A phase II study of AMN107, a novel inhibitor of Bcr-Abl, administered to imatinib resistant and intolerant patients (pts) with chronic myelogenous leukemia (CML) in chronic phase (CP).

6534 Background: AMN107 is a potent, highly selective, aminopyrimidine inhibitor which in vitro is 30-fold more potent than imatinib and active against 32/33 imatinib resistant Bcr-Abl mutations.,This open-label study was designed to evaluate the safety and efficacy of AMN107 (400 mg bid) defined by hematologic/cytogenetic response (HR/CyR) rates in imatinib resistant or intolerant CP pts.,For this study which remains open to enrollment, preliminary data are reported for 67 pts including 39 (58%) with imatinib-resistant and 27 (40%) imatinib-intolerant CML (1 pt unknown). The median age was 62 (range 31-80) yrs and the median time from first diagnosis to treatment was 52 (range 5-279) mos. BCR-ABL mutations associated with imatinib resistance were detected in 11/17 (65%) pts at baseline. The median duration of AMN107 exposure was 129 (range 3-225) days. Treatment is ongoing for 50 (75%) pts with 17 (25%) pts discontinued (9 adverse events, 2 disease progression, 6 other). Major CyR was observed in 13 (19%) pts (6 complete, 7 partial), minor CyR was observed in 4 (17%) pts, and minimal CyR in 5 (7%) pts. Complete HR was reported in 35 of 42 (83%) pts without a baseline CHR. AE's in ≥ 10% of pts were headache in 24 (36%) pts, fatigue in 21 (31%) pts (Gr 3/4 in 2 (3%)), pruritus in 19 (28.4%) pts (Gr 3/4 in 1 (2%)), rash in 18 (27%) pts (Gr 3/4 in 2 (3%)), nausea in 18 (27%) pts, diarrhea in 18 (27%) pts (Gr 3/4 in 1 (2%)), constipation in 11 (16%) pts, vomiting in 10 (15%) pts, thrombocytopenia in 10 (15%) pts (Gr 3/4 in 9 (13%)), anemia in 10 (14.9%) pts (Gr 3/4, 1 (2%)), neutropenia in 9 (13%) pts (Gr 3/4 in 8 (12%)), bone pain, muscle spasms, arthralgia, peripheral edema in 8 (12%) pts each, abdominal pain and myalgia in 7 (10%) pts each (Gr 3/4 in 1 (2%) each), and dyspnea in 7 (10%) pts. No deaths occurred.,AMN107 has clinical activity and an acceptable safety and tolerability in pts with imatinib-resistant or intolerant CML-CP. [Table: see text].