Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics.

摘要: Tandutinib (MLN518/CT53518) is a novel quinazoline-based inhibitor of the type III receptor tyrosine kinases: FMS-like kinase 3 (FLT3), platelet-derived growth factor (PDGFR), and KIT. Because correlation between FLT3 internal tandem duplication (ITD) mutations poor prognosis in acute myelogenous leukemia (AML), we conducted phase 1 trial tandutinib 40 patients with either AML or high-risk myelodysplastic syndrome (MDS). was given orally doses ranging from 50 mg to 700 twice daily The principal dose-limiting toxicity (DLT) reversible generalized muscular weakness, fatigue, both, occurring at 525 daily. Tandutinib's pharmacokinetics were characterized by slow elimination, achievement steady-state plasma concentrations requiring greater than week dosing. Western blotting showed that inhibited phosphorylation circulating leukemic blasts. Eight had FLT3-ITD mutations; 5 these evaluable for assessment tandutinib's antileukemic effect. Two patients, treated daily, evidence activity, decreases both peripheral bone marrow MTD (525 daily) should be evaluated more extensively better define its activity.