title: Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors.
abstract: OBJECTIVE
  This phase I study of the mitogen-activated protein/extracellular signal-regulated kinase inhibitor RO4987655 (CH4987655) assessed its maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetic/pharmacodynamic profile, and antitumor activity in patients with advanced solid tumors.
  
  
  METHODS
  An initial dose escalation was conducted using a once-daily dosing schedule, with oral RO4987655 administered at doses of 1.0 to 2.5 mg once daily over 28 consecutive days in 4-week cycles. Doses were then escalated from 3.0 to 21.0 mg [total daily dose (TDD)] using a twice-daily dosing schedule.
  
  
  RESULTS
  Forty-nine patients were enrolled. DLTs were blurred vision (n = 1) and elevated creatine phosphokinase (n = 3). The MTD was 8.5 mg twice daily (TDD, 17.0 mg). Rash-related toxicity (91.8%) and gastrointestinal disorders (69.4%) were the most frequent adverse events. The pharmacokinetic profile of RO4987655 showed dose linearity and a half-life of approximately 4 hours. At the MTD, target inhibition, assessed by suppression of extracellular signal-regulated kinase phosphorylation in peripheral blood mononuclear cells, was high (mean 75%) and sustained (90% of time >IC(50)). Of the patients evaluable for response, clinical benefit was seen in 21.1%, including two partial responses (one confirmed and one unconfirmed). 79.4% of patients showed a reduction in fluorodeoxyglucose uptake by positron emission tomography between baseline and day 15.
  
  
  CONCLUSIONS
  In this population of heavily pretreated patients, oral RO4987655 showed manageable toxicity, a favorable pharmacokinetics/pharmacodynamics profile, and promising preliminary antitumor activity, which has been further investigated in specific populations of patients with RAS and/or RAF mutation driven tumors.
authors: The Netherlands Cancer Institute, Amsterdam; Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors: Suzanne
authors: S
authors: Leijen
authors: Mark R
authors: MR
authors: Middleton
authors: Patricia
authors: P
authors: Tresca
authors: Françoise
authors: F
authors: Kraeber-Bodéré
authors: Veronique
authors: V
authors: Dieras
authors: Max E
authors: ME
authors: Scheulen
authors: Avinash
authors: A
authors: Gupta
authors: Vanesa
authors: V
authors: Lopez-Valverde
authors: Zhi-Xin
authors: ZX
authors: Xu
authors: Ruediger
authors: R
authors: Rueger
authors: Jean J L
authors: JJ
authors: Tessier
authors: Eliezer
authors: E
authors: Shochat
authors: Steve
authors: S
authors: Blotner
authors: Valerie Meresse
authors: VM
authors: Naegelen
authors: Jan H M
authors: JH
authors: Schellens
authors: Wilfried Ernst Erich
authors: WE
authors: Eberhardt
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010078:Oxazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D001549:Benzamides; C559138:CH 4987655; D010078:Oxazines; D047428:Protein Kinase Inhibitors; D020930:MAP Kinase Kinase Kinases