A Phase I Dose Escalation Study of KW-2449, an Oral Multi-Kinase Inhibitor Against FLT3, Abl, FGFR1 and Aurora in Patients with Relapsed/Refractory AML, Treatment Resistant/Intolerant CML, ALL and MDS.
Authors: Cortes Jorge , Roboz Gail J. , Kantarjian Hagop , Feldman Eric , Karp Judy , Pollack Allyson , Sandy Katrina , Rao Niranjan , Akinaga Shiro , Levis Mark 
Published: November 2019

Abstract
Background: Activating mutations of FMS-like tyrosine kinase 3 (FLT3) occur in 30% of patients (pts) with de novo AML and confer a worse prognosis. KW-2449 is an oral multi-kinase inhibitor highly potent against mutant FLT3 (IC50= 1–7 nmol/L) and other tyrosine kinases including FGFR1, TrkA, Abl (including T315I), JAK2, c-KIT, and c-SRC and Aurora A serine tyrosine kinase. Based on the anti-leukemia activity of KW-2449 demonstrated both in vitro and in vivo preclinical leukemia models, KW-2449 is being evaluated in hematologic conditions in the first-in-man study.
Methods: The study objectives were to assess the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic effects of KW-2449 in pts with refractory/relapsed AML or treatment resistant/intolerant CML/ALL and MDS. A range of daily doses of KW-2449 (25–500 mg/day) divided into q 12h dosing on 2 treatment schedules (14 days vs. 28 days) with a recovery period of 7–28 days between cycles. Dose limiting toxicity (DLT) and maximally tolerated dose were assessed for the 1st cycle. Serial samples for PK analysis were collected immediately before and after KW-2449 on treatment days 1, 14 and 28. The 28-day schedule was later eliminated. Plasma concentrations of KW-2449 and its active metabolite (M1) were analyzed by LC-MS/MS. A plasma inhibitory activity (PIA) assay [Blood 108(10) 3477–83] for P-FLT3 and P-STAT5 was used to measure FLT3 inhibition.
Results: To date, 29 pts (15 female) have been enrolled (median age 60 years; range 25–82) and treated at 5 dose levels: 25, 50, 100, 200, and 300 mg daily. Twenty-five pts had AML and 4 CML (3 with T315I mutation); 24 pts completed at least 1 cycle. KW-2449 was rapidly absorbed and metabolized to M1. Elimination half-lives were 2.8–3.9 h for KW-2449 and 3.8–5.5 h for M1. Plasma levels of M1 were lower on Days 14 and 28 compared to Day 1, suggesting inhibition of this pathway upon multiple dosing. A single DLT of grade 3 pneumonia was reported on 100 mg but no further DLTs were seen in the expanded cohort at that dose or at 200 or 300 mg daily. A total of 33 SAEs were reported of which 6 were considered possibly related (by the Investigator) to KW-2449: dyspnea, pneumonia, atrial fibrillation, cardiac ischemia, ventricular arrhythmia, and pleural effusion. There have been 5 deaths on study (none drug-related): disease progression (2), neutropenic sepsis, infection with renal failure, and pneumonia. Seven pts had stable disease after 1 cycle. Three pts with AML (2 FLT3+) had ≥ 50% reduction in peripheral and/or bone marrow blasts in the 1st cycle. In vivo FLT3 inhibition, as measured directly in patient blasts, correlated with blast reduction. The extent and duration of FLT3 inhibition increased with increases in dose.
Conclusions: KW-2449 appears safe and well tolerated at the dose levels evaluated. Transient decreases in peripheral blood and bone marrow blasts have been observed in a few patients justifying continued investigation with this agent. Accrual is ongoing and a different schedule to accommodate the short t1/2 will be explored.