Marimastat in patients with advanced pancreatic cancer - A dose-finding study

Patients with solid tumors, including carcinoma of the pancreas, express hi gh levels of matrix metalloproteinases (MMP), and these enzymes are believe d to be important for the growth, spread, and dissemination of most solid m alignant tumors. Marimastat is the first orally available MMP inhibitor (MM PI) to be tested in humans and has been shown to inhibit the spread and gro wth of pancreatic cancer in animal models. The purpose of the present study was to define the toxicities, safety, and tolerance of various doses of ma rimastat and also to get an early indication of potential biologic activity in patients with advanced pancreatic cancer. The authors prospectively stu died 64 patients with advanced carcinoma of the pancreas in whom standard t reatments had failed. Eligible patients had a progressive rise in CA 19/9 l evels of >25% over the 4-week period preceding their entry into the study. Patients were studied in groups of 8 to 10, with each group receiving escal ating dosages ranging from 5 mg twice daily to 75 mg twice daily and 10 to 25 mg daily. Patients were considered for long-term (beyond 4 weeks) contin uation treatment if clinical benefit, in the view of the investigator, was derived. Study endpoints were safety, tolerance, and changes in the rate of rise of CA 19/9, which were used as surrogate markers for disease progress ion. Marimastat was well tolerated. Musculoskeletal pain, stiffness, and te nderness emerged as dose-limiting toxicity. No other dose-related toxicitie s were observed. A reduced rate of rise of CA 19/9 was observed at dose lev els of 5, 10, and 25 mg twice daily. The overall median survival was 160 da ys, with a 1-year survival of 21%. Marimastat was associated with an accept able toxicity profile, and these preliminary data suggest that long-term or al administration is feasible and safe. Doses of 5, 10, and 25 mg twice dai ly were identified as the optimal doses to be tested in larger randomized s tudies.