A Phase II Study of Nilotinib, a Novel Tyrosine Kinase Inhibitor Administered to Patients with Imatinib Resistant or Intolerant Chronic Myelogenous Leukemia (CML) in Chronic Phase (CP), Accelerated Phase (AP) or Blast Crisis (BC) Who Have Also Failed Dasatinib Therapy.

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 cell lines with Bcr-Abl mutations. This open-label study was designed to evaluate the efficacy and safety as defined by hematologic and cytogenetic response rates (HR/CyR) of nilotinib administered at a daily dose of 400 mg bid to patients who previously received and either failed or were intolerant to imatinib and dasatinib. A total of 50 patients were enrolled and included CP (n=26), AP (n=10), and BC (n=14) patients. Of the 14 BC patients 10 were myeloid and 4 were lymphoid. Overall 8 (16%) patients had extramedullary disease at baseline. The median age was 57 (range 19–78) years and the median time from first diagnosis of CP, AP, or BC to treatment was 65 (range 8–213) months. The median duration of nilotinib exposure was 226 (range 3–379) days. A total of 28 (56%) patients remain on treatment, 22 (44%) discontinued (6 for adverse events, 11 for disease progression, 3 withdrew consent, and there were 2 deaths related to cerebral hemorrhages). Complete (HR) was reported in 9 of the 20 (45%) CP patients who did not have a CHR at baseline. Of the 26 CP patients, 8 (31%) had a major CyR (2 complete and 6 partial), 2 (8%) patients had minimal responses, and 9 (35%) patients had no response. Disease progression occurred in one CP patient and 6 patients were not evaluable. Confirmed hematologic responses were observed in 2 of 10 (20%) AP patients who had a return to chronic phase (RTC), 7 patients were not evaluable and there was one patient death. Of the 10 AP patients 1 (10%) each had CyR (partial, minor, minimal and no response). Of the 14 BC patients 1 had a CHR (7%), 2 (14%) had a return to chronic phase (RTC), 6 (43%) were not assessable for response, and 5 (36%) had progressive disease. Overall the most frequent Grade 3 or 4 adverse events reported were thrombocytopenia in 12 (24%), neutropenia in 11 (22%), and anemia in 5 (10%) patient. In summary, nilotinib has significant clinical activity and an acceptable safety and tolerability in CML-CP, AP, and BC patients who were resistant or intolerant to imatinib and have also failed dasatinib therapy.