Ambit drug found effective in Phase I leukemia trial

The Phase I trial is a multi-center, open-label, sequential dose-escalation study that will enroll 20-40 patients with relapsed or refractory acute myeloid leukemia (AML). The preliminary clinical data was based on an AC220 oral solution administered once daily for 14 days followed by a 14 day rest period or immediate continuous dosing. The first two cohorts were reported one at 12 mg/day and the other at 18 mg/day. Dose proportional increases in exposure were seen. Based on 11 patients, no hematological toxicity was observed, and the compound was well absorbed and tolerated. All patients achieved steady plasma levels of the drug within 8-14 days. At the 18 mg dose, trough levels of the drug (free fraction) were several fold greater than the concentration of the compound needed to inhibit the activity of its target, FLT3 kinase, by 50%.

With regard to hematological changes, 3 patients in the 18 mg/day cohort demonstrated improvements. One patient, who remains on AC220, demonstrated a greater than 50% reduction in bone marrow blasts, and one patient demonstrated major platelet-associated hematologic improvement.

In vitro data shows that AC220 has highly selective affinity for several class III RTKs including FLT3, KIT, CSF1R/FMS, RET and PDGFR. With respect to preclinical models of efficacy, in a mouse solid tumor xenograft of a cell line derived from an AML patient, AC220 inhibited tumor growth at 1 mg/kg dosage and caused tumor regression at 3 mg/kg.

Wendell Wierenga, executive vice president of R&D at Ambit, said: “Our kinase screening technology allowed us to optimize AC220 and gave us data on the compound that helped us shape its clinical potential.”