title: A dose-finding and pharmacokinetic study of the matrix metalloproteinase inhibitor MMI270 (previously termed CGS27023A) with 5-FU and folinic acid.
abstract: The orally bioavailable matrix metalloproteinase inhibitor MMI270 reduces tumour growth metastasis in preclinical models. We assessed the feasibility and pharmacokinetic interactions of combining MMI270 with 5-fluorouracil (5-FU) and folinic acid (FA). Entered into the study were 33 patients with advanced colorectal cancer. They received FA 200 mg/m2 over 2 h followed by 5-FU 400 mg/m2 over 15 min and 5-FU 600 mg/m2 over 22 h on days 1 and 2 of a 14-day cycle. MMI270 commenced with the second cycle at either 50 mg once daily, 150 mg three times daily or 300 mg twice daily. No dose-limiting toxicity was observed at any MMI270 dose level. Ten patients (61%) experienced joint symptoms independent of MMI270 dose, leading to interruption, modification, or discontinuation of treatment in seven patients (23%). MMI270 did not alter 5-FU pharmacokinetics. Six patients had a partial response and seven had stable disease. 5-FU/FA with MMI270 at a dose of 300 mg twice daily is well tolerated. MMI270 has no significant effect on 5-FU pharmacokinetics.
authors.affiliation: Cancer Research UK Department of Medical Oncology, Beatson Laboratories, Alexander Stone Building, Garscube Estate, Switchback Road, Glasgow, UK. martin.eatock@bch.n-i.nhs.uk
authors.forename: M
authors.initials: M
authors.lastname: Eatock
authors.forename: J
authors.initials: J
authors.lastname: Cassidy
authors.forename: J
authors.initials: J
authors.lastname: Johnson
authors.forename: R
authors.initials: R
authors.lastname: Morrison
authors.forename: M
authors.initials: M
authors.lastname: Devlin
authors.forename: R
authors.initials: R
authors.lastname: Blackey
authors.forename: S
authors.initials: S
authors.lastname: Owen
authors.forename: L
authors.initials: L
authors.lastname: Choi
authors.forename: C
authors.initials: C
authors.lastname: Twelves
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D008875:Middle Aged; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D012004:Rectal Neoplasms / Q000188:drug therapy*; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*
chemical_list: C097658:CGS 27023A; D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D013449:Sulfonamides; D008666:Metalloendopeptidases; D002955:Leucovorin; D005472:Fluorouracil