title: A phase II study of single-agent RO4929097, a gamma-secretase inhibitor of Notch signaling, in patients with recurrent platinum-resistant epithelial ovarian cancer: A study of the Princess Margaret, Chicago and California phase II consortia.
abstract: OBJECTIVE
  A phase II study was performed to evaluate the efficacy and safety of single-agent RO4929097 (a gamma-secretase inhibitor) in patients with recurrent platinum-resistant ovarian cancer.
  
  
  METHODS
  Women with progressive platinum-resistant ovarian cancer treated with ≤2 chemotherapy regimens for recurrent disease were enrolled in this trial. Patients received oral RO4929097 at 20 mg once daily, 3 days on/4 days off each week in a three week cycle. The primary endpoint was progression-free survival (PFS) rate at the end of 4 cycles. Secondary objectives included assessment of the safety of RO4929097 and exploration of molecular correlates of outcome in archival tumor tissue and serum.
  
  
  RESULTS
  Of 45 patients enrolled, 40 were evaluable for response. Thirty-seven (82%) patients had high-grade ovarian cancer. No objective responses were observed. Fifteen patients (33%) had stable disease as their best response, with a median duration of 3.1 months. The median PFS for the whole group was 1.3 months (1.2-2.5). Treatment was generally well tolerated with 10% of patients discontinuing treatment due to an adverse event. In high grade serous ovarian cancer patients, the median PFS trended higher when the expression of intracellular Notch (NICD) protein by immunohistochemistry was high versus low (3.3 versus 1.3 months, p=0.09). No clear relationship between circulating angiogenic factors and PFS was found despite a suggestion of an improved outcome with higher baseline VEGFA levels.
  
  
  CONCLUSIONS
  RO4929097 has insufficient activity as a single-agent in platinum-resistant ovarian cancer to warrant further study as monotherapy. Future studies are needed to explore the potential for cohort enrichment using NICD expression.
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Ivan
authors.initials: I
authors.lastname: Diaz-Padilla
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Wilson
authors.affiliation: Department of Laboratory Medicine, University of Toronto, Toronto, Canada.
authors.forename: Blaise A
authors.initials: BA
authors.lastname: Clarke
authors.affiliation: Division of Medical Oncology, Juravinski Cancer Centre, Hamilton, Ontario, Canada.
authors.forename: Hal W
authors.initials: HW
authors.lastname: Hirte
authors.affiliation: Division of Medical Oncology, London Regional Cancer Program, London, Ontario, Canada.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Welch
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Mackay
authors.affiliation: Department of Oncology, Cancer Centre of Southeastern Ontario, Kingston, Ontario, Canada.
authors.forename: Jim J
authors.initials: JJ
authors.lastname: Biagi
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Reedijk
authors.affiliation: Division of Gynecologic Oncology, The Ottawa Hospital, Ottawa, Ontario, Canada.
authors.forename: Johanne I
authors.initials: JI
authors.lastname: Weberpals
authors.affiliation: The University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: Gini F
authors.initials: GF
authors.lastname: Fleming
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Chantale
authors.initials: C
authors.lastname: Blattler
authors.affiliation: National Cancer Institute, Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program, Investigational Drug Branch, Rockville, MD, USA.
authors.forename: S Percy
authors.initials: SP
authors.lastname: Ivy
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Electronic address: amit.oza@uhn.ca.
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D001552:Benzazepines / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002140:California; D000077216:Carcinoma, Ovarian Epithelial; D002641:Chicago; D018572:Disease-Free Survival; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D009864:Ontario; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D005466:Fluorocarbons
chemical_list: D053829:Amyloid Precursor Protein Secretases; D001552:Benzazepines; D014408:Biomarkers, Tumor; 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: Gamma-secretase inhibitor; Notch; Ovarian cancer; Phase II clinical trial; RO4929097