title: A phase II study of RO4929097 in metastatic colorectal cancer.
abstract: BACKGROUND
  The Notch signalling pathway is activated in a variety of malignancies and has been implicated in colorectal cancer progression. One of the first steps in the Notch pathway activation is mediated by γ-secretase, a proteolytic enzyme which produces an activated intracellular Notch (ICN). RO4929097 is a selective inhibitor of γ-secretase. We tested the activity of RO4929097 in patients with metastatic, refractory colorectal cancer.
  
  
  METHODS
  Patients with metastatic colorectal cancer who had received at least two prior lines of systemic chemotherapy were enrolled on the study. Patients were treated with RO4929097 at its recommended phase II dose of 20mg daily, 3 days on and 4 days off continuously. Cycle length was 28 days. Imaging was performed every two cycles. Archival tissue specimens were stained immunohistochemically for components of the notch pathway: Notch1, ICN and the downstream target HES1.
  
  
  RESULTS
  Thirty-seven patients were enrolled of whom 33 were evaluable for toxicity and response. Immunohistochemical analysis of archival tissues demonstrated positive staining for the notch receptor as well as intracellular notch and the downstream gene HES1 in the majority of patients. Nevertheless, no objective radiographic responses were observed in this group and only six patients had stable disease as their best response. Median PFS was 1.8 months and median overall survival (OS) was 6.0 months.
  
  
  CONCLUSIONS
  In this study of RO4929097 in patients with refractory metastatic colorectal cancer, no radiographic responses were seen and time to progression was short, which suggests that RO4929097 at the study dose and schedule has minimal single agent activity in this malignancy.
authors.affiliation: Dept of GI Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, United States. jonathan.strosberg@moffitt.org
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Strosberg
authors.forename: Timothy
authors.initials: T
authors.lastname: Yeatman
authors.forename: Jill
authors.initials: J
authors.lastname: Weber
authors.forename: Domenico
authors.initials: D
authors.lastname: Coppola
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schell
authors.forename: Gang
authors.initials: G
authors.lastname: Han
authors.forename: Khaldoun
authors.initials: K
authors.lastname: Almhanna
authors.forename: Richard
authors.initials: R
authors.lastname: Kim
authors.forename: Tiffany
authors.initials: T
authors.lastname: Valone
authors.forename: Helen
authors.initials: H
authors.lastname: Jump
authors.forename: Dan
authors.initials: D
authors.lastname: Sullivan
mesh_terms: D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001552:Benzazepines / Q000008:administration & dosage / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019233:Retreatment; D005466:Fluorocarbons
chemical_list: D053829:Amyloid Precursor Protein Secretases; D000970:Antineoplastic Agents; D001552:Benzazepines; 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