A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias

We report the results of a Phase I dose escalation trial of the multikinase inhibitor sorafenib in relapsed/refractory acute leukemias using an intermittent dosing regimen. Fifteen patients with advanced leukemia (Acute myeloid leukemia(AML), 2=Acute lymphoblastic leukemia(ALL), 1 Biphenotypic) and a median age of 63 (range 37–85) years were enrolled and treated on a dose escalation trial. Toxicities ≥grade 3 were present in 55% of cycles and the maximum tolerated dose (MTD) was determined to be 400mg BID × 21days in a 28 day cycle. Plasma inhibitory assays of kinase targets ERK and FLT3-ITD demonstrated excellent target inhibition, with FLT3-ITD silencing occurring below the MTD. The N-oxide metabolite of sorafenib appeared to be a more potent inhibitor of FLT3-ITD than the parent compound. Despite marked ex vivo FLT-3 ITD inhibition, no patients met criteria for complete or partial response in this monotherapy study. Eleven of fifteen patients experienced stable disease as best response. Although sorafenib demonstrated only modest clinical activity as a single agent in this heavily treated population, robust inhibition of FLT3 and ERK suggest there may be a potential important role in combination therapies.