title: A randomized, double-blind phase II study evaluating cediranib versus cediranib and saracatinib in patients with relapsed metastatic clear-cell renal cancer (COSAK).
abstract: Preclinical work suggests SRC proteins have a role in the development of resistance to vascular endothelial growth factor (VEGF) targeted therapy in metastatic clear-cell renal cancer (mRCC). This hypothesis was tested in this trial using the SRC inhibitor saracatinib and the VEGF inhibitor cediranib.
  
  
  
  Patients with disease progression after ≥1 VEGF-targeted therapy were eligible to participate in this double-blind, randomized (1:1) phase II study. The study compared the combination cediranib 30 mg once daily (o.d.) and saracatinib 175 mg o.d. (CS) (n = 69) or cediranib 45 mg o.d. and placebo o.d. (C) (n = 69). Archived tissue was used for biomarker analysis [SRC, focal adhesion kinase (FAK), von Hippel-Lindau, protein tyrosine phosphatase 1b and hypoxia-inducible factor 2α : n = 86]. The primary end point was progression-free survival (PFS) by RECIST v1.1.
  
  
  
  Between 2010 and 2012, 138 patients were randomized across 16 UK sites. The characteristics of the two groups were well balanced. Partial responses were seen in 13.0% for C and 14.5% for CS (P > 0.05). There was no significant difference in PFS [5.4 months (3.6-7.3 months) for C and 3.9 (2.4-5.3 months) for CS; hazard ratio (HR) 1.18 (0.94-1.48)] or overall survival (OS) [14.2 months (11.2-16.8 months) for C and 10.0 (6.7-13.2 months) for CS; HR 1.28 (1.00-1.63)]. There was no significant difference in the frequency of key adverse events, dose reductions or drug discontinuations. None of the biomarkers were prognostic for PFS or OS. FAK overexpression correlated with an OS benefit [HR 2.29 (1.09-4.82), P > 0.05], but not PFS, for CS.
  
  
  
  Saracatinib did not increase the efficacy of a VEGF-targeted therapy (cediranib) in this setting. Biomarker analysis did not identify consistent predictive biomarkers.
  
  
  
  NCT00942877.
authors.affiliation: Department of Medical Oncology, The Royal Free NHS Foundation Trust, London Barts Cancer Institute, CRUK Experiment Cancer Medicine Centre, London thomas.powles@bartshealth.nhs.uk.
authors.forename: T
authors.initials: T
authors.lastname: Powles
authors.affiliation: Department of Medical Oncology, University of Sheffield, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield Department of Medical Oncology, University of Leeds, Leeds Teaching Hospitals NHS Trust, Leeds, West Yorkshire.
authors.forename: J
authors.initials: J
authors.lastname: Brown
authors.affiliation: Department of Medical Oncology, The Royal Marsden Hospital, London.
authors.forename: J
authors.initials: J
authors.lastname: Larkin
authors.affiliation: The Beatson Cancer Centre, University of Glasgow, Glasgow.
authors.forename: R
authors.initials: R
authors.lastname: Jones
authors.affiliation: Department of Medical Oncology, University of Leeds, Leeds Teaching Hospitals NHS Trust, Leeds, West Yorkshire.
authors.forename: C
authors.initials: C
authors.lastname: Ralph
authors.affiliation: Department of Medical Oncology, The Christie Hospital, Manchester.
authors.forename: R
authors.initials: R
authors.lastname: Hawkins
authors.affiliation: Department of Medical Oncology, Guys and St Thomas' NHS Foundation Trust, London.
authors.forename: S
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Department of Medical Oncology, The Royal Free NHS Foundation Trust, London.
authors.forename: E
authors.initials: E
authors.lastname: Boleti
authors.affiliation: Department of Oncology, University Hospital Bristol NHS Foundation trust, Bristol.
authors.forename: A
authors.initials: A
authors.lastname: Bhal
authors.affiliation: Addenbrooke's Cancer Centre, University of Cambridge, Cambridge.
authors.forename: K
authors.initials: K
authors.lastname: Fife
authors.affiliation: Department of Medical Oncology, West Sussex Cancer Centre, Brighton.
authors.forename: A
authors.initials: A
authors.lastname: Webb
authors.affiliation: Cancer Sciences Unit, Southampton NHS Foundation Trust, Southampton.
authors.forename: S
authors.initials: S
authors.lastname: Crabb
authors.affiliation: Department of Medical Oncology, Royal Bournemouth Hospital, Bournemouth.
authors.forename: T
authors.initials: T
authors.lastname: Geldart
authors.affiliation: Scottish Clinical Trials Research Unit (SCTRU), Partners in CaCTUS, Edinburgh.
authors.forename: R
authors.initials: R
authors.lastname: Hill
authors.affiliation: Scottish Clinical Trials Research Unit (SCTRU), Partners in CaCTUS, Edinburgh.
authors.forename: J
authors.initials: J
authors.lastname: Dunlop
authors.affiliation: Barts Cancer Institute, CRUK Experiment Cancer Medicine Centre, London.
authors.forename: P E
authors.initials: PE
authors.lastname: Hall
authors.affiliation: Edinburgh Cancer Centre, Western General Hospital, Edinburgh.
authors.forename: D
authors.initials: D
authors.lastname: McLaren
authors.affiliation: Barts Cancer Institute, CRUK Experiment Cancer Medicine Centre, London.
authors.forename: C
authors.initials: C
authors.lastname: Ackerman
authors.affiliation: Barts Cancer Institute, CRUK Experiment Cancer Medicine Centre, London.
authors.forename: L
authors.initials: L
authors.lastname: Beltran
authors.affiliation: Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, UK.
authors.forename: P
authors.initials: P
authors.lastname: Nathan
mesh_terms: D000368:Aged; D052117:Benzodioxoles / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D016016:Proportional Hazards Models; D011799:Quinazolines / Q000008:administration & dosage*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics; D007211:Indoles
chemical_list: D052117:Benzodioxoles; D014408:Biomarkers, Tumor; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; C467484:VEGFA protein, human; C515233:saracatinib; C500926:cediranib; D007211:Indoles
keywords: SRC; VEGF; biomarker; renal cell carcinoma; tyrosine kinase inhibitor