COMBINED ANALYSIS OF STUDIES OF THE EFFECTS OF THE MATRIX METALLOPROTEINASE INHIBITOR MARIMASTAT ON SERUM TUMOR-MARKERS IN ADVANCED CANCER - SELECTION OF A BIOLOGICALLY-ACTIVE AND TOLERABLE DOSE FOR LONGER-TERM STUDIES

This combined analysis investigated the effect of marimastat, a specif ic inhibitor of matrix metalloproteinases, on markers of tumor progres sion measured in patients with advanced cancer, By defining the tolera bility and biological activity of the drug, it aimed to establish an a ppropriate dose range for use in Phase III trials. Patients with advan ced, serologically progressive ovarian, prostatic, pancreatic, and col orectal cancer were recruited into six nonrandomized, dose ranging, mu lticenter clinical trials in North America and Europe. The biological activity of marimastat was assessed by serial measurements of the seru m tumor markers carcinoembryonic antigen, CA125, CA19-9, and prostate- specific antigen. Patients were recruited with tumor markers rising by more than 25% averaged over a 4-week screening period. A biological e ffect was defined as a level of tumor marker at the end of treatment n o greater than at study entry; a partial biological effect was defined as a rise in the level of tumor marker over the treatment period of 0 -25% per 4 weeks. Pharmacokinetic and safety data were collected and a ssessed as the studies progressed. All patients were followed up for s urvival, A total of 415 patients were recruited, with approximately eq ual numbers in each of the studies. Patient characteristics were simil ar across different studies and doses. The 11 different doses used in the studies were grouped according to similar trough blood levels of m arimastat, and analysis was made looking for dose-response. Marimastat exhibited dose-dependent biological activity as assessed by biologica l effect and partial biological effect (P = 0.01, Cochran-Mantel-Haens zel test for non-zero correlation). Comparison of screen and treatment rates of rise of tumor markers indicated that total daily doses of 20 mg and higher were associated with maximal activity. Musculoskeletal adverse events emerged as the principal drug-related toxicity of marim astat. These occurred in a dose-and time-dependent fashion and were mo re severe at a dose of 50 mg twice daily than at lower doses. Marimast at shows biological activity in patients with advanced malignancy, as measured by the effects on levels of tumor markers. Assessment of biol ogical activity by dose, together with safety and pharmacokinetic data , support doses of between 10 and 25 mg twice daily as appropriate for Phase III studies.