title: 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.affiliation: Department of Hematology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan, chiaki-nakaseko@faculty.chiba-u.jp.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Nakaseko
authors.forename: Naoto
authors.initials: N
authors.lastname: Takahashi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ishizawa
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Kazuteru
authors.initials: K
authors.lastname: Ohashi
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Miyamura
authors.forename: Masafumi
authors.initials: M
authors.lastname: Taniwaki
authors.forename: Masaya
authors.initials: M
authors.lastname: Okada
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shibata
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Fujii
authors.forename: Chiho
authors.initials: C
authors.lastname: Ono
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ohnishi
mesh_terms: D000328:Adult; D000368:Aged; D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D044466:Asian People; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007564:Japan; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use*; D010677:Philadelphia Chromosome; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D019233:Retreatment; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C471992:bosutinib