title: An open-label, phase 1 study evaluating safety, tolerability, and pharmacokinetics of linifanib (ABT-869) in Japanese patients with solid tumors.
abstract: OBJECTIVE
  This phase 1 study assessed the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of linifanib in Japanese patients with advanced solid tumors.
  
  
  METHODS
  Patients were assigned to one of four sequential cohorts (0.05, 0.10, 0.20, or 0.25 mg/kg) of oral, once-daily linifanib on a 21-day cycle. Adverse events (AEs) were assessed per common terminology criteria for adverse events v3.0; tumor responses were assessed by response evaluation criteria in solid tumors.
  
  
  RESULTS
  Eighteen patients were enrolled. Eleven (61%) received ≥3 prior therapies. Dose-limiting toxicities were Grade 3 ALT increase (0.10 mg/kg linifanib) and Grade 1 T-wave inversion (0.25 mg/kg linifanib) requiring dose interruption for >7 days and discontinuation on day 29. The most common linifanib-related AE was hypertension. Other significant treatment-related AEs included proteinuria, fatigue, and palmar-plantar erythrodysaesthesia. Linifanib pharmacokinetics were dose-proportional across 0.10-0.25 mg/kg. Two patients (11.1%) had confirmed partial responses, 12 had a best response of stable disease (11 had stable disease for ≥12 weeks), and four patients were not evaluable due to incomplete data. Four patients (lung cancer, breast cancer, thymic cancer, sarcoma) have continued linifanib for ≥48 weeks (range, 48-96+ weeks).
  
  
  CONCLUSIONS
  Linifanib was well tolerated with promising preliminary clinical activity in Japanese patients. Later-phase global studies examining linifanib efficacy will include Japanese patients.
authors.affiliation: Division of Thoracic Oncology, National Cancer Center Hospital (NCCH), 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Asahina
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Tamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nokihara
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Seki
authors.forename: Takashi
authors.initials: T
authors.lastname: Shibata
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Goto
authors.forename: Maki
authors.initials: M
authors.lastname: Tanioka
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.forename: Andrew
authors.initials: A
authors.lastname: Coates
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Chiu
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Li
authors.forename: Rajendra
authors.initials: R
authors.lastname: Pradhan
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ansell
authors.forename: Evelyn M
authors.initials: EM
authors.lastname: McKeegan
authors.forename: Mark D
authors.initials: MD
authors.lastname: McKee
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Carlson
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D007191:Indazoles / Q000009:adverse effects* / Q000493:pharmacokinetics; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality; D010671:Phenylurea Compounds / Q000009:adverse effects* / Q000493:pharmacokinetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007191:Indazoles; D008565:Membrane Proteins; C098069:PIGF protein, human; D010671:Phenylurea Compounds; C513486:linifanib; D020794:Receptor Protein-Tyrosine Kinases