Antineoplastic Agents

All Drugs and Chemicals

Talazoparib

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

Pfizer CT.gov Call Center

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.

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.

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

A PHASE 1, OPEN-LABEL STUDY TO ASSESS THE EFFECTS OF TALAZOPARIB ON CARDIAC REPOLARIZATION IN PATIENTS WITH ADVANCED SOLID TUMORS

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.

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

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.

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.

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.

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

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

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.

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%.

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.

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.

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.

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.

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.

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.

Medivation, Inc.

Pfizer

Talazoparib capsule was administered orally at 1 mg once daily (QD) for up to 22 days.

Talazoparib 1 mg QD

Mean Age

Age, Continuous

Sex: Female, Male

American Indian or Alaska Native

Black or African American

Native Hawaiian or other Pacific Islander

Other

White

Race/Ethnicity, Customized

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

Pfizer ClinicalTrials.gov Call Center

Day 1, 1 hour

Day 1, 2 hours

Day 1, 4 hours

Day 1, 6 hours

Day 2, pre-dose

Day 22, pre-dose

Day 22, 1 hour

Day 22, 2 hours

Day 22, 4 hours

Day 22, 6 hours

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.

Time-matched Mean Change From Baseline in Corrected QT Intervals Based on the Fridericia's Correction Fomulation (QTcF)

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.

Intercept of Predicted Linear Mixed Effects Models for Change From Baseline in QTcF Versus Plasma Talazoparib Concentrations at Day 22

Concentration Slope of Predicted Linear Mixed Effects Models for Change From Baseline in QTcF Versus Plasma Talazoparib Concentrations at Day 22

Time-matched Mean Change From Baseline in Corrected QT Intervals Based on the Bazett's Correction Fomulation (QTcB)

Time-matched Mean Change From Baseline in Heart Rate

Time-matched Mean Change From Baseline in PR Interval

Time-matched Mean Change From Baseline in QRS Interval

Time-matched Mean Change From Baseline in QT Interval

Time-matched Mean Change From Baseline in RR Interval

Number of Participants With Treatment-emergent Abnormalities in 12-lead Electrocardiogram (ECG) Morphpology

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 QTcB increase <=30 msec

Maximum QTcB increase: 30 to <=60 msec

Maximum QTcB 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%

Maximum heart rate decrease <50 bpm and >25%

Number of Participants With Clinically Significant Findings in 12-lead Electrocardiogram (ECG) Parameters Meeting Predefined Criteria

AEs related to study drug

SAEs

SAEs related to study drug

Discontinuations due to AEs

Deaths

AEs of special interest

Number of Participants With Treatment-emergent Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuation Due to AEs, AEs of Special Interest, and Deaths

High SBP (>=155 mmHg with increase >=30 mmHg)

Low SBP (<=90 mmHg with decrease >=20 mmHg)

Both high and low SBP

High 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

Oral body temperature <=35 degree

Number of Participants With Clinically Notable Changes in Vital Signs Measurements

Number of Participants With Clinically Significant Laboratory Test Abnormalities

Day 1

Day 22

Day 22 Subpopulation

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.

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

Maximum Plasma Concentration (Cmax) of Plasma Talazoparib on Day 1 and Day 22

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

Spots Global Cancer Trial Database for A Study to Assess the Effects of Talazoparib on Cardiac Repolarization in Patients With Advanced Solid Tumors

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

Useful links and downloads for this trial