Midostaurin does not prolong cardiac repolarization defined in a thorough electrocardiogram trial in healthy volunteers

Abstract

Purpose: Midostaurin (PKC412) is a multitargeted tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 receptor (FLT3), c-KIT, and other receptors. Midostaurin is active in patients with acute myeloid leukemia and systemic mastocytosis. Although no substantive risk for cardiac abnormalities has been observed with midostaurin in clinical studies thus far, some TKIs have been shown to affect cardiac repolarization. Here we evaluated midostaurin's effect on cardiac repolarization.

Methods: This phase I study evaluated the effect of midostaurin (75 mg twice daily for 2 days; 75 mg once on day 3) on the heart rate-corrected QT (QTc) interval in a parallel design with active (moxifloxacin) and placebo control arms in healthy volunteers.

Results: The maximum mean QTc change from baseline corrected using Fridericia's correction (QTcF) for midostaurin compared with placebo was 0.7 ms at 24 h post dose on day 3. The highest upper bound of the 1-sided 95% CI was 4.7 ms, which excluded 10 ms, demonstrating a lack of QTcF prolongation effect. Assay sensitivity was demonstrated by modeling the moxifloxacin plasma concentration versus QTcF change from baseline, which showed a clear positive increase in QTcF with increasing moxifloxacin plasma concentrations, as expected based on previous studies. In the 4-day evaluation period, a minority of participants (34.6%) experienced an adverse event; 97.0% were grade 1. No grade 3 or 4 adverse events were reported.

Conclusion: Midostaurin demonstrated a good safety profile in healthy volunteers, with no prolonged cardiac repolarization or other changes on the electrocardiogram.

Fig. 1

Study drug administration per treatment arm

Fig. 2

Estimated mean change (95% 1-sided CI boundaries indicated by bars) from time-matched baseline in heart rate–corrected QT intervals using Fridericia’s correction (QTcF) on day 3 compared with placebo (electrocardiogram data set). QTcF, heart rate–corrected QT interval corrected using Fridericia’s correction

Fig. 3

Plasma concentrations of midostaurin (a) and moxifloxacin (b) versus change from time-matched baseline in heart rate–corrected QT intervals using Fridericia’s correction (QTcF) on day 3 (electrocardiogram data set). The line represents the fixed effect of the fitted concentration–QTcF model. CI, confidence interval; C_max, maximum plasma concentration; QTcF, heart rate–corrected QT interval corrected using Fridericia’s correction

Fig. 4

Mean (standard deviation indicated by bars) concentration–time profiles for midostaurin on day 1 (a) and day 3 (b) and for moxifloxacin on day 3 (c)