title: A phase 1 study of linifanib in combination with carboplatin/paclitaxel as first-line treatment of Japanese patients with advanced or metastatic non-small cell lung cancer (NSCLC).
abstract: BACKGROUND
  Linifanib is a potent, orally active, and selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor kinase activities with clinical efficacy in non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study evaluated the pharmacokinetics, safety, and efficacy of linifanib in combination with carboplatin/paclitaxel in Japanese patients with advanced NSCLC.
  
  
  METHODS
  Carboplatin (AUC = 6 mg/mL/min) and paclitaxel (200 mg/m²) were administered on day 1 of each 21-day cycle up to a maximum of six cycles. Oral linifanib (7.5 mg) was given to six patients once daily throughout all cycles and escalated to 12.5 mg/day in a second cohort of six patients.
  
  
  RESULTS
  Twelve patients received at least one dose of linifanib. The most common adverse events were hematologic and consistent with expected toxicities with carboplatin/paclitaxel. With 12.5 mg linifanib, grade 3/4 neutropenia, leukopenia, and thrombocytopenia occurred in 100, 83, and 83 % of patients, respectively. Dose-limiting grade 4 thrombocytopenia occurred in one patient at each dose level. Linifanib pharmacokinetics was similar to that in non-Japanese patients. At 12.5 mg, linifanib Cmax was 0.32 μg/mL and AUC₂₄ was 4.29 μg h/mL. Linifanib Cmax occurred at 2-3 h with both doses and when given alone or in combination with carboplatin/paclitaxel. Exposure to linifanib appeared to be increased by carboplatin/paclitaxel, and exposure to paclitaxel appeared to be increased by linifanib. Partial responses were observed in nine patients.
  
  
  CONCLUSIONS
  Linifanib added to carboplatin/paclitaxel is well tolerated in Japanese patients with advanced/metastatic NSCLC. The recommended dose of linifanib with carboplatin/paclitaxel is 12.5 mg, same as for US patients.
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, Japan, hhorinou@ncc.go.jp.
authors.forename: Hidehito
authors.initials: H
authors.lastname: Horinouchi
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nokihara
authors.forename: Takeshi
authors.initials: T
authors.lastname: Horai
authors.forename: Makoto
authors.initials: M
authors.lastname: Nishio
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Ohyanagi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Horiike
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Masaaki
authors.initials: M
authors.lastname: Terashima
authors.forename: Takafumi
authors.initials: T
authors.lastname: Okabe
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Kaneda
authors.forename: Mark D
authors.initials: MD
authors.lastname: McKee
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Carlson
authors.forename: Hao
authors.initials: H
authors.lastname: Xiong
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002277:Carcinoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D064146:Chemotherapy-Induced Febrile Neutropenia / Q000503:physiopathology; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D007564:Japan; D007970:Leukopenia / Q000139:chemically induced / Q000503:physiopathology; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D012720:Severity of Illness Index; D013921:Thrombocytopenia / Q000139:chemically induced / Q000503:physiopathology; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D007191:Indazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D016190:Carboplatin; C513486:linifanib; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D017239:Paclitaxel