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

: The effect of repeated doses of aflibercept on ventricular repolarization in cancer patients was evaluated in an intensive electrocardiogram trial. This randomized, placebo-controlled, double-blind trial was conducted in 87 treated solid tumor patients. Treatment was with 6 mg/kg aflibercept, 1-hour intravenous (n = 43), or placebo (n = 44), combined with ≤75 mg/m docetaxel, every 3 weeks. Electrocardiograms were collected for 6 hours posttreatment using digital 12-lead Holter recorders, at day 1, in cycles 1 and 3. Free and vascular endothelial growth factor-bound aflibercept concentrations were assessed at similar time points. Eighty-four patients (43 placebo and 41 aflibercept) were evaluable for QT interval, Fridericia correction (QTcF) at cycle 1 and 59 (31 placebo and 28 aflibercept) at cycle 3. During cycle 3, from 30 minutes to 6 hours after the start of aflibercept, the maximum observed upper limit of the QTcF 90% confidence interval was 16 ms, for a mean of 8.4 ms. QTcF prolongation above 480 ms and 60 ms above baseline was observed in 1 aflibercept patient (2%). The slope of the relationship between free aflibercept concentration and QTcF was 0.048 (95% confidence interval, 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.

Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting.

OBJECTIVE: To compare the efficacy and tolerability of dronabinol, ondansetron, or the combination for delayed chemotherapy-induced nausea and vomiting (CINV) in a 5-day, double-blind, placebo-controlled study. RESEARCH DESIGN AND METHODS: Patients receiving moderately to highly emetogenic chemotherapy received dexamethasone (20 mg PO), ondansetron (16 mg IV) and either placebo or dronabinol (2.5 mg) prechemotherapy on day 1. Patients randomized to active treatment (dronabinol and/or ondansetron) also received dronabinol (2.5 mg) after chemotherapy on day 1. On day 2, fixed doses of placebo, dronabinol (10 mg), ondansetron (16 mg), or combination therapy were administered. On days 3-5, patients received placebo, flexible doses of dronabinol (10-20 mg), ondansetron (8-16 mg), or dronabinol and ondansetron (10-20 mg dronabinol, 8-16 mg ondansetron). MAIN OUTCOME MEASURES: Total response (TR = nausea intensity <5 mm on visual analog scale, no vomiting/retching, no rescue antiemetic), nausea (occurrence and intensity) and vomiting/retching episodes. RESULTS: Sixty-four patients were randomized; 61 analyzed for efficacy. TR was similar with dronabinol (54%), ondansetron (58%), and combination therapy (47%) versus placebo (20%). Nausea absence was significantly greater in active treatment groups (dronabinol, 71%; ondansetron, 64%; combination therapy, 53%) versus placebo (15%; p < 0.05 vs. placebo for all). Nausea intensity and vomiting/retching were lowest in patients treated with dronabinol. Active treatments were well tolerated. The low number of patients due to slow enrollment limits the interpretation of these data. CONCLUSIONS: Dronabinol or ondansetron was similarly effective for the treatment of CINV. Combination therapy with dronabinol and ondansetron was not more effective than either agent alone. Active treatments were well tolerated.