A phase I study of BMS-354825 in patients with imatinib-resistant and intolerant chronic phase chronic myeloid leukemia (CML): Results from CA180002

6519 Background: Resistance to imatinib in CML patients is often associated with Bcr-Abl point mutations which interfere with imatinib binding. BMS-354825 is a novel, orally available, dual SRC/ABL kinase inhibitor with more than 300-fold greater potency than imatinib and has preclinical activity against 14 of 15 imatinib resistant Bcr-Abl mutants (Shah et al, Science, 305:399, 2004). Methods: CA180002 is a phase I, dose-escalation study of BMS-354825 in CML patients with hematologic resistance or intolerance to imatinib. Intrapatient dose escalation is permitted. Patient samples are analyzed for pharmacokinetics (PK), Bcr-Abl kinase domain mutations, and CRKL, HCK, and LYN phosphorylation. Results: 36 chronic phase CML patients have been treated (31 resistant, 5 intolerant) with total daily doses ranging from 15 - 180 mg (given as single or divided doses). Mutations associated with imatinib resistance were identified in 27 patients. Thirty-one patients (86%) have had complete hematologic response (CHR). ...