A phase 1/2 study of bosutinib in Japanese adults with Philadelphia chromosome-positive chronic myeloid leukemia

• DOI: 10.1007/s12185-014-1722-8
• Publication Date: 2014-12-24T06:40:39Z
• Authors: Chiaki Nakaseko; Naoto Takahashi; Kenichi Ishizawa; Yukio Kobayashi; Kazuteru Ohashi; Yasunori Nakagawa; Kazuhito Yamamoto; Koichi Miyamura; Masafumi Taniwaki; Masaya Okada; Tatsuya Kawaguchi; Atsushi Shibata; Yosuke Fujii; Chiho Ono; Kazunori Ohnishi
• Keywords: Adult; Male; Aniline Compounds; Antineoplastic Agents; Middle Aged; 3. Good health; 03 medical and health sciences; Treatment Outcome; 0302 clinical medicine; Asian People; Japan; Drug Resistance, Neoplasm; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Nitriles; Retreatment; Disease Progression; Quinolines; Humans; Female; Philadelphia Chromosome; Protein Kinase Inhibitors; Aged; Neoplasm Staging

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.