title: Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial.
abstract: BACKGROUND
  Angiogenesis is a validated clinical target in advanced epithelial ovarian cancer. Cediranib is an oral antiangiogenic vascular endothelial growth factor receptor 1-3 inhibitor that has shown antitumour activity in recurrent ovarian cancer. We assessed efficacy and safety of cediranib in combination with platinum-based chemotherapy and as continued maintenance treatment in patients with first relapse of platinum-sensitive ovarian cancer.
  
  
  METHODS
  In this randomised, three-arm, double-blind, placebo-controlled phase 3 trial, we randomly assigned patients aged 18 years or older with relapsed platinum-sensitive ovarian cancer at 63 centres in Australia, Canada, New Zealand, Spain, and the UK. Participants received up to six cycles of platinum-based chemotherapy (once every 3 weeks) then entered a maintenance phase. Participants were randomly allocated (2:3:3), with five stratification factors and in alternating blocks, to receive placebo alongside chemotherapy and then placebo only maintenance (arm A; reference), cediranib 20 mg once-daily alongside chemotherapy then placebo only maintenance (arm B; concurrent), or cediranib 20 mg once-daily alongside chemotherapy then cediranib 20 mg once-daily maintenance (arm C; maintenance). Patients continued treatment to progression or excessive toxic effects. The primary efficacy endpoint was progression-free survival between arms A and C. Efficacy analysis was by intention to treat. Safety was assessed in all patients who received the allocated study drug. This trial is registered with ClinicalTrials.gov, number NCT00532194; the ISRCTN registry, number ISRCTN68510403; and ANZ Clinical Trials Registry, number ACTRN1261000016003.
  
  
  RESULTS
  We randomly assigned 486 [corrected] women between Nov 13, 2007, and Dec 23, 2011; results presented are for 456 patients randomly assigned subsequent to the 30mg safety phase. During a median of 19·5 months (IQR 14-26) follow-up, 113 (96%) of 118 women assigned to arm A and 141 (86%) of 164 assigned to arm C had disease progression. Median progression-free survival was 11·0 months (95% CI 10·4-11·7) in arm C and 8·7 months (7·7-9·4) in arm A (hazard ratio 0·56, 0·44-0·72, p<0·0001). 156 (90%) of 174 patients in arm B had disease progression, and median progression-free survival was 9·9 months (95% CI 9·4-10·5). Diarrhoea, neutropenia, hypertension, and voice changes were significantly more common, during chemotherapy with cediranib, and diarrhoea, hypothyroidism and voice changes were more common during maintenance. Poor compliance with cediranib was noted during maintenance treatment with toxic effects being the most common cause for discontinuation.
  
  
  CONCLUSIONS
  Cediranib, when given orally with chemotherapy and continued as maintenance, yielded a meaningful improvement [corrected] in progression-free survival in women with recurrent platinum-sensitive ovarian cancer, albeit with added toxic effects. The positive results in ICON6 could provide women with a new therapeutic option for recurrent ovarian cancer. Assessment of the secondary endpoint of overall survival will need longer follow-up.
  
  
  BACKGROUND
  Medical Research Council, Cancer Research UK, Canadian Cancer Society Research Institute, Cancer Australia, National Gynecological Cancer Centre, and AstraZeneca.
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, University College London and UCL Hospitals, London, UK. Electronic address: j.ledermann@ucl.ac.uk.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Ledermann
authors.affiliation: Medical Research Council Clinical Trials Unit at UCL, University College London, London, UK.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Embleton
authors.affiliation: University College London Hospitals, London, UK.
authors.forename: Fharat
authors.initials: F
authors.lastname: Raja
authors.affiliation: St James's Institute of Oncology and Leeds Institute of Cancer Medicine and Pathology, Leeds, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Perren
authors.affiliation: Christie Hospital and University of Manchester, Manchester, UK.
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Jayson
authors.affiliation: Mount Vernon Cancer Centre, Northwood, UK.
authors.forename: Gordon J S
authors.initials: GJS
authors.lastname: Rustin
authors.affiliation: Royal Marsden Hospital, London, UK.
authors.forename: Stan B
authors.initials: SB
authors.lastname: Kaye
authors.affiliation: Juravinski Cancer Centre and McMaster University, Hamilton, ON, Canada.
authors.forename: Hal
authors.initials: H
authors.lastname: Hirte
authors.affiliation: Canadian Cancer Trials Group (CCTG) and Queen's University, Kingston, ON, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Eisenhauer
authors.affiliation: Christchurch Hospital, Christchurch, New Zealand.
authors.forename: Michelle
authors.initials: M
authors.lastname: Vaughan
authors.affiliation: Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Friedlander
authors.affiliation: Spanish Group for Investigation in Ovarian Cancer (GEICO) and MD Anderson Cancer Center Madrid, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: González-Martín
authors.affiliation: University of Leeds, Leeds, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Stark
authors.affiliation: Medical Research Council Clinical Trials Unit at UCL, University College London, London, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Clark
authors.affiliation: Medical Research Council Clinical Trials Unit at UCL, University College London, London, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Farrelly
authors.affiliation: University of East Anglia, Norwich, UK.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Swart
authors.affiliation: Medical Research Council Clinical Trials Unit at UCL, University College London, London, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Cook
authors.affiliation: Medical Research Council Clinical Trials Unit at UCL, University College London, London, UK.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Kaplan
authors.affiliation: Medical Research Council Clinical Trials Unit at UCL, University College London, London, UK.
authors.forename: Mahesh K B
authors.initials: MKB
authors.lastname: Parmar
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D000077216:Carcinoma, Ovarian Epithelial; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011446:Prospective Studies; D011799:Quinazolines / Q000008:administration & dosage; D016896:Treatment Outcome; D007211:Indoles
chemical_list: D016190:Carboplatin; D011799:Quinazolines; C500926:cediranib; D007211:Indoles