LAUSR

PurposeTo evaluate the effect of lapatinib on the QTc interval and ECG parameters in patients with advanced solid tumors.MethodsThis was a multicenter, placebo-controlled study in subjects with advanced solid tumors. Subjects were administered two doses of matching placebo on day 1, 12 h apart and one dose in the morning on day 2. Two doses of lapatinib 2000 mg were administered orally on day 3, 12 h apart and one dose in the morning on day 4. Twelve-lead digital ECGs were extracted from continuous Holter recordings at pre-specified time points over the 24-h period on days 2 and 4. Venous blood samples for lapatinib concentrations were obtained immediately following the ECGs.ResultsA maximum mean baseline-adjusted, placebo time-matched increase in QTcF, (ddQTcF) in the evaluable, (EV) population (n = 37) of 8.8 ms (90% CI 4.1, 13.4) occurred approximately 10 h after the third lapatinib dose. These results were consistent with those in the pharmacodynamic, PD population, (n = 52) (ddQTcF = 7.9 ms; 90% CI 4.1, 11.7). No subject experienced QTcF increases from baseline of > 60 ms on lapatinib or placebo. The geometric mean lapatinib Cmax of 3902 ng/mL was observed at 3.6 h post-dose.ConclusionsThese data show a relevant, treatment-related increase in QTcF after treatment with three doses of lapatinib 2000 mg. This study confirms the need for caution in patients with solid tumors treated with lapatinib, and who are concomitantly receiving drugs that are strong CYP3A inhibitors and/or prolong the QTc.