AMN107, a Novel Aminopyrimidine Inhibitor of Bcr-Abl, Has Significant Activity in Imatinib-Resistant Chronic Myeloid Leukemia (CML) or Philadelphia-Chromosome Positive Acute Lymphoid Leukemia (Ph + ALL).

AMN107, a novel aminopyrimidine ATP-competitive inhibitor of Bcr-Abl, is 10-50 fold more potent than imatinib (IM) against Bcr-Abl expressing cell lines, including most IM-resistant Bcr-Abl mutants. In a Phase I study we treated 119 pts w/IM-resistant CML in blast crisis (BC), accelerated phase (AP) or chronic phase (CP), or Ph+ ALL, Median age was 60 (range 15–83) yrs. The study design was based on the two-sample modified continual reassessment method. Initial AMN107 daily doses (mg) were: 50 qd- 7 pts, 100 qd- 7 pts, 200 qd- 10 pts, 400 qd - 10 pts, 600 qd- 6 pts, 800 qd- 19 pts, 1200 qd- 10 pts, 400 bid- 32 pts, and 600 bid- 18 pts. Intra-pts dose escalations occurred in 48/69 pts in the qd cohorts & 1/32 in the 400 bid cohort escalated to 600 bid. As of June 15, 2005, pts have been treated for 1 to 385 (median 120) days. Results for each disease group are in Table 1. AMN107 was well-tolerated. The most common drug-related adverse events were: GI: constipation G1-2 (8%), nausea G1-2 (7%), vomiting G1-2 (3%). Liver & biliary: bilirubin increased G1-2 (8%), G3 (8%), lipase elevations G 1-2 (2%), G3 (4%) G4 (1%), ALT increased G1-2 (2%), G3 (3%). Skin: pruritis G1-2 (13%), G3 (1.7%), dry skin G1-2 (12%), exanthem G1-2 (9%) G3 (1%), rash G1-2 (5%), G3 (1%). Hematologic: thrombocytopenia G3 (9%), G4 (9%), neutropenia G3 (4%), G4 (8%), anemia G1-2 (2%), G3 (4%), bone marrow aplasia (2%). General: fatigue G1-2 (4%), G3 (1%). Other notable drug-related AEs: pancreatitis G2 (2%) and CNS bleed (2%). The regimen estimated to be the MTD was 600 bid; this dose level was associated w/more neutropenia & hyperbilirubinemia. The 400 bid dose was selected for Phase II trials. Among CML pts who harbored a Bcr-Abl mutation prior to treatment, 26/43 (60%) achieved a hematologic response & 14/34 (41%) achieved a cytogenetic response. Among CML pts who had no Bcr-Abl mutation prior to Rx, 31/43 (72%) achieved a hematologic response & 17/29 (59%) achieved a cytogenetic response. Among Ph+ ALL pts who harbored a mutation prior to Rx 2/6 (33%) achieved a response & 0/2 (0%) w/no detectable mutation prior to Rx achieved a response. Pharmacokinetic (PK) studies showed steady-states reached by day 8. Cmax & AUC were dose proportional from 50 to 400 qd but plateaued w/600-1200 qd. Increased exposure was observed w/bid dosing schedules. The apparent half-life was 15 hours. AMN107 has significant activity in advanced IM-resistant CML & Ph+ ALL.