title: Phase I and pharmacokinetic/pharmacodynamic study of RO5126766, a first-in-class dual Raf/MEK inhibitor, in Japanese patients with advanced solid tumors.
abstract: OBJECTIVE
  RO5126766, a highly selective dual Raf and MEK inhibitor, is a first-in-class tandem mitogen-activated protein kinase signaling pathway inhibitor. The objectives of this phase I study were to determine maximum-tolerated dose (MTD) and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of RO5126766 in Japanese patients with advanced solid tumors.
  
  
  METHODS
  Patients received a single oral dose of RO5126766 (0.8, 1.2, 1.8, or 2.25 mg) followed by continuous once-daily dosing at the same dosage in 28-day cycles. A 3 + 3 dose-escalation design was used. PD was evaluated by pMEK and pERK inhibition in peripheral blood mononuclear cells (PBMCs).
  
  
  RESULTS
  A total of 12 patients were enrolled in cohorts of 0.8, 1.2, 1.8, and 2.25 mg/day. In the dose range tested, no dose-limiting toxicity was observed, and therefore, MTD was not defined. Main adverse events included acneiform dermatitis, creatine phosphokinase elevation, and ocular disorders. The plasma exposure of RO5126766 appeared to increase in a dose-proportional manner with a long plasma half-life (t 1/2) of 45.8-93.7 h. Following multiple dose administration, a steady-state condition was reached by Cycle 1 Day 8 (240 h). The inhibitory effects of RO5126766 on both pERK and pMEK in PBMCs increased in a dose-dependent manner. Five out of 12 patients achieved stable diseases, including a melanoma case with over 20 % shrinkage.
  
  
  CONCLUSIONS
  RO5126766 has a manageable safety profile up to 2.25 mg/day once daily with a favorable PK/PD profile in Japanese patients with advanced solid tumors.
authors.affiliation: Division of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Honda
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nokihara
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Tamura
authors.forename: Hajime
authors.initials: H
authors.lastname: Asahina
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Suzuki
authors.forename: Naoya
authors.initials: N
authors.lastname: Yamazaki
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Ogita
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D003374:Coumarins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007564:Japan; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D016896:Treatment Outcome; D048490:raf Kinases / Q000037:antagonists & inhibitors*
chemical_list: D003374:Coumarins; D047428:Protein Kinase Inhibitors; C577924:RO5126766; D048490:raf Kinases