title: ENMD-2076, an oral inhibitor of angiogenic and proliferation kinases, has activity in recurrent, platinum resistant ovarian cancer.
abstract: OBJECTIVE
  The purpose was to assess the activity and side effect profile of ENMD-2076, an oral anti-angiogenic and anti-proliferative kinase inhibitor, in platinum-resistant recurrent epithelial ovarian cancer (EOC), fallopian tube or peritoneal cancer. Archival tumour tissue was obtained for correlative analyses.
  
  
  METHODS
  This was an open-label single-arm Phase II study of single agent ENMD-2076 taken daily orally (PO). The primary objective was to determine the progression free survival (PFS) rate at 6 months of ENMD-2076 in platinum-resistant cancer based on RECIST v1.1. Secondary objectives included response rate (RR), duration of response, overall survival (OS) and safety. An exploratory analysis of archival tissue for mitotic index and angiogenesis was conducted in an attempt to identify a sensitive or resistant patient phenotype.
  
  
  RESULTS
  64 patients were enrolled, and the PFS rate at 6 months was 22% with a median time to progression of 3.6 months. The median number of prior regimens was 2. The most common adverse events were fatigue, hypertension and diarrhoea with the most common Grade 3/4 events being hypertension and fatigue. None of the markers of mitotic index or angiogenesis evaluated in the archival tissue samples were predictive of greater benefit or resistance to ENMD-2076 treatment.
  
  
  CONCLUSIONS
  ENMD-2076 has activity in platinum-resistant ovarian cancer, and observed toxicities were similar to other PO kinase inhibitors. Additional studies with ENMD-2076 are warranted, especially in combination with active chemotherapeutic agents in platinum-resistant patients. Further work to determine appropriate biomarkers for ENMD-2076 should be incorporated into new clinical studies.
authors.affiliation: Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, United States. Ursula_matulonis@dfci.harvard.edu
authors.forename: Ursula A
authors.initials: UA
authors.lastname: Matulonis
authors.forename: Julie
authors.initials: J
authors.lastname: Lee
authors.forename: Brian
authors.initials: B
authors.lastname: Lasonde
authors.forename: William P
authors.initials: WP
authors.lastname: Tew
authors.forename: Afra
authors.initials: A
authors.lastname: Yehwalashet
authors.forename: Daniela
authors.initials: D
authors.lastname: Matei
authors.forename: Kian
authors.initials: K
authors.lastname: Behbakht
authors.forename: Jill
authors.initials: J
authors.lastname: Grothusen
authors.forename: Gini
authors.initials: G
authors.lastname: Fleming
authors.forename: Nita K
authors.initials: NK
authors.lastname: Lee
authors.forename: Jamie
authors.initials: J
authors.lastname: Arnott
authors.forename: Mark R
authors.initials: MR
authors.lastname: Bray
authors.forename: Graham
authors.initials: G
authors.lastname: Fletcher
authors.forename: Richard D
authors.initials: RD
authors.lastname: Brokx
authors.forename: Vincent
authors.initials: V
authors.lastname: Castonguay
authors.forename: Helen
authors.initials: H
authors.lastname: Mackay
authors.forename: Carolyn F
authors.initials: CF
authors.lastname: Sidor
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000401:mortality; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C551397:ENMD 2076; D011720:Pyrazoles; D011743:Pyrimidines