Marimastat: the clinical development of a matrix metalloproteinase inhibitor

Marimastat (BB-2516) is the first orally bioavailable matrix metalloprotein ase inhibitor to have entered clinical trials in the field of oncology. It has excellent bioavailability and has completed Phase I, II and some Phase III trials. In Phase I studies, which recruited patients with various malig nancies, the main toxicity observed was mild to severe joint and muscle pai n seen in > 60% of patients receiving a dose of marimastat > 50 mg b.i.d. T he symptoms were reversible on discontinuation of the drug and their incide nce has been reduced by using marimastat 10 mg b.i.d. In a number of Phase II studies in a variety of rumours, serum tumour markers were used as surro gate determinants of efficacy. Results were interpreted as indicating activ ity, but this has not yet translated into improved survival in the Phase II I studies, which have been completed in pancreatic or gastric carcinoma and glioma. It is likely that these drugs will be most effective in the settin g of minimal tumour volume such as in adjuvant treatment or maintenance the rapy following response to standard cytotoxics. Therefore, the analysis of Phase III studies in small cell lung cancer (SCLC) where this hypothesis ha s been tested is awaited with interest. Marimastat can be safely co-adminis tered with conventional cytotoxics and radiotherapy and Phase III studies u sing these approaches are currently ongoing.