Activity of AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, in imatinib-resistant bcr-abl positive lymphoid malignancies

Abstract

3015 Background: AMN107, a novel aminopyrimidine ATP-competitive inhibitor of Bcr-Abl. AMN107, is 10- to 50-fold more potent than imatinib against Bcr-Abl expressing cell lines, and is effective against most cell lines expressing imatinib-resistant Bcr-Abl mutants. In two p190-Bcr-Abl ALL cell lines, AMN107 was 30–40 times more potent than imatinib in inhibiting cellular proliferation and in inhibiting phosphorylation of p190 Bcr-Abl tyrosine kinase in cell lines and primary ALL cells. Methods: In an ongoing phase I study, AMN107 was given orally, once or twice daily dosing schedule. Results: Fifteen of 67 total pts entered had lymphoid disease: lymphoid blastic phase CML (CML LBP) 7 pts; Ph+ acute lymphocytic leukemia (Ph+ ALL) 8 patients. Median age was 53 years (range 28–80). AMN doses were: QD dose cohorts (mg/day); 50 (1 pt), 100 (2 pts), 200 (3 pts), 400 (1 pt), 600 (2 pts), 800 (4 pts), 1200 (1 pt); BID dose cohort; 400 mg BID (1 pt). Pts have been treated for 15 to 89 days. In the overall cohort, possible AMN-related Grade 3 or 4 hematologic adverse events were observed in 5/67 patients (3 responded) at doses ≥ 200 mg: Possible AMN-related non-hematologic Grade 3/4 events were: 600 mg, G3 skin rash (1 pt); ≥ 800 mg, G3 SGOT and/or SGPT elevations (2 pts), G3 indirect hyperbilirubinemia (2 pts), and at 1200 mg, G2 pancreatitis (1 pt). Clinical activity has been observed in 5 of the 14 with lymphoid disease treated with doses of ≥ 600 mg: hematological improvement (1 pt, Ph+ ALL), peripheral responses (2 pts, LBP), and bone marrow responses (marrow response/no evidence of leukemia, 2 pts, LBP) 1 pt with LBP had a cytogenetic CR. Mutational data are available for 3 of the responding patients: Y253H (hematologic improvement), T315I (peripheral response), and E355G (marrow response). Pharmacokinetic (PK) studies showed steady state was generally reached by day 8. Both Cmax and AUC were dose proportional from 50 to 400 mg with a median Tmax of 3 hours. The apparent half-life was 16 hours. Conclusions: AMN107 has significant activity in patients treated with ≥ 600 mg per day in imatinib-resistant CML LBP or Ph+ ALL Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis