Effect of Futibatinib on Cardiac Repolarization: Results of a Randomized, Controlled, Double‐Blind, QT/QTc, Phase 1 Study in Healthy Subjects

Abstract

Futibatinib, a fibroblast growth factor receptor (FGFR) 1-4 inhibitor, is being investigated for FGFR-aberrant tumors. A 4-period, crossover, phase 1 thorough QT/QTc study compared effects on Fridericia heart rate-corrected QT (QTcF) interval of single doses of futibatinib 20 and 80 mg (therapeutic and supratherapeutic doses, respectively), placebo, and moxifloxacin (positive control) in healthy subjects. The study objective was to assess the time-matched difference in change from baseline in QTcF (ddQTcF) between futibatinib and placebo. In addition, changes from baseline in QTcF and other electrocardiogram (ECG) parameters, pharmacokinetics, ECG morphology, and safety were assessed. Fortyeight subjects were randomized. ddQTcF upper limits of 2-sided 90%CIs remained <10 milliseconds (clinical threshold) for both futibatinib doses at all time points (range, 2.0-4.5 milliseconds). Assay sensitivity was demonstrated by lower limits of 2-sided 97.5%CIs of the dQTcF difference between moxifloxacin and placebo of >5 milliseconds. Futibatinib exposure increased in a dose-dependent manner, and no significant relationship was detected between plasma futibatinib concentration and ddQTcF. There were no significant effects on heart rate, other ECG parameters, or ECG morphology. No serious adverse events occurred. Futibatinib did not prolong QTcF or affect other cardiac measures at therapeutic or supratherapeutic doses.

Evaluation of the Mass Balance and Metabolic Profile of Futibatinib in Healthy Participants

“…Futibatinib 20 mg once daily was identified as the maximum tolerated dose and determined as the recommended Phase II dose. 6 Although the pharmacokinetic properties of futibatinib have been previously reported in Phase I studies, 6,[11][12][13] the metabolite profiling and elimination routes of futibatinib have yet to be characterized. Mass balance studies using 14 C-radiolabeled drugs provided valuable information on the absorption, distribution, metabolism, and excretion of drug candidates.…”