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

6520 Background: Response to imatinib in accelerated phase (AP) and blast phase (BP) CML is inferior to chronic phase (CP). Relapse is frequent and associated with Bcr-Abl point mutations which interfere with imatinib binding. BMS-354825 is an orally available, dual SRC/ABL kinase inhibitor with 300-fold greater potency than imatinib. BMS-354825 has preclinical activity against 14 of 15 imatinib resistant Bcr-Abl mutants (Shah et al, Science, 2004).,CA180002 is a phase I, dose-escalation study of BMS-354825 in patients with resistance or intolerance to imatinib. The study was initially restricted to CP CML but was amended to include AP and BP CML and Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ALL) patients. Intrapatient dose escalation is permitted. Patient samples are analyzed for pharmacokinetics (PK), Bcr-Abl mutations, and CRKL, HCK, and LYN phosphorylation.,From May through November 2004, 8 AP, 18 BP CML and 3 Ph+ ALL patients were treated with 35 mg - 90 mg BID. Imatinib-resistance mutations were identified in 16 of 28 patients with mutation data. The hematologic response rates (complete + partial) are 75% for AP, 76% (13/17) for BP and 100% for Ph+ALL (2/2) patients. Responses are durable for 2+ to 6+ months in 19 patients. The major cytogenetic response rate in BP patients is 53%. Responses occurred in 15 patients with imatinib-resistance mutations. 4 patients had primary resistanced documented after 2 months; 2 relapsed within 2-3 months after an initial response. The T315I mutation, which confers cross-resistance to both drugs in preclinical models, was identified in 4 of the 6 resistant patients. BMS-354825 has been well tolerated. Myelosuppression was observed, with grade 4 thrombocytopenia in 8 patients. Grade 3/4 fluid retention (1) and tumor lysis syndrome (2) occurred in 3 patients.,BMS-345825 appears to be safe, effective therapy for patients with imatinib-resistant advanced disease CML and Ph+ ALL, producing durable hematologic and cytogenetic responses. The phase I study is ongoing evaluating higher dose levels to determine the maximally tolerated dose. No significant financial relationships to disclose.