title: Phase I open-label study of cediranib, an oral inhibitor of VEGF signalling, in combination with the oral Src inhibitor saracatinib in patients with advanced solid tumours.
abstract: Combining different targeted anticancer agents may improve clinical outcomes. This Phase I study investigated cediranib, an oral inhibitor of vascular endothelial growth factor signalling in combination with saracatinib, an oral Src inhibitor. The primary endpoint was safety/tolerability. Secondary assessments included pharmacokinetics and preliminary efficacy.
  
  
  METHODS
  Patients with advanced solid tumours received cediranib 20, 30 or 45 mg/day for 7 days followed by daily treatment with cediranib at the same dose plus saracatinib 175 mg/day.
  
  
  RESULTS
  Thirty-nine patients received cediranib (20 mg, n = 6; 30 mg, n = 6; 45 mg, n = 27 [n = 20 in cohort expansion]) plus saracatinib. In the cediranib 45 mg cohort, 59% of patients required dose reduction/pause compared with 33% in each of the other two cohorts. There was one dose-limiting toxicity (hypertension; 45 mg cohort). The most common adverse events were hypertension (67%), diarrhoea (62%), dysphonia (46%) and fatigue (39%). There was no evidence of a clinically significant effect of saracatinib on cediranib pharmacokinetics and vice versa. 22/35 evaluable patients had a best response of stable disease.
  
  
  CONCLUSIONS
  All cediranib doses were tolerated; however, in patients with advanced solid tumours, for combination with saracatinib 175 mg/day, cediranib 20 or 30 mg/day was more sustainable than 45 mg/day.
authors: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisbug-Essen Essen, Hufelandstr. 55, 45122, Essen, Germany. tanja.trarbach@uk-essen.de
authors: Tanja
authors: T
authors: Trarbach
authors: Beate
authors: B
authors: Schultheis
authors: Thomas C
authors: TC
authors: Gauler
authors: Vesile
authors: V
authors: Schneider
authors: Dirk
authors: D
authors: Strumberg
authors: Wilfried E E
authors: WE
authors: Eberhardt
authors: Stephanie
authors: S
authors: Le Scouiller
authors: Marcelo
authors: M
authors: Marotti
authors: Kathryn H
authors: KH
authors: Brown
authors: Joachim
authors: J
authors: Drevs
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D052117:Benzodioxoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007211:Indoles
chemical_list: D052117:Benzodioxoles; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D019061:src-Family Kinases; C467484:VEGFA protein, human; C515233:saracatinib; C500926:cediranib; D007211:Indoles