Abstract
The aim of this phase 1 study was to determine the effects of sapanisertib on the heart rate–corrected QT (QTc) interval in patients with advanced solid tumors. Adult patients with advanced solid tumors were enrolled to receive a single sapanisertib 40‐mg dose. Blood samples for pharmacokinetic analysis were collected and electrocardiogram readings were recorded at baseline and up to 48 hours after dosing. Patients could continue to receive sapanisertib 30 mg once weekly in 28‐day cycles for up to 12 months. The primary objective was to characterize the effect of a single dose of sapanisertib (40 mg) on the QT interval. Secondary objectives were to evaluate safety, tolerability, and pharmacokinetics. Following a single sapanisertib 40‐mg dose in 44 patients, the maximum least squares mean (upper bound of 1‐sided 95% confidence interval) changes from time‐matched baseline were 7.1 milliseconds (11.4 milliseconds) for individual rate‐corrected QT interval at 24 hours after dosing, and 1.8 milliseconds (5.6 milliseconds) for Fridericia‐corrected QTc at 1 hour post‐dose. There was no sapanisertib plasma concentration‐dependent increase in the change from time‐matched baseline individual rate‐corrected QTc interval or Fridericia‐corrected QTc. The most common adverse events following sapanisertib 30 mg once‐weekly dosing were nausea (80%), fatigue (61%), vomiting (57%), and decreased appetite (45%). A single sapanisertib 40 mg dose did not produce clinically relevant effects on QTc interval in patients with advanced solid tumors. The safety profile of sapanisertib 30 mg once weekly was favorable, and no new safety signals were observed (NCT02197572, clinicaltrials.gov).
Highlights
Assessment of the potential of an investigational agent to cause delayed ventricular repolarization as a biomarker for ventricular tachycardia is an essential component of new drug development
Prolongation of the QT interval associated with polymorphic ventricular tachycardia represents one of the more commonly reported toxicities that have resulted in the withdrawal or restricted use of postmarket approved drugs.[1]
This open-label, single-arm, phase 1 study was conducted in compliance with the institutional review board (IRB) regulations stated in Title 21 of the United States Code of Federal Regulations (US CFR), Part 56; the study protocol and other study-related documents were approved by the following local or central IRB or independent ethics committees at all study sites: Biomedical Research Alliance of New York, LLC, Lake Success, New York; Washington University School of Medicine Human Research Protection Office, St
Summary
Assessment of the potential of an investigational agent to cause delayed ventricular repolarization as a biomarker for ventricular tachycardia is an essential component of new drug development. Drugs that cause delayed ventricular repolarization (QT interval/heart rate–corrected QT interval [QTc] prolongation) pose an increased risk for ventricular tachycardia and sudden cardiac death.[1,2]. Assessment of risk for QT/QTc prolongation is recommended for drugs in clinical development and, as per the International Conference on Harmonization (ICH) guidance, needs to be evaluated rigorously in a wellcontrolled, thorough QT/QTc (TQT) study. While some inhibition of transport proteins has been observed in vitro (breast cancer- resistance protein half maximal inhibitory concentration [IC50], 51.9 mM; organic cation transporter 1 IC50, 18.9-27.6 mM; organic cation transporter 2 IC50, 1.9 mM; Takeda data on file), plasma concentrations of sapanisertib at its highest clinical dose of 30 mg administered once weekly were not expected to reach concentrations that would inhibit these transporters. No clinical PK drug-drug interaction studies have been conducted with sapanisertib
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