title: A Phase II, randomized, double-blind study of zibotentan (ZD4054) in combination with carboplatin/paclitaxel versus placebo in combination with carboplatin/paclitaxel in patients with advanced ovarian cancer sensitive to platinum-based chemotherapy (AGO-OVAR 2.14).
abstract: BACKGROUND
  In platinum-sensitive relapsed ovarian cancer, paclitaxel plus carboplatin is a standard second-line treatment. Zibotentan (ZD4054) is an oral, specific ETA-receptor antagonist with demonstrated antitumour activity in xenograft models of human ovarian cancer.
  
  
  METHODS
  In this Phase II, randomized, placebo-controlled study, patients with relapsed ovarian cancer sensitive to platinum-based chemotherapy received zibotentan 10mg or placebo once-daily, plus paclitaxel 175 mg/m(2) iv followed by carboplatin iv (AUC 5) on day 1 of every 3-week cycle for a maximum of eight cycles. The primary endpoint was progression-free survival (PFS), evaluated by Response Evaluation Criteria In Solid Tumours (RECIST). Secondary and exploratory endpoints included objective tumour response rate, tumour size, CA-125/RECIST progression, and safety and tolerability.
  
  
  RESULTS
  A total of 120 patients were randomized (zibotentan: n=59; placebo: n=61). Addition of zibotentan 10mg/day to carboplatin and paclitaxel did not improve PFS compared with placebo (median PFS, 7.6 versus 10.0 months, respectively; HR=1.46, [80% CI: 1.10-1.94]; P=0.0870). No improvements in any of the secondary or exploratory efficacy endpoints were observed for patients receiving zibotentan compared with placebo. Median duration of total treatment exposure was 6.7 months. Total chemotherapy dose received was lower for zibotentan-treated versus placebo-treated patients (carboplatin: -16%; paclitaxel: -14%). The most common adverse events in the zibotentan arm were anaemia, nausea, alopecia, headache and neutropenia (43-48% of patients).
  
  
  CONCLUSIONS
  Zibotentan 10mg/day plus carboplatin and paclitaxel did not result in an improvement in PFS compared with chemotherapy alone in patients with advanced ovarian cancer sensitive to platinum-based chemotherapy. No unexpected safety concerns were identified.
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy. cognetti@ifo.it
authors.forename: F
authors.initials: F
authors.lastname: Cognetti
authors.forename: A
authors.initials: A
authors.lastname: Bagnato
authors.forename: N
authors.initials: N
authors.lastname: Colombo
authors.forename: A
authors.initials: A
authors.lastname: Savarese
authors.forename: G
authors.initials: G
authors.lastname: Scambia
authors.forename: J
authors.initials: J
authors.lastname: Sehouli
authors.forename: P
authors.initials: P
authors.lastname: Wimberger
authors.forename: R
authors.initials: R
authors.lastname: Sorio
authors.forename: P
authors.initials: P
authors.lastname: Harter
authors.forename: E
authors.initials: E
authors.lastname: Mari
authors.forename: S
authors.initials: S
authors.lastname: McIntosh
authors.forename: F
authors.initials: F
authors.lastname: Nathan
authors.forename: K
authors.initials: K
authors.lastname: Pemberton
authors.forename: K
authors.initials: K
authors.lastname: Baumann
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D000077216:Carcinoma, Ovarian Epithelial; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D010919:Placebos; D011759:Pyrrolidines / Q000008:administration & dosage / Q000009:adverse effects; D055815:Young Adult
chemical_list: D010919:Placebos; D011759:Pyrrolidines; C511404:ZD4054; D016190:Carboplatin; D017239:Paclitaxel