Phase 1 Study to Evaluate the Effect of the Investigational Anticancer Agent Sapanisertib on the QTc Interval in Patients With Advanced Solid Tumors

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).

Keywords: anticancer drugs; arrhythmia; drug safety; modeling and simulation; pharmacokinetics.

Conflict of interest statement

C.P., L.R., and K.V. are employees of Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; C.P. owns stocks of with Takeda Pharmaceuticals International Co.; S.G. received research funding for this trial from Millennium Pharmaceuticals, Inc.; J.W. serves as a paid consultant for this work for Millennium Pharmaceuticals, Inc.; Y.S. was an employee of Millennium Pharmaceuticals, Inc., at the time of this work and owns stocks with Takeda Pharmaceuticals International Co.; and M.P. and A.C.L. declare no conflicts of interest.

© 2020 Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Mean time‐matched changes from baseline in (A) QTcI and (B) QTcF. QT, measure of the time between the start of the Q wave and the end of the T wave in the electrical cycle of the heart; QTcF, rate corrected QT interval with Fridericia correction; QTcI, individual baseline corrected rate‐corrected QT interval; UCB, upper confidence bound.

Figure 2

Mean time‐matched changes from baseline in heart rate. bpm, beats per minute; UCB, upper confidence bound.

Figure 3

Mean (SD) plasma concentration–time profile of sapanisertib (semilogarithmic scale) following administration of a single dose of 40 mg.* SD, standard deviation. *All sapanisertib plasma concentrations that were below the limit of quantitation were set as zero and included in the calculation of mean values.

Figure 4

Relationship of ΔQTcI and ΔQTcF with plasma concentration of sapanisertib. (A) Plot of the linear mixed‐effects model of ΔQTcI vs sapanisertib plasma concentration. Dots represent differences in average QT interval from time‐matched baseline for individual patients at each time point corrected by regression analysis. Solid line and shaded region represent the fitted linear model and associated 95% confidence band, respectively. Dashed vertical reference lines denote the estimated maximum concentration for 4‐, 30‐, and 40‐mg doses of sapanisertib. Dashed horizontal reference lines indicate 10‐ and 20‐msec increases in QTcI. (B) Model‐predicted ΔQTcI as a function of sapanisertib plasma concentration with associated 90% prediction interval. Solid line represents estimated population mean function for ΔQTcI as a function of sapanisertib plasma concentration based on the fitted linear effects model for ΔQTcI, with the 90% prediction interval shaded in gray. Dashed vertical reference lines denote the estimated maximum concentration for 4‐, 30‐, and 40‐mg doses of sapanisertib. Dashed horizontal reference lines indicate 30‐ and 60‐msec increases in QTcI. (C) Plot of the linear mixed‐effects model of ΔQTcF vs sapanisertib plasma concentration. Dots represent differences in average QT interval from time‐matched baseline for individual patients at each time point corrected by regression analysis. Solid line and shaded region represent the fitted linear model and its associated 95% confidence band, respectively. Dashed vertical reference lines denote the estimated maximum concentration for 4‐, 30‐, and 40‐mg doses of sapanisertib. Dashed horizontal reference lines indicate 10‐ and 20‐msec increases in QTcF. (D) Model‐predicted ΔQTcF as a function of sapanisertib plasma concentration with associated 90% prediction interval. Solid line represents estimated population mean function for ΔQTcF as a function of sapanisertib plasma concentration based on the fitted linear effects model for ΔQTcI, with the 90% prediction interval shaded in gray. Dashed vertical reference lines denote the estimated maximum concentration for 4‐, 30‐, and 40‐mg doses of sapanisertib. Dashed horizontal reference lines indicate 30‐ and 60‐msec increases in QTcF. CI, confidence interval; df, degrees of freedom; msec, milliseconds; ΔQTcF, change from time‐matched baseline in QTcF; ΔQTcI, change from time‐matched baseline in QTcI; QT, measure of the time between the start of the Q wave and the end of the T wave in the electrical cycle of the heart; QTc, rate‐corrected QT interval; QTcF, rate‐corrected QT interval with Fridericia correction; QTcI, individual baseline corrected rate‐corrected QT interval; SE, standard error.