title: Phase 2 study of RO4929097, a gamma-secretase inhibitor, in metastatic melanoma: SWOG 0933.
abstract: BACKGROUND
  Aberrant Notch activation confers a proliferative advantage to many human tumors, including melanoma. This phase 2 trial assessed the antitumor activity of RO4929097, a gamma-secretase inhibitor of Notch signaling, with respect to the progression-free and overall survival of patients with advanced melanoma.
  
  
  METHODS
  Chemotherapy-naive patients with metastatic melanoma of cutaneous or unknown origin were treated orally with RO4929097 at a dose of 20 mg daily 3 consecutive days per week. A 2-step accrual design was used with an interim analysis of the first 32 patients and with continuation of enrollment if 4 or more of the 32 patients responded.
  
  
  RESULTS
  Thirty-six patients from 23 institutions were enrolled; 32 patients were evaluable. RO4929097 was well tolerated, and most toxicities were grade 1 or 2. The most common toxicities were nausea (53%), fatigue (41%), and anemia (22%). There was 1 confirmed partial response lasting 7 months, and there were 8 patients with stable disease lasting at least through week 12, with 1 of these continuing for 31 months. The 6-month progression-free survival rate was 9% (95% confidence interval [CI], 2%-22%), and the 1-year overall survival rate was 50% (95% CI, 32%-66%). Peripheral blood T-cell assays showed no significant inhibition of the production of interleukin-2, a surrogate pharmacodynamic marker of Notch inhibition, and this suggested that the drug levels were insufficient to achieve Notch target inhibition.
  
  
  CONCLUSIONS
  RO4929097 showed minimal clinical activity against metastatic melanoma in this phase 2 trial, possibly because of inadequate exposure to therapeutic drug levels. Although Notch inhibition remains a compelling target in melanoma, the results do not support further investigation of RO4929097 with this dose and schedule.
authors.affiliation: Seattle Cancer Care Alliance/University of Washington, Seattle, WA.
authors.forename: Sylvia M
authors.initials: SM
authors.lastname: Lee
authors.affiliation: SWOG Statistical Center, Seattle, WA.
authors.forename: James
authors.initials: J
authors.lastname: Moon
authors.affiliation: University of Michigan, Ann Arbor, MI.
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Redman
authors.affiliation: Columbus CCOP/Mid-Ohio Onc/Hem Inc, Columbus, OH.
authors.forename: Tarek
authors.initials: T
authors.lastname: Chidiac
authors.affiliation: Wayne State University/Karmanos Cancer Institute, Detroit, MI.
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Flaherty
authors.affiliation: University of Chicago, Chicago, IL.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zha
authors.affiliation: SWOG Statistical Center, Seattle, WA.
authors.forename: Megan
authors.initials: M
authors.lastname: Othus
authors.affiliation: UCLA Medical Center, Los Angeles, CA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: H. Lee Moffitt Cancer Center, Tampa, FL.
authors.forename: Vernon K
authors.initials: VK
authors.lastname: Sondak
authors.affiliation: University of Chicago, Chicago, IL.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
authors.affiliation: Seattle Cancer Care Alliance/University of Washington, Seattle, WA.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Margolin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001552:Benzazepines / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology; D005466:Fluorocarbons
chemical_list: D053829:Amyloid Precursor Protein Secretases; D001552:Benzazepines; D004791:Enzyme Inhibitors; D051880:Receptors, Notch; 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
keywords: Notch; RO4929097; gamma-secretase inhibitor; metastatic melanoma