Clinical trial NCT03070548
Conditions: Advanced Solid Tumors
Sponsor: Pfizer
Start date: 2016-09-01; Completion date: 2017-06-01
Enrollment: 6 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the mass balance of talazoparib after a single dose of talazoparib.

Detailed description:
Patients participating in this study with no clinically significant toxicities may be eligible to continue treatment on a separate extension protocol after discussion with the Principal Investigator and obtaining Sponsor permission..

Arms: arm 1: 1 mg talazoparib containing100 μCi of 14C-radiolabeled talazoparib
Interventions: intervention 1: Talazoparib
Intervention descriptions: intervention 1: 1 mg of talazoparib containing100 μCi of 14C-radiolabeled talazoparib

Protocol documents:
Prot_000.pdf: 
 
CLINICAL STUDY PROTOCOL 
 
 
MDV3800-03/MVE010PC-160106 
 
 
VERSION Final 3.0 – 07-Oct-2016 
 
 
Page 1 of 53 
CLINICAL STUDY PROTOCOL 
 
A Phase 1 Open-Label Study of 14 C-Labeled Talazoparib in Patients With Advanced 
Solid Tumors 
 
 
 
Sponsor Code: MDV3800-03 
 Code: MVE010PC-160106 
EudraCT Number: 2016-001394-33 
IND Number: 108708 
 
 
Investigational Product 
Talazoparib 
Clinical Phase 
1 
Indication to be studied 
Advanced solid tumors 
 
SPONSOR 
Medivation, Inc. and its Subsidiaries 
 
525 Market Street, 36th Floor 
 
San Francisco, CA 94105 
 
USA 
 
CONTRACT RESEARCH 
ORGANIZATION 
 
 
 
 
 
 
 Germany 
 
CLINICAL SITE 
 
 
 
 
 
Hungary 
 
 
 
PRINCIPAL INVESTIGATOR Prof. 
 MD 
 
Fax 
 
 
Phone 
 
 
E-mail 
 
 
 
 
 
 
PROTOCOL AUTHOR 
Dr. 
 Medical Writer, 
 
 
 
Version Final 3.0, 07-Oct-2016 
 
This study will be performed in compliance with the principles of Good Clinical Practice. 
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CLINICAL STUDY PROTOCOL 
MDV3800-03/MVE01 OPC-1601 06 
VERSION Final 3.0 - 07-0ct-2016 
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 
 Clinical Pharmacology & DMPK 
Signature: 
Date: 
 MD 
 Drug Safety & Pharmacovigilance 
 PhD 
 Biostatistics 
Signature: 
....
.... . 
 MD 
 
 Early Development 
Date: 
 
..
.......... . 
Date: 
............ . 
Date: 
······ 
 Regulatory Affairs 
Date: 
.. 
Page 2 of 53 
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CLINICAL STUDY PROTOCOL 
MDV3800-03/MVE01 OPC-1601 06 
VERSION Final 3.0 - 07-0ct-2016 
PROTOCOL SIGNATURE PAGE - Principal Investigator 
I have read this protocol, and I agree that it contains all necessary details for me and my staff to 
conduct this study as described. 
I understand that information contained in or pertaining to this protocol is confidential and should 
not be disclosed, other than to those directly involved in the execution or the ethical review of the 
study, without written authorization from the Sponsor. It is, however, permissible to provide 
information to a subject in order to obtain consent. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and. guidelines, and to conduct the study in 
accordance with the Declaration of Helsinki, International Conference on Harmonisation 
guidelines on Good Clinical Practice (lCH GCP), and applicable regional regulatory 
requirements. 
I agree to make available to Sponsor personnel, their representatives and relevant regUlatory 
authorities, my subjects' study records in order to verify the data that I have entered into the case 
report forms. I am aware of my responsibilities as an Investigator as provided by the Sponsor. 
I understand that the Sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study, I will communicate my intention 
immediately in writing to the Sponsor. 
 MD 
Principal Investigator 
.............. . 
Page 3 of 53 
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SERIOUS ADVERSE EVENT CONTACT INFORMATION 
In case of a serious adverse event (See Appendix 8.2.3), the Principal Investigator will 
complete a “Serious Adverse Event Form” and forward, within 24 hours of awareness, to 
Medivation Medical Monitor and to Medivation’s Safety vendor, 
 as noted 
below: 
Name: 
 
Fax: 
 
 
 
 
 (Hungary) 
Email: 
 
Phone: 
 
 
Medivation Medical Monitor: 
Name:  
 MD 
Telephone: 
 
Mobile:  
 (24-hr Contact Number) 
Email: 
 
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CONTACT INFORMATION 
Sponsor 
Medivation, Inc. and its Subsidiaries 
525 Market Street, 36th Floor 
San Francisco, CA 94105 
USA 
 
Sponsor's Contact 
 MD 
Telephone: 
 
Mobile:  
 (24-hr Contact Number) 
Email: 
 
 
 PhD 
Telephone: 
 
Mobile:  
 
Email: 
 
 
 
Contract Research Organization 
 
 
 Germany 
 
Project Manager 
 
Phone 
 
Fax: 
 
E-mail 
 
 
 
Clinical Site 
 
 
Hungary 
 
Principal Investigator 
 MD 
Fax 
 
Phone 
 
E-mail 
 
 
 
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Laboratories 
Safety Laboratory 
 
Dr. 
 
Address: 
 
Phone: 
 
Fax: 
 
 
Serology: 
 
 
Dr. 
 
Address: 
 
Phone: 
 
Fax: 
 
 
 
 
 
 
 
 Netherlands. 
 
Other Analyses 
 
 
 M.Sc. 
 
 
 
USA 
Phone: 
 
Fax: 
 
 
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SYNOPSIS 
Study Title 
A PHASE 1 OPEN-LABEL STUDY OF 14C-LABELED TALAZOPARIB IN PATIENTS WITH ADVANCED 
SOLID TUMORS 
 
Short Study Title 
14C-Talazoparib Mass Balance Study 
 
Study Codes 
Sponsor Code: 
MDV3800-03 
 Code: 
MVE010PC-160106 
EudraCT Number: 
2016-001394-33 
IND Number: 
108708 
 
Sponsor 
Medivation, Inc. and its Subsidiaries 
525 Market Street, 36th Floor 
San Francisco, CA 94105 
USA 
 
Contract Research Organization 
 
 
 
 Germany 
 
Clinical Site 
 
 
 
Hungary 
 
 
Principal Investigator 
Prof. 
 MD 
Fax 
 
Phone 
 
E-mail 
 
 
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Objectives 
Primary: 
• 
To determine the time course of excretion of 14C-radioactivity in urine and feces following a single 
1 mg oral dose of talazoparib containing 100 µCi 14C-talazoparib. 
• 
To determine the recovery of 14C radioactivity as a percentage of the administered dose. 
• 
To determine the plasma pharmacokinetics (PK) of talazoparib and/or potential metabolites. 
• 
To determine the PK of total radioactivity of 14C-talazoparib, (AUC0-inf, AUC0-last, Cmax, Tmax, T1/2, CL/F, 
and Vd/F) in plasma and whole blood. 
 
Secondary: 
 
• 
To assess the safety and tolerability of a single dose of 1 mg talazoparib containing 100 µCi 14C-
talazoparib. 
• 
To determine the percentage of 14C radioactivity of talazoparib associated with erythrocytes and whole 
blood over time. 
• 
To determine the amount of talazoparib in urine and feces. 
• 
To estimate the amount and probable structure of any significant metabolites of talazoparib in plasma, 
urine and feces. 
 
Design and Treatments 
This is a Phase 1, single-center, open-label study evaluating the mass balance of talazoparib after a single 
dose of 1 mg talazoparib 100 µCi (3.7 MBq) 14C-talazoparib; subjects may elect to continue treatment on 
an extension protocol. 
The study is planned to enroll at total of up to approximately 6 patients in order to obtain the data in at 
least 4 evaluable patients at a single Phase 1 unit. Patients will receive a single dose of 1 mg talazoparib 
oral solution containing approximately 100 µCi 14C-talazoparib on Day 1 after an overnight fast of at least 8 
hours. No food will be allowed for at least 2 hours post-dose. 
Within this food-restricted period the consumption of water is allowed. 
The patients will remain at the clinic for approximately 21 days. If scintillation count data are available, 
patients, on an individual basis, may be discharged prior to Day 22, if any of the following conditions are 
met: 
• 
≥ 90% of the administered radioactivity is recovered in the urine and feces (accounting for radioactivity 
in vomitus, if applicable) 
• 
The daily total excreted radioactivity is 1% or less of the administered dose on 2 consecutive days. 
Shipments for daily Quick Count will start on Day 10 
If a patient meets either of these conditions prior to the morning of Day 22, collection of blood, urine, and 
feces may be stopped following completion of all scheduled 24-hour collections for that day. At the 
conclusion of the blood, urine, and feces collection, the patients will be discharged following completion of 
any safety procedures scheduled at termination. 
If an individual patient does not demonstrate a cumulative amount of radioactivity recovered in urine and 
feces ≥ 90% or has not met the daily total excretion criteria of 1% or less of the administered dose on 2 
consecutive days, following consultation with the Sponsor, the Investigator may ask patient to return to the 
clinic on Day 28 for a 24 h collection of urine and feces. If, by Day 29, the patient has still not met release 
criteria, a discussion between the Sponsor and the Investigator will be conducted for possibility to collect 
additional 24 h collection of urine and feces on Day 35. 
Patients participating in this study with no clinically significant toxicities may be eligible to continue 
treatment on a separate extension protocol after discussion with the Principal Investigator and obtaining 
Sponsor permission. Decision to allow the patient to continue dosing with unlabeled (non-radioactive) 


 
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talazoparib in an open label study will be based on potential overall benefit-risk to patients, and patient 
eligibility for enrollment in the open-label extension study. 
Safety data for all patients who had received any amount of talazoparib will be analyzed in the safety 
analyses. 
 
Study Assessments 
Safety and tolerability of talazoparib will be monitored through evaluation of adverse events, clinical 
laboratory tests, vital signs, electrocardiogram (ECG) recordings and physical examinations. 
Serial PK blood, urine, and feces samples for talazoparib (plasma) and total radioactivity (whole blood, 
plasma, urine, feces, and vomitus, if applicable) analysis will be collected at predetermined times after the 
single oral dose administration, up to 504 hours (21 days), during which time the patients will be confined 
to the clinical research facility. Blood samples for plasma total radioactivity and for PK analysis of 
talazoparib and/or potential metabolite profiles and concentrations will be collected at pre-dose and 0.5, 1, 
2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 216, 264, 336, 384, 432 and 504 hours post-dose. Whole blood 
samples for total radioactivity will be collected at pre-dose and 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 
216, 264, 336, 384, 432 and 504 hours post-dose. Urine and feces samples will be collected for the 
analysis of total radioactivity and for analysis for talazoparib and/or metabolites. Urine samples will be 
collected at pre-dose and during 0–8 hour and 8–24 hour post-dose intervals on Day 1 and then continue 
in 24-hour intervals through Day 22. Feces samples will be collected pre-dose and post-dose at 24-hour 
intervals through the morning of Day 22. Additional blood samples for PK analysis may be taken at the 
prolongation observation period and additional (unscheduled) and follow-up visit(s). During these visits, all 
urine and feces for total radioactivity analysis will be collected. 
 
Key Eligibility Criteria 
This study will enroll patients with certain advanced solid tumors (i.e. platinum-resistant ovarian carcinoma, 
cervical adenocarcinoma, small cell lung carcinoma and triple-negative breast cancer) who are at least 18 
years of age and provide informed consent. Patients must abstain from the use of any prescription or 
nonprescription drugs or supplements with potential P-glycoprotein (P-gp) interaction within 7 days or 5 
half-lives (whichever is longer) before Day 1. Patients must not have eGFR (estimated glomerular filtration 
rate) ≤ 50 mL/min/1.73 m2 by MDRD (Modification of Diet in Renal Disease) equation at screening and 
baseline, human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. Patients who had major surgery 
within 8 weeks, or received any investigational drug within 4 weeks before screening are excluded. Female 
and male patients of childbearing potential must agree to use a highly effective birth control method 
starting on 21 days before the administration of talazoparib through 45 and 105 days after last dose of 
study drug, respectively. 
 
Duration of Study 
Approximately 3-4 weeks for each patient. 
 
Sample Size Considerations 
The study is planned to enroll a total of up to 6 patients in order to obtain the data in at least 4 evaluable 
subjects. This sample size is consistent with typical study designs for phase 1 mass balance studies for 
PK evaluation. Patients who discontinue before 85% of total drug is recovered from urine and feces may 
be replaced upon agreement of the Investigator and the Sponsor. 
 
Test Product, Dose, and Mode of Administration 
Talazoparib, chemical name (8S,9R) 
 
 
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Patients will receive a single dose of 1 mg talazoparib oral solution containing approximately 100 µCi of 
14C-talazoparib as a single dose. 
Reference Therapy, Dose, and Mode of Administration 
Not applicable. All patients will receive talazoparib. 
 
Statistical Methods 
Pharmacokinetic Analyses 
Radioactivity in urine and feces will be measured and reported as the percentage of the administered 
radioactivity excreted at each time interval and the total percent of dose excreted in urine and feces. 
talazoparib and/or potential metabolites will be also quantified in urine and feces and reported. Renal 
clearance will be calculated. 
Non-compartmental pharmacokinetic parameters will be calculated from the plasma and whole blood 
radioactivity concentration versus time data. Unchanged talazoparib and/or potential metabolites in plasma 
will be measured and reported. Non-compartmental pharmacokinetic parameters (AUC0-inf, AUC0-last, Cmax, 
Tmax, T1/2, CL/F, and Vd/F) will be calculated from the plasma and whole blood concentration time data. 
 
Efficacy Analyses 
No efficacy analyses are planned in this study, although baseline tumor assessments will be obtained in 
the event that patients choose to continue talazoparib treatment on a separate extension protocol. 
 
Safety Analyses 
All safety analyses will be performed using the safety population, defined as all patients who received any 
amount of talazoparib. Safety will be evaluated using summaries of adverse events (AEs), physical 
examinations (and weight), vital signs, ECG recordings, and laboratory evaluations. 
AEs will be coded to preferred term and system organ class using the Medical Dictionary for Regulatory 
Activities (MedDRA) and classified by severity using the National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4. The number and percentage of patients with AEs will be 
presented by MedDRA system organ class and preferred term, relationship to study treatment, severity, 
seriousness, and outcome (e.g., leading to permanent treatment discontinuation). 
Treatment-emergent safety data will be collected from Day 1 (the first and only dose of study drug) through 
14 days after the last day of mass balance phase and at least 30 days after Day 1 or before initiation of 
new cytotoxic chemotherapy, new investigational treatment, or the first day of extension protocol, 
whichever occurs first. 
Laboratory values will be classified by severity using the CTCAE Version 4. Change from baseline in 
laboratory values will be tabulated and summarized graphically. 
 


 
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Table 1 
Schedule of Assessments 
Study Day► 
-21 
to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
FUP1 
Event▼ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent, 
screening number 2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG assessment  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check-in questions 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X3 
 
 
 
 
 
 
 
X3 
 
 
 
 
 
 
X3 
 
 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Temperature 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Respiratory rate 
X 
X 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-Lead ECG 
(triplicates) 
X 
X 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Supine heart rate, 
blood pressure 
X 
X 
X5 
X4 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Adverse event review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication review  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administer 
talazoparib 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology for HIV, 
hepatitis B and C  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy 
test 6   
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Follicle-stimulating 
hormone 7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistry 
X 
X 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Hematology 
X 
X 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 


 
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Table 1 
Schedule of Assessments 
Study Day► 
-21 
to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
FUP1 
Event▼ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFR calculation 8 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine collection 
 
X9 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Feces collection 
 
X10 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood sample for PK 
 
 
X11 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
Collection of vomitus 
(if applicable) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
1 
Follow-up within 14 days after the last day of mass balance phase and at least 30 days after Day 1 or the first day of extension protocol, whichever occurs 
first; this follow-up can be an onsite visit or a phone call 
2 
Informed consent can be signed before the screening window. 
3 
Targeted, symptom oriented physical examination 
4 
To be performed on Day 2, 24 h after talazoparib dose on Day 1 
5 
On Day 1 at pre-dose and 2 hour post-dose. 
6 
Collect only for females 
7 
Collect only for females with no spontaneous menses for ≥12 months, who are <55 years old, and who do not have documented surgical sterilization. 
8 
Calculation of the estimated glomerular filtration rate (eGFR) by MDRD equation 
9 
Only one blank urine sample will be collected within 12 hours prior to study drug administration (Day-1 or Day 1 pre-dose) 
10 
Only one blank fecal sample will be collected within 48 hours prior to study drug administration (Day -1 or Day 1 pre-dose) 
11 
On talazoparib dosing day, collect blood sample for PK as shown in Table 3 
FUP: follow-up; ECOG: Eastern Co-Operative Oncology Group [Performance Status]; HIV: human immunodeficiency virus; PK: pharmacokinetic. 
 
 


 
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Table 2 
Study Schedule of Activities for Patients Staying Beyond 21 Days 
 
Study Day 
 
For patients who do not meet release 
criteria by Day 22 
23 to 27 
28 to 29 
FUP1 
For patients who do not meet release 
criteria by Day 29 
30 to 34 
35 to 36 
Event▼ 
 
 
 
Physical examination 
 
X 
 
Weight 
 
X 
 
12-lead electrocardiogram 
 
X 
 
Supine heart rate, blood pressure 
 
X 
 
Adverse event review  
X 
X 
X 
Concomitant medication review  
X 
X 
X 
Serum chemistry 
 
X 
 
Hematology 
 
X 
 
Urinalysis 
 
X 
 
Fecal collection2 
 
X 
 
Urine collection 2 
 
X 
 
Blood sample for PK 
 
X 
 
1 
Follow-up within 14 days after the last day of mass balance phase and at least 30 days after Day 1 or 
the first day of extension protocol, whichever occurs first. This follow-up can be an onsite visit or a 
phone call.  
2 
Patients will return to the unit on Day 28 until Day 29 for 24-hour urine and feces collection. In cases 
if the release criteria are still not met, the observation period may be prolonged to Day 35 and Day 
36, respectively (see Section 3.1.3.3). 
 


 
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Table 3 
Talazoparib Pharmacokinetic Sampling Schedule 
Sample collection time 
relative to dosing 
Blood† 
Urine † 
Feces † 
Study Day 
Time point 
1 
pre-dose 
X 
X 
X 
+0.50 h 
X 
X (0 - 8 h) 
X (0 - 24 h) 
+1 h 
X 
+2 h 
X 
+4 h 
X 
+8 h 
X 
+12 h 
X 
X (8 - 24 h) 
2 
+24 h 
X 
3 
+48 h 
X 
X (24 - 48 h) 
X (24 - 48 h) 
4 
+72 h 
X 
X (48 - 72 h) 
X (48 - 72 h) 
5 
+96 h 
X 
X (72 - 96 h) 
X (72 - 96 h) 
6 
+120 h 
X 
X (96 - 120 h) 
X (96 - 120 h) 
7 
 
 
X (120 - 144 h) 
X (120 - 144 h) 
8 
+168 h 
X 
X (144 - 168 h) 
X (144 - 168 h) 
9 
 
 
X (168 - 192 h) 
X (168 - 192 h) 
10 
+216 h 
X 
X (192 - 216 h) 
X (192 - 216 h) 
11 
 
 
X (216 - 240 h) 
X (216 - 240 h) 
12 
+264 h 
X 
X (240 - 264 h) 
X (240 - 264 h) 
13 
 
 
X (264 - 288 h) 
X (264 - 288 h) 
14 
 
 
X (288 - 312 h) 
X (288 - 312 h) 
15 
+336 h 
X 
X (312 - 336 h) 
X (312 - 336 h) 
16 
 
 
X (336 - 360 h) 
X (336 - 360 h) 
17 
+384 h 
X 
X (360 - 384 h) 
X (360 - 384 h) 
18 
 
 
X (384 - 408 h) 
X (384 - 408 h) 
19 
+432 h 
X 
X (408 - 432 h) 
X (408 - 432 h) 
20 
 
 
X (432 - 456 h) 
X (432 - 456 h) 
21 
 
 
X (456 - 480 h) 
X (456 - 480 h) 
22 
+504 h 
X 
X (480 - 504 h) 
X (480 - 504 h) 
28* 
+648 h 
X 
X (648 - 672 h) 
X (648 - 672 h) 
35* 
+816 h 
X 
X (816 - 840 h) 
X (816 - 840 h) 
† Identification of metabolites of talazoparib will be pursued if applicable 
* Only in case of prolonged in-house stay due to low radioactivity recovery (see Section 3.1.3.3) 
 
 


 
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TABLE OF CONTENTS 
TITLE PAGE ....................................................................................................................... 1 
PROTOCOL SIGNATURE PAGE – SPONSOR ................................................................. 2 
PROTOCOL SIGNATURE PAGE – PRINCIPAL INVESTIGATOR .................................... 3 
SERIOUS ADVERSE EVENT CONTACT INFORMATION................................................. 4 
CONTACT INFORMATION ................................................................................................. 5 
SYNOPSIS .......................................................................................................................... 7 
TABLE OF CONTENTS .................................................................................................... 15 
TABLE OF TABLES ......................................................................................................... 17 
TABLE OF FIGURES ........................................................................................................ 17 
LIST OF ABBREVIATIONS .............................................................................................. 18 
1. INTRODUCTION ......................................................................................................... 20 
1.1 
Background ................................................................................................................ 20 
1.1.1 Nonclinical Studies ......................................................................................... 20 
1.1.2 Clinical Studies ............................................................................................... 20 
1.2 
Study Rationale .......................................................................................................... 23 
1.2.1 Radioactively labeled dose (Mass Balance) of Talazoparib ......................... 23 
1.2.2 Unlabeled dose of talazoparib ........................................................................ 24 
1.2.3 Study Population Rationale ............................................................................ 24 
2. OBJECTIVES ............................................................................................................. 25 
2.1 
Primary ........................................................................................................................ 25 
2.2 
Secondary ................................................................................................................... 25 
3. INVESTIGATIONAL PLAN ......................................................................................... 26 
3.1 
Overall Study Design and Plan .................................................................................. 26 
3.1.1 Type of Study .................................................................................................. 26 
3.1.2 Screening Period............................................................................................. 26 
3.1.3 Treatment Period............................................................................................. 27 
3.2 
Extension Protocol ..................................................................................................... 28 
3.3 
Discussion of Study Design ...................................................................................... 28 
3.4 
Selection of Study Population ................................................................................... 28 
3.4.1 Inclusion Criteria ............................................................................................. 28 
3.4.2 Exclusion Criteria ............................................................................................ 30 
3.5 
Removal of Subjects from Therapy or Assessment ................................................ 31 
3.6 
Premature Discontinuation of the Trial ..................................................................... 32 
3.7 
Treatments .................................................................................................................. 32 
3.7.1 Treatments Administered ............................................................................... 32 
3.7.2 Identity of Investigational Product ................................................................. 32 
3.7.3 Treatment Assignment ................................................................................... 32 
3.7.4 Selection and Timing of Doses in the Study ................................................. 33 


 
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3.7.5 Meals During the Study .................................................................................. 33 
3.7.6 Blinding ........................................................................................................... 33 
3.7.7 Concomitant Medication and Other Restrictions During the Study ............ 33 
3.7.8 Treatment Compliance.................................................................................... 33 
3.8 
Pharmacokinetic, Efficacy and Safety Measurements and Variables ..................... 34 
3.8.1 Pharmacokinetic, Efficacy and Safety Measurements Assessed ................ 34 
3.8.2 Appropriateness of Measurements................................................................ 37 
3.8.3 Pharmacokinetic, Efficacy and Safety Variables .......................................... 37 
3.8.4 Drug Concentration Measurements ............................................................... 39 
3.9 
Statistical Procedures and Determination of Sample Size ...................................... 40 
3.9.1 Analysis Populations ...................................................................................... 40 
3.9.2 Statistical and Analytical Plan for Pharmacokinetic and Safety 
Evaluation ........................................................................................................ 40 
3.9.3 Determination of Sample Size ........................................................................ 42 
3.10 Data Quality Assurance ............................................................................................. 42 
4. ETHICS ....................................................................................................................... 43 
4.1 
Independent Ethics Committee ................................................................................. 43 
4.2 
Ethical Conduct of the Study ..................................................................................... 43 
4.3 
Subject Information and Consent ............................................................................. 44 
4.4 
Privacy ........................................................................................................................ 44 
5. STUDY ADMINISTRATIVE STRUCTURE .................................................................. 45 
5.1 
Distribution of Activities ............................................................................................ 45 
5.2 
Documentation ........................................................................................................... 46 
5.2.1 Archiving ......................................................................................................... 46 
5.2.2 Recording of Data in Source Documents and CRFs..................................... 46 
6. CONFIDENTIALITY AND PUBLICATION POLICY.................................................... 47 
7. REFERENCES ............................................................................................................ 48 
8. APPENDICES ............................................................................................................. 49 
8.1 
Drug Accountability ................................................................................................... 49 
8.2 
(Serious) Adverse Events Evaluation and Reporting .............................................. 49 
8.2.1 Adverse Events ............................................................................................... 49 
8.2.2 Grading of Severity ......................................................................................... 50 
8.2.3 Serious Adverse Events ................................................................................. 51 
8.2.4 Suspected Unexpected Serious Adverse Reactions .................................... 52 
8.2.5 Follow-up of Adverse Events ......................................................................... 52 
8.3 
Pregnancy ................................................................................................................... 52 
 


 
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TABLE OF TABLES 
Table 1 
Schedule of Assessments ............................................................................................ 11 
Table 2 
Study Schedule of Activities for Patients Staying Beyond 21 Days ............................... 13 
Table 3 
Talazoparib Pharmacokinetic Sampling Schedule ........................................................ 14 
 
 
TABLE OF FIGURES 
Figure 1 Study Design ................................................................................................................ 26 
 


 
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LIST OF ABBREVIATIONS 
ADL 
Activities of daily living 
ADME 
Absorption, distribution, metabolism and excretion 
ADP 
Adenosine diphosphate 
AE 
Adverse event  
ALARA 
As low [radioactive burden] as reasonably achievable 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
anti-HBc+ 
anti-hepatitis B core antigen, positive test result 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BCRP 
Breast cancer resistance protein 
BER 
Base excision repair 
BRCA 
Breast cancer susceptibility gene 
 
 
CLCR 
Creatinine clearance 
CPK 
Creatine phoshokinase 
CPMP 
Committee for Proprietary Medicinal Products; current name: Committee for Medicinal 
Products for Human Use (CHMP) 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Co-Operative Oncology Group [Performance Status] 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EU 
European Union 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GMP 
Good Manufacturing Practice 
HBsAg+ 
Hepatitis B surface antigen, positive test result 
HCV+ 
Hepatitis C virus, positive test result 
HIV+ 
Human immunodeficiency virus, positive test result 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICRP 
International Commission on Radiological Protection 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IV 
Intravenous 
LC-MS/MS 
Liquid chromatography with tandem mass spectrometry 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantitation 
LSC 
Liquid scintillation counting 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical dictionary for regulatory activities 
MGMT 
Methylguanine methyltransferase 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NYHA 
New York Heart Association 


 
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PARP 
Poly(ADP ribose) polymerase 
PDF 
Portable document format 
P-gp 
P-glycopotein 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
 
 
PT 
Prothrombin time 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCLC 
Small cell lung cancer 
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
WMA 
World Medical Association 
β-hCG 
β human chorionic gonadotropin 
 
Note: Definitions of pharmacokinetic (PK) parameters are provided in Section 3.8.3 
 


 
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1. 
INTRODUCTION 
1.1 
Background 
Talazoparib (also known as MDV3800, BMN 673) is a potent, orally bioavailable, small 
molecule poly(ADP-ribose) polymerase (PARP) inhibitor in development for the 
treatment of a variety of human cancers. PARP inhibitors, including talazoparib, exert 
cytotoxic effects via two mechanisms, catalytic inhibition of PARP1 and PARP2, and 
PARP trapping, a process in which PARP protein bound to an inhibitor does not readily 
dissociate from DNA, preventing DNA repair, replication, and transcription. 
Talazoparib is cytotoxic to human cancer cell lines harboring gene mutations that 
compromise DNA repair, an effect referred to as synthetic lethality. In breast cancer 
MX-1 cells that are breast cancer susceptibility gene (BRCA)1-deficient, talazoparib 
inhibits cell growth in vitro and inhibits tumor growth and/or induces tumor regression in 
mouse xenografts. Antitumor activity was also demonstrated in small cell lung cancer 
(SCLC) cell lines and xenograft models; single-agent talazoparib reduced tumor growth 
to a similar extent as cisplatin in two independent SCLC xenograft models. 
Nonclinical studies demonstrated increased cytotoxic effects when talazoparib was 
combined with certain DNA damaging chemotherapies such as alkylating agents or 
topoisomerase I inhibitors. Non-cytotoxic concentrations of temozolomide greatly 
enhanced the cytotoxic effects of talazoparib in tissue culture studies using prostate, 
leukemia, and Ewing sarcoma cells. Enhancement of talazoparib cytotoxic effects 
results from temozolomide induced cytotoxic DNA adducts that can be removed by O6 
methylguanine methyltransferase (MGMT) and also potentially lethal DNA adducts that 
are dependent on the base excision repair (BER) response. Temozolomide induces 
numerous sites for PARP-DNA complexes to form and become trapped by talazoparib. 
Similarly in an SCLC xenograft model in mice, combination treatment with talazoparib 
plus temozolomide resulted in a marked enhancement of antitumor effects compared 
with that observed with either agent alone. Tissue culture studies of talazoparib in 
combination with the active metabolite of irinotecan, SN38, also demonstrated 
enhanced pharmacologic effects of combination versus single agent treatment. 
For further details on topics in this section refer to the current Investigator's Brochure 
(IB) 1. 
1.1.1 
Nonclinical Studies 
The main nonclinical toxicology findings with talazoparib were early hematologic 
changes and subsequent bone marrow and lymphoid organ depletion, as well as focal 
atrophy and degeneration of testes after repeat-dose talazoparib. These findings are 
consistent with the exaggerated pharmacology of talazoparib and its tissue exposure 
pattern. The hematologic findings were generally reversible and the early hematologic 
changes represent sensitive and early markers of target organ toxicity. 
1.1.2 
Clinical Studies 
As of 30 Nov 2015, approximately 319 patients with hematologic malignancies and 
solid tumors and 18 healthy volunteers have received talazoparib at doses up to 
2 mg/day. The majority of available efficacy and safety data was obtained from studies 


 
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in solid tumors. A Phase 1 study in patients with advanced or recurrent solid tumors 
defined the maximum tolerated dose (MTD) of talazoparib as 1 mg/day. 
1.1.2.1 
Pharmacokinetics 
The pharmacokinetics (PK) of talazoparib as a single agent was evaluated in 142 adult 
patients with cancer. Of these, 109 patients had solid tumors (PRP-001) and 33 had 
hematologic malignancies (PRP-002). Doses of 0.025 to 2 mg/day were administered 
orally as a single dose or as multiple doses. This range bracketed the 1 mg/day dose 
used in ongoing safety and efficacy studies, and provided a framework for assessing 
dose linearity. As the PK of talazoparib was similar in patients with solid tumors and 
hematologic malignancies, and no differences were apparent between males and 
females, the results are summarized collectively for all 142 patients. 
Oral absorption of talazoparib was rapid and independent of dose after administration 
of single or once-daily doses. Peak talazoparib concentrations were generally achieved 
approximately 1 to 8 hours post-dose. Elimination appeared to follow biphasic kinetics, 
with a mean half-life (T1/2) that ranged from 52.9 to 229 hours. The mean T1/2 of 
talazoparib showed some evidence of decreasing with increasing dose. At 1 mg/day, 
the mean T1/2 was approximately 2 days. With daily administration, it took 
approximately 2 to 3 weeks to reach steady state. 
The apparent volume of distribution (V/F) of talazoparib appeared to decrease with 
increasing dose. At 1 mg/day, the mean V/F was 415 L, or approximately 10-fold 
greater than total body water (42 L), which is indicative of extensive extravascular 
distribution2. In vitro protein binding data showed that talazoparib is 78.7% bound to 
human plasma proteins. 
No clinical studies have investigated penetration of talazoparib into the brain or 
cerebrospinal fluid. Talazoparib showed negligible penetration across the blood-brain 
barrier in rats. 
Apparent total body clearance (CL/F) of talazoparib appeared to be dose linear. The 
mean CL/F across doses was approximately 5 L/hr. Clinical data showed that renal 
excretion is a major elimination pathway for unchanged parent talazoparib. Following 
oral administration, 44 to 90.6% of the dose was recovered in urine as unchanged 
parent drug over 24 hours at steady-state for doses up to 1 mg/day. Mean renal 
clearance ranged from 1.38 to 4.96 L/h, independent of dose, suggesting linear urinary 
elimination kinetics. The extent of metabolism was also minimal in nonclinical studies. 
Following oral administration of 14C-talazoparib to rats and dogs, talazoparib was 
cleared primarily via excretion of unchanged parent drug and metabolized to a minor 
extent via oxidation and dehydrogenation. In vitro metabolism studies in human hepatic 
microsomes demonstrated that 14C-talazoparib has high metabolic stability (> 90%) 
over 2 hours. A minimal extent or a lack of metabolism for 14C-talazoparib was 
observed in the presence of freshly isolated human hepatocytes or cryopreserved 
human hepatocytes. 
Following administration at 1 mg/day, talazoparib accumulated approximately 2.4-fold 
relative to a single dose. At steady state, the mean maximum observed plasma 
concentration (Cmax) was 21.0 ng/mL, the mean plasma trough concentration (Cmin) was 


 
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3.72 ng/mL, the mean area under the concentration-time curve (AUC) was 
202 ng•h/mL, and the mean peak-to-trough ratio was approximately 6. 
Food Effect 
A food-effect study (673-103) involving administration of a single 0.5 mg dose of 
talazoparib to 18 healthy male subjects both under fasting conditions and with a 
high-fat, high-calorie meal showed that food had no effect on the extent of absorption 
(AUC). Food decreased the rate of absorption (Cmax was 46% lower and Tmax was 
2.63 hours later); however this reduction in the rate of absorption following a single 
dose is not clinically relevant because talazoparib accumulates 2.4-fold at steady state 
after 1 mg once-daily dosing. Furthermore, it is thought that AUC or Cmin drives efficacy, 
not Cmax; therefore, talazoparib can be taken with or without food. Talazoparib is being 
administered without regard to meals in ongoing safety and efficacy trials. 
Pharmacokinetics in Special Populations 
A preliminary population PK analysis was performed with data from patients in studies 
PRP-001 and PRP-002 to assess the effects of renal function on PK parameters of 
talazoparib. Talazoparib apparent systemic clearance (CL/F) in patients with mild renal 
impairment (creatinine clearance [CLCR], 60-89 mL/min) was similar compared with 
patients with normal renal function (CLCR ≥ 90 mL/min). In patients with moderate renal 
impairment (CLCR, 30-59 mL/min), the talazoparib CL/F was decreased by 44%, 
resulting in higher talazoparib exposure. Therefore, patients with moderate or severe 
renal impairment (CLCR < 60 mL/min) may be at risk of elevated exposure ≥50%) to 
talazoparib. 
The effects of hepatic impairment on talazoparib PK have not been studied. 
Drug-Drug Interaction 
Talazoparib is unlikely to demonstrate clinically significant cytochrome P450 (CYP450) 
inhibition- or induction-based drug-drug interactions or drug transporter inhibition-based 
drug-drug interactions when co-administered with corresponding substrates. However, 
talazoparib is a substrate for P-glycoprotein (P-gp) and the breast cancer resistance 
protein (BCRP), and plasma talazoparib concentrations may increase or decrease 
when co-administered with P-gp or BCRP inhibitors or inducers, respectively. 
Efficacy 
Preliminary data demonstrated objective responses and/or likely clinical benefit in 
patients with breast, ovarian/peritoneal, and pancreatic cancer with deleterious 
germline mutations; SCLC; and Ewing’s sarcoma. A Phase 2 study and a Phase 3 
study in patients with locally advanced or metastatic breast cancer with deleterious 
germline BRCA mutations are both ongoing. Efficacy data are not yet available. 
The efficacy signals of talazoparib observed in the treatment of cancers with and 
without BRCA mutations warrant the continued development of talazoparib as a single 
agent at doses of 1 mg/day and support the hypothesis for enhanced cytotoxicity of 
talazoparib by the addition of DNA damaging agents. 


 
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Safety 
The most common adverse events (AEs) associated with talazoparib collected in 214 
patients participating three clinical studies (PRP-001, PRP-002, and 673-201) were 
myelosuppression (anemia, neutropenia, thrombocytopenia), gastrointestinal toxicity 
(nausea, vomiting, diarrhea), and fatigue. The most common National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 AEs and 
serious adverse events (SAE) were associated with myelosuppression. 
A total of 25 of 214 patients had SAEs that led to death (12 associated with 
malignancies, 3 disease progression, 2 each lung infection and pneumonia, and 1 each 
cardiorespiratory arrest, neutropenic sepsis, renal impairment, dyspnea, hypoxia, and 
respiratory failure). Of these, none was assessed as related to the study drug. 
Adverse events leading to dose interruptions occurred in approximately 45%, 49%, and 
57% of patients in company-sponsored studies PRP-002 and PRP-001, and 
investigator-sponsored study NCT02049593 (combination treatment), respectively. 
Adverse events leading to dose reductions occurred in approximately 6% of patients in 
PRP-002, more than 17% of patients in PRP-001, and more than 20% of patients in 
NCT02049593. Most dose modifications were due to myelosuppression. 
Potential risks associated with talazoparib include hepatotoxicity, neutropenic sepsis, 
and febrile neutropenia. 
1.2 
Study Rationale 
The aim of this trial is to evaluate the metabolism and mass balance (i.e., recovery) of 
talazoparib, to identify the major route(s) of talazoparib elimination, to identify 
talazoparib metabolites in plasma, urine and feces and to determine the plasma 
concentration-time profiles of talazoparib and its metabolites in humans. 
The need for mass balance trials in anticancer drug development has recently been 
emphasized by both the Food and Drug Administration (FDA) and the European 
Medicines Agency (EMA) in the ICH S9 and EU guidelines on the evaluation of 
anticancer medicinal products 2,4. 
1.2.1 
Radioactively labeled dose (Mass Balance) of Talazoparib 
Administration of an oral solution containing 100 µCi 14C-talazoparib is considered to 
be appropriate to reach the objectives of this study. 
The oral administration 100 µCi (3.7 MBq) 14C-talazoparib yields an estimated effective 
radiation burden of 0.3 mSv and which is within the accepted limits of up to 1 mSv 
according to the International Commission on Radiological Protection (ICRP), 2007, 
Guidelines for Category 2a studies5,6. 
The Hungarian National Institute for Quality- and Organizational Development in 
Healthcare and Medicines (GYEMSZI) accepts an exposure of humans to ionizing 
radiation using unsealed radioactive products in human trials up to an effective dose of 
1 mSv (in adults), in accordance with national Hungarian standard MSZ 62-7 (2011)7, 
local regulations 16/2000 EüM and 23/1997 NM and EU guidance8. 


 
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1.2.2 
Unlabeled dose of talazoparib 
As of 30 Nov 2015, approximately 250 patients have received 1 mg of talazoparib once 
daily in multiple dose studies. Based on this experience, 1 mg QD was found to be 
sufficiently well-tolerated in the oncology population and is considered the 
recommended single-agent dose. As this study includes only a single dose, without the 
accumulation that occurs after multiple doses, the proposed 1 mg dose is expected to 
be generally well-tolerated. See the Investigator’s Brochure for additional details. 
1.2.3 
Study Population Rationale 
Talazoparib has shown clinical activity in advanced solid tumor patient populations and 
is being developed further as a treatment for several cancers; a mass balance study in 
cancer patients is thus justified. In the present study, the patient population will be 
limited to neoplastic diseases which were already included in previous clinical trials 
with talazoparib, i.e. patients with platinum-resistant ovarian carcinoma, cervical 
adenocarcinoma, small cell lung carcinoma and triple-negative breast cancer. After first 
administration of the 14C-labeled investigational medicinal product (IMP) and the 
completion of all assessments related to absorption, distribution, metabolism and 
excretion (ADME) and mass balance, select study subjects may have the option to 
continue treatment with daily unlabeled (non-radioactive) talazoparib in an open label 
extension study after evaluation by the Principal Investigator (PI) and approval of 
Sponsor; a separate extension protocol will be prepared for this purpose. 


 
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2. 
OBJECTIVES 
2.1 
Primary 
• 
To determine the time course of excretion of 14C radioactivity in urine and feces 
following a single 1 mg oral dose of talazoparib containing 100 µCi 
14C-talazoparib. 
• 
To determine the recovery of 
14C radioactivity as a percentage of the 
administered dose. 
• 
To determine the plasma PK of talazoparib and/or potential metabolites. 
• 
To determine PK of total radioactivity of 14C-talazoparib (AUC0-inf, AUC0-last, Cmax, 
Tmax, T1/2, CL/F, and Vd/F) in plasma and whole blood . 
2.2 
Secondary 
• 
To assess the safety and tolerability of a single dose of 1 mg talazoparib 
containing 100 µCi 14C-talazoparib. 
• 
To determine the percentage of 14C radioactivity of talazoparib associated with 
erythrocytes and whole blood over time. 
• 
To determine the amount of talazoparib in urine and feces. 
• 
To estimate the amount and probable structure of any significant metabolites of 
talazoparib in plasma, urine and feces. 
 


 
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3. 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
3.1.1 
Type of Study 
This is a Phase 1, single-center, open-label, mass balance study with 14C-radiolabeled 
talazoparib in at least 6 patients with advanced solid tumors who qualify for treatment 
with talazoparib. Each eligible patient will receive an oral solution of 1 mg of talazoparib 
containing100 µCi of 14C-radiolabeled talazoparib. Patients who complete the mass-
balance part in this clinical study will have the option to continue treatment on an open-
label extension protocol (Figure 1). 
Figure 1 Study Design 
 
3.1.2 
Screening Period 
Patients will sign the study-specific informed consent form (ICF) prior to any 
study-specific screening procedures being performed within 21 days before dosing of 
talazoparib on Day 1. The written informed consent will be obtained for all patients, 
regardless of their eligibility for the study. 
Eligibility screening will consist of the assessments as presented in the schedule of 
assessments (Table 1). Patients may be enrolled if they are eligible according to the 
inclusion and exclusion criteria (Section 3.4). Details on the conduct of study-related 
assessments are given in Section 3.8. 
Screening
Day -21 to -1
ADME Part
Day 1 to 22
1 mg talazoparib
containing
100 µCi 14C
Day 1
Acceptable 14C-recovery rate?
No
Yes
Follow-up
Visit
30 (±5) days after
discharge from ADME Part
Prolongation I
Day 23 to 28
Urine/Feces collection
Day 28 to Day 29
Acceptable 14C-recovery rate?
(Release criteria met?)
Yes
Extension
Protocol
Optional for
eligible patients
No
Prolongation II
Day 29 to 35
Urine/Feces collection
Day 35 to Day 36


 
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3.1.3 
Treatment Period 
3.1.3.1 
Baseline 
Eligible patients will enter the clinical unit on Day –1 (one day before administration of 
talazoparib). Assessments will be performed as shown in the schedule of assessments 
(Table 1) and as detailed in Section 3.8. 
Once all baseline activities of Day –1 have been concluded and pending eligibility 
criteria have been confirmed patients will be eligible for enrollment and administration 
of talazoparib on Day 1. 
3.1.3.2 
Mass-Balance Part 
Patients will receive 1 mg of talazoparib as an oral solution that contains 100 µCi 
(3.7 MBq) of 14C-labeled talazoparib in the morning of Day 1. PK of radiolabeled 
compound will be performed together with potential metabolite profiling in blood, urine, 
feces as shown in Table 3. 
Assessments of safety and tolerability will be conducted according to the schedule of 
assessments (Table 1). 
Patients will be confined from Day –1 on and will be discharged from the study unit on 
Day 22 (504 h post-dose) after all study-related procedures have been concluded, 
assuming that the recovery of the radioactive material satisfies the conditions listed 
below (Section 3.1.3.3). 
3.1.3.3 
Early Discharge and Prolongation 
Patients will be discharged on Day 22, if any of the following conditions are met: 
• 
≥ 90% of the administered radioactivity is recovered in the urine and feces 
(accounting for radioactivity in vomitus, if applicable) 
• 
The daily total excreted radioactivity is 1% or less of the administered dose on 2 
consecutive days. Shipments for daily Quick Count will start on Day 10. 
Patients may be discharged on an individual basis prior to Day 22, if scintillation counts 
data are available and the above listed conditions are met. If the patient meet this early 
criteria prior to the morning of Day 22, collection of blood, urine, and feces may be 
stopped following completion of all scheduled 24-hour collections for that day. At the 
conclusion of the blood, urine, and feces collection, and completion of the same safety 
procedures as scheduled for Day 22 (in lieu of Day 22) the patients will be discharged. 
If an individual patient does not demonstrate a cumulative amount of radioactivity 
recovered in urine and feces ≥ 90% or has not met the daily total excretion criteria of 
1% or less of the administered dose on 2 consecutive days, following consultation with 
the Sponsor, the Investigator may ask patient to return to the clinic on Day 28 for a 
24 h collection of urine and feces (Table 2). If, by Day 29, the patient has still not met 
release criteria, a discussion between the Sponsor and the Investigator will be 
conducted for possibility to collect additional 24 h collection of urine and feces from 
Day 35 to Day 36 (Table 2). 


 
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3.1.3.4 
Follow-up 
Follow-up will be performed within 14 days after the last day of the mass balance 
phase and at least 30 days after Day 1, or the first day of extension protocol, whichever 
occurs first. This follow-up can be an onsite visit or a phone call (Table 1 and/or 
Table 2). 
3.2 
Extension Protocol 
Patients participating in this study with no clinically significant toxicities may be eligible 
to continue talazoparib treatment on a separate open-label extension protocol outside 
of this study. 
Decision to allow the patient to continue dosing with talazoparib in an open-label study 
will be based on potential clinical benefit and patient eligibility for enrollment to the 
open-label extension study. 
3.3 
Discussion of Study Design 
This is a clinical study to investigate the metabolism, excretion pattern, and mass 
balance of talazoparib following the administration of 14C-talazoparib. The terminal half-
life of talazoparib at 1 mg is approximately 2 days. Urine and feces collection for up to 
21 days should ensure that >90% of the dose is excreted. Talazoparib is being 
developed for the treatment of a variety of solid tumors either as a single agent or in 
combination with established therapies. No blinding, comparator treatment or 
randomization was considered necessary for this study. No formal sample size 
calculation has been carried out. The administration of the 14C-IMP is based on the 
ALARA principle (as low radioactive burden as reasonably achievable) set forth in the 
96/29/EURATOM directive. 
For dose justification and risk-benefit assessment, please see Section 1.2. 
3.4 
Selection of Study Population 
The study is planned to enroll a total of 6 patients with advanced solid cancer in order 
to obtain data in at least 4 evaluable subjects. 
3.4.1 
Inclusion Criteria 
Each patient eligible to participate in this study must meet all of the following criteria: 
1. 
At least 18 years of age and willing and able to provide informed consent. 
2. 
Histologically confirmed advanced solid tumor (limited to platinum-resistant ovarian 
carcinoma, cervical adenocarcinoma, small cell lung carcinoma or triple-negative 
breast cancer) judged by the Investigator to not be appropriate for standard 
therapy. 
3. 
Eastern Co-Operative Oncology Group (ECOG) performance status ≤ 2 at 
screening and Day –1. 
4. 
Expected life expectancy of ≥ 3 months. 
5. 
Able to swallow the study drug and comply with study requirements. 
6. 
Female subjects may be enrolled if they are 


 
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a. 
considered not of childbearing potential including those who are surgically 
sterile (bilateral salpingectomy, bilateral oophorectomy, or hysterectomy ≥6 
months before enrollment, with documentation of the procedure) or who are 
post-menopausal, defined as: 
─ 
≥ 55 years of age with no spontaneous menses for ≥ 12 months before 
randomization 
─ 
< 55 years of age with no spontaneous menses for ≥ 12 months before 
randomization and with a postmenopausal follicle-stimulating hormone 
(FSH) concentration > 30 IU/L (or meeting criteria for post-menopausal 
status by the local laboratory) 
or 
b. 
of childbearing potential using a highly effective form of contraception from 
screening or at least 21 days prior to study drug administration (whichever is 
earlier) until 45 days after last intake of study medication and having a 
negative serum pregnancy test at Screening and Day -1 defined as at least 
one of the following: 
─ 
Established use of an oral, intravaginal, or transdermal combined (estrogen 
an 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 
─ 
Placement of an intrauterine device or intrauterine hormone-releasing 
system 
─ 
Sexual partner(s) vasectomized for ≥ 6 months before enrollment 
─ 
Sexual abstinence when in relation to the preferred and usual lifestyle of 
the subject 
and 
c. 
do not donate eggs from the time point of IMP administration until at least 45 
days thereafter. 
7. 
Males with partners of childbearing potential may be enrolled if they 
a. 
use a condom when having sex with a pregnant woman or with a woman of 
childbearing potential from 21 days before the first dose of study drug 
through 105 days after last dose of study drug. Contraception should be 
considered for a nonpregnant female partner of childbearing potential. 
and 
b. 
do not donate sperm from the time point of study drug administration until at 
least 105 days thereafter. 
8. 
Female patients must not be breastfeeding at screening and during the study 
participation until 45 days after the last dose of the study drug. 
9. 
Willingness and ability to comply with scheduled visits, treatment plan, laboratory 
tests, and other trial procedures. 


 
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3.4.2 
Exclusion Criteria 
Each patient eligible to participate in this study must NOT meet any of the following 
exclusion criteria: 
1. 
Treatment within 14 days or five half-lives prior to dosing with any type of systemic 
anticancer therapy or any investigational agent, whichever is longer. 
2. 
Major surgery within 8 weeks before screening. 
3. 
Serious accompanying disorder or impaired organ function, including the following: 
a. 
Cardiac: 
─ 
Myocardial infarction or symptomatic cardiac ischemia within 6 months 
before enrollment. 
─ 
Heart failure of severity grade class III or IV according to New York Heart 
Association (NYHA) within 3 months before enrollment. 
─ 
Clinically significant cardiac arrhythmias if not adequately treated or 
controlled (e.g. by medication, or pacemaker). 
─ 
History of Mobitz II second degree or third degree heart block unless a 
permanent pacemaker is in place. 
─ 
Hypotension as indicated by systolic blood pressure < 86 mm Hg at 
screening or Day –1. 
─ 
Bradycardia as indicated by a heart rate of < 45 beats per minute on the 
screening electrocardiogram (ECG) at screening. 
─ 
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 if initial reading is believed to be atypical for the 
patient. 
─ 
Screening QTcF ≥ 450 ms in males or ≥ 480 ms in females. 
b. 
Renal: eGFR (estimated glomerular filtration rate) ≤ 50 mL/min/1.73 m2 by 
MDRD (Modification of Diet in Renal Disease) equation [available via 
www.mdrd.com]) at screening and Day –1 
c. 
History or nephrectomy or renal transplant 
d. 
Clinically significant renal disease within three months of enrollment. 
e. 
Total serum bilirubin > 1.5 times upper limit of normal (ULN); (> 3 times ULN 
for patients with Gilbert’s syndrome or for whom indirect bilirubin 
concentrations suggest an extrahepatic source of elevation) 
f. 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
≥ 2.5 times ULN 
g. 
Bone marrow reserve: neutrophils < 1500/µL, platelets < 100,000/µL, or 
hemoglobin < 9 g/dL (blood samples collected after ≥ 14 days without growth 
factor support or transfusion). 
h. 
Albumin < 3.0 g/dL. 
4. 
Symptomatic or impending spinal cord compression or cauda equina syndrome. 
5. 
Non-healing wound, ulcer, or bone fracture, not including a pathological bone 
fracture caused by a pre-existent pathological bone lesion. 
6. 
Known myelodysplastic syndrome. 
7. 
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HCV+; HIV+. 
8. 
Serious or unstable medical condition that interferes with ability to tolerate 
treatment or assessments associated with the protocol. 
9. 
Gastrointestinal disorder affecting absorption. 
10. 
Known hypersensitivity to any of the talazoparib solution components. 
11. 
Use of a strong P-gp inhibitor (e.g., dronedarone, quinidine, ranolazine, verapamil, 
itraconazole, ketoconazole), strong P-gp inducer (e.g. rifampin, tipranavir, 
ritonavir), or strong inhibitor of BCRP (e.g., elacridar [GF120918]) within 7 days or 
5 half-lives, whichever is longer, before Day 1. Patients must also abstain from the 
use of any other prescription or nonprescription drugs or supplements with 
potential P-glycoprotein (P-gp) and BCRP interaction within 7 days or 5 half-lives 
(whichever is longer) before Day 1. 
12. 
Any condition or reason that interferes with ability to participate in the study, 
causes undue risk, or complicates the interpretation of safety data, in the opinion of 
the Investigator or Sponsor (e.g. non-compliance, excessive alcohol consumption, 
intake of drugs of abuse unless these drugs are medically indicated [e.g. opiates 
for pain relief]). 
3.5 
Removal of Subjects from Therapy or Assessment 
Participation in the study is strictly voluntary. A patient has the right to withdraw from 
the study at any time for any reason. 
The Investigator has the right to terminate participation of a patient for any of the 
following reasons: 
• 
Occurrence of an exclusion criterion which is clinically relevant and affects the 
subject’s safety, if discontinuation is considered necessary by the Investigator 
and/or Sponsor 
• 
Intolerable toxicity as evidenced by the occurrence of severe AEs, or SAEs 
• 
Non-compliance that is likely to affect the validity of the data obtained from the 
subject. 
If a subject withdraws or is removed from further study participation end-of-treatment 
and follow-up visits will be conducted as described in Section 3.1.3.4. 
The main objectives of this study can be pursued after the dosing with the 
14C-radiolabeled drug on Day 1. Provided that the collection of the PK and 
mass-balance samples is completed, the subject will not be withdrawn from the main 
analysis. 
If a patient is withdrawn from the study, the Sponsor will be informed immediately. If 
there is a medical reason for withdrawal, the patient will remain under the supervision 
of the Investigator until satisfactory health has returned. 
Patients who discontinue before 85% of total drug is recovered from urine and feces 
may be replaced upon agreement of the Investigator and the Sponsor. 
The decision regarding the replacement of subjects will be documented. 
The Investigator will make every effort to ensure that non-completers and dropouts who 
have received study drug complete the safety follow-up assessments. 


 
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3.6 
Premature Discontinuation of the Trial 
The whole trial may be discontinued prematurely in the event of any of the following: 
• 
New information leading to unfavorable risk-benefit judgment of the IMP, e.g., 
due to: 
─ 
Occurrence of significant previously unknown adverse reactions or 
unexpectedly high intensity or incidence of known adverse reactions, or 
─ 
Other unfavorable safety findings. 
• 
Sponsor’s decision. 
• 
Poor enrollment of subjects making completion of the trial within an acceptable 
time frame unlikely. 
• 
Discontinuation of development of the Sponsor’s IMP. 
Health authorities and IECs (Independent Ethics Committees) will be informed about 
the discontinuation of the trial in accordance with applicable regulations. 
The whole trial may be terminated or suspended upon request of health authorities. 
3.7 
Treatments 
3.7.1 
Treatments Administered 
Patients will only receive a single 1 mg dose of talazoparib containing 100 µCi 
14C-labeled talazoparib on Day 1. No other doses of talazoparib will be administered 
throughout the remainder of this study. 
3.7.2 
Identity of Investigational Product 
Active substance: 
Talazoparib, chemical name (8S,9R)
Indication: 
Advanced solid tumors 
Dose: 
1 mg talazoparib and 100 µCi 14C-talazoparib, once 
Note: Preparation of the 14C-radiolabeled and unlabeled IMP will be carried out according to the 
guide on Good Manufacturing Practice (GMP) for the manufacturing of active pharmaceutical 
ingredients. 
For details concerning drug storage and drug accountability see Appendix 8.1. 
3.7.3 
Treatment Assignment 
After obtaining informed consent, patients will be screened according to the inclusion 
and exclusion criteria. Enrolled patients will receive a unique patient number (01 to 06) 
prior to dosing. The patient number will ensure identification throughout the study. 
Replacement patients will receive the number of the patient to be replaced, increased 
by 10 (e.g. 11 replacement number for patient number 01), and will be administered the 
same treatment. 
CCI


 
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Patients who drop out or withdraw for any reason without completing all screening 
evaluations successfully, will be considered as “screening failures“. The Investigator or 
authorized designee will keep a screening log of all patients screened in order to 
assess the numbers and characteristics of the excluded patients, and the reasons for 
their exclusion. 
3.7.4 
Selection and Timing of Doses in the Study 
The dose of 1 mg talazoparib is the MTD for daily administration and considered to be 
the recommended single-agent dose. 
Details on preparation and administration of study drug will be provided in the 
pharmacy manual. 
A solution for oral administration containing 1 mg talazoparib together with 100 µCi of 
14C-labeled talazoparib will be administered in the morning of Day 1 (Table 1). 
3.7.5 
Meals During the Study 
Subjects will be required to be fasting overnight from at least 8 hours before until at 
least 2 hours after the administration of talazoparib. Within this food-restricted period 
the consumption of water is allowed. 
All safety laboratory assessments (clinical chemistry, hematology and coagulation) 
should be performed in a fasted condition of the patients (i.e. overnight, before 
breakfast). 
3.7.6 
Blinding 
Not applicable. This is an uncontrolled, open-label clinical study. 
3.7.7 
Concomitant Medication and Other Restrictions During the Study 
Patients must abstain from the use of inhibitors or inducers of P-gp or BCRP within 7 
days or 5 half-lives (whichever is longer) before Day 1 (see FDA: Table of Substrates, 
Inhibitors and Inducers). 
Note: Restrictions that apply to the period before admission are described in the eligibility 
criteria in Section 3.4. 
3.7.8 
Treatment Compliance 
Talazoparib will be administered orally by the Investigator or his/her designee. 
Compliance will be confirmed by bioanalytical assessment of the IMP in blood, urine, 
and feces samples. 
The exact times of study drug administration and the number of units administered will 
be recorded in the eCRF. 


 
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3.8 
Pharmacokinetic, Efficacy and Safety Measurements and Variables 
3.8.1 
Pharmacokinetic, Efficacy and Safety Measurements Assessed 
3.8.1.1 
Pharmacokinetic Measurements 
3.8.1.1.1 
Blood Sampling 
For PK of talazoparib, for potential metabolite profiling of talazoparib and assessment 
of total 14C-radioactivity blood samples will be taken as outlined in the PK sampling 
schedule (Table 3). The exact times of each blood collection will be recorded in the 
eCRF. 
The details of sample acquisition, processing, storage and shipment will be issued in a 
laboratory manual. 
3.8.1.1.2 
Urine Collection 
During the intervals defined in PK sampling schedule (Table 3), urine will be collected 
for the analysis of talazoparib, and potential metabolites or degradation products for the 
analysis of total radioactivity and for quick counts of total radioactivity. The subjects will 
be instructed to empty their bladders completely before study drug administration and 
at the end of each collection interval. A blank urine sample will be collected within 12 
hours prior to study drug administration. The exact times of urine collection and the 
total urine volume of each entire interval will be recorded in the eCRF. 
The details of sample acquisition, processing, storage and shipment will be issued in a 
laboratory manual. 
3.8.1.1.3 
Feces and Vomitus Collection 
During the intervals defined in PK sampling schedule (Table 3), all fecal excretions 
(and vomitus, if applicable) will be collected for the analysis of talazoparib, and 
potential metabolites products for the analysis of total radioactivity, for quick counts of 
total radioactivity and/or for metabolite profiling. A blank fecal sample will be collected 
within 48 hours prior to study drug administration. The exact times of feces collection 
and the fecal weight of each entire interval will be recorded in the eCRF. This applies 
also to vomitus, if applicable. 
The details of sample acquisition, processing, storage and shipment will be issued in a 
laboratory manual. 
3.8.1.2 
Efficacy Measurements 
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 on a 
separate extension protocol. 
3.8.1.3 
Safety Measurements 
Safety and tolerability assessments will consist of AEs, clinical laboratory, vital signs, 
12-lead ECG, and physical examination. Assessments will be performed in accordance 
with the schedules of assessments (Table 1 and Table 2). 


 
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3.8.1.3.1 
Adverse Events 
Adverse events will be recorded following the first dose of study drug until completion 
of the follow-up visit. Any clinically significant observations in results of clinical 
laboratory, 12-lead ECGs, vital signs or physical examinations will be recorded as AEs. 
A treatment-emergent AE (TEAE) is defined as any event not present prior to 
administration of the study drug or any event already present that worsens in either 
severity or frequency following exposure to the study drug. 
Treatment-emergent safety data will be collected from Day 1 (the first and only dose of 
study drug) through 14 days after the last day of mass balance phase and at least 30 
days after Day 1 or before initiation of new cytotoxic chemotherapy, new investigational 
treatment, or the first day of extension protocol, whichever occurs first. 
An AE which occurs prior to (the first) administration of the study drug will be 
considered a pre-treatment AE and documented on the medical history eCRF. 
At several time points before and after drug administration, subjects will be asked 
non-leading questions to determine the occurrence of AEs. Subjects will be asked in 
general terms about any AEs at regular intervals during the study. In addition, all AEs 
reported spontaneously during the course of the study will be recorded. Events that 
meet serious criteria will be reported as detailed in Appendix 8.2. 
All answers will be coded by the Investigator using the Medical Dictionary for 
Regulatory Activities (MedDRA; most recent version) for AEs and will be recorded in 
the AEs Record. Details on the rating of the severity of the AEs and relationship to the 
study treatment are given in Appendix 8.2. 
Pregnancy of female subjects and female partners of male subjects will be monitored 
along with follow-up, if warranted (see also Appendix 8.3). 
3.8.1.3.2 
Eastern Co-Operative Oncology Group Performance Status (ECOG) 
The performance status will be determined according to the ECOG Performance Status 
scale 9: 
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 or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
3.8.1.3.3 
Clinical Laboratory 
The below listed tests will be performed by the local laboratory at time points indicated 
in the schedule of assessments (Table 1 and Table 2). 
 


 
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Clinical Laboratory Tests 
Hematology and 
Coagulation 
Serum Chemistry 
Urinalysis 
Additional Tests 
Hemoglobin 
Sodium 
pH 
Serology: anti- HIV-1/2, 
HbsAg and anti-HBc, 
HCV 
Hematocrit 
Potassium 
Specific gravity 
Erythrocytes 
Chloride 
Color 
Platelets 
Calcium 
Protein 
FSH test  
Collect only for females 
with no spontaneous 
menses for ≥12 months, 
who are <55 years old, 
and who do not have 
documented surgical 
sterilization. 
Leukocytes 
Inorganic phosphate 
Glucose 
Neutrophils 
Urea 
Ketones 
Eosinophils 
Creatinine 
(including calculation 
eGFR) 
Hemoglobin 
(erythrocytes)  
Lymphocytes 
 
Monocytes 
Total bilirubin 
Leukocytes 
Serum pregnancy test for 
women of childbearing 
potential, including 
women whose last 
menstruation was less 
than 1 year before 
screening 
Basophils 
Direct bilirubin§ 
Microscopic 
analysis, if urine is 
positive for protein, 
leukocytes or 
hemoglobin 
INR* 
ALT 
aPTT* 
AST 
PT* 
GGT 
 
ALP 
 
 
LDH 
 
Urine drugs of abuse test 
including but not limited to 
cannabinoids, 
amphetamines, 
methamphetamines, 
opiates, methadone, 
cocaine, 
benzodiazepines, and 
barbiturates 
 
CPK 
 
 
 
 
 
 
 
 
Triglycerides* 
 
 
Total cholesterol* 
 
 
Total protein* 
 
 
Albumin* 
 
 
Glucose 
 
Alcohol breath test. 
* At screening only 
§ Direct bilirubin will be measured only if total bilirubin is higher than upper limit of normal 
range 
The clinical laboratory will clearly mark all laboratory test values that are outside the 
normal range and the Investigator will indicate the clinically significance according to 
the applicable 
 SOP. Detailed information about follow-up of 
abnormal laboratory results is given in Appendix 8.2.2.2. 
3.8.1.3.4 
Vital Signs 
Systolic and diastolic blood pressure and pulse will be recorded in supine position after 
the subject has been resting for at least 5 minutes in a sitting or semi recumbent 
position. These assessments will be made using an automated device. Body 
temperature and respiratory rate will be measured subsequently. 


 
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3.8.1.3.5 
Electrocardiogram 
A standard 12-lead ECG will be recorded in triplicates after the subject has been 
resting for at least 5 minutes in a supine position. The ECG will be recorded using an 
ECG machine equipped with computer based interval measurements. The following 
ECG parameters will be recorded: heart rate, PR-interval, QRS-duration, QT-interval, 
QTc-interval (Fridericia's) and the interpretation of the ECG profile by the Investigator. 
3.8.1.3.6 
Physical Examination 
A complete physical examination will be performed consisting of all body systems (with 
the exception of genitalia, anus/rectal, and breast examinations, which will only be 
performed 
if 
medically 
indicated). 
Unscheduled 
symptom-directed 
physical 
examinations may be conducted at any time per the Investigator’s discretion. 
3.8.1.4 
Total of Blood Volume 
During the course of this clinical study, a maximum volume of approximately 320 mL 
blood will be collected for PK and safety assessments. In this calculation a maximum 
prolonged observation period is taken into account (Section 3.1.3.3). 
If deemed necessary by the Investigator, additional blood samples for safety or PK 
analysis may be taken at additional (unscheduled) and follow-up visit(s) up to an 
additional volume of 30 mL. 
3.8.2 
Appropriateness of Measurements 
The assessments, which will be made in this study are standard for mass-balance 
studies, and generally recognized as reliable, accurate and relevant. 
3.8.2.1 
Timing of Assessments 
For PK, pre-dose samples will be obtained between waking up and dosing. Post-dose 
samples up to 60 minutes post-dose will be obtained with a time window of ±1 minute. 
From after 60 minutes until 12 hours post-dose, samples will be obtained with time 
margins of ±10 minutes. Thereafter, samples should be obtained within ±30 minutes of 
the scheduled time points. The ±30 minutes time window also applies to the start and 
end times of urine collection intervals. 
For safety, pre-dose assessments will be performed between waking up and dosing. 
Post-dose assessments will be performed with time margins of ±60 minutes of the 
planned scheme time. 
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. 
3.8.3 
Pharmacokinetic, Efficacy and Safety Variables 
3.8.3.1 
Pharmacokinetic Parameters 
Plasma and whole blood as appropriate, the following PK parameters will be calculated 
as data allows for talazoparib and/or metabolite concentrations in plasma and for 


 
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radioactivity in plasma and whole blood (i.e. nanogram equivalents from radioactivity). 
PK variables will be computed using WinNonlin Professional or another appropriate 
software. As appropriate, additional PK parameters may be calculated and reported. A 
complete list of PK parameters will be provided in the Statistical Analysis Plan (SAP). 
 
Cmax 
Maximum observed plasma/whole blood concentration 
Tmax 
Time to attain maximum observed plasma/whole blood concentration 
AUC0-last 
Area under the plasma concentration-time curve up to time t, where t is the 
last point with concentrations above the lower limit of quantitation (LLOQ)  
AUC0-inf 
Area under the plasma concentration-time curve from time 0 to infinity 
calculated as: AUC0-inf = AUC0-t + Clast/kel, 
where Clast is the last measurable plasma concentration  
kel 
Terminal elimination rate constant 
t1/2 
Terminal elimination half-life, calculated as 0.693/kel 
CL/F 
Clearance 
Vd/F 
Volume of distribution at terminal phase 
 
 
PK parameters derived from metabolite profiling will be evaluated if applicable. 
3.8.3.2 
Urine 
The following parameters will be calculated as data allows form individual urine 
concentration of talazoparib and/or metabolites and radioactivity in urine (i.e., 
nanogram equivalent from radioactivity counts) using non-compartmental approaches. 
Appropriate validated PK software (e.g., Phoenix WinNonlin or SAS) will be used. 
Curine 
Urine concentration 
Aeurine 
Amount excreted during each collection interval, calculated as Curine x 
urine volume 
CumAeurine 
Cumulative amount of drug excreted in urine 
%Doseurine 
Percentage of dose recovered in urine over the collection interval 
Cum%Doseurine) 
Cumulative percent of dose recovered in urine 
CLr 
Renal clearance calculated as CLr = CumAeurine/AUC0-last 
3.8.3.3 
Feces 
The following parameters will be calculated as data allows form individual 
concentration of talazoparib and/or metabolites and radioactivity in feces (i.e. 
nanogram equivalent from radioactivity counts) using non-compartmental approaches. 
Appropriate validated PK software (e.g. Phoenix WinNonlin or SAS) will be used. 


 
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Cfeces 
Fecal concentration 
Aefeces 
Amount excreted during each collection interval, calculated as 
Curine x fecal weight 
CumAefeces 
Cumulative amount of drug excreted in feces 
%Dosefeces 
Percentage of dose recovered in feces over the collection interval 
Cum%Dosefeces 
Cumulative percent of dose recovered in feces 
CumAevomit 
Cumulative amount of drug excreted in vomitus 
Cum%Dosetotal 
Cumulative percent of dose recovered in urine and feces 
3.8.3.4 
Analysis of Mass Balance 
Mass balance will be calculated as the percent of total administered radioactivity 
recovered in urine and feces. 
For the purpose of calculating mass balance, the amount of administered radioactivity 
is defined as the total radioactivity in the dosing solution minus any radioactivity lost 
due to non-collected vomitus (if any occurred), adsorption to the dosing cup, etc. 
3.8.3.5 
Metabolic Profiling 
Details regarding metabolic profiling, as well as results and a report (if applicable), will 
be prepared under separate cover by 
 
3.8.3.6 
Efficacy Variable(s) 
Not applicable. 
3.8.3.7 
Safety Variables 
The safety variables to be measured include but are not limited to the variables as 
given below. A complete list of safety variables will be provided in the SAP. 
• 
AEs 
• 
Clinical laboratory 
• 
Vital signs 
• 
ECG 
• 
Physical examination 
3.8.4 
Drug Concentration Measurements 
Talazoparib and potential metabolites will be analyzed using a validated LC-MS/MS 
method. 14C-quick counts will be performed in urine and feces to assess the discharge 
criteria in the ADME part (at least 90% recovery). Less than 1% excretion in urine plus 
feces per 24-h interval on at least 2 consecutive days will be assessed by a validated 
LSC method. Total 14C in whole blood, plasma, urine and feces will be analyzed using 
validated LSC methods. 
Metabolite profiling and identification will be done in plasma, urine and feces, if 
applicable. 


 
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3.9 
Statistical Procedures and Determination of Sample Size 
3.9.1 
Analysis Populations 
3.9.1.1 
Safety Population 
All subjects who have received at least 1 dose of talazoparib. 
3.9.1.2 
Pharmacokinetic Population 
All subjects who have received talazoparib, including the radiolabeled IMP, and 
provided sufficient bioanalytical assessments to calculate reliable estimates of the PK 
parameters. The concentrations of talazoparib (and potential metabolites) in blood, 
urine and/or feces will be displayed for the safety population. 
3.9.2 
Statistical and Analytical Plan for Pharmacokinetic and Safety Evaluation 
An SAP will be generated by the Biostatistics Department of 
 the SAP will be 
finalized prior to database lock. Full details of the analysis to be performed will be 
included in the SAP. 
Any deviation from the SAP will be reported in the Section “Changes in Planned 
Analysis” in the Clinical Study Report. 
3.9.2.1 
Demographic and Other Baseline Characteristics 
Summary statistics (arithmetic mean, standard deviation, median, minimum and 
maximum for quantitative variables) will be presented. Frequency tables for qualitative 
data will be provided. Medical history findings will be summarized using MedDRA 
terms. 
3.9.2.2 
Pharmacokinetic Evaluation 
The concentration-times courses of total radioactivity in whole blood and plasma and of 
talazoparib in plasma and – if appropriate – of its metabolites 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 
standard deviation (re-transformed standard deviation of the logarithms),geometric CV, 
minimum, median, maximum value and the number of measurements. Concentrations 
below LLOQ will be set to zero when calculating descriptive statistics. Means at any 
post-dose time will only be reported if the mean ≥ LLOQ; for mean < LLOQ, “missing” is 
reported in the tables. In tables showing mean values, where values below LLOQ are 
included in the calculation of mean values, these means will be marked. 
Individual and geometric mean concentration vs time curves of total radioactivity in 
whole blood and plasma and of talazoparib in plasma and – if appropriate – of its 
metabolites in plasma (using the actual sampling times for individual plots and the 
planned sampling times for mean plots) will be plotted using both linear and 
semi-logarithmic scale. Post-dose concentrations < LLOQ will not be plotted; pre-dose 
concentrations < LLOQ will be set to zero. The amount (%) of talazoparib and – if 
appropriate – its metabolites excreted into urine and feces will be graphically illustrated 


 
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for each sampling interval as well as for the whole sampling period (bar charts for the 
individual data and for the arithmetic means including standard deviation). 
PK parameters of total radioactivity in whole blood and plasma and of talazoparib in 
plasma and of its metabolites in plasma (Tmax excluded) will be summarized by 
arithmetic mean, standard deviation and CV, geometric mean, geometric standard 
deviation, geometric CV, minimum, median, maximum value and the number of 
evaluable observations. The PK characteristics of Tmax will be described utilizing 
minimum, maximum and median as well as frequency counts. In calculation of PK 
parameters, pre-dose concentrations < LLOQ are set to zero; all post-dose 
concentrations < LLOQ are set as missing value. 
The same method will be used for the analysis of the drug related radioactivity in blood, 
plasma, urine and feces. Summary statistics and bar charts will be provided for the 
cumulative excretion of total radioactivity in urine, feces, vomitus (if applicable) and 
urine plus feces (plus vomitus [if applicable]) to assess mass balance of total 
radioactivity. 
For total radioactivity the ratio of whole blood to plasma based on AUC0-inf, Cmax and 
AUC0-last will be calculated and summarized. 
To determine the percentage of radioactivity associated with erythrocytes in whole 
blood over time (calculated only for time points that whole blood is collected), the 
following will be calculated: 
The amount of radioactivity in plasma versus whole blood, adjusted for the hematocrit, 
at the specific time points of comparison Xe/Xb= 1-[Cp*(1-Hct)/Cb], where Xe and Xb 
stand for amount of radioactivity in erythrocyte or plasma, respectively, and Cp and Cb 
stands for radioactivity concentration in plasma and blood, respectively. Hematocrit 
values for Days –1, 1 and 22 will be averaged for use in this calculation. 
Additional analyses of the concentrations of talazoparib and its metabolites (if 
applicable) in plasma, urine, and feces (vomitus, if applicable) as determined by radio-
chromatographic methods as well as the corresponding PK parameters will be reported 
under separate cover. 
3.9.2.3 
Evaluation of Safety and Tolerability 
All safety analyses will be performed using the safety population, defined as all patients 
who received talazoparib. Safety will be evaluated using summaries of AEs, physical 
examinations (and weight), vital signs, ECG recordings, and laboratory evaluations. 
3.9.2.3.1 
Adverse Events 
Adverse events will be coded to preferred term and system organ class using MedDRA 
and classified by severity using NCI CTCAE. The number and percentage of patients 
with AEs will be presented by MedDRA system organ class and preferred term, 
relationship to study treatment, severity, seriousness, and outcome (e.g. leading to 
permanent treatment discontinuation). 


 
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3.9.2.3.2 
Clinical Laboratory 
Clinical laboratory data will be listed accompanied by an indication if the parameter is 
outside the reference range. A summary of all data outside the reference range of the 
clinical laboratory will be provided. Clinical laboratory data will be presented 
descriptively, where applicable. 
Laboratory values will be classified by severity using the CTCAE. Change from 
baseline in laboratory values will be tabulated and summarized graphically, where 
applicable. 
3.9.2.3.3 
Vital Signs and Electrocardiograms 
Vital signs and ECG parameters will be listed and they will be presented descriptively, 
where applicable. 
3.9.2.3.4 
Physical Examination 
Clinically significant changes will be considered as AEs. 
3.9.3 
Determination of Sample Size 
At least 6 patients will be enrolled to target 4 evaluable subjects. This sample size is 
consistent with typical study designs for Phase 1 mass balance studies for PK 
evaluation. 
3.10 
Data Quality Assurance 
The study may be audited to assess adherence to the Clinical Study Protocol (CSP) 
and Quality System. During the conduct of the study, process-related audits may be 
performed as well. An audit certificate will be provided in the appendices of the final 
Clinical Study Report (CSR) outlining the audit performed and other related activities. 
The clinical research site will be monitored by the study monitor to ensure correct 
performance of the study procedures and assure that the study will be conducted 
according to the relevant regulatory requirements. eCRF entries will be verified with the 
source documentation, if applicable. 
Regulatory authorities, the IEC and/or the Sponsor’s clinical quality assurance group 
may request access to all source documents, eCRFs, and other study documentation 
for on-site audit or inspection. Direct access to these documents must be guaranteed 
by the Investigator, who must provide support at all times for these activities. 
Quality control principles will be applied throughout the performance of this study. 
Review procedures will be followed at 
 for all documents that are generated in 
relation with the study. 
An explanation will be given for all missing, unused and spurious data in the relevant 
sections of the CSR. 
 


 
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4. 
ETHICS 
4.1 
Independent Ethics Committee 
Prior to commencement of the study, the protocol, any amendments, subject 
information and ICF, any other written information to be provided to the subject, subject 
recruitment procedures, if any, IB, information about payments and compensation 
available to subjects, if not mentioned in the subject information, the Investigator’s 
current curriculum vitae and/or other documentation evidencing qualifications, and 
other documents as required by the regulatory authorities and IEC will be submitted. 
The submission letter will clearly identify (by study identification number, including 
version, EudraCT no., title and/or date of the document) which documents have been 
submitted. Written approval/favorable opinion must be obtained from regulatory 
authorities/IEC prior to commencement of the study. 
During the study, the Investigator must promptly in accordance with local requirements 
report the following to the IEC (central or local IEC, as applicable): updates to IB, 
unexpected SAEs where a causal relationship cannot be ruled out, substantial 
amendments to the protocol, non-substantial amendments according to local 
requirements, deviations to the protocol implemented to eliminate immediate hazards 
to the subjects, new information that may affect adversely the safety of the subjects or 
the conduct of the study (including new risk/benefit analysis in case it will have an 
impact on the planned follow-up of the subjects), annually written summaries of the 
study status and other documents as required by the local IEC. 
Substantial amendments must not be implemented before approval/favorable opinion 
of the IEC, unless necessary to eliminate hazards to the subjects. 
The Investigator must maintain an accurate and complete record of all submissions 
made to the IEC. The records should be filed in the Investigator’s study file and copies 
must be sent to the Sponsor. 
4.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that have their 
origin in the World Medical Association (WMA) Declaration of Helsinki, adopted by the 
18th WMA General Assembly, Helsinki, Finland, June 1964, and subsequent 
amendments10. 
This study is also designed to comply with ICH E6 Guideline for GCP (ICH Harmonised 
Tripartite Guideline, E6: Guideline for Good Clinical Practice [CPMP/ICH/135/95], Jan, 
1997)11, the EU Clinical Trial Directive 2001/20/EC (Directive of the European 
Parliament and of the Council of 4 April 2001 on the approximation of the laws, 
regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct, 4th April 2001)12, Commission 
Directive 2005/28/EC13 and the applicable regulatory requirements. 
ICH adopted guidelines and other relevant international guidelines, recommendations 
and requirements will be taken into account as comprehensively as possible, as long 
as they do not violate local law. 


 
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The Investigator will be responsible for the care of the subjects throughout the study. If 
the Investigator is not present in the clinical site, he/she will leave instructions for the 
staff and a telephone number where he/she can be reached. 
The Investigator will be responsible for the medical follow up of the subjects. 
4.3 
Subject Information and Consent 
All subjects will be informed verbally and in writing regarding the objectives, procedures 
and risks of study participation in local language. The language used in doing so must 
be chosen so that the information can be fully and readily understood by lay persons. 
The ICF contains information about the objectives of the study, about the procedures 
followed during the study and about the risks and restrictions of the study, with special 
reference to possible side effects of the medication and potential interactions. In 
addition, insurance coverage provided during the study is explained. The subjects will 
have to sign the ICF before any study related procedures are started. The Investigator 
will retain the original of each subject's signed consent form at the study site. 
Additionally, the process of obtaining informed consent should be documented in the 
subject’s source documents. 
If a protocol amendment is required, the ICF may need to be revised to reflect the 
changes to the protocol. If the ICF is revised, it must be reviewed and approved by the 
appropriate IEC, and signed by all subjects subsequently enrolled in the study as well 
as those currently enrolled in the study. 
The elements addressed in the ICF are according to the ICH E6 Guideline for GCP 
(CPMP/ICH/135/95) 11. 
4.4 
Privacy 
All personal details will be treated as confidential by the Investigator and involved site 
and 
 and handling of personal data will be in compliance 
with the local data protection and privacy regulations. 
The Investigator will particularly pay attention that source documents or additional 
documents handed over to the Sponsor obscure subject names and other confidential 
personal details, as per local regulations. 


 
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5. 
STUDY ADMINISTRATIVE STRUCTURE 
5.1 
Distribution of Activities 
Preparation of study drug 
The study drug will be prepared at 
 
 Netherlands. 
 
Laboratory assessments 
The analysis of talazoparib and/or possible metabolites in plasma (and urine and feces) 
samples will be performed at the 
 USA or its 
designated USA partner. 
The analysis of whole blood, plasma, urine and feces for total radioactivity will be 
conducted at the 
 Netherlands). 
The analysis of quick counts will be conducted at the 
 
Netherlands). 
Metabolite profiling (if applicable) in plasma, urine and feces samples will be conducted 
at 
 USA or its designated 
USA partner. 
The analysis of clinical laboratory samples will be performed at the local safety 
laboratory as detailed in the laboratory manual. 
The design of the eCRF will be prepared with the computer program Oracle Clinical 
(Oracle, Redwood Shores, Redwood City, CA, USA) by the Database Programming 
Department of 
 
 
Data management 
Data management will be performed with the computer programs Oracle Clinical 
(Oracle, Redwood Shores, Redwood City, CA, USA), SAS for Windows® (SAS Institute 
Inc., Cary, NC, USA) and 
 
 
 
 
 
Statistics 
An SAP will be provided by the Biostatistics Department of 
 The safety analysis 
and the statistical evaluation of PK and PD parameters will be conducted by the 
Biostatistics Department of 
 Non-compartmental analyses (NCA) will be 
performed with WinNonlinTM Professional, Version 6.3 or higher. Statistical analysis will 
be performed with the computer program SAS for Windows® (SAS Institute Inc., Cary, 
NC, USA). 
 
CSR writing 
The CSR, structured in accordance with the guideline ‘Structure and Content of Clinical 
Study Reports - ICH E314, will be written by 
 


 
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5.2 
Documentation 
5.2.1 
Archiving 
All documents concerning the study will be kept on file in the Central Archives of 
 
for at least 15 years after conduct of the study. The Sponsor will receive the completed 
eCRFs (upon request, as PDF file). 
5.2.2 
Recording of Data in Source Documents and CRFs 
All data will be recorded as source data first and entered later into the eCRF. A Data 
Management Plan will be written by the Data Management Department of 
 which 
will be finalized prior to performing any data validation. 


 
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6. 
CONFIDENTIALITY AND PUBLICATION POLICY 
By signing this CSP, the Investigator reaffirms to the Sponsor that he/she will maintain 
in confidence all information furnished to him/her, or resulting from this study. He/She 
will only divulge such information as may be necessary to the IEC and the members of 
the staff and the subjects who are involved in this study. 
 
All relevant aspects regarding publication will be part of the contract (or similar 
document) between the Sponsor and 
 
 


 
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7. 
REFERENCES 
1. 
Talazoparib Investigator’s Brochure, Medivation, Inc. and its Subsidiaries, v8.0, 
08 Jul 2016. 
2. 
Davies B, Morris T. Physiological parameters in laboratory animals and humans. 
Pharm Res. 1993 Jul;10(7):1093-5. 
3. 
EMA Guideline on the evaluation of anticancer medicinal products in man. 
EMA/CHMP/205/95/rev.4. 13 December 2012. Oncology Working Party 
4. 
ICH Topic S 9 Nonclinical Evaluation for Anticancer Pharmaceuticals 
(EMEA/CHMP/ICH/646107/2008), European Medicines Agency, 2008 
5. 
ICRP, 2007. The 2007 Recommendations of the International Commission on 
Radiological Protection. ICRP Publication 103. Ann. ICRP 37 (2-4) 
6. 
Study Dosimetry, PRA HealthSciences, Version3, 31 Mar 2016 
7. 
MSZ 62-7:2011. Protection against ionizing radiation. Radiation protection at 
the application of unsealed radioactive products. 
8. 
Guidance on Medical Exposures in Medical and Biomedical Research, 
European Commission 1998 
9. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol.1982;5:649-55. 
10. 
WMA Declaration of Helsinki (18th WMA General Assembly 1964), revised at 64th 
World Medical Association General Assembly, Fortaleza, Brazil, October 2013 
11. 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite 
Guideline, E6: Guideline for Good Clinical Practice (CPMP/ICH/135/95), Jan 1997 
12. 
Directive 2001/20/EC of the European Parliament and of the Council of 4 April 
2001 on the approximation of the laws, regulations and administrative provisions of 
the Member States relating to the implementation of good clinical practice in the 
conduct of clinical trials on medicinal products for human use 
13. 
Commission Directive 2005/28/EC of 8 April 2005 laying down principles and 
detailed guidelines for good clinical practice as regards investigational medicinal 
products for human use, as well as the requirements for authorisation of the 
manufacturing or importation of such products 
14. 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite 
Guideline, E3: Structure and Content of Clinical Study Reports 
(CPMP/ICH/137/95), Nov 1995 
15. 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite 
Guideline, E2A: Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting, Note for Guidance on Clinical Safety Data Management, 
June 1995 
16. 
Common Terminology Criteria for Adverse Events v4.0 (CTCAE), US department 
of Health and Human Services, National Institutes of Health, National Cancer 
Institute 2009 
 


 
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8. 
APPENDICES 
8.1 
Drug Accountability 
Upon receipt of the study drug, it will be inspected and counted by the Investigator or 
the responsible pharmacist. If necessary, all study drug will be re-packed per dosing 
occasion, and labeled according to 
 SOPs. 
The study drug will be kept in the 
 Pharmacy or in a locked and secured storage 
facility accessible only to those authorized by the Investigator to dispense the study 
drug. 
The responsible pharmacist will keep an inventory. This will include a description of the 
formulation and the quantity of study drug received for the study and a record of what is 
dispensed, to whom and when. 
Preparation of the study drug will be performed at 
 by a licensed expert on 
radioactivity. 
On termination of the study the Investigator or delegate will conduct a final inventory of 
the study drug supply and will record the results of this inventory in the Drug 
Accountability Form. Unused study drug will be returned to the Sponsor at the end of 
the study or will be locally destroyed according to 
 standard procedures. 
8.2 
(Serious) Adverse Events Evaluation and Reporting 
The safety management of this study will comply with all applicable national and 
international regulatory requirements and adhere to the full requirements of ICH 
Guidelines for Clinical Safety Data Management, Definitions and Standards for 
Expedited Reporting, Topic E2A (International Conference on Harmonization of 
Technical Requirements for Registration of Pharmaceuticals for Human Use, October, 
1994)15. 
8.2.1 
Adverse Events 
An AE is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medical 
treatment or procedure that may or may not be considered related to the medical 
treatment or procedure. AE definitions will be followed as stated in the ‘Note for 
Guidance on clinical safety data management: definitions and standards for expedited 
reporting’ (ICH topic E2A).15 
SAEs will be collected from the time the subject signs Informed Consent. Non-serious 
AEs will be collected from the time the subject receives first dose of study drug. 
The Investigator will report in the eCRF all AEs observed, spontaneously reported or 
noted (verbally or e.g. in a diary) by subjects. In addition, trial subjects will be 
questioned by site personnel about AEs at regular intervals using standard non-leading 
questions, such as "have you experienced anything new or different since your 
previous study visit?" 
Grading of severity, clinical significance, causality and seriousness will be determined 
by the Investigator using the CTCAE scale and will be reported in the eCRF. 


 
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8.2.2 
Grading of Severity 
The severity of AEs will be graded using the most current version of the Common 
Terminology Criteria for Adverse Events (CTCAE) 5-point scale16: 
• 
Mild (Grade 1): Asymptomatic or mild symptoms: clinical or diagnostic 
observations only; intervention not indicated. 
• 
Moderate (Grade 2): Minimal, local or non-invasive intervention indicated; limited 
age-appropriate instrumental activities of daily living (ADL). Intervention may or 
may not be indicated. 
• 
Severe (Grade 3): Medically significant but not necessarily life-threatening; 
severe is not the same as serious; determination of serious vs. life-threatening 
will be based upon subject’s condition / anticipated outcome, e.g. serious is 
usually reserved for an event which poses an immediate threat to subject’s life or 
could pose a threat to subject’s life if not treated promptly 
• 
Life-threatening (Grade 4): Life-threatening consequences; urgent intervention 
indicated. 
• 
Death (Grade 5) related to AE. 
It is emphasized that the term severe is a measure of severity: thus a severe AE is not 
necessarily “serious” as per regulatory definition. For example, itching for several days 
may be rated as severe, but may not meet regulatory definition of ‘serious’ 
(Section 8.2.3). 
8.2.2.1 
Grading of Relationship (Causality) 
The relationship of any AE to the study drug will be assessed and graded as related or 
not related as following: 
Not Related 
A clinical event, including laboratory test abnormality, with a 
temporal relationship to drug administration that makes a causal 
relationship improbable, and/or in which other drugs, chemicals, 
or underlying disease provide plausible explanations.  
Possible 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, but that 
could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or 
unclear. 
Probable 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to 
be attributed to concurrent disease or other drugs or chemicals, and 
that follows a clinically reasonable response on re-administration 
(rechallenge) or withdrawal (dechallenge). 
8.2.2.2 
Test results and physical examination findings 
Test findings and physical examination findings can result in AEs if they are: 
• 
Associated with accompanying symptoms 
• 
Requires additional diagnostic testing or medical/surgical intervention, and / 


 
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• 
Leads to a change in study dosing or discontinuation of the study medication; 
results in the addition of significant additional concomitant drug treatment or other 
therapy 
• 
Leads to any of the outcomes included in the definition of a SAE 
• 
Is considered to be an AE by the Investigator 
Reporting an AE should not be triggered by: 
• 
Merely needing to repeat an abnormal test, or, 
• 
Any abnormal test result that is determined to be an error, e.g. it is not 
reproducible or sustainable on repeat. 
8.2.3 
Serious Adverse Events 
An SAE is any untoward medical occurrence that, on the basis of medical and scientific 
judgment: 
• 
Results in death 
• 
Is life-threatening (This refers to an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe) 
• 
Requires inpatient hospitalization for a medical reason or prolongation of 
existing hospitalization (This refers to hospital admission required for treatment of 
the AE). 
Note: This does not include confinement in a skilled nursing unit; rehabilitation facility; the 
clinical research unit; or confinement due to a planned reason unrelated to study 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
An important medical event (Medically Significant Event) that is considered by the 
Investigator to be serious but that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed above. Examples of such events include 
but are not limited to intensive treatment in an Emergency Department or at the site 
for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization. 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or may require intervention to prevent one of the other outcomes 
listed in the definition above. These should also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 
SAEs will be collected from the time the subject signs Informed Consent until 30 days 
post dosing. SAEs that are related to the investigational drug and continue beyond the 
normal collection period (i.e., are ongoing at the time a subject exits the study) will be 


 
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followed until resolution or until stabilized with sequelae. SAEs that begin after the 
subject’s participation in the study is complete, but that the Investigator considers to be 
related to study drug, may be reported at any time. 
The Investigator or clinical site personnel must notify Medivation’s vendor 
 and Medivation’s Medical Monitor of all SAEs, regardless of 
relationship to the investigational drug, within 24 hours of clinical site personnel 
becoming aware of the event. 
The Investigator will provide the initial notification by sending a completed “Serious 
Adverse Event Report Form”, which must include the Investigator’s assessment of the 
relationship of the event to investigational drug, and must be signed by the Investigator. 
In addition, notification is sent by the Investigator to the IEC, and the subject’s General 
Practitioner, if applicable. 
Follow-up information, or new information regarding an ongoing SAE, must be provided 
promptly as per all SAEs to Medivation’s vendor 
 and Medivation 
Medical Monitor. 
All SAE (initial and follow-up) reports should be sent to the SAE reporting contacts 
provided on Page 4. 
8.2.4 
Suspected Unexpected Serious Adverse Reactions 
A SAE the nature or severity of which is not consistent with the applicable product 
information (e.g., Investigator‘s Brochure for an unapproved investigational product or 
summary of product characteristics for an approved product) and which has reasonable 
relationship to IMP administration is called a Suspected Unexpected Serious Adverse 
Reaction (SUSAR). 
The Sponsor (Medivation Drug Safety) will determine which talazoparib SAEs meet 
regulatory reporting requirements as a SUSAR. Medivation Drug Safety will: 
1. 
Submit all SUSARs to the applicable local regulatory authority (Hungary) 
2. 
Issue SUSARs to 
 and/or Investigator whose responsibility will be to report the 
SUSAR to the applicable IEC 
Talazoparib SUSARs will derive from this study as well as other talazoparib clinical 
studies for cross-reporting to local regulatory authority. 
8.2.5 
Follow-up of Adverse Events 
Follow-up of AEs will continue until resolution, stabilization or death. In case of ongoing 
AEs at the moment of database closure, the data obtained at the moment of database 
closure will be used in the statistical analysis. The follow-up of the AE will be 
documented in the source documents and will be described in the final report only if 
considered relevant by the Investigator. 
8.3 
Pregnancy 
Pregnancies occurring up to 90 days after the completion of the study drug must be 
reported to the Investigator. The subject should be counseled by a specialist, to 


 
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discuss the risks of continuing with the pregnancy and the possible effects on the fetus. 
Monitoring of the subject should continue until the outcome of the pregnancy is known. 
The Investigator should report all pregnancies of female clinical study subjects to 
Medivation’s vendor 
 within 24 hours of becoming aware of them 
using the Pregnancy Reporting Form as per the contact information provided on 
Page 4: SAE Contact Information. 
If the Investigator becomes aware of a pregnancy occurring in the partner of a subject 
participating in the study, the pregnancy should be reported to Medivation’s vendor 
 within 24 hours of obtaining written consent from the pregnant 
partner. 
 must report all pregnancies (subject or subject partner) to the 
Sponsor. Pregnancy outcome will also be reported to the Sponsor within 24 hours of 
awareness. The Investigator will make arrangements for the partner to be counseled by 
a specialist, to discuss the risks of continuing with the pregnancy and the possible 
effects on the fetus. Monitoring of the partner should continue until the outcome of the 
pregnancy is known. 

SAP_001.pdf: 
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