title: Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers.
abstract: OBJECTIVE
  Biliary cancers (BCs) carry a poor prognosis, but targeting the RAS/RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is of significance. Selumetinib is an inhibitor of MEK1/2, so this trial was designed to determine the safety and efficacy of selumetinib in BC.
  
  
  METHODS
  This was a multi-institutional phase II study of selumetinib at 100 mg given orally twice per day to patients with advanced BC. The primary end point was response rate. All patients were required to provide tissue before enrolling. The levels of phosphorylated ERK (pERK) and AKT (pAKT) were assessed by immunohistochemistry. Tumors were genotyped for the presence of BRAF- and/or RAS-activating mutations.
  
  
  RESULTS
  Twenty-eight eligible patients with a median age of 55.6 years were enrolled. Thirty-nine percent of patients had received one prior systemic therapy. Three patients (12%) had a confirmed objective response. Another 17 patients (68%) experienced stable disease (SD), 14 of whom (56%) experienced prolonged SD (> 16 weeks). Patients gained an average nonfluid weight of 8.6 pounds. Median progression-free survival was 3.7 months (95% CI, 3.5 to 4.9) and median overall survival was 9.8 months (95% CI, 5.97 to not available). Toxicities were mild, with rash (90%) and xerostomia (54%) being most frequent. Only one patient experienced grade 4 toxicity (fatigue). All patients had tissue available for analysis. No BRAF V600E mutations were found. Two patients with short-lived SD had KRAS mutations. Absence of pERK staining was associated with lack of response.
  
  
  CONCLUSIONS
  Selumetinib displays interesting activity and acceptable tolerability in patients with metastatic BC. Our results warrant further evaluation of selumetinib in patients with metastatic BC.
authors.affiliation: The Ohio State University Comprehensive Cancer Center--James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA. Tanios.Bekaii-Saab@osumc.edu
authors.forename: Tanios
authors.initials: T
authors.lastname: Bekaii-Saab
authors.forename: Mitch A
authors.initials: MA
authors.lastname: Phelps
authors.forename: Xiaobai
authors.initials: X
authors.lastname: Li
authors.forename: Motoyasu
authors.initials: M
authors.lastname: Saji
authors.forename: Laura
authors.initials: L
authors.lastname: Goff
authors.forename: John Sae Wook
authors.initials: JS
authors.lastname: Kauh
authors.forename: Bert H
authors.initials: BH
authors.lastname: O'Neil
authors.forename: Stephanie
authors.initials: S
authors.lastname: Balsom
authors.forename: Catherine
authors.initials: C
authors.lastname: Balint
authors.forename: Ryan
authors.initials: R
authors.lastname: Liersemann
authors.forename: Vasily V
authors.initials: VV
authors.lastname: Vasko
authors.forename: Mark
authors.initials: M
authors.lastname: Bloomston
authors.forename: William
authors.initials: W
authors.lastname: Marsh
authors.forename: L Austin
authors.initials: LA
authors.lastname: Doyle
authors.forename: Gilian
authors.initials: G
authors.lastname: Ellison
authors.forename: Michael
authors.initials: M
authors.lastname: Grever
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Ringel
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Villalona-Calero
mesh_terms: D000328:Adult; D000368:Aged; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis / Q000188:drug therapy; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins