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
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
50
Orteronel 400-mg plus prednisone 5-mg will be administered BID orally continuously throughout the treatment cycle of the study.
Pinnacle Oncology
Scottsdale, Arizona, United States
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.
Time frame: 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
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.
Time frame: 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.
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Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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).
Time frame: 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.
Time frame: Baseline up to 30 days after last dose of study drug (Day 86)