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: M Eatock, J Cassidy, J Johnson, R Morrison, M Devlin, R Blackey, S Owen, L Choi, C Twelves
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 55 Issue 1 Pg. 39-46 (Jan 2005) ISSN: 0344-5704 [Print] Germany
• PMID: 15368080 (Publication Type: Clinical Trial, Journal Article)

Chemical References

• CGS 27023A
• Hydroxamic Acids
• Protease Inhibitors
• Pyrazines
• Sulfonamides
• Metalloendopeptidases
• Leucovorin
• Fluorouracil

Topics

• Administration, Oral
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacokinetics, therapeutic use)
• Colonic Neoplasms (drug therapy)
• Drug Interactions
• Female
• Fluorouracil (administration & dosage)
• Humans
• Hydroxamic Acids (administration & dosage, adverse effects, pharmacokinetics)
• Leucovorin (administration & dosage)
• Male
• Metalloendopeptidases (antagonists & inhibitors)
• Middle Aged
• Protease Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Pyrazines (administration & dosage, adverse effects, pharmacokinetics)
• Rectal Neoplasms (drug therapy)
• Sulfonamides (administration & dosage, adverse effects, pharmacokinetics)