Study to Investigate the Effects of Orteronel on the QT/QTc Interval in Patients With Metastatic Castration-Resistant Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this phase 2, open-label, single-arm, multidose, multicenter study is to investigate the effects of Orteronel plus Prednisone on the QT/QTc interval in patients with Metastatic Castration-Resistant Prostrate Cancer

Official Title
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A Phase 2, Open-Label, Single-Arm, Multidose Study to Investigate the Effects of Orteronel on the QT/QTc Interval in Patients With Metastatic Castration-Resistant Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Orteronel+Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary written consent Screening PSA ≥ 2ng/ml Patients must have a diagnosis of mCRPC Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 Prior surgical or medical castration with testosterone at screening < 50 ng/dL Exclusion Criteria: Prior chemotherapy for prostate cancer within 6 months prior to screening. (Any prior therapy with cabazitaxel, mitoxantrone, or anthracyclines is exclusionary.) Documented central nervous system metastases Clinically significant heart disease Patients who have an abnormal 12-lead ECG result at screening including one or more of the following: QRS>110 ms, QTcF>480ms, PR interval>200 ms Patients who have a history of risk factors for TdP including unexplained syncope, known long QT syndrome, heart failure, angina, or clinically significant abnormal laboratory assessments Please note that there are additional inclusion and exclusion criteria. The study center will determine if you meet all of the criteria. Site personnel will explain the trial in detail and answer any question you may have if you do qualify for the study. You can then decide whether or not you wish to participate. If you do not qualify for the trial, site personnel will explain the reasons

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Orteronel+Prednisone<br> | Drug: Orteronel+Prednisone<br>* Orteronel 400-mg plus prednisone 5-mg will be administered BID orally continuously throughout the treatment cycle of the study.<br>* Other names: TAK-700;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Change From Baseline in QTc Interval Based on the Fridericia Correction (QTcF) Method | Triplicate 12-lead electrocardiogram (ECG) measurements (each recording separated by approximately 1 minute) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR). Results of change in QTcF analyzed from 12-lead ECGs performed at each time point were averaged for analysis and a maximum across all post-dosing time points was used. Baseline is defined as the average of the triplicate 12-lead ECG measurements taken at the specified time prior to dosing. | Cycle 1 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose; Cycle 2 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Change From Baseline in QTc Based on the Bazett Correction (QTcB) Method, PR, QRS and Uncorrected QT Interval | Triplicate 12-lead ECG measurements (each recording separated by approximately 1 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Bazette's formula (QTcB = QT divided by square root of RR). Results of change in QTcB, PR, QRS and uncorrected QT analyzed from 12-lead ECGs performed at each time point were averaged for analysis and a maximum across all post-dosing time points was used. Baseline is defined as the average of the triplicate 12-lead ECG measurements taken at the specified time prior to dosing. | Cycle 1 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose; Cycle 2 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose | 
| Changes From Baseline in Heart Rate | Triplicate 12-lead Electrocardiogram (ECG) measurements were performed and average was calculated. Supine heart rate was measured as beats per minute (bpm). Results of change in heart rate analyzed from 12-lead ECGs performed at each time point were averaged for analysis and a maximum across all post-dosing time points was used. Baseline is defined as the average of the triplicate 12-lead ECG measurements taken at the specified time prior to dosing. | Cycle 1 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose; Cycle 2 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose | 
| Number of Participants Reporting Change From Baseline in ECG Morphology | Participants with incidence of ECG morphology abnormalities were observed. Types of abnormalities included appearance of abnormal U waves, T waves inversion, elevation of ST segment, depression of ST segment, second or third degree heart block, right or left bundle branch block, atrial fibrillation/flutter, and myocardial infarction. New morphological changes were observed in abnormal U waves, depression of ST segment, and T waves inversion. Here, 'new' refers to change not present at baseline, ie, at any evaluation predose, and only seen postbaseline. Results of change in ECG morphology analyzed from 12-lead ECGs at each time point were averaged for analysis and a maximum across all post-dosing time points was used. Baseline is defined as the average of the triplicate 12-lead ECG measurements taken at the specified time prior to dosing. | Cycle 1 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose; Cycle 2 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose | 
| Correlation Between the QTcF Change From Baseline and Plasma Concentrations of Orteronel | Coefficient of correlation was measured using linear mixed effects model for the association between two variables; change from baseline versus the plasma concentration. Participant's effects on the intercept and plasma concentration slope were included in the model as random effects terms. Plasma concentrations were re scaled for model convergence. Average results at each time point were analyzed and a maximum across all post-dosing time points was used. Baseline is defined as the average of the triplicate 12-lead ECG measurements taken at the specified time prior to dosing. | Cycle 1 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose; Cycle 2 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose | 
| AUC(0-6): Area Under the Plasma Concentration-Time Curve From Time 0 to 6 Hours Postdose for Orteronel and M-I Metabolite | AUC(0-6) is measure of area under the curve over the dosing interval (tau) (AUC(0-tau]), where tau is the length of the dosing interval - 6 hours in this study). Average results at each time point were analyzed and a maximum across all post-dosing time points was used. Baseline is defined as the average of the triplicate 12-lead ECG measurements taken at the specified time prior to dosing. | Cycle 1 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose; Cycle 2 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose | 
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Orteronel and M-I Metabolite | Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax. Average results at each time point were analyzed and a maximum across all post-dosing time points was used. Baseline is defined as the average of the triplicate 12-lead ECG measurements taken at the specified time prior to dosing. | Cycle 1 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose; Cycle 2 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose | 
| Cmax: Maximum Observed Plasma Concentration for Orteronel and M-I Metabolite | Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. Average results at each time point were analyzed and a maximum across all post-dosing time points was used. Baseline is defined as the average of the triplicate 12-lead ECG measurements taken at the specified time prior to dosing. | Cycle 1 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose; Cycle 2 (28 day cycle), Day 1: pre-dose and at multiple timepoints (up to 6 hours) post-dose | 
| Number of Participants Reporting One or More Treatment-emergent Adverse Events | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. | Baseline up to 30 days after last dose of study drug (Day 86) | 
| Number of Participants Reporting Clinically Significant Abnormalities in Laboratory Values | The number of participants with any clinically significant abnormalities in safety laboratory values collected throughout study. | Baseline up to 30 days after last dose of study drug (Day 86) | 
| Number of Participants Reporting Clinically Significant Abnormalities in Vital Signs | The number of participants with any clinically significant abnormalities in vital signs collected throughout study. Vital signs included body temperature (oral), sitting blood pressure (after the participant has rested for at least 5 minutes), and pulse (bpm). | Baseline up to 30 days after last dose of study drug (Day 86) | 
| Number of Participants Reporting Clinically Significant Abnormalities in Physical Findings | Physical examination consists of examinations of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) physical examinations other than body systems described in (1) to (10). | Baseline up to 30 days after last dose of study drug (Day 86) | 
| Number of Participants Reporting Clinically Significant Abnormalities in ECG | The number of participants who reported clinically significant abnormalities in ECG were measured throughout study. ECGs were performed after the participant had been supine for at least 10 minutes. | Baseline up to 30 days after last dose of study drug (Day 86) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic castrate resistant prostate cancer, mCRPC, orteronel, TAK-700, Phase 2, QT, QTc