A Phase II Study of Nilotinib, a Novel Tyrosine Kinase Inhibitor Administered to Imatinib-Resistant and -Intolerant Patients with Chronic Myelogenous Leukemia (CML) in Chronic Phase (CP).

Nilotinib 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, as defined by hematologic/cytogenetic response rates (HR/CyR) of nilotinib administered at a daily dose of 400 mg bid to imatinib resistant or intolerant CML-CP patients. Daily doses of nilotinib could be escalated to 600 mg BID for patients who did not adequately respond to treatment, and in the absence of safety concerns. Data are available for 132 patients including 91 (69%) with imatinib resistance and 41 (31%) imatinib intolerant. Of the 132 patients, 45 (34%) had a CHR at baseline and 87 (66%) did not. Overall 77 (58%) patients had additional chromosomal abnormalities at baseline, and 16 (12%) had extramedullary involvement. Median age was 58 (range 26–85) years and the median time from first diagnosis to treatment was 57 (range 5–275) months. There were 72 males and 60 females. Nearly half (49%) of the patients had CML for ≥ 5 years and the median overall duration of prior imatinib was 978 days (range 9 to 3468). Treatment with nilotinib is ongoing for 82 of the 132 (62%) patients. A total of 50 (38%) patients have discontinued treatment (26 for adverse events, 15 for disease progression, 7 for other/administrative reasons, and there were two patient deaths (one myocardial infarction in a patient with previous infarctions noted on autopsy, and one with progressive disease). The median duration of nilotinib exposure was 226 (range 3–379) days. The median average dose intensity (mg/days) for all patients, with and without dose escalations, was 800 (range 134 to 1106). CHR was reported in 60 of 87 (69%) patients without a baseline CHR. The median time to CHR was 1.4 months (range 0.3 to 13). Major CyR was observed in 55 (42%), of which 33 (25%) were complete, 22 (17%) partial, 10 (8%) minor, 15 (11%) minimal, 21 (16%) had no cytogenetic response and 4 (3%) had disease progression. The median time to MCyR was 2.6 months (range 0.9 to 8.4). Overall the most frequent Grade 3 or 4 adverse events included thrombocytopenia 34 (26%), neutropenia in 24 (18%), elevated serum lipase in 10 (8%) and anemia in 9 (7%). In summary, nilotinib has demonstrated significant clinical activity as defined by 69% CHR and 42% MCR rates, and an acceptable safety and tolerability profile in patients with imatinib resistant or intolerant CML-CP. Updated information will be presented at the meeting.