Abstract C116: Lenvatinib (E7080) does not prolong the QTc interval: Results from a thorough QT study in healthy volunteers.

Abstract

Abstract Lenvatinib is an orally administered, tyrosine kinase inhibitor targeting VEGFR1–3, FGFR1–4, PDGFRβ, RET, and KIT, which is currently being studied in patients with solid tumors in doses of 24 mg daily. A previous study in patients with solid tumors treated continuously with 25 mg QD, suggested that Lenvatinib had little or no effect on the QTc interval (mean change-from-baseline QTcF [ΔQTcF] of 2.4 ms). This thorough QT study was conducted to exclude a QTc effect of concern in preparation for phase 3 development. Methods: The effect of Lenvatinib on the QTc interval and on other ECG parameters was studied in 52 healthy male and female volunteers in a randomized, partially double-blinded, 3-way crossover study. The effect of a single dose of 32 mg Lenvatinib on ECG parameters was assessed and the study's ability to detect a small QTc effect was tested by the inclusion of a positive control, moxifloxacin. Using 12-lead continuous ECG recordings, up to 10 ECGs were collected at each predefined time point before and after dosing. Measurements were performed with the High Precision QT (HAQT) measurement technique. Results: The mean placebo-corrected change from baseline QTcF (ΔΔQTcF) was negative at most timepoints post-dosing and the upper bound of the 90% confidence interval did not exceed 10 ms at any timepoint. Concentration effect modeling (CEM) demonstrated a negative slope of −0.0045 ms/ng/mL with an intercept of −2.96 ms. At the observed geometric mean peak Lenvatinib plasma concentration (370 ng/mL; 90% CI 332 to 412), the predicted ΔΔQTcF was −4.62 ms (90% CI: −5.86 to −3.38), which is consistent with the time matched analysis. Based on CEM, it can also be shown that the ΔΔQTcF effect at plasma concentration up to levels observed in patients with impaired clearance of the drug will not exceed 10 ms. Moxifloxacin prolonged ΔΔQTcF with a peak effect of 12.6 ms and the lower bound of the 90% confidence interval (CI) exceeded 5 ms at all 4 pre-specified timepoints, thereby demonstrating the study's ability to detect a small QT effect. The precision of the QTc measurement using High Precision QT was very high with a standard deviation of ΔQTcF across treatments of 5.85 ms. No effect of Lenvatinib on the PR and QRS intervals or on T-wave morphology was observed. Lenvatinib seemed to exert a mild heart rate lowering effect of 3 to 8 beats per minute, without correlation to the peak plasma levels. The incidence of treatment emergent AEs (TEAEs) in subjects who received Lenvatinib was similar to that observed in subjects who received moxifloxacin or placebo. Most TEAEs were mild in severity. No severe AEs were observed in this study. Conclusion: In this Phase I thorough QTc study in healthy subjects, at clinically relevant plasma concentrations, Lenvatinib did not prolong the QTc interval and had no other clinically relevant ECG effects. A single dose of 32 mg Lenvatinib was safe and well tolerated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C116.