A Study to Assess the Effects of Talazoparib on Cardiac Repolarization in Patients With Advanced Solid Tumors

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03042910
• Collaborator: Medivation, Inc. (Industry)
• Enrollment: 38
• Locations: 19
• Arm: 1
• Actual Duration (Months): 8.3
• Patients Per Site: 2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study is designed to evaluate the effects of talazoparib on cardiac repolarization in patients with advanced solid tumors with no available standard treatment options.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumor	Drug: Talazoparib	Phase 1

Detailed Description

For further talazoparib treatment, patients must enroll and initiate continued talazoparib treatment in a separate open label extension study within 30 days after the last dose of study drug.

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A PHASE 1, OPEN-LABEL STUDY TO ASSESS THE EFFECTS OF TALAZOPARIB ON CARDIAC REPOLARIZATION IN PATIENTS WITH ADVANCED SOLID TUMORS
• Actual Study Start Date: Oct 13, 2016
• Actual Primary Completion Date: May 30, 2017
• Actual Study Completion Date: Jun 22, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Patients with advanced solid tumors Talazoparib 1 mg daily	Drug: Talazoparib; Talazoparib 1 mg orally once daily.; Other Names: MDV3800 BMN673

Outcome Measures

Primary Outcome Measures

1. Time-matched Mean Change From Baseline in Corrected QT Intervals Based on the Fridericia's Correction Fomulation (QTcF) [Baseline (Day -1 time matched for each time point); 1, 2, 4 and 6 hours post-dose on Day 1; pre-dose on Day 2; pre-dose, 1, 2, 4 and 6 hours post-dose on Day 22]

   QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole.

2. Intercept of Predicted Linear Mixed Effects Models for Change From Baseline in QTcF Versus Plasma Talazoparib Concentrations at Day 22 [Baseline (Day -1) to Day 22]

   A linear mixed effects modeling approach was used to examine the relationship between the change from baseline in QTcF and the plasma concentration of talazoparib. The model included plasma concentration, time (categorical), and treatment with random participant effects on plasma concentration and the intercept. Equation used for modeling was: Y_lkt= μ_l+ p_t+ θ × C_lkt + W_k + D_k × C_kt + ε_lkt, where the dependent variable Y_lkt was for the l (treatment), k (participants) and t (time point). Parameter were: μ_l was the treatment specific intercept, θ was the slope, C was the concentration, W_k was the random patient effect on the intercept, D_k was the random patient effect on the slope, p_t was the time effect on the intercept and ε_lkt was the residual error.

3. Concentration Slope of Predicted Linear Mixed Effects Models for Change From Baseline in QTcF Versus Plasma Talazoparib Concentrations at Day 22 [Baseline (Day -1) to Day 22]

   A linear mixed effects modeling approach was used to examine the relationship between the change from baseline in QTcF and the plasma concentration of talazoparib. The model included plasma concentration, time (categorical), and treatment with random participant effects on plasma concentration and the intercept. Equation used for modeling was: Y_lkt= μ_l+ p_t+ θ × C_lkt+ W_k+ D_k × C_kt+ ε_lkt, where the dependent variable Y_lkt was for the l (treatment), k (participants) and t (time point). Parameter were: μ_l was the treatment specific intercept, θ was the slope, C was the concentration, W_k was the random patient effect on the intercept, D_k was the random patient effect on the slope, p_t was the time effect on the intercept and ε_lkt was the residual error.

Secondary Outcome Measures

1. Time-matched Mean Change From Baseline in Corrected QT Intervals Based on the Bazett's Correction Fomulation (QTcB) [Baseline (Day -1 time matched for each time point); 1, 2, 4 and 6 hours post-dose on Day 1; pre-dose on Day 2; pre-dose, 1, 2, 4 and 6 hours post-dose on Day 22]

   QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole.

2. Time-matched Mean Change From Baseline in Heart Rate [Baseline (Day -1 time matched for each time point); 1, 2, 4 and 6 hours post-dose on Day 1; pre-dose on Day 2; pre-dose, 1, 2, 4 and 6 hours post-dose on Day 22]

3. Time-matched Mean Change From Baseline in PR Interval [Baseline (Day -1 time matched for each time point); 1, 2, 4 and 6 hours post-dose on Day 1; pre-dose on Day 2; pre-dose, 1, 2, 4 and 6 hours post-dose on Day 22]

   PR interval is the time between the beginning of the P wave and the start of the QRS interval, corresponding to the end of atrial depolarization and onset of ventricular depolarization.

4. Time-matched Mean Change From Baseline in QRS Interval [Baseline (Day -1 time matched for each time point); 1, 2, 4 and 6 hours post-dose on Day 1; pre-dose on Day 2; pre-dose, 1, 2, 4 and 6 hours post-dose on Day 22]

   QRS interval is the time from electrocardiogram Q wave to the end of the S wave, corresponding to ventricle depolarization.

5. Time-matched Mean Change From Baseline in QT Interval [Baseline (Day -1 time matched for each time point); 1, 2, 4 and 6 hours post-dose on Day 1; pre-dose on Day 2; pre-dose, 1, 2, 4 and 6 hours post-dose on Day 22]

   QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole.

6. Time-matched Mean Change From Baseline in RR Interval [Baseline (Day -1 time matched for each time point); 1, 2, 4 and 6 hours post-dose on Day 1; pre-dose on Day 2; pre-dose, 1, 2, 4 and 6 hours post-dose on Day 22]

   RR interval is the time elapsing between two consecutive R waves in the electrocardiogram.

7. Number of Participants With Treatment-emergent Abnormalities in 12-lead Electrocardiogram (ECG) Morphpology [Baseline to Day 22]

   Morphological analyses were performed with regard to the ECG waveform interpretation as defined by the central ECG laboratory's cardiologist. Numbers of participants with new onsets for the following variables were counted: atrial fibrillation or flutter, second-degree heart block, third degree heart block, complete right bundle branch block, complete left bundle branch block, ST segment depression, ST segment elevation, T-wave abnormalities (negative T waves only), myocardial infarction pattern, and any new abnormal U waves. "New" was defined as "not present on any baseline ECG but present on any on-treatment ECG". Number of participants with abnormality in any of the variables were reported.

8. Number of Participants With Clinically Significant Findings in 12-lead Electrocardiogram (ECG) Parameters Meeting Predefined Criteria [Baseline (mean of all ECGs on Day -1 and pre-dose on Day 1) to Day 22]

   Criteria for clinically significant: Maximum QTcF >450 msec, Maximum QTcF >480 msec, Maximum QTcF >500 msec, Maximum QTcB >450 msec, Maximum QTcB >480 msec, Maximum QTcB >500 msec, Maximum QT Interval >500 msec, Maximum QTcF Increase <=30 msec, Maximum QTcF Increase 30 to <=60 msec, Maximum QTcF Increase <=60 msec, Maximum PR interval increase >200 msec and >=25%, Maximum QRS interval increase >100 msec and >=25%, Maximum heart rate increase >100 bpm and >25% and Maximum heart rate decrease <50 bpm and >25%.

9. Number of Participants With Treatment-emergent Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuation Due to AEs, AEs of Special Interest, and Deaths [Day 1 to follow-up (30 days post last dose, i.e. up to 52 days)]

   An adverse event(AE)was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not related to the study drug. A serious adverse event(SAE)was an AE that resulted in: death; persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; congenital anomaly/birth defect; was life-threatening (immediate risk of death); hospitalization or prolongation of existing hospitalization; or considered to be an important medical event. Treatment-emergent AEs (TEAEs) are AEs occurred on or after the administration of study drug. AEs related to study drug was any AE with at least a possible relationship to the study drug as assessed by the investigator. AEs of special interest were diagnosis of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and abnormal liver test results that met predefined criteria.

10. Number of Participants With Clinically Notable Changes in Vital Signs Measurements [Screening (Day -29 to Day -2) to follow-up (30 days post last dose on Day 22)]

    Clinically notable changes included: High systolic blood pressure (SBP):>=155 millimeters of mercury (mmHg) with increase >=30 mmHg, low SBP <=90 mmHg with decrease >=20 mmHg, Both high and low SBP (i.e high SBP >=155 mmHg with increase >=30 mmHg and low SBP <=90 mmHg with decrease >=20 mmHg), High diastolic blood pressure (DBP):>=100 mmHg with increase >=15 mmHg), Low DBP (<=50 mmHg with decrease >=15 mmHg), Both high and low DBP, Heart rate >=100 bpm with increase >=30 bpm, Heart rate <=50 bpm with decrease >=15 bpm, Respiratory rate >=25 bpm, Respiratory rate <10 bpm, Oral body temperature >39 degree and Oral body temperature <=35 degree.

11. Number of Participants With Clinically Significant Laboratory Test Abnormalities [Baseline to follow-up (30 days post last dose on Day 22, i.e. up to Day 52)]

    Laboratory test included: hematology (hematocrit, hemoglobin, mean corpuscular volum, red blood cell count, platelet count, white blood cell count with differential [total neutrophils, eosinophils, monocytes, basophils, and lymphocytes]),chemistry (albumin, total protein, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, blood urea nitrogen, creatinine, non-fasting glucose, carbon dioxide, calcium, chloride, magnesium, phosphate, potassium, sodium and lactate dehydrogenase), and additional tests (urine or serum pregnancy tests for women of childbearing potential). Clinically significant laboratory abnormality was determined by the investigator.

12. Area Under the Plasma Concentration-time Profile From Time 0 to 24 Hours After Dosing (AUC24) of Plasma Talazoparib on Day 1 and Day 22 [Pre-dose, 1, 2, 4, 6, and 24 hours post-dose on Day 1; pre-dose, 1, 2, 4, and 6 hours post-dose on Day 22]

    Day 22 subpopulation: amongst the participants with reported pharmacokinetic (PK) parameters on Day 22, exclusion of values from the summary statistics calculations due to dose modifications (eg, dose interruptions, dose reductions) was handled on a case by case basis, resulting in a subpopulation of participants with no prior dose modifications.

13. Maximum Plasma Concentration (Cmax) of Plasma Talazoparib on Day 1 and Day 22 [Pre-dose, 1, 2, 4, 6, and 24 hours post-dose on Day 1; pre-dose, 1, 2, 4, and 6 hours post-dose on Day 22]

    Day 22 subpopulation: amongst the participants with reported pharmacokinetic (PK) parameters on Day 22, exclusion of values from the summary statistics calculations due to dose modifications (eg, dose interruptions, dose reductions) was handled on a case by case basis, resulting in a subpopulation of participants with no prior dose modifications.

14. Time for Cmax (Tmax) of Plasma Talazoparib on Day 1 and Day 22 [Pre-dose, 1, 2, 4, 6, and 24 hours post-dose on Day 1; pre-dose, 1, 2, 4, and 6 hours post-dose on Day 22]

    Day 22 subpopulation: amongst the participants with reported pharmacokinetic (PK) parameters on Day 22, exclusion of values from the summary statistics calculations due to dose modifications (eg, dose interruptions, dose reductions) was handled on a case by case basis, resulting in a subpopulation of participants with no prior dose modifications.

15. Predose Concentration (Ctrough) of Plasma Talazoparib on Day 22 [Pre-dose, Day 22]

    Day 22 subpopulation: amongst the participants with reported pharmacokinetic (PK) parameters on Day 22, exclusion of values from the summary statistics calculations due to dose modifications (eg, dose interruptions, dose reductions) was handled on a case by case basis, resulting in a subpopulation of participants with no prior dose modifications.

16. Apparent Clearance After Oral Dose (CL/F) of Plasma Talazoparib on Day 22 [Pre-dose, 1, 2, 4, and 6 hours post-dose on Day 22]

    Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood (rate at which a drug is metabolized or eliminated by normal biological processes). Clearance obtained after intravenous infusion dose (apparent clearance) is influenced by the fraction of the dose absorbed. Day 22 subpopulation: amongst the participants with reported pharmacokinetic (PK) parameters on Day 22, exclusion of values from the summary statistics calculations due to dose modifications (eg, dose interruptions, dose reductions) was handled on a case by case basis, resulting in a subpopulation of participants with no prior dose modifications.

17. Accumulation Ratio (Rac) of Plasma Talazoparib on Day 22 [Pre-dose, 1, 2, 4, and 6 hours post-dose on Day 22]

    Rac was calculated as, area under the curve from time zero to end of dosing interval on Day 22 (AUCtau) divided by area under the curve from time zero to end of dosing interval on Day 1 (AUCtau). Area under the concentration curve from time 0 to end of dosing interval (AUCtau), where dosing interval was 6 hours. Day 22 subpopulation: amongst the participants with reported pharmacokinetic (PK) parameters on Day 22, exclusion of values from the summary statistics calculations due to dose modifications (eg, dose interruptions, dose reductions) was handled on a case by case basis, resulting in a subpopulation of participants with no prior dose modifications.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. At least 18 years of age and willing and able to provide informed consent.

2. Histologically or cytologically confirmed advanced solid tumor with no available standard treatment options in the opinion of the investigator.

3. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

4. Estimated life expectancy of ≥ 3 months.

5. Able to swallow the study drug, have no known intolerance to the study drug or excipients, and comply with study requirements.

6. Female patients of childbearing potential must have a negative pregnancy test at screening and must agree to use a highly effective birth control method from the time of the first dose of study drug through 45 days after last dose of study drug.

7. Male patients must use a condom when having sex with a pregnant woman or with a woman of childbearing potential from the time of 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.

8. Male and female patients must agree not to donate sperm or eggs, respectively, from the first dose of study drug through 105 days and 45 days after the last dose of study drug, respectively.

9. Female patients may not be breastfeeding at screening and must not breastfeed during study participation through 45 days after the last dose of study drug.

Exclusion Criteria:

1. Use of antineoplastic therapies within 21 days before day 1.

2. Use of any other investigational agent within 21 days before day 1.

3. Have not recovered (recovery is defined as National Cancer Institute Common Terminology Criteria for Adverse Events [CTCAE] grade ≤ 1) from the acute toxicities of previous therapy, except treatment related alopecia or laboratory abnormalities otherwise meeting eligibility requirements.

4. Electrolyte abnormality that has not responded to correction, including hypokalemia or hypocalcemia less than the lower limit of normal, or hyperkalemia or hypercalcemia greater than the upper limit of normal (ULN).

5. Major surgery within 14 days before day 1.

6. Diagnosis of myelodysplastic syndrome (MDS) or a hematologic malignancy.

7. Clinically significant cardiovascular disease.

8. Significant organ dysfunction.

9. Gastrointestinal disorder affecting absorption.

10. Current or anticipated use of a strong P-gp inhibitor, strong P-gp inducer, or strong inhibitor of BCRP.

11. Any condition (concurrent disease, infection, or comorbidity) 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 medical monitor.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CBCC Global Research, Inc. at Comprehensive Blood and Cancer Center	Bakersfield	California	United States	93309
2	UCLA Hematology/Oncology - Burbank	Burbank	California	United States	91505
3	St. Jude Hospital Yorba Linda DBA St. Joseph Heritage Healthcare	Fullerton	California	United States	92835
4	UCLA West Medical Pharmacy, Attn: Steven L. Wong, Pharm.D.	Los Angeles	California	United States	90095-7349
5	Ronald Reagan UCLA Medical Center, Drug Information Center	Los Angeles	California	United States	90095
6	TRIO-US Central Administration	Los Angeles	California	United States	90095
7	UCLA Hematology/Oncology	Los Angeles	California	United States	90095
8	UCLA West Medical Pharmacy. Attn: Steven L. Wong, Pharm.D.	Los Angeles	California	United States	90095
9	UCLA Hematology/Oncology - Pasadena	Pasadena	California	United States	91105
10	UCLA Hematology/Oncology - Porter Ranch	Porter Ranch	California	United States	91326
11	Torrance Health Association, DBA Torrance Memorial Physician Network/Cancer Care Associates	Redondo Beach	California	United States	90277
12	UCLA Hematology/Oncology - Santa Monica	Santa Monica	California	United States	90404
13	UCLA Hematology/Oncology - Santa Clarita	Valencia	California	United States	91355
14	Memorial Cancer Institute at Memorial Regional Hospital	Hollywood	Florida	United States	33021
15	Memorial Regional Hospital	Hollywood	Florida	United States	33021
16	Orlando Health, Inc.	Orlando	Florida	United States	32806
17	Memorial Hospital West	Pembroke Pines	Florida	United States	33028
18	Fort Wayne Medical Oncology and Hematology, Inc.	Fort Wayne	Indiana	United States	46804
19	Fort Wayne Medical Oncology and Hematology, Inc.	Fort Wayne	Indiana	United States	46845

Sponsors and Collaborators

• Pfizer
• Medivation, Inc.

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

• Study Protocol - Aug 19, 2016
• Statistical Analysis Plan - Mar 9, 2017

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT03042910
• Other Study ID Numbers: MDV3800-14; C3441005
• First Posted: Feb 3, 2017
• Last Update Posted: Dec 17, 2019
• Last Verified: Dec 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Neoplasms; Talazoparib

Study Results

Participant Flow

Pre-assignment Detail	Study was conducted in 4 countries from 07-Nov-2016 to 18 Dec 2017.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Period Title: Overall Study
STARTED	38
Treated	37
COMPLETED	31
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Overall Participants	37
Age (YEARS) [Mean (Standard Deviation) ]
Mean Age	64.1 (12.82)
Sex: Female, Male (Count of Participants)
Female	23 62.2%
Male	14 37.8%
Race/Ethnicity, Customized (Number) [Number]
American Indian or Alaska Native	1 2.7%
Black or African American	2 5.4%
Native Hawaiian or other Pacific Islander	1 2.7%
Other	2 5.4%
White	31 83.8%

Outcome Measures

1. Primary Outcome

Title	Time-matched Mean Change From Baseline in Corrected QT Intervals Based on the Fridericia's Correction Fomulation (QTcF)
Description	QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole.
Time Frame	Baseline (Day -1 time matched for each time point); 1, 2, 4 and 6 hours post-dose on Day 1; pre-dose on Day 2; pre-dose, 1, 2, 4 and 6 hours post-dose on Day 22

Outcome Measure Data

Analysis Population Description

Electrocardiographic analysis population: all enrolled participants who received at least 1 dose of talazoparib, and had at least 1 available baseline and 1 on-treatment electrocardiogram (ECG) data.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Measure Participants	37
Day 1, 1 hour	3.9
Day 1, 2 hours	3.5
Day 1, 4 hours	1.6
Day 1, 6 hours	-0.3
Day 2, pre-dose	-3.5
Day 22, pre-dose	-1.3
Day 22, 1 hour	6.9
Day 22, 2 hours	4.7
Day 22, 4 hours	3.0
Day 22, 6 hours	0.5

2. Primary Outcome

Title	Intercept of Predicted Linear Mixed Effects Models for Change From Baseline in QTcF Versus Plasma Talazoparib Concentrations at Day 22
Description	A linear mixed effects modeling approach was used to examine the relationship between the change from baseline in QTcF and the plasma concentration of talazoparib. The model included plasma concentration, time (categorical), and treatment with random participant effects on plasma concentration and the intercept. Equation used for modeling was: Y_lkt= μ_l+ p_t+ θ × C_lkt + W_k + D_k × C_kt + ε_lkt, where the dependent variable Y_lkt was for the l (treatment), k (participants) and t (time point). Parameter were: μ_l was the treatment specific intercept, θ was the slope, C was the concentration, W_k was the random patient effect on the intercept, D_k was the random patient effect on the slope, p_t was the time effect on the intercept and ε_lkt was the residual error.
Time Frame	Baseline (Day -1) to Day 22

Outcome Measure Data

Analysis Population Description

Pharmacokinetic-Pharmacodynamic analysis population: participants who received at least 1 dose of talazoparib, had at least 1 available baseline and 1 on-treatment ECG data, had at least 1 time-matched pair of plasma concentration and ECG measurement obtained at the same nominal time point and met the additional requirements for PK-PD analysis.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Measure Participants	37
Number (95% Confidence Interval) [msec]	4.6

3. Primary Outcome

Title	Concentration Slope of Predicted Linear Mixed Effects Models for Change From Baseline in QTcF Versus Plasma Talazoparib Concentrations at Day 22
Description	A linear mixed effects modeling approach was used to examine the relationship between the change from baseline in QTcF and the plasma concentration of talazoparib. The model included plasma concentration, time (categorical), and treatment with random participant effects on plasma concentration and the intercept. Equation used for modeling was: Y_lkt= μ_l+ p_t+ θ × C_lkt+ W_k+ D_k × C_kt+ ε_lkt, where the dependent variable Y_lkt was for the l (treatment), k (participants) and t (time point). Parameter were: μ_l was the treatment specific intercept, θ was the slope, C was the concentration, W_k was the random patient effect on the intercept, D_k was the random patient effect on the slope, p_t was the time effect on the intercept and ε_lkt was the residual error.
Time Frame	Baseline (Day -1) to Day 22

Outcome Measure Data

Analysis Population Description

Pharmacokinetic-Pharmacodynamic analysis population: participants who received at least 1 dose of talazoparib, had at least 1 available baseline and 1 on-treatment ECG data, had at least 1 time-matched pair of plasma concentration and ECG measurement obtained at the same nominal time point and met the additional requirements for PK-PD analysis.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Measure Participants	37
Number (95% Confidence Interval) [msec/nanogram/milliliter (msec/ng/mL)]	-0.14

4. Secondary Outcome

Title	Time-matched Mean Change From Baseline in Corrected QT Intervals Based on the Bazett's Correction Fomulation (QTcB)
Description	QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole.
Time Frame	Baseline (Day -1 time matched for each time point); 1, 2, 4 and 6 hours post-dose on Day 1; pre-dose on Day 2; pre-dose, 1, 2, 4 and 6 hours post-dose on Day 22

Outcome Measure Data

Analysis Population Description

Electrocardiographic analysis population: all enrolled participants who received at least 1 dose of talazoparib, and had at least 1 available baseline and 1 on-treatment electrocardiogram (ECG) data.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Measure Participants	37
Day 1, 1 hour	0.6
Day 1, 2 hours	4.7
Day 1, 4 hours	2.9
Day 1, 6 hours	-0.4
Day 2, pre-dose	-1.7
Day 22, pre-dose	-2.4
Day 22, 1 hour	1.1
Day 22, 2 hours	2.2
Day 22, 4 hours	1.6
Day 22, 6 hours	0.0

5. Secondary Outcome

Title	Time-matched Mean Change From Baseline in Heart Rate
Time Frame	Baseline (Day -1 time matched for each time point); 1, 2, 4 and 6 hours post-dose on Day 1; pre-dose on Day 2; pre-dose, 1, 2, 4 and 6 hours post-dose on Day 22

Outcome Measure Data

Analysis Population Description

Electrocardiographic analysis population: all enrolled participants who received at least 1 dose of talazoparib, and had at least 1 available baseline and 1 on-treatment electrocardiogram (ECG) data.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Measure Participants	37
Day 1, 1 hour	-3.0
Day 1, 2 hours	1.4
Day 1, 4 hours	1.4
Day 1, 6 hours	0.1
Day 2, pre-dose	2.3
Day 22, pre-dose	-1.1
Day 22, 1 hour	-6.0
Day 22, 2 hours	-2.8
Day 22, 4 hours	-1.4
Day 22, 6 hours	-0.1

6. Secondary Outcome

Title	Time-matched Mean Change From Baseline in PR Interval
Description	PR interval is the time between the beginning of the P wave and the start of the QRS interval, corresponding to the end of atrial depolarization and onset of ventricular depolarization.
Time Frame	Baseline (Day -1 time matched for each time point); 1, 2, 4 and 6 hours post-dose on Day 1; pre-dose on Day 2; pre-dose, 1, 2, 4 and 6 hours post-dose on Day 22

Outcome Measure Data

Analysis Population Description

Electrocardiographic analysis population: all enrolled participants who received at least 1 dose of talazoparib, and had at least 1 available baseline and 1 on-treatment electrocardiogram (ECG) data.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Measure Participants	37
Day 1, 1 hour	-2.3
Day 1, 2 hours	-2.2
Day 1, 4 hours	-3.2
Day 1, 6 hours	-1.1
Day 2, pre-dose	-4.5
Day 22, pre-dose	-1.0
Day 22, 1 hour	0.5
Day 22, 2 hours	-0.1
Day 22, 4 hours	-0.1
Day 22, 6 hours	-2.4

7. Secondary Outcome

Title	Time-matched Mean Change From Baseline in QRS Interval
Description	QRS interval is the time from electrocardiogram Q wave to the end of the S wave, corresponding to ventricle depolarization.
Time Frame	Baseline (Day -1 time matched for each time point); 1, 2, 4 and 6 hours post-dose on Day 1; pre-dose on Day 2; pre-dose, 1, 2, 4 and 6 hours post-dose on Day 22

Outcome Measure Data

Analysis Population Description

Electrocardiographic analysis population: all enrolled participants who received at least 1 dose of talazoparib, and had at least 1 available baseline and 1 on-treatment electrocardiogram (ECG) data.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Measure Participants	37
Day 1, 1 hour	2.9
Day 1, 2 hours	2.0
Day 1, 4 hours	1.1
Day 1, 6 hours	0.9
Day 2, pre-dose	2.6
Day 22, pre-dose	0.7
Day 22, 1 hour	2.6
Day 22, 2 hours	1.3
Day 22, 4 hours	1.7
Day 22, 6 hours	0.7

8. Secondary Outcome

Title	Time-matched Mean Change From Baseline in QT Interval
Description	QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole.
Time Frame	Baseline (Day -1 time matched for each time point); 1, 2, 4 and 6 hours post-dose on Day 1; pre-dose on Day 2; pre-dose, 1, 2, 4 and 6 hours post-dose on Day 22

Outcome Measure Data

Analysis Population Description

Electrocardiographic analysis population: all enrolled participants who received at least 1 dose of talazoparib, and had at least 1 available baseline and 1 on-treatment electrocardiogram (ECG) data.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Measure Participants	37
Day 1, 1 hour	10.2
Day 1, 2 hours	1.8
Day 1, 4 hours	-0.9
Day 1, 6 hours	0.0
Day 2, pre-dose	-6.5
Day 22, pre-dose	0.8
Day 22, 1 hour	17.6
Day 22, 2 hours	9.1
Day 22, 4 hours	5.2
Day 22, 6 hours	1.2

9. Secondary Outcome

Title	Time-matched Mean Change From Baseline in RR Interval
Description	RR interval is the time elapsing between two consecutive R waves in the electrocardiogram.
Time Frame	Baseline (Day -1 time matched for each time point); 1, 2, 4 and 6 hours post-dose on Day 1; pre-dose on Day 2; pre-dose, 1, 2, 4 and 6 hours post-dose on Day 22

Outcome Measure Data

Analysis Population Description

Electrocardiographic analysis population: all enrolled participants who received at least 1 dose of talazoparib, and had at least 1 available baseline and 1 on-treatment electrocardiogram (ECG) data.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Measure Participants	37
Day 1, 1 hour	42.9
Day 1, 2 hours	-7.8
Day 1, 4 hours	-15.1
Day 1, 6 hours	2.1
Day 2, pre-dose	-17.9
Day 22, pre-dose	16.0
Day 22, 1 hour	69.8
Day 22, 2 hours	30.5
Day 22, 4 hours	15.6
Day 22, 6 hours	4.1

10. Secondary Outcome

Title	Number of Participants With Treatment-emergent Abnormalities in 12-lead Electrocardiogram (ECG) Morphpology
Description	Morphological analyses were performed with regard to the ECG waveform interpretation as defined by the central ECG laboratory's cardiologist. Numbers of participants with new onsets for the following variables were counted: atrial fibrillation or flutter, second-degree heart block, third degree heart block, complete right bundle branch block, complete left bundle branch block, ST segment depression, ST segment elevation, T-wave abnormalities (negative T waves only), myocardial infarction pattern, and any new abnormal U waves. "New" was defined as "not present on any baseline ECG but present on any on-treatment ECG". Number of participants with abnormality in any of the variables were reported.
Time Frame	Baseline to Day 22

Outcome Measure Data

Analysis Population Description

Electrocardiographic analysis population: all enrolled participants who received at least 1 dose of talazoparib, and had at least 1 available baseline and 1 on-treatment electrocardiogram (ECG) data.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Measure Participants	37
Count of Participants [Participants]	0 0%

11. Secondary Outcome

Title	Number of Participants With Clinically Significant Findings in 12-lead Electrocardiogram (ECG) Parameters Meeting Predefined Criteria
Description	Criteria for clinically significant: Maximum QTcF >450 msec, Maximum QTcF >480 msec, Maximum QTcF >500 msec, Maximum QTcB >450 msec, Maximum QTcB >480 msec, Maximum QTcB >500 msec, Maximum QT Interval >500 msec, Maximum QTcF Increase <=30 msec, Maximum QTcF Increase 30 to <=60 msec, Maximum QTcF Increase <=60 msec, Maximum PR interval increase >200 msec and >=25%, Maximum QRS interval increase >100 msec and >=25%, Maximum heart rate increase >100 bpm and >25% and Maximum heart rate decrease <50 bpm and >25%.
Time Frame	Baseline (mean of all ECGs on Day -1 and pre-dose on Day 1) to Day 22

Outcome Measure Data

Analysis Population Description

Electrocardiographic analysis population: all enrolled participants who received at least 1 dose of talazoparib, and had at least 1 available baseline and 1 on-treatment electrocardiogram (ECG) data.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Measure Participants	37
Maximum QTcF >450 msec	5 13.5%
Maximum QTcF >480 msec	1 2.7%
Maximum QTcF >500 msec	0 0%
Maximum QTcB >450 msec	13 35.1%
Maximum QTcB >480 msec	2 5.4%
Maximum QTcB >500 msec	0 0%
Maximum QT Interval >500 msec	0 0%
Maximum QTcF increase <=30 msec	33 89.2%
Maximum QTcF increase: 30 to <=60 msec	4 10.8%
Maximum QTcF increase >60 msec	0 0%
Maximum QTcB increase <=30 msec	34 91.9%
Maximum QTcB increase: 30 to <=60 msec	3 8.1%
Maximum QTcB increase >60 msec	0 0%
Maximum PR interval increase >200 msec and >=25%	0 0%
Maximum QRS interval increase >100 msec and >=25%	1 2.7%
Maximum heart rate increase >100 bpm and >25%	1 2.7%
Maximum heart rate decrease <50 bpm and >25%	0 0%

12. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuation Due to AEs, AEs of Special Interest, and Deaths
Description	An adverse event(AE)was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not related to the study drug. A serious adverse event(SAE)was an AE that resulted in: death; persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; congenital anomaly/birth defect; was life-threatening (immediate risk of death); hospitalization or prolongation of existing hospitalization; or considered to be an important medical event. Treatment-emergent AEs (TEAEs) are AEs occurred on or after the administration of study drug. AEs related to study drug was any AE with at least a possible relationship to the study drug as assessed by the investigator. AEs of special interest were diagnosis of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and abnormal liver test results that met predefined criteria.
Time Frame	Day 1 to follow-up (30 days post last dose, i.e. up to 52 days)

Outcome Measure Data

Analysis Population Description

Safety population: all participants who received any amount of talazoparib.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Measure Participants	37
AEs	28 75.7%
AEs related to study drug	17 45.9%
SAEs	3 8.1%
SAEs related to study drug	1 2.7%
Discontinuations due to AEs	0 0%
Deaths	0 0%
AEs of special interest	0 0%

13. Secondary Outcome

Title	Number of Participants With Clinically Notable Changes in Vital Signs Measurements
Description	Clinically notable changes included: High systolic blood pressure (SBP):>=155 millimeters of mercury (mmHg) with increase >=30 mmHg, low SBP <=90 mmHg with decrease >=20 mmHg, Both high and low SBP (i.e high SBP >=155 mmHg with increase >=30 mmHg and low SBP <=90 mmHg with decrease >=20 mmHg), High diastolic blood pressure (DBP):>=100 mmHg with increase >=15 mmHg), Low DBP (<=50 mmHg with decrease >=15 mmHg), Both high and low DBP, Heart rate >=100 bpm with increase >=30 bpm, Heart rate <=50 bpm with decrease >=15 bpm, Respiratory rate >=25 bpm, Respiratory rate <10 bpm, Oral body temperature >39 degree and Oral body temperature <=35 degree.
Time Frame	Screening (Day -29 to Day -2) to follow-up (30 days post last dose on Day 22)

Outcome Measure Data

Analysis Population Description

Safety population: all participants who received any amount of talazoparib.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Measure Participants	37
High SBP (>=155 mmHg with increase >=30 mmHg)	0 0%
Low SBP (<=90 mmHg with decrease >=20 mmHg)	2 5.4%
Both high and low SBP	0 0%
High DBP (>=100 mmHg with increase >=15 mmHg)	1 2.7%
Low DBP (<=50 mmHg with decrease >=15 mmHg)	1 2.7%
Both high and low DBP	0 0%
Heart rate >=100 bpm with increase >=30 bpm	0 0%
Heart rate <=50 bpm with decrease >=15 bpm	0 0%
Respiratory rate >=25 bpm	0 0%
Respiratory rate <10 bpm	0 0%
Oral body temperature >39 degree	0 0%
Oral body temperature <=35 degree	0 0%

14. Secondary Outcome

Title	Number of Participants With Clinically Significant Laboratory Test Abnormalities
Description	Laboratory test included: hematology (hematocrit, hemoglobin, mean corpuscular volum, red blood cell count, platelet count, white blood cell count with differential [total neutrophils, eosinophils, monocytes, basophils, and lymphocytes]),chemistry (albumin, total protein, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, blood urea nitrogen, creatinine, non-fasting glucose, carbon dioxide, calcium, chloride, magnesium, phosphate, potassium, sodium and lactate dehydrogenase), and additional tests (urine or serum pregnancy tests for women of childbearing potential). Clinically significant laboratory abnormality was determined by the investigator.
Time Frame	Baseline to follow-up (30 days post last dose on Day 22, i.e. up to Day 52)

Outcome Measure Data

Analysis Population Description

Safety population: all participants who received any amount of talazoparib.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Measure Participants	37
Count of Participants [Participants]	3 8.1%

15. Secondary Outcome

Title	Area Under the Plasma Concentration-time Profile From Time 0 to 24 Hours After Dosing (AUC24) of Plasma Talazoparib on Day 1 and Day 22
Description	Day 22 subpopulation: amongst the participants with reported pharmacokinetic (PK) parameters on Day 22, exclusion of values from the summary statistics calculations due to dose modifications (eg, dose interruptions, dose reductions) was handled on a case by case basis, resulting in a subpopulation of participants with no prior dose modifications.
Time Frame	Pre-dose, 1, 2, 4, 6, and 24 hours post-dose on Day 1; pre-dose, 1, 2, 4, and 6 hours post-dose on Day 22

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis population: all participants who had sufficient concentration data to derive at least 1 PK parameter. Here, number analyzed signifies participants with available date for the specified time point.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Measure Participants	37
Day 1	54200 (42)
Day 22	209000 (36)
Day 22 Subpopulation	208000 (37)

16. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of Plasma Talazoparib on Day 1 and Day 22
Description	Day 22 subpopulation: amongst the participants with reported pharmacokinetic (PK) parameters on Day 22, exclusion of values from the summary statistics calculations due to dose modifications (eg, dose interruptions, dose reductions) was handled on a case by case basis, resulting in a subpopulation of participants with no prior dose modifications.
Time Frame	Pre-dose, 1, 2, 4, 6, and 24 hours post-dose on Day 1; pre-dose, 1, 2, 4, and 6 hours post-dose on Day 22

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis population: all participants who had sufficient concentration data to derive at least 1 PK parameter. Here, number analyzed signifies participants with available date for the specified time point.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Measure Participants	37
Day 1	4350 (47)
Day 22	16300 (32)
Day 22 Subpopulation	16400 (32)

17. Secondary Outcome

Title	Time for Cmax (Tmax) of Plasma Talazoparib on Day 1 and Day 22
Description	Day 22 subpopulation: amongst the participants with reported pharmacokinetic (PK) parameters on Day 22, exclusion of values from the summary statistics calculations due to dose modifications (eg, dose interruptions, dose reductions) was handled on a case by case basis, resulting in a subpopulation of participants with no prior dose modifications.
Time Frame	Pre-dose, 1, 2, 4, 6, and 24 hours post-dose on Day 1; pre-dose, 1, 2, 4, and 6 hours post-dose on Day 22

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis population: all participants who had sufficient concentration data to derive at least 1 PK parameter.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Measure Participants	37
Day 1	2.00
Day 22	2.00
Day 22 Subpopulation	2.00

18. Secondary Outcome

Title	Predose Concentration (Ctrough) of Plasma Talazoparib on Day 22
Description	Day 22 subpopulation: amongst the participants with reported pharmacokinetic (PK) parameters on Day 22, exclusion of values from the summary statistics calculations due to dose modifications (eg, dose interruptions, dose reductions) was handled on a case by case basis, resulting in a subpopulation of participants with no prior dose modifications.
Time Frame	Pre-dose, Day 22

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis population: all participants who had sufficient concentration data to derive at least 1 PK parameter.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Measure Participants	37
Day 22	4990 (53)
Day 22 Subpopulation	4950 (56)

19. Secondary Outcome

Title	Apparent Clearance After Oral Dose (CL/F) of Plasma Talazoparib on Day 22
Description	Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood (rate at which a drug is metabolized or eliminated by normal biological processes). Clearance obtained after intravenous infusion dose (apparent clearance) is influenced by the fraction of the dose absorbed. Day 22 subpopulation: amongst the participants with reported pharmacokinetic (PK) parameters on Day 22, exclusion of values from the summary statistics calculations due to dose modifications (eg, dose interruptions, dose reductions) was handled on a case by case basis, resulting in a subpopulation of participants with no prior dose modifications.
Time Frame	Pre-dose, 1, 2, 4, and 6 hours post-dose on Day 22

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis population: all participants who had sufficient concentration data to derive at least 1 PK parameter. Here, number analyzed signifies participants with available date for the specified time point.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Measure Participants	37
Day 22	4.8 (36)
Day 22 Subpopulation	4.8 (37)

20. Secondary Outcome

Title	Accumulation Ratio (Rac) of Plasma Talazoparib on Day 22
Description	Rac was calculated as, area under the curve from time zero to end of dosing interval on Day 22 (AUCtau) divided by area under the curve from time zero to end of dosing interval on Day 1 (AUCtau). Area under the concentration curve from time 0 to end of dosing interval (AUCtau), where dosing interval was 6 hours. Day 22 subpopulation: amongst the participants with reported pharmacokinetic (PK) parameters on Day 22, exclusion of values from the summary statistics calculations due to dose modifications (eg, dose interruptions, dose reductions) was handled on a case by case basis, resulting in a subpopulation of participants with no prior dose modifications.
Time Frame	Pre-dose, 1, 2, 4, and 6 hours post-dose on Day 22

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis population: all participants who had sufficient concentration data to derive at least 1 PK parameter. Here, number analyzed signifies participants with available date for the specified time point.

Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
Measure Participants	37
Day 22	3.96
Day 22 Subpopulation	3.98

Adverse Events

Time Frame	Day 1 to follow-up (30 days post last dose, i.e. up to 52 days)
Arm/Group Title	Talazoparib 1 mg QD
Arm/Group Description	Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.
All Cause Mortality
	Talazoparib 1 mg QD
	Affected / at Risk (%)	# Events
Total	0/37 (0%)
Serious Adverse Events
	Talazoparib 1 mg QD
	Affected / at Risk (%)	# Events
Total	3/37 (8.1%)
Blood and lymphatic system disorders
Anaemia	1/37 (2.7%)
Spontaneous Haemorrhage	1/37 (2.7%)
Gastrointestinal disorders
Large intestinal obstruction	1/37 (2.7%)
Injury, poisoning and procedural complications
Toxicity to various agents	1/37 (2.7%)
Nervous system disorders
Syncope	1/37 (2.7%)
Other (Not Including Serious) Adverse Events
	Talazoparib 1 mg QD
	Affected / at Risk (%)	# Events
Total	23/37 (62.2%)
Blood and lymphatic system disorders
Anaemia	4/37 (10.8%)
Thrombocytopenia	3/37 (8.1%)
Gastrointestinal disorders
Abdominal pain upper	3/37 (8.1%)
Constipation	3/37 (8.1%)
Diarrhoea	5/37 (13.5%)
Nausea	8/37 (21.6%)
Vomiting	4/37 (10.8%)
General disorders
Fatigue	9/37 (24.3%)
Investigations
Platelet count decreased	3/37 (8.1%)
Metabolism and nutrition disorders
Decreased appetite	2/37 (5.4%)
Nervous system disorders
Headache	3/37 (8.1%)
Respiratory, thoracic and mediastinal disorders
Cough	3/37 (8.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.