Abstract #2335: AC220, a uniquely potent and selective FLT3 inhibitor, provides sustained protection in a FLT3 ITD driven model of acute myeloid leukemia
Authors: Barbara Belli, Daniel Brigham, Michael Breider, Shripad Bhagwat, Robert Armstrong
Journal: Cancer Research (2009)

Activating mutations in the receptor tyrosine kinase FLT3 are present in up to 30% of acute myeloid leukemia (AML) patients, implicating FLT3 as a potential target for kinase inhibitor therapy. The efficacy of AC220, a potent and selective FLT3 inhibitor, was determined in a SCID mouse model where intravenously inoculated FLT3-ITD-dependent MV4-11 cells disseminate to the bone marrow, comparing a 30 day dosing regimen to continuous dosing. In the vehicle control group, median survival time following inoculation was 47 days, with mortality preceded by clinical signs of disease and detection of MV4-11 cells in the blood. No specific clinical signs or body weight loss were attributed to the study drug .  AC220 demonstrated dose-dependent efficacy from 0.1 mg/kg to 10 mg/kg orally once per day for 30 days. The 0.1 mg/kg group had a marginal (10%) increase in life span (ILS) relative to vehicle control, while a significant increase of survival was observed at the 1.0 mg/kg dose (55% ILS). The 10 mg/kg dose led to 80% survival of the animals at day 172 when the study was terminated (>250% ILS). Prolonged survival with AC220 correlated with delayed disease onset as measured by clinical signs and detection of circulating MV4-11 cells. Continuous dosing in the 1.0 mg/kg group further delayed disease onset and mortality with an ILS of 155% relative to vehicle, and 63% relative to 30-day dosing. Continuous dosing with 10 mg/kg AC220 provided similar benefit to the 30 day dosing paradigm. A 28 day dosing study was conducted to examine the relationship between bone marrow engraftment, tumor burden in peripheral blood and disease onset. At day 20, engraftment was detected only in the bone marrow. At day 35, when clinical signs of disease are typically apparent, levels of tumor cells as high as 80% and 35% were detected in the bone marrow and peripheral blood respectively. AC220 dosed at 1.0mg/kg delayed median onset of disease by 24 days (63%), with tumor burden undetectable in the absence of clinical signs of disease. AC220 dosed at 10.0mg/kg completely inhibited disease onset, with minimal tumor burden detected in either blood or bone marrow in only 1 of 8 animals through the end of the study (terminated on day 130, >200% ILS). Anti-leukemic effects of traditional chemotherapy are commonly accompanied by significant myelosuppression. Although 30-day and continuous dosing of AC220 suppressed myeloid leukemic cell counts at all doses, there was no generalized myelosuppression at the 1 mg/kg dose as indicated by absolute neutrophil counts. Continuous 10 mg/kg dosing led to approximately a 2-fold reduction in neutrophils. These data correlate with observations in an MV4-11 solid tumor model where AC220 showed substantial and dose dependent efficacy when dosed orally once a day for 28 days (Cortes  et al .: Blood 2007). AC220 is currently under evaluation in a phase I clinical trial in relapsed or refractory AML patients.     Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2335.