A Phase II Study of Nilotinib A Novel Tyrosine Kinase Inhibitor Administered to Imatinib-Resistant or Intolerant Patients with Chronic Myelogenous Leukemia (CML) in Accelerated Phase (AP).

Nilotinib is a potent, highly selective, aminopyrimidine inhibitor of Bcr-Abl which in vitro is 30-fold more potent than imatinib. It is 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 (HR/CyR) rates of nilotinib at a dose of 400 mg bid in imatinib resistant or intolerant AP 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. Safety and efficacy data are reported for 64 patients of which 52 (81%) are resistant and 12 (19%) are intolerant to imatinib. More than half (63%) of the patients had CML for ≥ 5 years. The median age was 61 (range 24-79) years and the median time from CML diagnosis and AP diagnosis were 74 (range 2 to 298), and 2 (range 0-106) months, respectively. Of the 64 patients, 17 (27%) had extramedullary disease at baseline. The median duration of nilotinib exposure was 141 (range 2–380) days and the median average dose intensity (mg/days) for all patients, with and without dose escalations, was 797 (range 157 to 1136). Treatment is ongoing for 33 (52%) patients, and 31 (48%) have discontinued (14 for disease progression, 8 for adverse events, 1 each for an abnormal laboratory value, administrative problems, lost to follow up, 4 patients withdrew consent and there were 2 deaths listed as the primary reason for discontinuation). Overall, there were 7 deaths including 4 for disease progression, one related to progressive disease complicated by a cerebral hemorrhage, one cardiac failure and one due to sepsis. Confirmed HR occurred in 28 (44%) patients, of which 11 (17%) were complete, 5 (8%) were marrow responses/no evidence of leukemia, 12 (19%) were return to chronic phase. There were 7 (11%) patients with stable disease/no response, 6 (9%) with disease progression and 21 (33%) patients were not evaluable. Major CyR occurred in 20 (31%) patients, of which 11 (17%) were complete, 9 (14%) were partial, 11 (17%) were minor, and 15 (23%) were minimal.

There were 6 patients (9%) that did not respond. The rate of major CyR for the resistant and intolerant patients was 16 (31%) and 3 (25%), respectively. The majority of Grade 3 or 4 adverse events included thrombocytopenia in 21 (33%), neutropenia in 17 (27%), anemia in 10 (16%) patients, decreased hemoglobin in 4 (6%) patients, and increased lipase in 5 (8%). In summary, these data suggest nilotinib is clinically active and has an acceptable safety and tolerability profile when administered to patients with CML-AP. Updated information will be presented at the meeting.