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

Abstract

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.

• 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
• Journal: International journal of hematology (Int J Hematol) Vol. 101 Issue 2 Pg. 154-64 (02 2015) ISSN: 1865-3774 [Electronic] Japan
• PMID: 25540064 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aniline Compounds
• Antineoplastic Agents
• Nitriles
• Protein Kinase Inhibitors
• Quinolines
• bosutinib

Topics

• Adult
• Aged
• Aniline Compounds (pharmacology, therapeutic use)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Asian People
• Disease Progression
• Drug Resistance, Neoplasm
• Female
• Humans
• Japan
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics, mortality, pathology)
• Male
• Middle Aged
• Neoplasm Staging
• Nitriles (pharmacology, therapeutic use)
• Philadelphia Chromosome
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Quinolines (pharmacology, therapeutic use)
• Retreatment
• Treatment Outcome
• Young Adult