title: Phase I dose-escalation study to determine the safety, pharmacokinetics and pharmacodynamics of brivanib alaninate in combination with full-dose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy.
abstract: BACKGROUND
  The objectives of this phase I study were to determine the safety, pharmacokinetics (PK), pharmacodynamics and efficacy of brivanib combined with full-dose cetuximab in patients with advanced gastrointestinal malignancies.
  
  
  METHODS
  Patients with advanced gastrointestinal malignancies who had failed prior therapies received brivanib (320, 600 or 800 mg daily) plus cetuximab (400 mg m(-2) loading dose then 250 mg m(-2) weekly). Assessments included adverse events, PK, tumour response, 2[18F]fluoro-2-deoxyglucose positron-emitting tomography and K-Ras mutation analyses.
  
  
  RESULTS
  Toxicities observed were manageable; the most common treatment-related toxicities (>10% of patients) were fatigue, diarrhoea, anorexia, increase in aspartate aminotransferase and alanine aminotransferase, acneiform dermatitis, headache, mucosal inflammation, nausea, dry skin, vomiting, hypertension, pruritus, proteinuria and weight loss. Of 62 patients, 6 (9.7%) had objective radiographic partial responses, with an overall response rate of 10%. Median duration of response was 9.2 months; median progression-free survival was 3.9 months.
  
  
  CONCLUSIONS
  The acceptable toxicity profile and efficacy of brivanib observed in this study were promising. These findings are being further evaluated in a phase III study of brivanib plus cetuximab vs cetuximab alone in patients previously treated with combination chemotherapy for K-Ras wild-type advanced metastatic colorectal cancer.
authors.affiliation: Department of Gastrointestinal Oncology, Unit 426, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA. cgarrett@mdanderson.org
authors.forename: C R
authors.initials: CR
authors.lastname: Garrett
authors.forename: L L
authors.initials: LL
authors.lastname: Siu
authors.forename: A
authors.initials: A
authors.lastname: El-Khoueiry
authors.forename: J
authors.initials: J
authors.lastname: Buter
authors.forename: C M
authors.initials: CM
authors.lastname: Rocha-Lima
authors.forename: J
authors.initials: J
authors.lastname: Marshall
authors.forename: P
authors.initials: P
authors.lastname: LoRusso
authors.forename: P
authors.initials: P
authors.lastname: Major
authors.forename: J
authors.initials: J
authors.lastname: Chemidlin
authors.forename: O
authors.initials: O
authors.lastname: Mokliatchouk
authors.forename: L
authors.initials: L
authors.lastname: Velasquez
authors.forename: W
authors.initials: W
authors.lastname: Hayes
authors.forename: D
authors.initials: D
authors.lastname: Feltquate
authors.forename: S
authors.initials: S
authors.lastname: Syed
authors.forename: S
authors.initials: S
authors.lastname: Ford
authors.forename: G
authors.initials: G
authors.lastname: Kollia
authors.forename: S
authors.initials: S
authors.lastname: Galbraith
authors.forename: D S A
authors.initials: DS
authors.lastname: Nuyten
mesh_terms: D000328:Adult; D000368:Aged; D000409:Alanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D000068818:Cetuximab; D004359:Drug Therapy, Combination; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000473:pathology; D016879:Salvage Therapy; D015996:Survival Rate; D014018:Tissue Distribution; D016896:Treatment Outcome; D014227:Triazines / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014227:Triazines; C509922:brivanib; D040301:Vascular Endothelial Growth Factor Receptor-2; D000409:Alanine; D000068818:Cetuximab