title: Cediranib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trial.
abstract: BACKGROUND
  Patients treated with standard chemotherapy for metastatic or relapsed cervical cancer respond poorly to conventional chemotherapy (response achieved in 20-30% of patients) with an overall survival of less than 1 year. High tumour angiogenesis and high concentrations of intratumoural VEGF are adverse prognostic features. Cediranib is a potent tyrosine kinase inhibitor of VEGFR1, 2, and 3. In this trial, we aimed to assess the effect of the addition of cediranib to carboplatin and paclitaxel chemotherapy in patients with metastatic or recurrent cervical cancer.
  
  
  METHODS
  In this randomised, double-blind, placebo-controlled phase 2 trial, which was done in 17 UK cancer treatment centres, patients aged 18 years or older initially diagnosed with metastatic carcinoma or who subsequently developed metastatic disease or local pelvic recurrence after radical treatment that was not amenable to exenterative surgery were recruited. Eligible patients received carboplatin AUC of 5 plus paclitaxel 175 mg/m(2) by infusion every 3 weeks for a maximum of six cycles and were randomised centrally (1:1) through a minimisation approach to receive cediranib 20 mg or placebo orally once daily until disease progression. The stratification factors were disease site, disease-free survival after primary therapy or primary stage IVb disease, number of lines of previous treatment, Eastern Cooperative Oncology Group performance status, and investigational site. All patients, investigators, and trial personnel were masked to study drug allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat, and the safety analysis included all patients who received at least one dose of study drug. This trial is registered with the ISCRTN registry, number ISRCTN23516549, and has been completed.
  
  
  RESULTS
  Between Aug 19, 2010, and July 27, 2012, 69 patients were enrolled and randomly assigned to cediranib (n=34) or placebo (n=35). After a median follow-up of 24·2 months (IQR 21·9-29·5), progression-free survival was longer in the cediranib group (median 8·1 months [80% CI 7·4-8·8]) than in the placebo group (6·7 months [6·2-7·2]), with a hazard ratio (HR) of 0·58 (80% CI 0·40-0·85; one-sided p=0·032). Grade 3 or worse adverse events that occurred in the concurrent chemotherapy and trial drug period in more than 10% of patients were diarrhoea (five [16%] of 32 patients in the cediranib group vs one [3%] of 35 patients in the placebo group), fatigue (four [13%] vs two [6%]), leucopenia (five [16%] vs three [9%]), neutropenia (10 [31%] vs four [11%]), and febrile neutropenia (five [16%] vs none). The incidence of grade 2-3 hypertension was higher in the cediranib group than in the control group (11 [34%] vs four [11%]). Serious adverse events occurred in 18 patients in the placebo group and 19 patients in the cediranib group.
  
  
  CONCLUSIONS
  Cediranib has significant efficacy when added to carboplatin and paclitaxel in the treatment of metastatic or recurrent cervical cancer. This finding was accompanied by an increase in toxic effects (mainly diarrhoea, hypertension, and febrile neutropenia).
  
  
  BACKGROUND
  Cancer Research UK and AstraZeneca.
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester, UK. Electronic address: rps8@le.ac.uk.
authors.forename: R Paul
authors.initials: RP
authors.lastname: Symonds
authors.affiliation: University of Edinburgh Cancer Research UK Centre, MRC IGMM, Edinburgh, UK.
authors.forename: Charlie
authors.initials: C
authors.lastname: Gourley
authors.affiliation: The Christie NHS Foundation Trust, Manchester, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Davidson
authors.affiliation: Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Carty
authors.affiliation: Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Elaine
authors.initials: E
authors.lastname: McCartney
authors.affiliation: Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Debbie
authors.initials: D
authors.lastname: Rai
authors.affiliation: Gynaecology Unit, Royal Marsden Hospital NHS Foundation Trust, London, UK.
authors.forename: Susana
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Institute of Oncology, Leeds Cancer Centre, St James's University Hospital, Leeds UK.
authors.forename: David
authors.initials: D
authors.lastname: Jackson
authors.affiliation: Clatterbridge Centre for Oncology, University of Liverpool, Liverpool, UK.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Lord
authors.affiliation: Oncology Department, University College Hospital, London, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: McCormack
authors.affiliation: Velindre Hospital, Cardiff, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Hudson
authors.affiliation: Beatson West of Scotland Cancer Centre, Gartnavel General Hospital, Glasgow, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Reed
authors.affiliation: Oncology Department, Poole Hospital, Dorset, UK.
authors.forename: Maxine
authors.initials: M
authors.lastname: Flubacher
authors.affiliation: Musgrove Park Hospital, Taunton and Somerset NHS Foundation Trust, Taunton, UK.
authors.forename: Petra
authors.initials: P
authors.lastname: Jankowska
authors.affiliation: St Bartholomew's Hospital, London, UK.
authors.forename: Melanie
authors.initials: M
authors.lastname: Powell
authors.affiliation: Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
authors.affiliation: Institute of Cancer Sciences, University of Manchester, Manchester, UK.
authors.forename: Catharine M L
authors.initials: CML
authors.lastname: West
authors.affiliation: Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: James
authors.initials: J
authors.lastname: Paul
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D007211:Indoles
chemical_list: D000970:Antineoplastic Agents; D016190:Carboplatin; D017239:Paclitaxel; D011799:Quinazolines; C500926:cediranib; D007211:Indoles