A randomized, double blind, placebo-controlled study to assess QTc interval prolongation of standard dose aflibercept in cancer patients treated with docetaxel

ABSTRACT: The effect of repeated doses of aflibercept on ventricular repolarization in cancer patients was evaluated in an intensive ECG trial. This randomized, placebo-controlled, double blind trial was conducted in 87 treated solid tumor patients. Treatment was with aflibercept 6 mg/kg, 1-hr IV (n=43) or placebo (n=44), combined with docetaxel ≤75 mg/m, q3 weeks. ECGs were collected for 6 hours post-treatment using digital 12-lead Holter recorders, at day 1, in Cycles 1 and 3. Free and VEGF-bound aflibercept concentrations were assessed at similar time points. Eighty-four patients (43 placebo, 41 aflibercept) were evaluable for QTcF at Cycle 1 and 59 (31 placebo, 28 aflibercept) at Cycle 3. During Cycle 3, from 30 min to 6 hours after the start of aflibercept, the maximum observed upper limit of the QTcF 90%CI was 16 ms, for a mean of 8.4 ms. QTcF prolongation above 480 ms and 60 ms above baseline was observed in one aflibercept patient (2%). The slope of the relationship between free aflibercept concentration and QTcF was 0.048 (95%CI, 0.013 - 0.082), corresponding to a 5 ms increase per 100 µg/mL increase in concentration. These results exclude a clinically important effect of aflibercept on ventricular repolarization.