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The investigational second-generation kinase inhibitors bosutinib and nilotinib are clinically active in the treatment of chronic myelogenous leukemia that is resistant to or intolerant of imatinib, according to separate Italian studies.
Bosutinib (SKI-606), a synthetic quinolone derivative and oral dual inhibitor of the Src and Abl tyrosine kinases, was active across a wide range of mutations in a phase I/II trial that studied 110 patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL).
All patients were either imatinib (Gleevec) resistant or intolerant.
Sixteen different imatinib-resistant mutations were found in 36 of 59 evaluable patients, including nine P-loop and eight T3151 mutations, lead investigator Dr. Carlo Gambacorti-Passerini said. Complete hematologic response and major cytogenetic response rates did not differ substantially in patients with no mutations, P-loop mutations, or non-P-loop mutations, according to Dr. Gambacorti-Passerini of the Ospedale San Gerardo-Monza, Italy.
Phase I of the continuous dosing trial included 76 patients with chronic-phase CML. They were treated with 400, 500, or 600 mg of bosutinib per day. The dose was fixed at 500 mg per day in phase II, which enrolled 34 additional patients with all phases of CML and ALL.
Among patients with no prior exposure to kinase inhibitors other than imatinib, complete hematologic response was reported in 33 of 36 chronic CML patients (92%) and 8 of 9 ALL patients (89%). Major cytogenetic remission was achieved by 13 of 31 CML patients (42%) and 3 of 5 ALL patients (60%). Response rates were lower in patients with prior drug exposure, said Dr. Gambacorti-Passerini, who added that the durability of response requires further follow-up.
Side effects included diarrhea during the first week of treatment, nausea, rash, and fatigue. Hematologic toxicity was low, possibly due to the lack of Kit kinase inhibition, he said. There were three pleural effusions, including one grade 3/4, all in CML patients.
The median duration of treatment was 2.8 months. Treatment was stopped temporarily in 40 patients and reduced in 25, reported Dr. Gambacorti-Passerini, who received research support from and is an investigator for the study's sponsor, Wyeth Pharmaceuticals.
There are several ongoing phase II trials of nilotinib (AMN107), a highly selective inhibitor of Bcr-Abl kinase activity that has been found, in vitro, to be active against 32 of the 33 most common Bcr-Abl mutations known to cause imatinib resistance. Dr. Gianantonio Rosti presented safety and efficacy data from a phase II open-label trial in which 320 patients with Philadelphia chromosome-positive chronic-phase CML received 400 mg of oral nilotinib twice daily for 6 months or more.
The study's primary end point of major cytogenetic response (MCyR) was achieved in 56% of patients, and a complete cytogenetic response was achieved in 40%.
MCyR rates were similar among patients who were imatinib-resistant (54% of 226) or imatinib-intolerant (60% of 94) at baseline, said Dr. Rosti of the Institute of Hematology and Medical Oncology "Serągnoli" at the University of Bologna, Italy. Kaplan-Meier analysis of all patients gave a 95% survival rate at 1 year.
Dr. Rosti characterized nilotinib as a "very nicely tolerated drug."
Rash was the most frequent adverse event (34% all grades, 2% grade 3/4), but it occurred early on and resolved rapidly. Myelosuppression was manageable, with grade 3/4 neutropenia and thrombocytopenia observed in 31% and 33% of patients, respectively, Dr. Rossi reported. He is a consultant and speaker for the study's sponsor, Novartis Pharmaceuticals Corp., and a speaker for Bristol-Myers Squibb Co.
Gambacorti-Passerini C. et al. Bosutinib (SKI-606) exhibits clinical activity in patients with Philadelphia chromosome positive CML or ALL who failed imatinib. Abstract 7006.
Rosti G. et al. A phase II study of nilotinib administered to imatinib resistant and intolerant patients with chronic myelogenous leukemia (CML) in chronic phase (CP). Abstract 7007.