Phase I dose escalation trial of sorafenib as a single agent for adults with relapsed and refractory acute leukemias

7065 Background: Sorafenib is a multikinase inhibitor with activity against B-raf, VEGF, and FLT3. Based on preclinical activity in FLT3 mutant AML, sorafenib was studied in refractory acute leukemia. Methods: The primary objective was to determine the safety and tolerability of sorafenib in refractory acute leukemias. Secondary objectives included pharmacokinetics (PK) and pharmacodynamic (PD) effects of sorafenib on FLT3 phosphorylation. Dose escalation began at 400 mg BIDx14days per month, and proceeded through 600 mg BID x 21 days per month. Plasma concentration of sorafenib and its primary metabolite sorafenib N-oxide were measured by LC/MS//MS method. The plasma inhibitory assay was used to measure target inhibition of phosphorylated FLT3 and phosphorylated Erk. Results: Fifteen patients (13 = AML, 2 = ALL) were enrolled (ages 37–85) and treated on three dosing schedules (400 mg BID x 14 d, 400 mg BID x 21 days, 600 mg BID x 21days) of single agent sorafenib. The maximally tolerated dose was 400 mg ...