title: A phase II study of the gamma secretase inhibitor RO4929097 in patients with previously treated metastatic pancreatic adenocarcinoma.
abstract: OBJECTIVE
  The notch pathway is overexpressed in pancreatic adenocarcinoma. RO4929097, an oral inhibitor of the γ-secretase enzyme has been safely given as a single agent in patients with advanced solid tumors. We aimed to evaluate the efficacy of RO4929097 in patients with pancreatic adenocarcinoma (PDA).
  
  
  METHODS
  A two-stage, single-arm Phase II trial was conducted in patients with previously treated metastatic PDA. RO4929097 was administered at a dose of 20 mg daily on days 1-3, 8-10 and 15-17 of 21-day cycles. The primary endpoint was survival at 6 months. Secondary endpoints included overall survival (OS), response rate, toxicities, pharmacokinetic and pharmacodynamic analyses.
  
  
  RESULTS
  Eighteen patients were recruited, 17 in the first stage and one in the 2nd stage. It was decided to stop further enrollment after RO4929097 was discontinued by the sponsor and was no longer a development candidate. Three (25 %) of 12 evaluable patients achieved stable disease. The 6-month survival rate was 27.8 % (95 % CI 9.7-53.5). The median OS was 4.1 months (95 % CI 2.7-5.8 months) and median progression-free survival was 1.5 months (95 % CI 1.3-1.6 months). Pharmacokinetic properties of RO4929097 in patients (n = 5) with PDA was similar to that previously reported in other patient populations. There was a trend towards a decrease in HeyL (p = 0.08) gene expression in three patients following study drug administration.
  
  
  CONCLUSIONS
  RO4929097 was well-tolerated in patients with previously treated PDA. Development of RO4929097 has been discontinued, but development of other notch-targeting agents in pancreatic cancer is continuing.
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St. CRB1-4M08, Baltimore, MD, 21287, USA, adejesu1@jhmi.edu.
authors.forename: Ana
authors.initials: A
authors.lastname: De Jesus-Acosta
authors.forename: Daniel
authors.initials: D
authors.lastname: Laheru
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: John
authors.initials: J
authors.lastname: Arcaroli
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: Arvind
authors.initials: A
authors.lastname: Dasari
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Blatchford
authors.forename: Kevin
authors.initials: K
authors.lastname: Quackenbush
authors.forename: Wells
authors.initials: W
authors.lastname: Messersmith
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001552:Benzazepines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015996:Survival Rate; D005466:Fluorocarbons
chemical_list: D053829:Amyloid Precursor Protein Secretases; D000970:Antineoplastic Agents; D001552:Benzazepines; D004791:Enzyme Inhibitors; C545185:2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; D005466:Fluorocarbons