title: Phase I/II study of sunitinib malate in Japanese patients with gastrointestinal stromal tumor after failure of prior treatment with imatinib mesylate.
abstract: OBJECTIVE
  To establish a recommended sunitinib dosing schedule in Japanese patients with imatinib-resistant/intolerant gastrointestinal stromal tumor (GIST) and to evaluate the efficacy, safety/tolerability, pharmacokinetics, and pharmacodynamics of sunitinib using this schedule.
  
  
  METHODS
  In the phase I part of this open-label phase I/II trial, Japanese GIST patients received 25, 50, or 75 mg/day of sunitinib on Schedule 4/2 (4 weeks on treatment; 2 weeks off treatment) following imatinib failure. In phase II, patients received the recommended (maximum tolerated) dose on this schedule; the primary endpoint was clinical benefit rate (CBR; percent objective responses or stable disease [SD] ≥22 weeks). Additional efficacy, safety, pharmacokinetic, and biomarker analyses were performed.
  
  
  RESULTS
  In phase I (12 patients), the recommended dose was determined to be 50 mg/day. Sunitinib pharmacokinetics were similar to those observed in studies with Western patients. In the phase II part (36 patients), the CBR was 39% (95% CI: 23–57%; 11% partial responses, 28% SD ≥22 weeks). The most common treatment-related non-hematologic adverse events (AEs) were hand–foot syndrome (86%) and fatigue (67%). A trend towards a correlation between decreases from baseline in plasma soluble KIT levels and improved CB was found.
  
  
  CONCLUSIONS
  The pharmacokinetics observed and clinical outcomes achieved in Japanese GIST patients on sunitinib (50 mg/day, Schedule 4/2) after imatinib failure appeared similar to those of Western patients in previous sunitinib trials. Although some serious AEs were observed, AEs were generally manageable using dose interruption/modification and/or standard medical treatments.
authors.affiliation: Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan. kshirao@med.oita-u.ac.jp
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Shirao
authors.forename: Toshirou
authors.initials: T
authors.lastname: Nishida
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Doi
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Komatsu
authors.forename: Kei
authors.initials: K
authors.lastname: Muro
authors.forename: Yinhua
authors.initials: Y
authors.lastname: Li
authors.forename: Eiji
authors.initials: E
authors.lastname: Ueda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D044466:Asian People; D001549:Benzamides; D014408:Biomarkers, Tumor / Q000097:blood; D003710:Demography; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007564:Japan; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000097:blood; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012995:Solubility; D000077210:Sunitinib; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D014408:Biomarkers, Tumor; D007211:Indoles; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D011758:Pyrroles; D000068877:Imatinib Mesylate; D000077210:Sunitinib