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 BID x 21 days per month. Grade 3 or greater toxicities were experienced in 55% of cycles, most common grade 3 or greater toxicities being fatigue (16%) and hypokalemia (13%). No patients met criteria for complete or partial response, but 11 of 15 (73%) patients experienced stable disease as best response, with 6 showing a reduction in bone marrow blasts after only one cycle, half of who experienced a >50% reduction in bone marrow blasts. Interestingly, 2 pts with FLT3-ITD mutations both showed marrow blast response (1 pt >50%). Sorafenib resulted in sustained complete inhibition of FLT3 and Erk as demonstrated in all patients assessed (n = 11). Importantly, this inhibition was maintained throughout treatment cycle and 3/5 pts had FLT3 inhibitory activity 7 days post their last dose. Correlative studies suggest sorafenib N-oxide is an active metabolite. CONCLUSIONS Sorafenib is a potent inhibitor of FLT3 with favorable PK and PD properties. Clinical activity as a single agent was limited to transient reductions in bone marrow blast counts and dose escalation was limited due to toxicities. Based on PK data in conjunction with standard curves for inhibition of FLT3 by sorafenib in plasma, the minimum FLT3 inhibitory dose of sorafenib is likely less than 400 mg BID. No significant financial relationships to disclose.