Background Futibatinib is an oral selective irreversible FGFR inhibitor with clinical activity in cholangiocarcinoma and other FGFR-deregulated tumors. A phase 1 thorough QT study was conducted to evaluate the effect of futibatinib on the heart rate (HR)-corrected QT (QTc) interval. Methods Healthy nonsmoking adults 18-55 years of age were randomized to receive single doses of each of the following treatments in different sequences: futibatinib (20 or 80 mg [therapeutic and supratherapeutic doses, respectively]), placebo, or moxifloxacin (positive QTc-prolongation control; 400 mg). At least 7 days were allowed between administration of each of the 4 treatments. Administration of futibatinib and placebo was double-blind; that of moxifloxacin was open-label. The primary endpoint was the difference in change from baseline in QTcF (QT interval corrected using Fridericia's formula) between futibatinib and placebo (ddQTcF) at the time points tested. Upper limits of the 2-sided 90% confidence intervals (CIs) of these differences of <10 ms indicated lack of QTc prolongation (per ICH E14 guidance). Secondary endpoints included change from baseline in other electrocardiogram (ECG) parameters, pharmacokinetics (PK), and safety. Results Enrolled participants (N=48) received ≥1 dose of futibatinib, were evaluable for futibatinib PK, and were included in the analysis population. The ddQTcF ranged from 0.13 to 2.47 ms with 20 mg futibatinib and from -0.04 to 2.46 ms with 80 mg futibatinib from 0.5 to 24 h after dosing. Upper limits of the 2-sided 90% CIs of these values remained well below 10 ms (<5 ms) throughout. The lower limits of 2-sided 97.5% CIs of the difference in change from baseline in QTcF between moxifloxacin and placebo all exceeded 5 ms (8.06-11.43 ms) at the time points analyzed (1.5, 2, 3, and 4 h), demonstrating assay sensitivity. No clinically significant effects of futibatinib on HR, other ECG parameters (eg, PR, QRS, or QT intervals), or ECG morphology were identified. Exposure-response modeling indicated no significant relationship between plasma futibatinib concentration and the QTcF interval. The futibatinib area under the concentration curve from time 0 to infinity and maximum plasma concentration (Cmax) increased by 4.5- and 3.3-fold, respectively, after administration of a single dose of 80 vs 20 mg. The Cmax values observed with 80 mg futibatinib (median, 553 ng/mL; range, 71-1160) exceeded any Cmax observed or expected with the 20-mg daily therapeutic dose at steady state. Seven participants (15%) experienced adverse events of any cause after receiving either futibatinib dose, all grade 1/2. Conclusions A single therapeutic or supratherapeutic dose of futibatinib did not prolong the QTc interval or adversely affect other measures of heart function. Futibatinib exposure increased dose-dependently, and administration was safe and well tolerated in healthy participants.

Citation Format: Ikuo Yamamiya, John Laabs, Daryl Sonnichsen, Mark Mina, Yaohua He, Karim Benhadji. Effect of futibatinib on QT/QTc interval: a randomized, controlled, double-blind study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT128.