A dose-finding and pharmacokinetic study of the matrix metalloproteinase inhibitor MMI270 (previously termed CGS27023A) with 5-FU and folinic acid

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/m(2) over 2 h followed by 5-FU 400 mg/m(2) over 15 min and 5-FU 600 mg/m(2) 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, modi. cation, 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.