Pharmacokinetics (PK) and pharmacodynamics (PD) of midostaurin (PKC412) in patients with acute myeloid leukemia (AML)

7064 Background: Midostaurin (N-benzoylstaurosporin) is a novel potent inhibitor of class III receptor tyrosine kinases, including FLT3 and c-KIT. We evaluated the PK and PD of midostaurin in a phase I/II clinical trial in patients with AML. Methods: Midostaurin was administered at 75 mg tid to 20 patients with FLT3-mutated (FLT3mut) AML. A second cohort of 95 patients with either wild-type (FLT3WT) (n=60) or FLT3mut (n=35) AML was randomized to receive midostaurin at 50 mg bid or 100 mg bid. Plasma concentrations of midostaurin and its two active metabolites (CGP62221 and CGP52421) were determined by an LC-MS-MS method, and peripheral blood blasts were measured to determine PD responses. Patients were classified into PD groups based on their blast responses: (1) stable responders who had at least a ≥50% decrease in blood blasts and did not relapse during the entire treatment period; (2) partial responders who initially showed a ≥50% decrease in blood blasts but later relapsed; (3) non-responders who fail...