title: Phase 1 study of trebananib (AMG 386), an angiogenesis targeting angiopoietin-1/2 antagonist, in Japanese patients with advanced solid tumors.
abstract: OBJECTIVE
  To evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of trebananib (AMG 386)--a first-in-class angiopoietin-1/2 antagonist peptide-Fc fusion protein--in Japanese patients, we conducted a phase 1, dose escalation study.
  
  
  METHODS
  Eligible patients were men or women, aged between 20 and 74 years, who had histologically or cytologically confirmed advanced solid tumors refractory to standard treatment. Trebananib (3, 10, and 30 mg/kg) was administered intravenously over 60 min in weekly cycles.
  
  
  RESULTS
  From June 2009 to April 2010, a total of 18 patients (6 for each dose cohort) were enrolled into the study. Trebananib was tolerated at all dose levels. No dose-limiting toxicities were observed. The most common adverse events were peripheral edema, constipation, fatigue, and pyrexia. Exposure to trebananib appeared to increase according to the dose administered. Serum clearance appeared to be similar across the dose range with the mean terminal-phase half-life ranging from 93.9 to 95.9 h. No neutralizing antibodies were detected. Tumor response was assessed in 18 patients. Of these, one patient with colon cancer in the 3-mg/kg cohort and one with bladder cancer in the 30-mg/kg cohort had partial responses as their best responses. These 2 patients were on treatment at the time of data cutoff (January 17, 2012).
  
  
  CONCLUSIONS
  Trebananib was tolerated and showed acceptable safety profile in Japanese patients with advanced solid tumors. The pharmacokinetic profiles were similar to those in the previous studies in the United States. Trebananib also showed evidence of durable antitumor activity in some patients.
authors.affiliation: National Cancer Center Hospital East, Kashiwa, Chiba, Japan. tdoi@east.ncc.go.jp
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Doi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
authors.forename: Nozomu
authors.initials: N
authors.lastname: Fuse
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshino
authors.forename: Makoto
authors.initials: M
authors.lastname: Tahara
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shibayama
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Takubo
authors.forename: David M
authors.initials: DM
authors.lastname: Weinreich
mesh_terms: D000328:Adult; D000368:Aged; D042683:Angiopoietin-1 / Q000037:antagonists & inhibitors*; D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007564:Japan; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; C551398:trebananib