Mmp Inhibitors In Clinical Trials For Cancer

A third study with 29 is focused on patients with the least aggressive cancers. Two of the four trials due to be reported in 2000 involve patients with small-cell lung cancer. These patients have already responded to chemotherapy, so their tumor burden has been reduced to some extent. The other two studies are for patients with glioblastoma and ovarian cancer, both of which are aggressive cancers with high tumor burdens.

Prinomastat (AG-3340, 30) is being developed for the treatment of cancer and age-related macular degeneration. In May of 1999, 30 entered Phase III trials for lung and prostate cancers. The recommended dose for these trials was 5 to 25 mg, b.i.d. Following the demonstration of an enhanced efficacy of chemotherapy when supplemented with 30, pilot combination studies and double-blinded, placebo-controlled Phase III trials in 700 patients are in progress for the treatment of non-small cell lung cancer (NSCLC) or advanced hormone-refractory prostate cancer (69). A Phase III clinical trial of 30 in combination with chemotherapy in patients with advanced NSCLC has been initiated. This trial is designed to evaluate the safety and efficacy of 30 as part of first-line therapy in combination with chemotherapy. This trial advances the ongoing clinical development of 30 in combination with the anticancer drugs paclitaxel/carboplatin for the treatment of advanced NSCLC and with mitoxantrone/prednisone for the treatment of hormone-refractory prostate cancer. The primary objective of this study is to compare time of overall survival between patients receiving 30 or placebo in combination with gemcitabine and cisplatin (70).

Prinomastat (30) is well tolerated at doses of up to 100 mg, 30 b.i.d., p.o., are generally well tolerated. In most studies, no dose-limiting toxicities occur during the first four weeks of treatment. Musculoskeletal and joint-related events can occur after four weeks of treatment with higher doses. These events include joint stiffness, swollen joints and, in a few patients, some limits on the mobility of certain joints. The side effects typically begin in the shoulders, knees or hands, with involvement of additional joints in a dose- and time-dependent manner. These side effects are reversible and can be managed by treatment rests for two to four weeks and subsequent dose reduction. In some studies, fatigue, believed to be attributable to prinomastat administration, has been observed.

The carboxylate BAY 12-9566 (32) was being developed as a potential treatment for preventing metastasis in several types of neoplasm as well as for osteoarthritis. In September 1999, all trials for all indications with 32 were halted following recommendation from an independent safety monitoring board that the Phase III NSCLC trial be stopped. The NSCLC trial was terminated following the discovery that 32 performed worse than placebo. The compound had also reached Phase III clinical trials in pancreatic cancer, Phase II trials in several other types of cancer and in osteoarthritis. This inhibitor was also being developed the for the potential treatment of rheumatoid arthritis, for which early Phase II studies had been initiated.

The thiol compound D-2163 (BMS-275,291, 34) is an inhibitor of a broad range of MMPs known to be associated with the growth and spread of tumors, but does not inhibit metalloproteinase-mediated shedding events, which may be involved in the side effects associated with the first generation MMP inhibitors (71). In preclinical studies 34 did not exhibit any deleterious effects on tendons or joints. The inhibitor 34 demonstrates ten-fold increase in systemic exposure for a given dose when compared with 24 (qv), as well as having a superior selectivity profile. No histopathological effects were observed in a marmoset model of joint pain and tendinitis. In a single-dose Phase I study (25 mg to 900 mg), 34 demonstrated excellent blood levels. Phase II patient studies conducted by BMS started in the first quarter of 1999. A similar compound, D-1927 (35), is being developed for inflammation.

Several other MMP inhibitors are also in various stages of clinical development for cancer and arthritis (Table 2). As of March 31, 2000 Trocade (Ro 32-3555, 36), which was in Phase III clinical trials for arthritis, has been withdrawn from all future clinical studies.

Table 2. M MP Inhibitors in Clinical Trials for Cancer and Arthritis

Structure

Comments

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British Biotech Batimastat BB-94 Cancer Phase II

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Agouron AG-3433 Cancer Phase 1

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British Biotech Matimastat BB-2516 Cancer Phase III

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