title: Multicenter phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766 in patients with advanced cancer.
abstract: OBJECTIVE
  To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 86-9766, a selective, potent, orally available, small-molecule allosteric inhibitor of mitogen-activated protein kinase 1/2 in patients with advanced solid tumors.
  
  
  METHODS
  BAY 86-9766 was administered orally daily in 28-day courses, with doses escalated to establish the maximum-tolerated dose (MTD). An expanded cohort was evaluated at the MTD. Pharmacokinetic and pharmacodynamic parameters were assessed, with extracellular signal-regulated kinase (ERK) phosphorylation evaluated in paired biopsies from a subset of the expanded MTD cohort. Tumor specimens were evaluated for mutations in select genes.
  
  
  RESULTS
  Sixty-nine patients were enrolled, including 20 patients at the MTD. The MTD was 100 mg given once-daily or in two divided doses. BAY 86-9766 was well-tolerated. The most common treatment-related toxicities were acneiform rash and gastrointestinal toxicity. BAY 86-9766 was well-absorbed after oral administration (plasma half-life ~12 hours), and displayed dose proportional pharmacokinetics throughout the tested dose range. Continuous daily dosing resulted in moderate accumulation at most dose levels. BAY 86-9766 suppressed ERK phosphorylation in biopsied tissue and tetradecanoylphorbol acetate-stimulated peripheral blood leukocytes. Of 53 evaluable patients, one patient with colorectal cancer achieved a partial response and 11 patients had stable disease for 4 or more courses. An ocular melanoma specimen harbored a GNAQ-activating mutation and exhibited reduced ERK phosphorylation in response to therapy.
  
  
  CONCLUSIONS
  This phase I study showed that BAY 86-9766 was well-tolerated, with good oral absorption, dose proportional pharmacokinetics, target inhibition at the MTD, and some evidence of clinical benefit across a range of tumor types.
authors: University of Colorado Cancer Center, Aurora, Colorado 80045, USA.
authors: Colin D
authors: CD
authors: Weekes
authors: Daniel D
authors: DD
authors: Von Hoff
authors: Alex A
authors: AA
authors: Adjei
authors: Diane P
authors: DP
authors: Leffingwell
authors: S Gail
authors: SG
authors: Eckhardt
authors: Lia
authors: L
authors: Gore
authors: Karl D
authors: KD
authors: Lewis
authors: Glen J
authors: GJ
authors: Weiss
authors: Ramesh K
authors: RK
authors: Ramanathan
authors: Grace K
authors: GK
authors: Dy
authors: Wen W
authors: WW
authors: Ma
authors: Beth
authors: B
authors: Sheedy
authors: Cory
authors: C
authors: Iverson
authors: Jeffrey N
authors: JN
authors: Miner
authors: Zancong
authors: Z
authors: Shen
authors: Li-Tain
authors: LT
authors: Yeh
authors: Ronald L
authors: RL
authors: Dubowy
authors: Michael
authors: M
authors: Jeffers
authors: Prabhu
authors: P
authors: Rajagopalan
authors: Neil J
authors: NJ
authors: Clendeninn
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: C544830:N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D004159:Diphenylamine; D019950:Mitogen-Activated Protein Kinase 1