A phase II study of AMN107, a novel inhibitor of Bcr-Abl, administered to imatinib-resistant or intolerant patients (pts) with Ph+ chronic myelogenous leukemia (CML) in blast crisis (BC) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL)

Abstract

6536 Background: AMN107 is a highly selective, aminopyrimidine which is 30-fold more potent in vitro than imatinib and active against 32/33 imatinib resistant Bcr-Abl mutations. Methods: This open-label study evaluated safety and efficacy of AMN107 (400 mg bid) by hematologic/cytogenetic response (HR/CyR) rates in imatinib resistant/ intolerant BC or relapsed/refractory ALL pts. Results: Preliminary data from this ongoing study are presented for 18 BC and 6 ALL (5 relapsed/refractory, 1 minimal residual disease) pts. Baseline mutation data are available for 6 BC and 2 ALL pts: 2 and 1, respectively, had Bcr-Abl mutations. The overall median age was 54 yrs and the overall median exposure was 84 days. Seven patients remain on treatment (5 BC, 2 ALL) and 17 discontinued (3 adverse events, 9 progressive disease (PD), 3 deaths, 2 other). Two BC pts died of PD. 1 ALL pt had sudden cardiac death. HR was reported in 7 (38%) BC pts; 5 complete HR and 2 marrow responses/no evidence of leukemia. 3 BC pts had CyR (2 complete, 1 minor). Complete remission was reported in 2 (33%) ALL (1 relapsed/refractory and 1 MRD) pts. Adverse events in ≥ 10% were rash in 9 (37%) pts, thrombocytopenia in 8 (33%) pts (Gr 3/4 in 7 (29%), nausea in 7 (29%) pts, pyrexia in 7 (29%) pts (Gr 3/4 in 2 (8%)); vomiting in 7 (29%) pts (Gr 3/4 in 1 (4%), diarrhea, fatigue in 6 (25%) pts each, headache in 6 (25%) pts (Gr 3/4 in 1 (4%)), neutropenia in 6 (25%) pts (all Gr 3/4), anemia in 5 (21%) pts (Gr 3/4 in 4 (17%)), pain in extremity in 5 (21%) pts (Gr 3/4 in 1 (4%)), pain, peripheral edema in 4 (17%) pts each, pruritus in 4 (17%) pts (Gr 3/4 in 1 (4%)), leukocytosis in 3 (13%) pts (Gr 3/4 in 1 (4%)), arthralgia, pharyngolaryngeal pain, and upper abdominal pain 3 (13%) each. Conclusions: AMN107 has clinical activity and an acceptable safety and tolerability profile in pts with imatinib-resistant or intolerant BC and relapsed/refractory Ph+ ALL pts [Table: see text]