title: Phase I study of cediranib in combination with oxaliplatin and infusional 5-Fluorouracil in patients with advanced colorectal cancer.
abstract: OBJECTIVE
  Cediranib is a potent oral inhibitor of the tyrosine kinase activity associated with all subtypes of vascular endothelial growth factor receptor. Purposes of this study were to determine the recommended phase II dose of cediranib in combination with standard doses of modified FOLFOX-6 (mFOLFOX-6), and the tolerability, safety, pharmacokinetics, and antitumor activity of this combination in patients with untreated metastatic colorectal cancer.
  
  
  METHODS
  Cediranib was administered daily orally at a starting dose of 30 mg and escalated to 45 mg daily, and mFOLFOX-6 was repeated every 14 days. Pharmacokinetic studies were done for oxaliplatin, 5-fluorouracil, and cediranib. Response was assessed by Response Evaluation Criteria in Solid Tumors every four cycles.
  
  
  RESULTS
  Sixteen patients received 150 cycles of treatment (median, 6; range, 1-20 cycles). Of 9 patients enrolled at the 30-mg dose level, 1 patient experienced grade 3 diarrhea during cycle 1. No dose-limiting toxicity was observed in 7 patients at the 45-mg dose level. Common grade 3 toxicities related to cediranib included hypertension, diarrhea, fatigue, and anorexia. Of 14 patients evaluable for response, there were 6 partial responses (42.9%; 95% confidence interval, 17.7-71.1%) and 6 stable disease. The median progression-free survival was 9.3 months. There were no pharmacokinetic interactions between cediranib and 5-fluorouracil or free plasma intact oxaliplatin.
  
  
  CONCLUSIONS
  Toxicities of this combination were manageable and consistent with previous studies. The recommended phase II dose is cediranib at 30 mg daily continuously in combination with standard doses of mFOLFOX-6. Cediranib and mFOLFOX-6 has promising antitumor activity and this combination warrants further investigation.
authors.affiliation: The National Cancer Institute of Canada, Clinical Trials Group, Kingston, ON, Canada. eric.chen@uhn.on.ca
authors.forename: Eric
authors.initials: E
authors.lastname: Chen
authors.forename: Derek
authors.initials: D
authors.lastname: Jonker
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gauthier
authors.forename: Martha
authors.initials: M
authors.lastname: MacLean
authors.forename: Julie
authors.initials: J
authors.lastname: Wells
authors.forename: Jean
authors.initials: J
authors.lastname: Powers
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007211:Indoles
chemical_list: D005472:Fluorouracil; D002955:Leucovorin; D009944:Organoplatinum Compounds; D011799:Quinazolines; C500926:cediranib; D007211:Indoles