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

• ClinicalTrials.gov Identifier: NCT03042910
• Recruitment Status: Completed
• First Posted: February 3, 2017
• Results First Posted: December 17, 2019
• Last Update Posted: December 17, 2019
• Sponsor: Pfizer
• Collaborator: Medivation, Inc.
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: December 22, 2016
• First Posted Date: February 3, 2017
• Results First Submitted Date: May 24, 2018
• Results First Posted Date: December 17, 2019
• Last Update Posted Date: December 17, 2019
• Actual Study Start Date: October 13, 2016
• Actual Primary Completion Date: May 30, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 13, 2019)

• Time-matched Mean Change From Baseline in Corrected QT Intervals Based on the Fridericia's Correction Fomulation (QTcF) [ 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 ]
  QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole.
• Intercept of Predicted Linear Mixed Effects Models for Change From Baseline in QTcF Versus Plasma Talazoparib Concentrations at Day 22 [ Time Frame: 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.
• Concentration Slope of Predicted Linear Mixed Effects Models for Change From Baseline in QTcF Versus Plasma Talazoparib Concentrations at Day 22 [ Time Frame: 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.

Original Primary Outcome Measures (submitted: February 1, 2017)

• Time-matched plasma PK concentration [ Time Frame: Baseline and days 1 and 22 ]
• Pharmacokinetic samples will be taken on days 1 and 22. A linear mixed effects modeling approach will be used to examine the relationship between the change from baseline in QTc intervals (QTcF and QTcB) and the plasma concentration of talazoparib. [ Time Frame: Days 1 and 22 ]

Current Secondary Outcome Measures (submitted: December 13, 2019)

• Time-matched Mean Change From Baseline in Corrected QT Intervals Based on the Bazett's Correction Fomulation (QTcB) [ 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 ]
  QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole.
• 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 ]
• Time-matched Mean Change From Baseline in PR Interval [ 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 ]
  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-matched Mean Change From Baseline in QRS Interval [ 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 ]
  QRS interval is the time from electrocardiogram Q wave to the end of the S wave, corresponding to ventricle depolarization.
• Time-matched Mean Change From Baseline in QT Interval [ 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 ]
  QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole.
• Time-matched Mean Change From Baseline in RR Interval [ 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 ]
  RR interval is the time elapsing between two consecutive R waves in the electrocardiogram.
• Number of Participants With Treatment-emergent Abnormalities in 12-lead Electrocardiogram (ECG) Morphpology [ Time Frame: 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.
• Number of Participants With Clinically Significant Findings in 12-lead Electrocardiogram (ECG) Parameters Meeting Predefined Criteria [ Time Frame: 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%.
• Number of Participants With Treatment-emergent Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuation Due to AEs, AEs of Special Interest, and Deaths [ Time Frame: 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.
• Number of Participants With Clinically Notable Changes in Vital Signs Measurements [ Time Frame: 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.
• Number of Participants With Clinically Significant Laboratory Test Abnormalities [ Time Frame: 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.
• 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 [ 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 ]
  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.
• Maximum Plasma Concentration (Cmax) of Plasma Talazoparib on Day 1 and Day 22 [ 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 ]
  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 for Cmax (Tmax) of Plasma Talazoparib on Day 1 and Day 22 [ 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 ]
  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.
• Predose Concentration (Ctrough) of Plasma Talazoparib on Day 22 [ Time Frame: 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.
• Apparent Clearance After Oral Dose (CL/F) of Plasma Talazoparib on Day 22 [ Time Frame: 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.
• Accumulation Ratio (Rac) of Plasma Talazoparib on Day 22 [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: February 1, 2017)

• Safety as assessed by percentage of patients with any Adverse Event (AE), AE leading to Study Drug Discontinuation, AE leading to death, Serious Adverse Event (SAE), AE related to study drug, SAE related to study drug [ Time Frame: Anticipated in about 10 months following first patient enrolled ]
• Time-matched change from baseline in QTc, (measured in milliseconds) corrected for HR based on the Bazett correction method (QTcB) method (∆QTcB) [ Time Frame: Anticipated in about 10 months following first patient enrolled ]
• Maximum Plasma Concentration (Cmax) [ Time Frame: Days 1 and 22 ]
• Area Under the Curve (AUC) [ Time Frame: Days 1 and 22 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Assess the Effects of Talazoparib on Cardiac Repolarization in Patients With Advanced Solid Tumors
• Official Title: A PHASE 1, OPEN-LABEL STUDY TO ASSESS THE EFFECTS OF TALAZOPARIB ON CARDIAC REPOLARIZATION IN PATIENTS WITH ADVANCED SOLID TUMORS
• 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.
• 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 Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Solid Tumor

Intervention

Drug: Talazoparib

Talazoparib 1 mg orally once daily.

Other Names:

• MDV3800
• BMN673

Study Arms

Experimental: Patients with advanced solid tumors

Talazoparib 1 mg daily

Intervention: Drug: Talazoparib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 26, 2018): 38
• Original Estimated Enrollment (submitted: February 1, 2017): 30
• Actual Study Completion Date: June 22, 2017
• Actual Primary Completion Date: May 30, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03042910
• Other Study ID Numbers: MDV3800-14; C3441005 ( Other Identifier: Alias Study Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

• Responsible Party: Pfizer
• Study Sponsor: Pfizer
• Collaborators: Medivation, Inc.

Investigators

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

• PRS Account: Pfizer
• Verification Date: December 2019