title: An NCIC CTG phase I/pharmacokinetic study of the matrix metalloproteinase and angiogenesis inhibitor BAY 12-9566 in combination with 5-fluorouracil/leucovorin.
abstract: BACKGROUND
  This phase I study was performed to evaluate the safety, tolerability, and efficacy of the oral matrix metalloproteinase inhibitor BAY 12-9566 in combination with 5-fluorouracil/leucovorin in patients with advanced solid tumours, and to identify the maximum tolerated dose and the dose for use in future studies.
  
  
  METHODS
  BAY 12-9566 and 5-fluorouracil/leucovorin were administered to 17 patients in 3 cohorts. Each patient served as his/her own control, with 5-fluorouracil being given alone on days 1-5 of cycle 1. In cohort 1, BAY 12-9566 at 800 mg p.o. b.i.d. was given with 350 mg/m2 5-fluorouracil/20 mg/m2 leucovorin x 5 days q28 days. In cohort 2, the BAY 12-9566 dose was reduced to 400 mg p.o. b.i.d., with the 5-fluorouracil/leucovorin doses remaining unchanged. Finally, in cohort 3, BAY 12-9566 400 mg bid was given with 5-fluorouracil 400 mg/m2/day. Patients were continued on therapy until unacceptable toxicity or tumour progression occurred. Pharmacokinetic analyses for both BAY 12-9566 and 5-fluorouracil were performed.
  
  
  RESULTS
  The maximum tolerated dose was 400 mg p.o. b.i.d. BAY 12-9566 plus 5-fluorouracil/leucovorin at 400 mg/m2/day and 20 mg/m2/day, respectively. Thrombocytopenia necessitated a decrease of the dose of BAY 12-9566 by 50% from cohort 1 to cohort 2. Two dose-limiting toxicities occurred in cohort 3 consisting of neutropenic fever, and ileitis, causing severe diarrhea. Of 17 patients treated on study, 7 of 14 patients evaluable for response achieved stable disease. Pharmacokinetic analysis suggested there was no interaction between BAY 12-9566 and 5-fluorouracil.
  
  
  CONCLUSIONS
  BAY 12-9566 400 mg bid and 5-fluorouracil 350 mg/m2 plus leucovorin 20 mg/m2 can be co-administered. Although there is some evidence of a clinical interaction, there is no apparent pharmacokinetic interaction. Future studies with these 2 types of agents administered in combination are warranted.
authors.affiliation: Ottawa Regional Cancer Centre, Ottawa, Ontario, Canada. rgoel@ottawahospital.on.ca
authors.forename: R
authors.initials: R
authors.lastname: Goel
authors.forename: E
authors.initials: E
authors.lastname: Chouinard
authors.forename: D J
authors.initials: DJ
authors.lastname: Stewart
authors.forename: S
authors.initials: S
authors.lastname: Huan
authors.forename: H
authors.initials: H
authors.lastname: Hirte
authors.forename: S
authors.initials: S
authors.lastname: Stafford
authors.forename: B
authors.initials: B
authors.lastname: Waterfield
authors.forename: J
authors.initials: J
authors.lastname: Roach
authors.forename: C
authors.initials: C
authors.lastname: Lathia
authors.forename: V
authors.initials: V
authors.lastname: Agarwal
authors.forename: R
authors.initials: R
authors.lastname: Humphrey
authors.forename: W
authors.initials: W
authors.lastname: Walsh
authors.forename: S
authors.initials: S
authors.lastname: Matthews
authors.forename: L
authors.initials: L
authors.lastname: Seymour
mesh_terms: D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics*; D001713:Biphenyl Compounds; D002170:Canada; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply / Q000378:metabolism*; D002955:Leucovorin / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000098:blood supply / Q000378:metabolism*; D008175:Lung Neoplasms / Q000098:blood supply / Q000378:metabolism*; D008207:Lymphatic Metastasis / Q000473:pathology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020714:Maximum Tolerated Dose; D009930:Organic Chemicals / Q000008:administration & dosage; D010654:Phenylbutyrates; D012449:Safety; D016879:Salvage Therapy
chemical_list: D020533:Angiogenesis Inhibitors; D001713:Biphenyl Compounds; D061965:Matrix Metalloproteinase Inhibitors; D009930:Organic Chemicals; D010654:Phenylbutyrates; C113281:Bay 12-9566; D002955:Leucovorin; D005472:Fluorouracil