title: Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial.
abstract: BACKGROUND
  Cisplatin and gemcitabine is the standard first-line chemotherapy regimen for patients with advanced biliary tract cancer; expression of VEGF and its receptors is associated with adverse outcomes. We aimed to assess the effect of the addition of cediranib (an oral inhibitor of VEGF receptor 1, 2, and 3) to cisplatin and gemcitabine on progression-free survival.
  
  
  METHODS
  In this multicentre, placebo-controlled, randomised phase 2 study, we recruited patients aged 18 years or older with histologically confirmed or cytologically confirmed advanced biliary tract cancer from hepatobiliary oncology referral centres in the UK. Patients were eligible if they had an ECOG performance status of 0-1 and an estimated life expectancy of longer than 3 months. Patients were given first-line cisplatin and gemcitabine chemotherapy (25 mg/m(2) cisplatin and 1000 mg/m(2) gemcitabine [on days 1 and 8 every 21 days, for up to eight cycles]) with either 20 mg oral cediranib or placebo once a day until disease progression. We randomly assigned patients (1:1) with a minimisation algorithm, incorporating the stratification factors: extent of disease, primary disease site, previous treatment, ECOG performance status, and centre. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00939848, and was closed on Sept 30, 2014; results of the final analysis for the primary endpoint are presented.
  
  
  RESULTS
  Between April 5, 2011, and Sept 28, 2012, we enrolled 124 patients (62 in each group). With a median follow-up of 12·2 months (IQR 7·3-18·5), median progression-free survival was 8·0 months (95% CI 6·5-9·3) in the cediranib group and 7·4 months (5·7-8·5) in the placebo group (HR 0·93, 80% CI 0·74-1·19, 95% CI 0·65-1·35; p=0·72). Patients who received cediranib had more grade 3-4 toxic effects than did patients who received placebo: hypertension (23 [37%] vs 13 [21%]; p=0·05), diarrhoea (eight [13%] vs two [3%]; p=0·05); platelet count decreased (ten [16%] vs four [6%]; p=0·09), white blood cell decreased (15 [24%] vs seven [11%]; p=0·06) and fatigue (16 [24%] vs seven [11%]; p=0·04).
  
  
  CONCLUSIONS
  Cediranib did not improve the progression-free survival of patients with advanced biliary tract cancer in combination with cisplatin and gemcitabine, which remains the standard of care. Although patients in the cediranib group had more adverse events, we recorded no unexpected toxic effects. The role of VEGF inhibition in addition to chemotherapy for patients with advanced biliary tract cancer remains investigational.
  
  
  BACKGROUND
  Cancer Research UK and AstraZeneca Pharmaceuticals.
authors.affiliation: Institute of Cancer Studies, University of Manchester, Manchester, UK; The Christie NHS Foundation Trust, Manchester, UK. Electronic address: juan.valle@manchester.ac.uk.
authors.forename: Juan W
authors.initials: JW
authors.lastname: Valle
authors.affiliation: Imperial College Healthcare NHS Trust, London, UK.
authors.forename: Harpreet
authors.initials: H
authors.lastname: Wasan
authors.affiliation: Cancer Research UK and UCL Cancer Clinical Trials Centre, London, UK.
authors.forename: Andre
authors.initials: A
authors.lastname: Lopes
authors.affiliation: Institute of Cancer Studies, University of Manchester, Manchester, UK.
authors.forename: Alison C
authors.initials: AC
authors.lastname: Backen
authors.affiliation: University of Liverpool and Clatterbridge Cancer Centre, Liverpool, UK.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Palmer
authors.affiliation: Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Morris
authors.affiliation: Cancer Research UK and UCL Cancer Clinical Trials Centre, London, UK.
authors.forename: Marian
authors.initials: M
authors.lastname: Duggan
authors.affiliation: The Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.affiliation: St James University Hospital, The Leeds Teaching Hospital Trust, Beckett Street, Leeds, UK.
authors.forename: D Alan
authors.initials: DA
authors.lastname: Anthoney
authors.affiliation: Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
authors.forename: Pippa
authors.initials: P
authors.lastname: Corrie
authors.affiliation: Nottingham City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Madhusudan
authors.affiliation: Hull York Medical School, Castle Hill Hospital, Hull, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Maraveyas
authors.affiliation: Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Ross
authors.affiliation: Kent Oncology Centre, Maidstone Hospital, Kent, UK.
authors.forename: Justin S
authors.initials: JS
authors.lastname: Waters
authors.affiliation: Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust, Leicester, UK.
authors.forename: Will P
authors.initials: WP
authors.lastname: Steward
authors.affiliation: Southampton University Hospitals NHS Foundation Trust, Southampton, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Rees
authors.affiliation: Cancer Research UK and UCL Cancer Clinical Trials Centre, London, UK.
authors.forename: Sandy
authors.initials: S
authors.lastname: Beare
authors.affiliation: Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
authors.affiliation: UCL Cancer Institute, London, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Bridgewater
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D008297:Male; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom; D000093542:Gemcitabine; D007211:Indoles
chemical_list: D002945:Cisplatin; D003841:Deoxycytidine; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; D000093542:Gemcitabine; C500926:cediranib; D007211:Indoles