Marimastat in recurrent colorectal cancer: exploratory evaluation of biological activity by measurement of carcinoembryonic antigen

Marimastat is a specific inhibitor of matrix metalloproteinases that has be en shown to be effective in cancer models. A pilot, escalating-dose study o f oral marimastat was performed in patients with recurrent colorectal cance r, in whom evaluation of serological response was made by measurement of ca rcinoembryonic antigen (CEA) levels. The study assessed the safety and tole rability of 4 weeks administration of marimastat, and determined a dose ran ge producing detectable serological effects. Patients were recruited with a serum CEA level greater than 5 ng ml(-1), and rising by more than 25% over a 4-week screening period. Patients were treated for 28 days and entered i nto a continuation protocol if a serological response or clinical benefit w as observed. Pharmacokinetic and safety data determined that groups of pati ents were recruited sequentially at 25 mg and 50 mg twice daily, and, there after, 10 mg twice daily, 10 mg once daily, 5 mg once daily and 20 mg once daily. A biological effect (BE) was defined as a CEA value on day 28 no gre ater than on day 0; a partial biological effect (PBE) was defined as a rise in CEA over the 28-day treatment period of less than 25%. Of 70 patients r ecruited, 63 completed the 28-day treatment period, and 55 were eligible fo r cancer antigen analysis. Examination of the dose-effect relationships pro vides evidence for a causal relationship between marimastat and biological effects: the proportion of patients with BE or PBE was higher with twice da ily dosing (16 out of 25, 64%) than with once daily dosing (11 out of 30, 3 7%) (P = 0.043, chi(2) test). Furthermore, the median rates of rise of CEA fell markedly during treatment compared with the screening period for patie nts receiving twice! daily marimastat (P < 0.0001), but not for patients re ceiving marimastat once daily (P = 0.25). Musculoskeletal adverse events em erged as the principal drug-related toxicity of marimastat, occurring in a dose- and time-dependent fashion. it was concluded that marimastat was asso ciated with dose-dependent biological effects in cancer patients. The occur rence of musculoskeletal side-effects define 25 mg twice daily as the upper limit of the dose range for continuous use in further studies. Therefore, a dose range of 20 mg once daily to 25 mg twice daily seems appropriate for further studies, which should aim to demonstrate the efficacy of the drug in terms of conventional clinical end points;Ind describe the long-term tol erability of this novel agent.