title: Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers.
abstract: OBJECTIVE
  To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer.
  
  
  METHODS
  In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters. In part B, patients were stratified by cancer type (melanoma v other) and randomly assigned to receive the MTD or 50% MTD. Biopsies were collected to determine inhibition of ERK phosphorylation, Ki-67 expression, and BRAF, KRAS, and NRAS mutations.
  
  
  RESULTS
  Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD (100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade 1 or 2. The PKs were less than dose proportional, with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated >or= 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. Nine patients had stable disease (SD) for >or= 5 months, including two patients with SD for 19 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles.
  
  
  CONCLUSIONS
  AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing.
authors.affiliation: Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. alex.adjei@roswellpark.org
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
authors.forename: Wilbur
authors.initials: W
authors.lastname: Franklin
authors.forename: Clive
authors.initials: C
authors.lastname: Morris
authors.forename: David
authors.initials: D
authors.lastname: Wilson
authors.forename: Julian R
authors.initials: JR
authors.lastname: Molina
authors.forename: Lorelei J
authors.initials: LJ
authors.lastname: Hanson
authors.forename: Lia
authors.initials: L
authors.lastname: Gore
authors.forename: Laura
authors.initials: L
authors.lastname: Chow
authors.forename: Stephen
authors.initials: S
authors.lastname: Leong
authors.forename: Lara
authors.initials: L
authors.lastname: Maloney
authors.forename: Gilad
authors.initials: G
authors.lastname: Gordon
authors.forename: Heidi
authors.initials: H
authors.lastname: Simmons
authors.forename: Allison
authors.initials: A
authors.lastname: Marlow
authors.forename: Kevin
authors.initials: K
authors.lastname: Litwiler
authors.forename: Suzy
authors.initials: S
authors.lastname: Brown
authors.forename: Gregory
authors.initials: G
authors.lastname: Poch
authors.forename: Katie
authors.initials: K
authors.lastname: Kane
authors.forename: Jerry
authors.initials: J
authors.lastname: Haney
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D049109:Cell Proliferation / Q000187:drug effects; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; C117307:KRAS protein, human; D019394:Ki-67 Antigen; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C482128:MAP2K2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins