title: Multi-Center Randomized Phase II Study Comparing Cediranib plus Gefitinib with Cediranib plus Placebo in Subjects with Recurrent/Progressive Glioblastoma.
abstract: BACKGROUND
  Cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, failed to show benefit over lomustine in relapsed glioblastoma. One resistance mechanism for cediranib is up-regulation of epidermal growth factor receptor (EGFR). This study aimed to determine if dual therapy with cediranib and the oral EGFR inhibitor gefitinib improved outcome in recurrent glioblastoma.
  
  
  RESULTS
  This was a multi-center randomized, two-armed, double-blinded phase II study comparing cediranib plus gefitinib versus cediranib plus placebo in subjects with first relapse/first progression of glioblastoma following surgery and chemoradiotherapy. The primary outcome measure was progression free survival (PFS). Secondary outcome measures included overall survival (OS) and radiologic response rate. Recruitment was terminated early following suspension of the cediranib program. 38 subjects (112 planned) were enrolled with 19 subjects in each treatment arm. Median PFS with cediranib plus gefitinib was 3.6 months compared to 2.8 months for cediranib plus placebo (HR; 0.72, 90% CI; 0.41 to 1.26). Median OS was 7.2 months with cediranib plus gefitinib and 5.5 months with cediranib plus placebo (HR; 0.68, 90% CI; 0.39 to 1.19). Eight subjects (42%) had a partial response in the cediranib plus gefitinib arm versus five patients (26%) in the cediranib plus placebo arm.
  
  
  CONCLUSIONS
  Cediranib and gefitinib in combination is tolerated in patients with glioblastoma. Incomplete recruitment led to the study being underpowered. However, a trend towards improved survival and response rates with the addition of gefitinib to cediranib was observed. Further studies of the combination incorporating EGFR and VEGF inhibition are warranted.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01310855.
authors.affiliation: University College London Hospitals, London, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Brown
authors.affiliation: The Christie NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: McBain
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Nash
authors.affiliation: Bristol Haematology and Oncology Centre, Bristol, United Kingdom.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hopkins
authors.affiliation: Hall Edwards Radiotherapy Research Group, University Hospital Birmingham, Birmingham, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Sanghera
authors.affiliation: Department of Radiotherapy and Paediatric Oncology, Royal Marsden NHS Trust, Sutton, United Kingdom.
authors.forename: Frank
authors.initials: F
authors.lastname: Saran
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Phillips
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, United Kingdom.
authors.forename: Fiona
authors.initials: F
authors.lastname: Dungey
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Clifton-Hadley
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, United Kingdom.
authors.forename: Katharina
authors.initials: K
authors.lastname: Wanek
authors.affiliation: Department of Academic Oncology, Royal Free Hospital, London, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Krell
authors.affiliation: Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Jeffries
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, United Kingdom.
authors.forename: Iftekhar
authors.initials: I
authors.lastname: Khan
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Smith
authors.affiliation: UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Mulholland
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D010919:Placebos; D011788:Quality of Life; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D012008:Recurrence; D012449:Safety; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D007211:Indoles
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077156:Gefitinib; D010919:Placebos; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; C512478:EGFR protein, human; C500926:cediranib; D007211:Indoles