title: Phase I clinical and pharmacokinetic study of 3-weekly, 3-h infusion of ixabepilone (BMS-247550), an epothilone B analog, in Japanese patients with refractory solid tumors.
abstract: BACKGROUND
  Ixabepilone (BMS-247550) is the first in a new class of anti-neoplastic agents, the epothilone analogs, and is a highly active non-taxane anti-microtubule agent. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety profile, pharmacokinetics, and antitumor activity of ixabepilone in Japanese patients.
  
  
  METHODS
  Patients with solid tumors previously treated with up to four chemotherapy regimens received a 3-h intravenous infusion of ixabepilone every 3 weeks.
  
  
  RESULTS
  Fourteen patients received 43 cycles (median 3, range 1-8). The most common adverse events were neutropenia, mild-to-moderate fatigue, anemia, and peripheral neuropathy. DLTs occurred in one patient receiving 40 mg/m2 (grade 4 neutropenia for 9 days) and in two patients receiving 50 mg/m2 (grade 3 mucositis, ileus and febrile neutropenia; grade 4 neutropenia for 10 days). One paclitaxel- and docetaxel-pretreated patient with non-small cell lung cancer achieved a partial response lasting for 3 months; six additional patients (43%) achieved disease stabilization with tumor shrinkage of 3-35%. The plasma concentration-time profiles of ixabepilone during cycle 1 were similar across all doses evaluated.
  
  
  CONCLUSIONS
  The MTD of ixabepilone is 50 mg/m2 given over 3 h every 3 weeks. The recommended phase II dose is 40 mg/m2, which is well tolerated and active. Data from Japanese patients are consistent with published phase I data from non-Japanese patients.
authors.affiliation: Division of Internal Medicine, National Cancer Center Hospital, Chuo-ku, Tokyo 104-0045, Japan. tshimizu@nara.med.kindai.ac.jp
authors.forename: Toshio
authors.initials: T
authors.lastname: Shimizu
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Fujisaka
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamada
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takayama
authors.forename: Takuto
authors.initials: T
authors.lastname: Tokudome
authors.forename: Judith
authors.initials: J
authors.lastname: Klimovsky
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D044466:Asian People; D004305:Dose-Response Relationship, Drug; D034261:Epothilones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007564:Japan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; C430592:ixabepilone