title: A phase I dose escalation study of the matrix metalloproteinase inhibitor BAY 12-9566 administered orally in patients with advanced solid tumours.
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 patients with advanced solid tumours, and to identify the maximum tolerated dose and dose for use in subsequent studies.
  
  
  METHODS
  BAY 12-9566 was administered to 29 patients at doses ranging from 100 mg o.d. to 1600 mg (given either 400 mg q.i.d. or 800 mg b.i.d.). Blood samples for pharmacokinetic analyses were drawn on days 1-5, day 15 and days 29 and 30. Patients were continued on daily oral treatment of BAY 12-9566 until a dose limiting toxicity or tumour progression occurred.
  
  
  RESULTS
  A maximum tolerated dose was not defined because plasma levels of BAY 12-9566 could not be sufficiently increased, even with escalating doses of drug. Pharmacokinetic analysis suggested that absorption was saturable at higher doses. The predominant toxicities related to drug were asymptomatic reversible effects on platelets and transaminases and mild anemia. There were no significant musculoskeletal toxicities. No objective responses were seen at the doses tested, but stable disease was observed in some patients based on tumour measurements.
  
  
  CONCLUSIONS
  The recommended dose of BAY 12-9566 for further studies is 800 mg b.i.d. as this dose provides maximal plasma levels that can be achieved with a convenient dosing schedule for a chronically administered oral agent.
authors.affiliation: Hamilton Regional Cancer Centre, Ontario, Canada. hal.hirte@hrcc.on.ca
authors.forename: H
authors.initials: H
authors.lastname: Hirte
authors.forename: R
authors.initials: R
authors.lastname: Goel
authors.forename: P
authors.initials: P
authors.lastname: Major
authors.forename: L
authors.initials: L
authors.lastname: Seymour
authors.forename: S
authors.initials: S
authors.lastname: Huan
authors.forename: D
authors.initials: D
authors.lastname: Stewart
authors.forename: J
authors.initials: J
authors.lastname: Yau
authors.forename: A
authors.initials: A
authors.lastname: Arnold
authors.forename: S
authors.initials: S
authors.lastname: Holohan
authors.forename: B
authors.initials: B
authors.lastname: Waterfield
authors.forename: S
authors.initials: S
authors.lastname: Bates
authors.forename: K
authors.initials: K
authors.lastname: Bennett
authors.forename: W
authors.initials: W
authors.lastname: Walsh
authors.forename: I
authors.initials: I
authors.lastname: Elias
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001713:Biphenyl Compounds; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009930:Organic Chemicals; D010654:Phenylbutyrates
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D009930:Organic Chemicals; D010654:Phenylbutyrates; C113281:Bay 12-9566