A phase 1/2 study of bosutinib in Japanese adults with Philadelphia chromosome-positive chronic myeloid leukemia
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This phase 1/2 study evaluated the safety and pharmacokinetics (part 1) and efficacy and safety (part 2) of bosutinib in Japanese Philadelphia chromosome-positive (Ph+) chronic-phase (CP) or advanced-phase chronic myeloid leukemia (CML) patients resistant/intolerant to previous imatinib (2L) or imatinib+dasatinib/nilotinib (3L). Based on dose-limiting toxicities and previous studies, the part 2 bosutinib starting dose was 500 mg/day (n = 63). For CP CML 2L (n = 28), the cumulative major cytogenetic response (MCyR) rate by week 24 was 36 % (primary endpoint); the cumulative major molecular response (MMR) rate through the study was 43 %. Transformation to accelerated/blast phase (AP/BP) was observed in one patient. Progression-free survival (PFS) and overall survival (OS) rates at 96 weeks were 94 and 96 %, respectively. Of seven advanced-phase 2L patients, one had confirmed complete hematologic response at week 84, and one had AP/BP transformation. PFS and OS rates at week 96 were 21 and 43 %. For 3L (n = 11), cumulative MCyR rate by week 24 was 18 %; cumulative MMR rate was 18 %; no transformations occurred. Common non-hematologic adverse events (AEs) were diarrhea (95 %), rash (57 %), and nasopharyngitis (51 %). Sixteen patients discontinued due to adverse events; no deaths occurred within 30 days of the last dose. Bosutinib 500 mg/day demonstrated efficacy and manageable toxicity in Japanese Ph+ CML patients resistant/intolerant to imatinib.
KeywordsPhase 1/2 Bosutinib Tyrosine kinase inhibitor Chronic myeloid leukemia Japan
Editorial and medical writing support was provided by Simon J. Slater, PhD, of Complete Healthcare Communications, Inc., and was funded by Pfizer Inc. This study was sponsored by Wyeth Research, which was acquired by Pfizer Inc in October 2009.
Conflict of interest
Dr. Nakaseko reports Grants and scholarship support from Pfizer Inc. Dr. Takahashi reports Grants, personal fees and non-financial support from Pfizer Inc during the conduct of the study; Grants and personal fees from Novartis, Bristol-Myers Squibb, Kyowa Hakko Kirin, Chugai Pharma, Dainippon Sumitomo Pharma, Celgene, Janssen Pharma; Grants from Takeda Pharma; and personal fees from Asahikasei Pharma outside the submitted work. Dr. Kobayashi reports Grants from Pfizer Inc during the conduct of the study; Grants from ARIAD Pharmaceuticals, Inc., Boehringer Ingelheim, Novartis Pharma K·K., Otsuka Pharmaceuticals Co., Ltd., and Onconova Therapeutics, Inc., outside the submitted work. Dr. Yamamoto reports Grants and non-financial support from Pfizer Inc during the conduct of the study; Grants and non-financial support from Novartis Pharma K·K and Grants from ARIAD Pharmaceuticals, Inc, outside the submitted work. Dr. Kawaguchi reports Grants from Pfizer Inc during the conduct of the study. Dr. Ishizawa reports personal fees from Chugai Pharma, Takeda Pharma, Celgene, Janssen Pharma, and Sanofi, outside the submitted work. Dr. Taniwaki reports Grants from Pfizer Inc during the conduct of the study; Grants and/or personal fees from Bristol-Myers Squibb, Novartis, Kyowa Hakko Kirin, Chugai Pharma, Dainippon Sumitomo Pharma, Celgene, Janssen Pharma, Takeda Pharma, and Asahikasei Pharma, outside the submitted work. Drs. Ono, Fujii, and Shibata are employees of Pfizer Japan and contributed to this clinical trial as follows: protocol development (pharmacokinetics components) and data analysis (Dr. Ono; clinical pharmacologist); protocol development (statistical components) and data analysis (Dr. Fujii; study statistician); protocol development (clinical components), trial management, and data analysis (Dr. Shibata; study clinician). Drs. Ohashi, Nakagawa, Ohnishi, Miyamura, and Okada have nothing to disclose.
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