Clinical trial NCT03077607
Conditions: Advanced Solid Tumors
Sponsor: Pfizer
Start date: 2016-11-07; Completion date: 2018-01-20
Enrollment: 36 participants; Allocation: NON_RANDOMIZED; Intervention model: 

Brief summary:
This is a study in patients with advanced solid tumors for the investigation of P-gp inhibition and induction on the PK of talazoparib.

Detailed description:
Subjects participating in this study with no clinically significant toxicities and no disease progression may be eligible to continue treatment on a separate extension protocol (MDV3800-13).

Arms: arm 1: Subjects will receive a 0.5 mg talazoparib and 100 mg itraconazole. arm 2: Subjects will receive 1 mg talazoparib and 600 mg rifampin.
Interventions: intervention 1: Talazoparib intervention 2: Itraconazole intervention 3: Rifampin
Intervention descriptions: intervention 1: Arm A: 0.5 mg oral dose Arm B: 1 mg oral dose intervention 2: 100 mg oral dose intervention 3: 600 mg oral dose

Protocol documents:
Prot_001.pdf: 
090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)


090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)


090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)


 
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090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)


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090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)


 
CLINICAL STUDY PROTOCOL 
 
 
MDV3800-04/MVE011PC-160116 
 
VERSION Final 3.0 – 11-Oct-2016 
 
 
Page 7 of 55 
Objectives 
Primary: 
• 
To separately assess the effect of P-glycoprotein (P-gp) inhibitor (itraconazole) and P-gp inducer 
(rifampin) on the single-dose pharmacokinetics (PK) of talazoparib in patients with advanced solid 
tumors. 
Secondary: 
 
• 
To assess the safety and tolerability of a single dose of talazoparib with and without itraconazole or 
rifampin in patients with advanced solid tumors. 
 
Design and Treatments 
This is a Phase 1, open-label, two-armed, fixed-sequence drug-drug interaction (DDI) study in patients 
with advanced solid tumors for the investigation of the effect of P-gp inhibition and induction on the PK of 
talazoparib. Talazoparib is a substrate for P-gp, and itraconazole as well as rifampin will be used as a 
potent inhibitor and a potent inducer of P-gp, respectively. This study will evaluate the effect of multiple 
doses of itraconazole or rifampin on the pharmacokinetic profile of a single dose of talazoparib in patients 
with advanced solid tumors. A secondary objective is to evaluate the safety and tolerability of these 
combinations. All study subjects will be monitored for adverse events (AE) throughout the study. 
The study will enroll approximately 18 subjects per arm (total of 36 subjects). 
• 
Arm A: Subjects will receive a single oral dose of 0.5 mg talazoparib on Day 1 of Period 1, followed by 
a 14-day wash-out (Days 2–15). An oral dose of 100 mg itraconazole will be administered twice daily 
for 7 days (Days 16–22). In Period 2, on Day 23, a single dose of 0.5 mg talazoparib will be co-
administered with 100 mg itraconazole in the morning, followed by 100 mg itraconazole alone in the 
evening. Oral doses of 100 mg itraconazole twice daily will continue throughout Days 24-36. For both 
periods, subjects will receive talazoparib under fasted conditions, defined as an overnight fast of at 
least 8 hours. No food will be allowed for at least 2 hours post-dose. Water is allowed as desired. 
• 
Arm B: Subjects will receive a single oral dose of 1 mg talazoparib on Day 1 of Period 1, followed by a 
14-day wash-out (Days 2–15). Oral doses of 600 mg rifampin will be administered once daily for 9 
days (Days 16–24). In Period 2, on Day 25, a single oral dose of 1 mg talazoparib will be co-
administered with 600 mg rifampin. Rifampin 600 mg once daily will continue throughout Days 26-38. 
For both periods, subjects will receive talazoparib under fasted conditions as defined above. 
Subjects participating in this study with no clinically significant toxicities may be eligible to continue 
treatment on a separate extension protocol (MDV3800-13). Safety data for all subjects who had received 
any amount of talazoparib will be analyzed in the safety analyses for this study. 
 
Study Assessments 
Serial blood samples will be collected for PK analysis at pre-determined times after talazoparib 
administration, up to 336 hours (14 days). Blood samples for PK analysis will be drawn at the following 
selected time-points during each treatment period: pre-dose and 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 
168, 216, 264, and 336 hours after talazoparib dosing in both arms. 
 
Key Eligibility Criteria 
This study will enroll patients with advanced solid tumors who are at least 18 years of age and provide 
informed consent. Subjects must abstain from the use of any drugs with potential P glycoprotein (P-gp) 
interaction within 7 days or 5 half-lives (whichever is longer) before Day 1. Subjects must not have eGFR 
(estimated glomerular filtration rate) ≤ 50 mL/min/1.73 m2 by the MDRD equation (Modification of Diet in 
Renal Disease [available via www.mdrd.com]) at screening and baseline, human immunodeficiency virus 
(HIV), hepatitis B, or hepatitis C. Subjects who had major surgery within 8 weeks before screening, or 
received any investigational or anti-cancer drug within 28 days before screening are excluded. Female and 
male subjects of childbearing potential must agree to use a highly effective birth control method starting 21 
090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)


 
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090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)


 
CLINICAL STUDY PROTOCOL 
 
 
MDV3800-04/MVE011PC-160116 
 
VERSION Final 3.0 – 11-Oct-2016 
 
 
Page 9 of 55 
Efficacy Analyses 
No efficacy analyses are planned in this study, although baseline tumor assessments will be obtained in 
the event that subjects choose to continue talazoparib treatment on a separate open label extension 
protocol. 
 
Safety Analyses 
All safety analyses will be performed using the safety population, defined as all subjects who received at 
least one dose of talazoparib. Safety will be evaluated using summaries of AEs, physical examinations 
(and weight), vital signs, electrocardiograms (ECGs), 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 AEs (CTCAE Version 4). The number and percentage of subjects 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). 
Adverse events will be recorded following the first dose of study drug (Day 1) until completion of the follow 
up visit. Serious adverse events will be collected starting at Informed Consent Signing until completion of 
the follow-up visit. 
Laboratory values will be classified by severity using the CTCAE. Laboratory shift tables of baseline results 
to each subsequent visit will be produced as appropriate. Change from baseline in laboratory values will 
be tabulated and summarized graphically. 
 
090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)


 
CLINICAL STUDY PROTOCOL 
 
 
MDV3800-04/MVE011PC-160116 
 
 
VERSION Final 3.0 – 11-Oct-2016 
 
 
Page 10 of 55 
Table 1 
Schedule of Assessments Arm A (Itraconazole Arm) 
 
Screening 
Baseline 
Period 1 
Study Day► 
–28 to –2 
–1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Event▼ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ambulatory 
X 
 
 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
Confinement 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent, SCR Number 1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG assessment  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor assessments  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria / confirmation 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
 
 
 
X2 
 
 
 
 
 
 
X2 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-Lead ECG 
X 
X 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital signs5 
X 
X 
X4 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
Adverse event review 6 
 
 
X3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review  
X 
X 
X3 
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 7 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follicle-stimulating hormone 8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistry 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Hematology 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)


 
CLINICAL STUDY PROTOCOL 
 
 
MDV3800-04/MVE011PC-160116 
 
 
VERSION Final 3.0 – 11-Oct-2016 
 
 
Page 11 of 55 
Table 1 
Schedule of Assessments Arm A (Itraconazole Arm) 
 
Screening 
Baseline 
Period 1 
Study Day► 
–28 to –2 
–1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Event▼ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
eGFR Calculation 9 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for PK 10 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
1 
2 
3 
4 
5 
6 
 
7 
8 
9 
10 
Informed consent can be obtained on a separate visit 
Symptom-oriented physical examination 
On Day 1 pre-dose 
On Day 1, pre-dose and 2 hours post-dose. Pre-dose ECG is triplicate 1 – 2 minutes apart (all other ECG recordings are single) 
Vital signs comprise supine blood pressure, heart rate, body temperature, respiratory rate after ≥5 minutes rest 
SAE will be collected starting from informed consent signature of the subject; non-serious AEs will be collected following the first dose of study drug on 
Day 1. 
Collect only for females of childbearing potential. 
Collect only for females with no spontaneous menses for ≥12 months, who are <55 years old, and who do not have documented surgical sterilization. 
Calculation of the estimated glomerular filtration rate (eGFR) by MDRD equation. 
For details see Table 3 
SCR: screening; HIV: human immunodeficiency virus; PK: pharmacokinetics  
 
090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)


 
CLINICAL STUDY PROTOCOL 
 
 
MDV3800-04/MVE011PC-160116 
 
 
VERSION Final 3.0 – 11-Oct-2016 
 
 
Page 12 of 55 
Table 1 
Schedule of Assessments Arm A (Itraconazole Arm) 
continued 
 
Period 2 
F/u1 
Study Day► 
16-21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
 
Event▼ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ambulatory 
 
 
 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
Confinement 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
X2 
 
 
 
 
 
 
 
X2 
 
 
 
 
 
 
X 
 
Weight 
 
 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-Lead ECG 
 
X4 
X4 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Vital signs5 
 
X3 
X3 
X3 
X3 
 
 
 
 
X3 
 
 
 
 
 
 
X 
X 
Adverse event review  
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 
Administer talazoparib 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer itraconazole 
X 
X 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum chemistry 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Hematology 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Urinalysis 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Blood sample for PK7 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
1 
 
 
 
2 
3 
4 
 
5 
6 
7 
Follow-up visit 20±3 days after the last dose of itraconazole. In the event of early withdrawal of a subject, the follow-up contact should occur no sooner 
than 30 days after the last dose of talazoparib, unless the subject enrolls directly in the extension study, in which case the follow-up may occur earlier. If 
the subject is eligible to and chooses to participate in the separate open-label extension study and the screening for the open label extension study occurs 
within 30 days after the last dose of talazoparib, the follow up visit will not be required. 
Symptom-oriented physical examination 
Pre-dose 
Triplicate ECG (1 to 2 minutes apart); before and 2.5 hours after itraconazole dose on Days 22 and 23 (all other ECG recordings are single in the morning 
at pre-dose, if applicable) 
Vital signs comprise supine blood pressure, heart rate, body temperature, respiratory rate after ≥5 minutes rest 
Itraconazole to be administered 30 minutes before talazoparib 
For details see Table 3 
F/u: follow-up; PK: pharmacokinetics 
090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)


CLINICAL STUDY PROTOCOL 
MDV3800-04/MVE011PC-160116 
VERSION Final 3.0 – 11-Oct-2016 
Page 13 of 55 
Table 2 
Schedule of Assessments Arm B (Rifampin Arm) 
Screening 
Baseline 
Period 1 
Study Day► 
–28 to –2
–1
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Event▼ 
Ambulatory 
X 
X 
X 
X 
X 
X 
X 
X 
Confinement 
X 
X 
X 
X 
Informed consent, SCR Number1 
X 
ECOG assessment 
X 
X 
Tumor assessments 
X 
Medical history 
X 
X 
Demographics 
X 
Eligibility criteria / confirmation 
X 
X 
Enrollment 
X 
Physical examination 
X 
X 
X2 
X2 
Height 
X 
Weight 
X 
X3 
X 
12-Lead electrocardiogram 
X 
X 
X4 
X 
Vital signs5 
X 
X 
X4 
X 
X 
X 
X 
Adverse event review 6 
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 
Administer talazoparib 
X 
Alcohol breath test 
X 
X 
Urine drug screen 
X 
X 
Serology for HIV, hepatitis B and C 
X 
Serum pregnancy test 7 
X 
X 
Follicle-stimulating hormone 8 
X 
Serum chemistry 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
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Table 2 
Schedule of Assessments Arm B (Rifampin Arm) 
 
Screening 
Baseline 
Period 1 
Study Day► 
–28 to –2 
–1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Event▼ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
eGFR Calculation 9 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for PK 10 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
1 
2 
3 
4 
5 
6 
 
7 
8 
9 
10 
Informed consent can be obtained on a separate visit 
Symptom-oriented physical examination 
On Day 1 pre-dose 
On Day 1, pre-dose and 2 hours post-dose. Pre-dose ECG is triplicate 1 – 2 minutes apart (all other ECG recordings are single) 
Vital signs comprise supine blood pressure, heart rate, body temperature, respiratory rate after ≥5 minutes rest 
SAE will be collected starting from informed consent signature of the subject; non-serious AEs will be collected following the first dose of study drug on 
Day 1. 
Collect only for females of childbearing potential. 
Collect only for females with no spontaneous menses for ≥12 months, who are <55 years old, and who do not have documented surgical sterilization. 
Calculation of the estimated glomerular filtration rate (eGFR) by MDRD equation 
For details see Table 3 
SCR: screening; HIV: human immunodeficiency virus; PK: pharmacokinetics  
 
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Table 2 
Schedule of Assessments Arm B (Rifampin Arm) 
continued 
 
Period 2 
F/u1 
Study Day► 
16–23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
 
Event▼ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ambulatory 
 
 
 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
Confinement 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
X2 
 
 
 
 
 
 
 
X2 
 
 
 
 
 
 
X 
 
Weight 
 
 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-Lead electrocardiogram  
 
X4 
X4 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Vital signs5 
 
X3 
X3 
X3 
X3 
 
 
 
 
X3 
 
 
 
 
 
 
X 
X 
Adverse event review  
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 
Administer talazoparib 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer rifampin 
X 
X 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum chemistry 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Hematology 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Urinalysis 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Blood sample for PK7 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
1 
 
 
 
2 
3 
4 
 
5 
6 
7 
Follow-up visit 20±3 days after the last dose of rifampin. In the event of early withdrawal of a subject, the follow-up contact should occur no sooner than 30 
days after the last dose of talazoparib, unless the subject enrolls directly in the extension study, in which case the follow-up may occur earlier. If the subject 
is eligible to and chooses to participate in the separate open-label extension study, and the screening for the open label extension study occurs within 30 
days after the last dose of talazoparib, the follow up visit will not be required 
Symptom-oriented physical examination 
Pre-dose 
Triplicate ECG (1 to 2 minutes apart); before and 2.5 hours after rifampin dose on Days 24 and 25 (all other ECG recordings are single in the morning at 
pre-dose, if applicable). 
Vital signs comprise supine blood pressure, heart rate, body temperature, respiratory rate after ≥5 minutes rest 
Rifampin be administered 30 minutes before talazoparib 
For details see Table 3 
F/u, follow-up; PK, pharmacokinetic. 
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Table 3 
Talazoparib Pharmacokinetic Sampling Schedule 
Sample collection time relative to talazoparib dosing 
Study Day 
Time point 
Period 1 
Period 2 
 
Arm A 
Arm B 
Arm A 
Arm B 
 
1 
23 
25 
pre-dose 
+0.50 h 
+1 h 
+2 h 
+4 h 
+8 h 
+12 h 
2 
24 
26 
+24 h 
3 
25 
27 
+48 h 
4 
26 
28 
+72 h 
5 
27 
29 
+96 h 
6 
28 
30 
+120 h 
7 
29 
31 
 
8 
30 
32 
+168 h 
9 
31 
33 
 
10 
32 
34 
+216 h 
11 
33 
35 
 
12 
34 
36 
+264 h 
13 
35 
37 
 
14 
36 
38 
 
15 
37 
39 
+336 h 
 
 
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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 .......................................................................................................................... 6 
TABLE OF CONTENTS .................................................................................................... 17 
TABLE OF TABLES ......................................................................................................... 19 
TABLE OF FIGURES ........................................................................................................ 19 
LIST OF ABBREVIATIONS .............................................................................................. 20 
1. INTRODUCTION ......................................................................................................... 22 
1.1 
Background ................................................................................................................ 22 
1.1.1 Nonclinical Studies ......................................................................................... 22 
1.1.2 Clinical Studies ............................................................................................... 22 
1.2 
Study Rationale .......................................................................................................... 25 
1.2.1 Risk-Benefit Assessment ............................................................................... 25 
2. OBJECTIVES ............................................................................................................. 27 
2.1 
Primary ........................................................................................................................ 27 
2.2 
Secondary ................................................................................................................... 27 
3. INVESTIGATIONAL PLAN ......................................................................................... 28 
3.1 
Overall Study Design and Plan .................................................................................. 28 
3.1.1 Type of Study .................................................................................................. 28 
3.1.2 Screening Period............................................................................................. 29 
3.1.3 Treatment Period............................................................................................. 29 
3.2 
Extension Protocol ..................................................................................................... 31 
3.3 
Discussion of Study Design ...................................................................................... 31 
3.4 
Selection of Study Population ................................................................................... 31 
3.4.1 Inclusion Criteria ............................................................................................. 31 
3.4.2 Exclusion Criteria ............................................................................................ 33 
3.5 
Removal of Subjects from Therapy or Assessment ................................................ 35 
3.6 
Premature Discontinuation of the Trial ..................................................................... 35 
3.7 
Treatments .................................................................................................................. 36 
3.7.1 Treatments Administered ............................................................................... 36 
3.7.2 Identity of Investigational Products ............................................................... 36 
3.7.3 Treatment Assignment ................................................................................... 37 
3.7.4 Selection of Doses in the Study ..................................................................... 37 
3.7.5 Timing of Doses in the Study ......................................................................... 37 
3.7.6 Meals During the Study .................................................................................. 38 
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3.7.7 Blinding ........................................................................................................... 38 
3.7.8 Concomitant Medication and Other Restrictions During the Study ............ 38 
3.7.9 Treatment Compliance.................................................................................... 38 
3.8 
Pharmacokinetic, Efficacy and Safety Measurements and Variables ..................... 39 
3.8.1 Pharmacokinetic, Efficacy and Safety Measurements Assessed ................ 39 
3.8.2 Appropriateness of Measurements................................................................ 42 
3.8.3 Pharmacokinetic, Efficacy and Safety Variables .......................................... 42 
3.8.4 Drug Concentration Measurements ............................................................... 43 
3.9 
Statistical Procedures and Determination of Sample Size ...................................... 43 
3.9.1 Analysis Populations ...................................................................................... 43 
3.9.2 Statistical and Analytical Plan for Pharmacokinetic and Safety 
Evaluation ........................................................................................................ 43 
3.9.3 Determination of Sample Size ........................................................................ 45 
3.10 Data Quality Assurance ............................................................................................. 45 
4. ETHICS ....................................................................................................................... 46 
4.1 
Independent Ethics Committee ................................................................................. 46 
4.2 
Ethical Conduct of the Study ..................................................................................... 46 
4.3 
Subject Information and Consent ............................................................................. 47 
4.4 
Privacy ........................................................................................................................ 47 
5. STUDY ADMINISTRATIVE STRUCTURE .................................................................. 48 
5.1 
Distribution of Activities ............................................................................................ 48 
5.2 
Documentation ........................................................................................................... 48 
5.2.1 Archiving ......................................................................................................... 48 
5.2.2 Recording of Data in Source Documents and CRFs..................................... 48 
6. CONFIDENTIALITY AND PUBLICATION POLICY.................................................... 49 
7. REFERENCES ............................................................................................................ 50 
8. APPENDICES ............................................................................................................. 51 
8.1 
Drug Accountability ................................................................................................... 51 
8.2 
(Serious) Adverse Events Evaluation and Reporting .............................................. 51 
8.2.1 Adverse Events ............................................................................................... 51 
8.2.2 Grading of Severity ......................................................................................... 52 
8.2.3 Serious Adverse Events ................................................................................. 53 
8.2.4 Suspected Unexpected Serious Adverse Reactions .................................... 54 
8.2.5 Follow-up of Adverse Events ......................................................................... 54 
8.3 
Pregnancy ................................................................................................................... 55 
 
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TABLE OF TABLES 
Table 1 
Schedule of Assessments Arm A (Itraconazole Arm) .................................................... 10 
Table 2 
Schedule of Assessments Arm B (Rifampin Arm) ......................................................... 13 
Table 3 
Talazoparib Pharmacokinetic Sampling Schedule ........................................................ 16 
 
TABLE OF FIGURES 
Figure 1 Study Design ................................................................................................................ 29 
 
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LIST OF ABBREVIATIONS 
ADL 
Activities of daily living 
ADP 
Adenosine diphosphate 
AE 
Adverse event  
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
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 
CI 
Confidence interval 
CLCR 
Creatinine clearance 
CPK 
Creatine phosphokinase 
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 
CYP 
Cytochrome P450 
DDI 
Drug-drug interaction 
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 
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 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
LC-MS/MS 
Liquid chromatography with tandem mass spectrometry 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantitation 
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 
PARP 
Poly(ADP ribose) polymerase 
PDF 
Portable document format 
P-gp 
P-glycoprotein 
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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 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 once 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 subjects with mild renal 
impairment (creatinine clearance [CLCR], 60-89 mL/min) was similar compared with 
subjects with normal renal function (CLCR ≥ 90 mL/min). In subjects with moderate 
renal impairment (CLCR, 30-59 mL/min), the talazoparib CL/F was decreased by 44%, 
resulting in higher talazoparib exposure. Therefore, subjects 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 (CYP) 
inhibition- or induction-based drug-drug interactions or drug transporter inhibition-based 
drug-drug interactions (DDI) when co-administered with corresponding substrates. 
However, talazoparib is a substrate for P-glycoprotein (P-gp) and breast-cancer 
resistance protein (BCRP), and plasma talazoparib concentrations may increase or 
decrease when co-administered with P-gp or BCRP inhibitors or inducers, respectively. 
Efficacy 
Preliminary data demonstrated objective responses and/or 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 (AE) 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. 
AEs 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. AEs 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. 
Additional detail information can be found in the Investigational Brochure (IB). 
1.2 
Study Rationale 
This study will investigate the DDIs between talazoparib and itraconazole and rifampin, 
respectively, and are compliant with the principles of the US and EU guidelines on 
these matters3,4. 
Itraconazole and rifampin are a potent inhibitor and a potent inducer of P-gp, 
respectively. This study will evaluate the effect of multiple doses of itraconazole or 
rifampin on the pharmacokinetic profile of a single dose of talazoparib in patients with 
advanced solid tumors. A secondary objective is to evaluate the safety and tolerability 
of these combinations. 
1.2.1 
Risk-Benefit Assessment 
Talazoparib has shown clinical activity in advanced solid tumor patient populations and 
is being developed further as a treatment for several cancers. The adverse event 
profile reported indicates that talazoparib is generally well-tolerated. Myelosuppression 
is managed by supportive care and dose interruption and dose reduction, as 
necessary. Nausea and vomiting may be managed by supportive care as well. 
Transaminase monitoring is recommended with dose interruption or discontinuation 
based on the extent of transaminase elevation. Based on the cumulative safety profile 
and the potential benefit afforded by the mechanism of action of talazoparib, the 
potential benefits appear to outweigh the observed risks. 
The components used as interactors for P-gp modulation are established for the 
purpose of DDI studies5,6, and are administered at therapeutic doses following the 
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recommendations in their respective Summaries of Product Characteristics (SmPC) 7,8. 
The administration is conducted within a close-observation Phase 1 unit with 
appropriate clinical and laboratory monitoring of relevant AEs on an inpatient basis. 
The ongoing development program seeks to identify tumor molecular characteristics 
that will identify patients more likely to derive benefit. The safety profile is acceptable in 
both treatment and maintenance settings. 
Patients participating in this study with no clinically significant toxicities may be eligible 
to continue treatment on a separate open-label extension protocol after evaluation by 
PI and approval of Sponsor. 
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2. 
OBJECTIVES 
2.1 
Primary 
• 
To separately assess the effect of P-gp inhibitor (itraconazole) and P-gp inducer 
(rifampin) on the single-dose PK of talazoparib in patients with advanced solid 
tumors. 
2.2 
Secondary 
• 
To assess the safety and tolerability of a single dose of talazoparib with and 
without itraconazole or rifampin in patients with advanced solid tumors. 
 
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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, open-label, two-armed, fixed-sequence DDI study in patients with 
advanced solid tumors for the investigation of the effect of P-gp inhibition and induction 
on the PK of talazoparib. 
The main objective of this study is to evaluate the effect of multiple doses of 
itraconazole (used as P-gp inhibitor) or rifampin (used as P-gp inducer) on the PK 
profile of a single oral dose of talazoparib (0.5 mg of talazoparib alone or with 
itraconazole in Arm A, and 1.0 mg of talazoparib alone or with rifampin in Arm B, 
respectively) in patients with advanced solid tumors. A secondary objective is to 
evaluate the safety and tolerability of these combinations. All study subjects will be 
monitored for AEs throughout the study. 
Each eligible subject will receive a single oral dose of 0.5 mg (Arm A) or 1 mg (Arm B) 
talazoparib in Period 1 (Day 1 – 15) to assess the PK of talazoparib without P-gp 
modulation. In Period 2, 18 subjects per study arm will receive either 100 mg oral 
itraconazole twice daily for 22 days (Arm A), or 600 mg oral rifampin daily for 24 days 
(Arm B), respectively. Subjects from the itraconazole arm (Arm A) will receive 0.5 mg 
talazoparib with the morning dose of the eighth day of itraconazole dosing. Likewise, 
subjects of the rifampin arm will receive 1.0 mg talazoparib on the tenth day of rifampin 
dosing (Figure 1). Itraconazole or rifampin will be taken 30 minutes before talazoparib. 
Subjects participating in this study with no clinically significant toxicities may be eligible 
to continue talazoparib treatment on a separate extension protocol. 
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3.1.3.2 
Period 1 
In Arm A, subjects will receive 0.5 mg of oral talazoparib in the morning of Day 1. In 
Arm B, subjects will receive 1.0 mg of oral talazoparib in the morning of Day 1. 
Sampling of talazoparib for PK will be performed as shown in Table 3. 
Assessments of safety and tolerability will be conducted according to the schedule of 
assessments (Table 1 and Table 2). 
Subjects will be confined from Day –1 on until all study-related assessments of Day 3 
have been concluded. They will present themselves on an ambulatory base for PK and 
safety assessments (i.e. physical examination [including weight], ECG recording, vital 
signs [blood pressure, heart rate, body temperature, respiratory rate]) according to the 
schedule of assessments (Table 1 and Table 2). AEs and concomitant medication can 
be recorded in a subject's diary on days when no other assessments are to be 
performed. 
3.1.3.3 
Period 2 
Arm A will receive 100 mg oral itraconazole twice daily, and Arm B will receive 600 mg 
oral rifampin daily. Both study arms will receive their interacting drug starting from 
Day 16 on. Dosing instructions and drug will be provided to subjects on the Day 15 
visit. 
In Arm A, 0.5 mg of oral talazoparib will be administered together with the morning 
dose of itraconazole on Day 23. Itraconazole will be taken 30 minutes before 
talazoparib. 
In Arm B, 1.0 mg of oral talazoparib will be administered together with rifampin in the 
morning of Day 25. Rifampin will be taken 30 minutes before talazoparib. 
In Arm A, twice daily oral administration of itraconazole will be continued until Day 36, 
and in Arm B, once daily administration of rifampin will be continued until Day 38. 
Sampling of talazoparib for PK will be performed as shown in Table 3. 
Subjects will be confined from Day 22 on until Day 25 for Arm A, and from Day 24 until 
Day 28 for Arm B. They will present themselves on an ambulatory base for PK and 
safety assessments according to the schedule of assessments (Table 1 and Table 2, 
continued). AEs and concomitant medication can be recorded in a subject's diary on 
days when no other assessments are to be performed. 
3.1.3.4 
Follow-up 
An ambulatory visit will be performed 20±3 days after the last dose of study drug 
(itraconazole or rifampin, respectively). In the event of early withdrawal of a subject, the 
follow-up visit should occur no sooner than 30 days after the last dose of talazoparib, 
unless the subject enrolls directly in the extension stud. If the subject is eligible to and 
chooses to participate in the separate open-label extension study and the screening for 
the open label extension study occurs within 20±3 days after the last dose of 
itraconazole or rifampin, the follow up visit will not be required. 
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3.2 
Extension Protocol 
Subjects 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. 
3.3 
Discussion of Study Design 
This present study is designed according to the principles of the guidelines on DDI 
studies3,4. The principal aim of these guidelines is to assess the concomitant 
medications that alter the metabolism or drug transport in individuals who receive 
particular dose of a drug. Such an alteration in metabolism or transport can change the 
exposure of a drug and potentially affect the safety and efficacy of a drug. 
This clinical study will investigate the impact of itraconazole and rifampin on the PK of 
talazoparib. Itraconazole and rifampin are known agents which inhibit and induce the 
intestinal P-gp transport5,6, respectively. Talazoparib is a substrate for P-gp1 and its 
exposure as well as its elimination may be influenced by compounds which affect the 
intestinal P-gp transport, and thus may alter the safety and efficacy of talazoparib. 
3.4 
Selection of Study Population 
The study is planned to enroll a total of 36 patients with advanced solid cancer in order 
to have 18 participants per study arm. 
3.4.1 
Inclusion Criteria 
Each subject eligible to participate in this study must meet all of the following criteria: 
1. 
Arm A: At least 18 years of age and <65 years of age (at the time point of consent) 
and willing and able to provide informed consent. 
Arm B: At least 18 years of age (at the time point of consent) and willing and able 
to provide informed consent. 
2. 
Histologically confirmed advanced solid tumor judged by the Investigator to not be 
appropriate for standard therapy. 
3. 
ECOG performance status ≤ 2 at screening and at time of enrollment. 
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 
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 
Day -1 
─ 
< 55 years of age with no spontaneous menses for ≥ 12 months before 
Day -1 and with a postmenopausal follicle-stimulating hormone (FSH) 
concentration > 30 IU/L (or meeting criteria for post-menopausal status by 
the local laboratory) 
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or 
b. 
 
Arm A: 
of childbearing potential but having a negative serum pregnancy test at Screening 
and Day -1 AND also 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 defined as: 
─ 
Placement of an intrauterine device  
─ 
Sexual partner(s) vasectomized for ≥ 6 months before enrollment 
─ 
Sexual abstinence when in relation to the preferred and usual lifestyle of 
the subject 
Arm B: 
of childbearing potential but having a negative serum pregnancy test at Screening 
and Day -1 AND also 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, 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 
─ 
Must also use a double-barrier method (e.g. condom or diaphragm plus 
spermicide) together with one of the 3 contraceptive methods listed above. 
─ 
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 investigational medicinal product 
(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 non-pregnant 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 subjects must not be breastfeeding at screening and during the study 
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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. 
3.4.2 
Exclusion Criteria 
Each subject eligible to participate in this study must NOT meet any of the following 
exclusion criteria: 
1. 
Treatment within 14 days or 5 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 screening. 
- 
Arm A: Heart failure of severity grade class II, III or IV according to New 
York Heart Association (NYHA) within 6 months of enrollment. 
Arm B: Heart failure of severity grade class III or IV according to NYHA 
within 3 months of 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. May be repeated in 15 minutes if initial reading is 
believed to be atypical for the subject. 
- 
Bradycardia as indicated by a heart rate of < 45 beats per minute on the 
screening electrocardiogram (ECG). 
- 
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 
subject. 
- 
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 
the MDRD equation (Modification of Diet in Renal Disease [available via 
www.mdrd.com]) at screening and Day –1. 
c. 
Total serum bilirubin > 1.5 times ULN (> 3 times ULN for subjects with 
Gilbert’s syndrome or for whom indirect bilirubin concentrations suggest an 
extrahepatic source of elevation) 
d. 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
≥ 2.5 times ULN  
e. 
Arm A: History of clinically significant liver injury or other adverse reaction to 
azole antifungals; Arm B: History of clinically significant liver injury or other 
adverse reaction to rifampin, rifamycin or other rifamycin derivatives. 
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f. 
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). 
g. 
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. 
Subjects with the following serologies should be excluded: HBsAg+ or anti-HBc+; 
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 capsule components. 
11. 
Co-administration of the following drugs (including alimentary supplements and 
herbal medicines, if applicable, within 7 days or 5 half-lives before Day 1, 
whichever is longer, until end of Period 2; with exception of intake of itraconazole in 
Arm A and rifampin in Arm B as per study design): 
- 
Arm A: 
Use of a strong P-gp inhibitor (e.g., dronedarone, quinidine, ranolazine, 
verapamil, itraconazole, ketoconazole), strong P-gp inducer (e.g. rifampin, 
tipranavir, ritonavir), CYP3A4 substrates (see P450 Drug Interaction Table 
of DMIU: http://medicine.iupui.edu/clinpharm/ddis/main-table/), or strong 
inhibitor of BCRP (e.g., elacridar [GF120918]). Subjects must also abstain 
from the use of any other prescription or nonprescription drugs or 
supplements with potential P-glycoprotein (P-gp) and BCRP interaction. 
Refer to the following website for a complete list: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentReso
urces/DrugInteractionsLabeling/ucm093664.htm#inhibitors. 
Contra-indicated drugs from the itraconazole label: methadone, 
disopyramide, dofetilide, ergot alkaloids (such as dihydroergotamine, 
ergometrine [ergonovine], ergotamine, methylergometrine 
[methylergonovine]), irinotecan, lurasidone, oral midazolam, pimozide, 
triazolam, nisoldipine, felodipine, ranolazine, eplerenone and cisapride. 
- 
Arm B: 
Use of a strong P-gp inhibitor (e.g., dronedarone, quinidine, ranolazine, 
verapamil, itraconazole, ketoconazole), strong P-gp inducer (e.g. rifampin, 
tipranavir, ritonavir), CYP3A4 substrates (see P450 Drug Interaction Table 
of DMIU: http://medicine.iupui.edu/clinpharm/ddis/main-table/), or strong 
inhibitor of BCRP (e.g., elacridar [GF120918]). Subjects must also abstain 
from the use of any other prescription or nonprescription drugs or 
supplements with potential P-glycoprotein (P-gp) and BCRP interaction. 
Refer to the following website for a complete list: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentReso
urces/DrugInteractionsLabeling/ucm093664.htm#inhibitors. 
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Contra-indicated drugs from the rifampin label: protease inhibitors (e.g. 
amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, 
nelfinavir, tipranavir and saquinavir – with and without ritonavir), broad-
spectrum tri-azole antifungal agent (e.g. itraconazole, voriconazole), 
potentially hepatotoxic narcotic agent (e.g. halothane). 
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 subject has the right to withdraw from 
the study at any time for any reason. 
The Investigator has the right to terminate participation of a subject 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, the follow-up visit 
will be conducted as described in Section 3.1.3.4. In the event of early withdrawal, the 
follow-up visit should not take place sooner than 30 days after the last dose of 
talazoparib, unless the subject enrolls directly in the extension study, in which case the 
follow-up may occur earlier. 
If a subject is withdrawn from the study, the Sponsor will be informed immediately. If 
there is a medical reason for withdrawal, the subject will remain under the supervision 
of the Investigator until satisfactory health has returned. 
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. 
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. 
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3.7.3 
Treatment Assignment 
After obtaining informed consent, subjects will be screened according to the inclusion 
and exclusion criteria. Enrolled subjects will receive a unique subject number (01 to 36) 
prior to dosing. The subject number will ensure identification throughout the study. 
Replacement subjects will receive the number of the subject to be replaced, increased 
by 100 (e.g. 101 replacement number for subject number 01), and will be administered 
the same treatment. 
After enrollment, subjects will be assigned to Arm A or Arm B of the study based on 
meeting the respective eligibility criteria and investigator decision. 
Subjects 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 subjects screened in order to 
assess the numbers and characteristics of the excluded subjects, and the reasons for 
their exclusion. 
3.7.4 
Selection of Doses in the Study 
The dose of 0.5 mg talazoparib is 50% of MTD for daily administration. The reduction 
of the MTD is aimed to increase the safety margin when itraconazole is administered in 
Arm A, as the interacting drug may increase the exposure of talazoparib. For Arm B, 
1.0 mg of talazoparib will be administered which is the recommended daily dose for the 
treatment of solid tumors as a single-agent therapy. As it is expected that rifampin may 
reduce the exposure of talazoparib. No general safety issues are expected. 
Refer to the IB1 (Section 6.1) for most recent guidance on the formulation, dosage and 
administration of talazoparib. 
The doses of itraconazole and rifampin were selected following the dosing 
recommendations for their use as antifungal and antimicrobial agent, in the respective 
SmPCs 7,8. 
3.7.5 
Timing of Doses in the Study 
In Period 1, talazoparib will be administered without the interacting drugs in the 
morning of Day 1 under fasted conditions (8 hours before until 2 hours after dosing). 
In Period 2, talazoparib will be administered in combination with the interacting drugs in 
the morning of Day 23 (itraconazole), and of Day 25 (rifampin) under fasted conditions 
(8 hours before until 2 hours after dosing). On these days, itraconazole or rifampin will 
be taken 30 minutes before talazoparib. 
Itraconazole will be administered twice daily, once in the morning and once in the 
evening (approximately 12 hours apart) from Day 16 to Day 22 and from Day 23 to 
Day 36 in Period 2 immediately after the meal (breakfast and dinner, respectively). 
Rifampin will be administered once daily in the morning from Day 16 to Day 24 and 
from Day 26 to Day 38 in Period 2 at least 30 minutes before breakfast. 
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3.7.6 
Meals During the Study 
Subjects will be required to be fasting overnight from at least 8 hours before until at 
least 2 hour after the administration of talazoparib. Within this food-restricted period the 
consumption of water is allowed. Grapefruit juice is prohibited at least 24 hours prior to 
dosing of talazoparib on Days 1 and 23 until 24 hours after dose. 
According to the respective SmPCs7,8, itraconazole should be administered 
immediately after the meal, and rifampin should be administered at least 30 minutes 
before a meal in order to achieve optimum intestinal absorption. In case of concomitant 
administration with talazoparib, the interactors must be administered following the 
fasting restrictions of talazoparib on Days 23 and 25, respectively. 
3.7.7 
Blinding 
Not applicable. This is an uncontrolled, open-label clinical study. 
3.7.8 
Concomitant Medication and Other Restrictions During the Study 
Any concomitant medication will be administered under supervision of the medical staff 
of the unit during the in-house period. On days when talazoparib, itraconazole or 
rifampin is administered, any concomitant medication (including H2-blockers 
[cimetidine, ranitidine, famotidine etc.], PPIs [omeprazole, pantoprazole etc.], and anti-
acids) will be administered at least 2 hours thereafter. 
The use of warfarin is allowed with careful monitoring of international normalized ratio 
(INR) and the dose can be adjusted as needed. 
For statins which are CYP3A4 substrates, using with itraconazole might increase the 
plasma concentration of statins. Careful monitoring is recommended and the dose can 
be adjusted as needed. 
Patients on verapamil are excluded from the study unless the subject and Investigator 
agree to switch to an alternative, allowed antihypertensive. Any such switch must begin 
at least 7 days before Day 1 and additional blood pressure monitoring will be 
performed as considered medically necessary by the investigator to monitor blood 
pressure control. The patient should be switched back to verapamil after the last PK 
sample is taken, again with appropriate blood pressure monitoring, unless medically 
contraindicated in the opinion of the investigator. 
3.7.9 
Treatment Compliance 
Talazoparib will be administered orally under supervision of the Investigator or his/her 
designee. Compliance will be confirmed by bioanalytical assessment of the IMP in 
blood samples. 
The exact times of study drug administration and the number of units administered will 
be recorded in the eCRF. 
The administration of itraconazole and rifampin will be supervised by the Investigator 
on days when co-administration with talazoparib occurs. On all other days, the subjects 
will self-administer these drugs and record the dose, the time and date of the intake in 
a diary. 
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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 
For PK of talazoparib 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. 
3.8.1.2 
Efficacy Measurements 
No efficacy analysis is planned in this study, although baseline tumor assessments will 
be obtained in the event that eligible subjects 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). 
3.8.1.3.1 
Adverse Events 
Adverse events will be recorded following the first dose of study drug (Day 1) until 
completion of the follow-up visit. SAE will be collected from the time the subjects signs 
Informed Consents until completion of the follow-up visit. AEs which are still active at 
the conclusion of the follow-up visit will be monitored until resolution, or as deemed 
necessary by the Investigator or Sponsor. 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. 
An AE which occurs prior to (the first) administration of the talazoparib 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. 
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Page 40 of 55 
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 
scale10: 
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 Schedules of Assessments (Table 1 and Table 2) and before dosing, if 
applicable (talazoparib, as well as itraconazole and/or rifampin, respectively). 
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 
(ß-hCG) 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, 
 
CPK 
 
 
 
 
 
 
 
 
Triglycerides* 
 
 
Total cholesterol* 
 
090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)


 
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090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)


 
CLINICAL STUDY PROTOCOL 
 
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Page 42 of 55 
3.8.2 
Appropriateness of Measurements 
The assessments, which will be made in this study are standard for DDI 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. 
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 
The following PK parameters will be calculated as data allows for talazoparib 
concentrations in plasma. 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 concentration 
Tmax 
Time to attain maximum observed plasma concentration 
AUC0-last 
Area under the plasma concentration-time curve up to time t, where t 
is the last time 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 
Apparent Clearance 
Vd/F 
Volume of distribution at terminal phase 
 
PK parameters derived from metabolite profiling will be evaluated if applicable. 
3.8.3.2 
Efficacy Variable(s) 
Not applicable. 
090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)


 
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090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)


 
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VERSION Final 3.0 – 11-Oct-2016 
 
 
Page 44 of 55 
CV, minimum, median, maximum value and the number of measurements. 
Concentrations below LLOQ will be set to zero when calculating descriptive statistics. 
Means at any time will only be reported if the mean ≥ 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. 
The PK characteristics of Tmax will be described utilizing minimum, maximum and 
median. In calculation of PK parameters, pre-dose concentrations < LLOQ are set to 
zero; all post-dose concentrations < LLOQ are set as missing value. 
Statistical analyses will be performed to assess the effect of steady-state itraconazole 
and rifampin on the PK of talazoparib using the treatment in combination with 
talazoparib as Test and the treatment with talazoparib alone as Reference. Only 
subjects with data for both Reference and Test treatments will be included in the 
analysis. A linear mixed effects model that includes treatment as a fixed factor and 
subjects nested within the sequence as a random factor will be fitted to the log 
transformed PK parameters (AUC0-inf, AUC0-last and Cmax). A point estimate and the 
corresponding 90% CI for the difference between least squares means of Test and 
Reference treatment (Test – Reference) will be calculated. The antilogarithm of this 
value will be calculated to obtain the point estimate and the 90% CI for the ratio 
(Test/Reference) of the geometric means on the untransformed scale. 
3.9.2.3 
Evaluation of Safety and Tolerability 
All safety analyses will be performed using the safety population. Safety will be 
evaluated using summaries of adverse events, physical evaluation (and weight), vital 
signs, electrocardiograms (ECGs), 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 subjects 
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). 
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 NCI CTCAE. Change from 
baseline in laboratory values will be tabulated and summarized graphically. 
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. 
090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)


 
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090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)


 
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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 
18 h WMA General Assembly, Helsinki, Finland, June 1964, and subsequent 
amendments11. 
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)12, 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)13, Commission 
Directive 2005/28/EC14 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. 
090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)


 
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090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)


 
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Page 50 of 55 
7. 
REFERENCES 
1. 
Talazoparib Investigator’s Brochure, Medivation, Inc. and its Subsidiaries, v, v.8.0, 
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 Investigation of Drug Interactions. 
CPMP/EWP/560/95/Rev. 1, 21 June 2012. 
4. 
FDA Draft Guidance for Industry Drug Interaction Studies — Study Design, Data 
Analysis, Implications for Dosing, and Labeling Recommendations. U.S. 
Department of Health and Human Services Food and Drug Administration Center 
for Drug Evaluation and Research (CDER), February 2012 
5. 
Shimizu M, Uno T, Sugawara K, Tateishi T. Effects of single and multiple doses of 
itraconazole on the pharmacokinetics of fexofenadine, a substrate of 
P-glycoprotein. Br J Clin Pharmacol. 2006 Sep; 62(3):372-6. 
6. 
Geick A, Eichelbaum M, Burk O. Nuclear receptor response elements mediate 
induction of intestinal MDR1 by rifampin. J Biol Chem 2001; 276: 14581-14587. 
7. 
Summary of Product Characteristics: Itraconazole (Hungary: OrungalTM, Poland: 
TrioxalTM) 
8. 
Summary of Product Characteristics: Rifampin (Hungary: RifamedTM; Poland; 
Rifampicyna TZFTM) 
9. 
Guidance on Medical Exposures in Medical and Biomedical Research, European 
Commission 1998 
10. 
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. 
11. 
WMA Declaration of Helsinki (18th WMA General Assembly 1964), revised at 64th 
World Medical Association General Assembly, Fortaleza, Brazil, October 2013 
12. 
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 
13. 
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 
14. 
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 
15. 
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 
16. 
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 
17. 
Common Terminology Criteria for Adverse Events v4.0 (CTCAE), US department 
of Health and Human Services, National Institutes of Health, National Cancer 
Institute 2009 
090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)


 
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8.2.2 
Grading of Severity 
The severity of AEs will be graded using the most current version of the NCI TCAE 
5-point scale17: 
• 
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 probable, 
possible 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 subject 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, for example, a respite unit; a skilled nursing unit; 
rehabilitation facility; the clinical research unit; or confinement due to planned reason, unrelated 
to study participation. 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
Any other situation, such as an important medical 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 subject 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 subject 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 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 followed 
until resolution or until stabilized with sequelae. SAEs that begin after the subject’s 
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090177e19002e96f\Approved\Approved On: 18-Dec-2018 07:49 (GMT)

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CCI
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