy) will be those that start and end prior to first dose of study 
drug. Concomitant therapy includes any medication used by a patient from 28 days prior to 
enrollment until 30 days after the last dose of study drug or before initiation of a new 
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anticancer therapy (standard or investigational treatment) or the first day of OLE study 
whichever occurs first. Concomitant medications will be those that have a known end date 
after the first dose of study drug or have a missing end date (Appendix 1: Imputation rules 
for missing CM dates). Medications will be listed by patient including Anatomical 
Therapeutic Chemical (ATC) classification, preferred term and reported term; the start and 
end dates (or ongoing status); and dose, unit and indication. Medications will be summarized 
by hepatic impairment group.
4.7. Treatment Compliance
Treatment compliance will be assessed based on patients’ used and unused study drug 
containers and their completed study drug diary at Day 8, Day 15 and Day 22. Percent
compliance will be calculated by the number of capsules taken during dosing period divided 
by the expected number of capsules dispensed, multiplied by 100%. Treatment compliance 
along with duration of treatment, dose intensity, dose interruption and duration of dose 
interruption will be listed for all patients and will be summarized by hepatic impairment 
group.
4.8. Pharmacokinetic Analysis
4.8.1. Plasma and Urine Concentrations
Presentations for talazoparib concentrations will include the following:
•
Individual listing of plasma concentrations and amount in urine will be sorted by 
hepatic function group (present in heading), then subject id, by day and nominal time 
postdose.  The concentration listing will also include the actual times.  Deviations 
from the nominal time will be provided as well. 
•
Summary of plasma concentrations and amount in urine will be presented by hepatic 
function group, day and nominal time postdose, where the set of statistics will include 
the number of measurements, arithmetic mean, SD and %CV, geometric mean, 
geometric %CV, Min, median, Max value and the number of concentrations above 
the lower limit of quantification. 
•
Individual concentration vs time plots of talazoparib in plasma (using the actual 
sampling times) will be presented by hepatic group for Day 1 and Day 22 (each group 
on the separate page) in both linear and semi-logarithmic scales. 
•
Median plasma concentrations time plot (on both linear and semi-log scales) against 
nominal time postdose by hepatic function groups will be generated for Day 1 and 
Day 22. All hepatic function groups medians will be presented on the same plot. 
•
Similarly, arithmetic mean plasma concentrations time plot (on both linear and semi-
log scales) against nominal time postdose by hepatic function groups will be 
generated for Day 1 and Day 22. All hepatic function groups means will be presented 
on the same plot. 
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•
Unbound fractions (fu) will be listed and summarized descriptively by hepatic 
function group.
Care must be taken to ensure that imputed concentrations are only used for the calculation of
AUC0-24, AUC0-24u, and Ctrough PK parameters on Day 22 and are not mistakenly included in 
any listings, tables, or figures of reported concentrations.
4.8.2. Pharmacokinetic Parameters
PK parameters for talazoparib will be derived for patients in the PK Parameter and PK 
Evaluable Analysis Population using a non-compartmental model with WinNonlin (Version 
6.3 or higher). The following PK parameters will be derived, as applicable (Table 2).
Table 2.
PK Parameters
Parameter
Description
Calculation
Single
Dose
Multiple 
Dose
Ae0-24
Amount of drug excreted 
in urine from time 0 to 24 
hours
Ae0-24 = C0-12ur•V0-12ur + C12-24ur•V12-24ur
X
X
Ae0-24%
Amount of drug excreted 
in urine from time 0 to 
24 hours expressed as 
percentage of administered 
dose
Ae0-24% =100•Ae0-24/Dose
X
X
AUC0-24
Area under the free 
concentration time curve
from 0 to 24 hours 
By linear trapezoidal rule during the 
ascending phase and log trapezoidal rule 
during the descending phase
X
X
AUC0-24u
Unbound AUC0-24
AUC0-24u = fu•AUC0-24
X
X
Cmax
Maximum observed 
plasma concentration 
Observed data
X
X
Cmaxu
Unbound Cmax
Cmaxu = fu•Cmax
X
X
Ctrougha
Predose plasma 
concentration that meet 
acceptance criteriaa
Observed data
X
CL/F
Apparent clearance of the 
drug from plasma after oral 
administration
CL/F = Dose/AUC0-24
X
CLu/F
Unbound CL/F
CLu/F = Dose/AUC0-24u
X
CLr
Renal clearance
CLr = Ae0-24/AUC0-24 
X
fu
Fraction of unbound drug
Obtained from measurement of protein 
binding
X
X
Rac
Accumulation ratio 
Rac = AUC0-24 (Day 22)/ AUC0-24 (Day 1)
X
Tmax
Time of Cmax
Observed data
X
X
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Parameter
Description
Calculation
Single
Dose
Multiple 
Dose
a.
Acceptance criteria for Ctrough on Day 15 and Day 22: received 10 consecutive days of 
dosing immediately before PK sampling day; Sample drawn within 24 ±2 hrs of the 
previous dose, and not more than +10 min after the drug administration on the PK 
collection day. Ctrough on Day 8: received 7 consecutive days of dosing immediately 
before PK sampling day; Sample drawn within 24 ±2 hrs of the previous dose, and not 
more than +10 min after the drug administration on the PK collection day.
Additional PK parameters will be calculated as applicable.
At the discretion of the clinical pharmacologist, missing pre-dose PK sample collections on 
Day 22 may be imputed from the 24-hour PK sample collections on Day 22 (and vice versa) 
when a 24-hour sample is present but the pre-dose sample is missing (and vice versa), when 
steady-state conditions can be assumed, for the purposes of calculating and reporting Day 22 
Ctrough, AUC0-24 and AUC0-24u.
Individual plasma and urine PK parameters will be listed (PK Parameter Population) and 
summarized by hepatic group for Day 1 (PK Parameter Population) and Day 22 (PK 
Evaluable Population).
PK parameters of talazoparib (Tmax excluded) will be summarized using arithmetic mean, 
standard deviation and %CV, geometric mean, geometric %CV, minimum, median, and 
maximum value. For Tmax values, number of observations, minimum, maximum and median. 
Geometric %CV = sqrt(exp(variance of log transformed data)-1)*100.
Box and whisker plots for individual subject parameters AUC 0-24, AUC0-24u, Cmax and Cmaxu
(Day 1 (PK Parameter Analysis Population) and Day 22 (PK Evaluable Population)) against 
hepatic function group will be generated and overlaid with geometric means.
For each hepatic function group, spaghetti plots for individual Ctrough concentrations against
Day 8, Day 15 and Day 22 (X-axis) will be generated. These plots will include only subjects 
in the PK Evaluable Population with all three Ctrough collections. 
4.8.3. Comparative Analyses of PK Parameters
PK parameters AUC0-24, Cmax, AUC0-24u, and Cmaxu on Day 1(PK Parameter Population) and 
Day 22 (PK Evaluable population) will be natural log-transformed and analyzed using an 
analysis of variance (ANOVA) model with group as a fixed effect to compare each hepatic
impairment group (mild, moderate or severe; Test) with the normal hepatic function group 
(Reference). Additional analysis will be conducted using an analysis of covariance 
(ANCOVA) model with hepatic function group as a fixed effect and weight and age as 
covariates (at the significance level of 0.05). Estimates of the adjusted mean differences 
(Test/Reference) and corresponding 90% confidence intervals for all listed above PK 
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parameters will be obtained from the model. The adjusted mean differences and
90% confidence intervals for the differences will be exponentiated to provide estimates of the
ratio of adjusted geometric means (Test/Reference) and 90% confidence intervals for the 
ratios.
The comparison of PK parameters (AUC0-24, Cmax, AUC0-24u, and Cmaxu) of each hepatic
impairment group to the normal hepatic function group will be presented using geometric 
mean, its ratio and 90% CI.
Exploratory ANOVA/ANCOVA analysis of log transformed PK parameters (AUC0-24, Cmax, 
AUC0-24u, and Cmaxu) Day 1 (PK Parameter Population) and Day 22 (PK Evaluable 
Population) using hepatic impairment group classified by Child-Pugh Scores may be 
performed. 
The relationship between hepatic functional measures (eg, TB and AST) and selected PK 
parameters (eg, AUC0-24, Cmax, AUC0-24u or Cmaxu) on Day 22 (PK Evaluable Population) may 
be explored as appropriate.
4.9. Efficacy Analysis
No efficacy analysis is planned in this study.
4.10. Safety Analysis
Safety evaluations will be based on the incidence, intensity, and relatedness of adverse events 
(AEs), physical examination findings (captured as AEs), study discontinuation information,
clinical laboratory tests, ECG, ECOG and vital signs. 
Safety variables will be tabulated and presented for all patients in the Safety Population.
4.10.1. Study Product Exposure/Administration
Study drug exposure/administration will be listed by hepatic impairment group and patient, 
indicating dose date and time and administration start and end dates. Any deviations will be 
documented. Duration of treatment or duration of exposure, cumulative dose and relative 
dose intensity will be summarized by hepatic impairment group using the Safety Population.
4.10.2. Adverse Events
AEs are collected 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. Serious AEs (SAEs) will be 
collected from the time the patient signs the Patient Informed Consent Form until the end of 
study visit. All AEs will be coded and classified according to MedDRA (Version 19.1). The 
intensity of adverse events is judged by the investigator as Grade 1 (mild), Grade 2 
(moderate), Grade 3 (severe), Grade 4 (life-threatening) or Grade 5 (death) according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)
v4.03, and the relationship to study drug is judged by the investigator as probable, possible or 
not related. Adverse events occurring prior to the date and time of first dose of study drug 
are considered non-treatment emergent events. Events occurring after the date and time of 
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the first dose of study drug up to 30 days following the last dose of study drug are considered 
treatment emergent AEs (TEAEs). 
All TEAEs will be summarized as the number and percentage of patients by System Organ 
Class, Preferred Term, maximum CTCAE grade, and hepatic impairment group. Separate 
summaries will be created for treatment-emergent treatment related AEs. If the same AE 
(preferred term) is reported more than once for the same patient, it will only be counted once 
in the summary table. For summary tables by severity and relationship to study drug, if the 
same AE (preferred term) is reported more than once for the same patient, the highest 
severity grade or the strongest relationship to treatment 
(probable > possible > not related) will be counted in the summary table.
All AEs will be listed, and a flag will indicate if the AE is treatment emergent or not. 
All SAEs will be listed, and a flag will indicate if the SAE is treatment emergent or not.
All AEs leading to temporary and permanent study drug discontinuation will be listed by 
patient. 
All SAEs leading to temporary and permanent study drug discontinuation will be listed by 
patient.
Imputation rules for missing AE dates are included in the Appendix 1.
All death will be displayed by patient.
4.10.3. Clinical Laboratory Assessments
Clinical laboratory parameters, including hematology, coagulation, blood chemistry, 
urinalysis and urine culture evaluations will be performed at the screening visit, enrollment 
visit, on Day 8, Day 15 and Day 22 post-dose, and at the safety follow up visit (ie, end of 
study visit).
Clinical laboratory test parameters, with associated reference ranges provided by the 
laboratory, will be listed for individual patients by hepatic group. Clinical laboratory test 
results outside the laboratory’s reference ranges will be flagged with “L” for low and “H” for 
high. Observed values and changes from baseline visit will be summarized by hepatic 
impairment group and visit.
Shifts in toxicity from baseline to maximum post-baseline results of laboratory parameters 
and liver function test elevations will be summarized by hepatic impairment group. The 
toxicity of laboratory parameters will be graded as 1 (mild), 2 (moderate), 3 (severe), 4 (life-
threatening) or 5 (death) according to the NCI CTCAE v4.03.
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4.10.4. Vital Signs Assessments
Evaluation of vital signs, including blood pressure, pulse rate, respiratory rate, and weight 
will be performed at the screening visit, enrollment visit, on Day 8, Day 15 and Day 22 
post-dose, and at the safety follow up visit (ie, end of study visit). Temperature will be 
performed at the screening visit, enrollment visit and at the safety follow up visit. 
Temperature will be listed by hepatic group and patient. Other vital signs results will be 
listed by hepatic impairment group and patient. Summary statistics for observed values and 
changes from baseline will be displayed by hepatic impairment group and visit. 
4.10.5. Resting 12-Lead ECGs
All ECG results will be listed by hepatic impairment group and patient.  Observed values and 
changes from baseline will be summarized by hepatic impairment group and visit.
The number (%) of subjects with maximum post dose QTcF values and maximum increases 
from baseline in the following categories will be tabulated by hepatic impairment group: 
QTc
Borderline (msec)
Prolonged (msec)
Absolute Value
≥450 - <480
≥480
Absolute Change
30-<60
≥60
In addition, the number of subjects with corrected and uncorrected QT values ≥500 msec will 
be summarized.
4.10.6. Physical Examinations 
Physical examinations will be performed by qualified personnel at the screening visit, 
enrollment visit, on Day 8, Day 15 and Day 22 post-dose, and at the safety follow up visit.
4.10.7. ECOG Performance Status
Assessment of ECOG performance status will be performed at the screening visit, pre-dose 
and the safety follow up visit.  ECOG performance status assessment will be listed by hepatic 
impairment group and patient and summarized by hepatic impairment group and visit.
4.11. Interim Analysis
No formal interim analyses are planned for this study. However, as this is an open-label 
study, the sponsor may conduct unblinded reviews of the data during the study for the 
purpose of safety and pharmacokinetics assessment and/or supporting clinical development.
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4.12. Statistical Programming and Deliverables 
All statistical analyses, tables and listings will be generated using SAS (version 9.3 or later) 
with appropriate documentation and programming validation. Supplemental document will 
include table of contents of all tables, listings, and figures along with Tables, Listings and 
Figures shells.
4.13. Changes to the Planned Analysis
Any deviation(s) of consequence from the SAP will be documented and justified in an 
amended SAP and/or in the final report or addressed in a separate document, as appropriate. 
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5. REFERENCES
1.
CT-40 GCSOP Clinical and Medical Controlled Document (Cmcd) Standard Operating 
Procedure.
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Appendix 1. Table 1
Domain
Dataset
Label
Imputation Rule
Concomitant 
Medications
ADCM
Analysis 
Start Date
Numeric date derived from CM.CMSTDTC. 
1. If CM start day is missing and CM start month
and year are not missing: if CM start year is the 
same as the first dose year and CM start month is 
the same as first dose month, then impute CM start 
day using the day of first dose. If this leads to a date 
after the CM end date, use CM end date instead. 
Otherwise impute the CM start day using the first 
day of the month.
2. If CM start month is missing and CM start year is
not missing: If CM start year is equal to the first 
dose year, use the first dose day and month. If this 
leads to a date after the CM end date, use CM end 
date instead.If CM start year is different from the 
first dsoe year, use 01 January. 
3. If CM start year is missing: impute CM start date
using the day of first dose. If this leads to a date 
after the CM end date, use CM end date instead.
Concomitant 
Medications
ADCM
Analysis 
End Date
Numeric date derived from CM.CMENDTC.
1. If end day is missing, and end month and year are
not missing: impute the end date using the last day 
of the month.
2. If end month is missing, and end year is not
missing: impute the end date using 31 December as 
the day and month.
3. If end year is missing and the medication is a
prior medication, then impute the end date using the 
first dose intake date - 1. If the medication is a 
concomitant medication, then impute end date using 
the end of follow up date.
Adverse 
Event
ADAE
Analysis 
Start Date
Numeric date derived from AE.AESTDTC. 
1. Missing day only:
- If the year and the month were same as the year 
and month of first dosing date, 
then the day of the first dosing date was assigned 
to the missing day.
- If the year and the month were before the year 
and month of first dosing date, 
then the last day of the month was assigned to the 
missing day.
- If the year and the month were after the year and 
month of first dosing date, 
then the first day of the month was assigned to the 
missing day.
2. Missing day and month or missing month only:
-If the year was the same as the year of first dosing 
date, 
then the day and month of the first dosing date 
were assigned to the missing fields.
-If the year was prior to the year of first dosing 
date, then December 31 was assigned to the missing
fields.
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-If the year was after the year of first dosing date, 
then January 1 was assigned to the missing fields.
3. Missing year:
-If the year was missing, the onset date was set to 
the first dosing date, even if the day and month were 
present.
4. If the imputed AE start date was later than the
reported AE stop date, the imputed AE start date 
was equal to the reported AE stop date.
Adverse 
Event
ADAE
Analysis 
End Date
Numeric date derived from AE.AEENDTC. 
1. Missing day only: The last day of the month was
assigned to the missing day.
2. Missing day and month or missing month only:
December 31 was assigned to the missing fields.
3. Missing year: If the year was missing, the stop
date was set to the study completion/discontinuation 
date.
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