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Marimastat (BB2516): current status of development
1Department of Oncology, Leicester Royal Infirmary, UK. wsteward@lri.org.uk
Abstract:
Marimastat (BB-2516) is the first matrix metalloproteinase inhibitor to have entered clinical trials in the field of oncology. It has excellent bioavailability and has completed phase I and II trials. Phase I studies involved healthy volunteers who received short courses of marimastat; these were well tolerated. Symptoms experienced by many patients with various malignancies included severe joint and muscle pain which were debilitating in >60% of patients at doses >50 mg bid. These symptoms were reversible on discontinuation of the drug, and their incidence has been decreased by using marimastat 10 mg bid, the dose used in current studies. Phase II studies involved the use of serum tumor markers as surrogate indicators of antitumor activity. Six studies in colorectal, ovarian, and prostate cancer have been completed and pooled analysis has demonstrated a dose-dependent biological effect (as defined by the authors); 58% of patients respond at doses >50 mg bid. Effects on tumor markers were associated with increased survival. Small phase II studies have suggested potential activity in pancreatic and gastric cancer and have demonstrated the safety of combining cytotoxic chemotherapeutic agents with marimastat. Ongoing phase III studies are investigating the effects of marimastat in addition to chemotherapy in the treatment of small cell lung cancer and pancreatic and gastric carcinoma.
Insights
Marimastat, a matrix metalloproteinase inhibitor, shows promise in oncology trials. Lower doses reduce side effects, and it demonstrates a dose-dependent biological effect on tumor markers, potentially improving survival in cancer patients.
Area of Science:
- Oncology
- Pharmacology
- Cancer Research
Background:
- Marimastat (BB-2516) is a novel matrix metalloproteinase inhibitor.
- It is the first in its class to enter clinical oncology trials.
- The drug exhibits excellent bioavailability.
Purpose of the Study:
- To evaluate the safety and efficacy of Marimastat in cancer patients.
- To assess the impact of Marimastat on tumor markers as surrogate indicators of antitumor activity.
- To explore the potential of Marimastat in combination with chemotherapy.
Main Methods:
- Phase I studies in healthy volunteers to assess tolerability.
- Phase II studies in colorectal, ovarian, prostate, pancreatic, and gastric cancers using serum tumor markers.
- Dose-ranging studies to identify optimal and tolerable dosages.
- Evaluation of Marimastat in combination with cytotoxic chemotherapy.
Main Results:
- Phase I studies showed Marimastat was well tolerated at lower doses.
- Higher doses (>50 mg bid) caused debilitating joint and muscle pain in over 60% of patients, reversible upon discontinuation.
- Reduced incidence of side effects observed at 10 mg bid.
- Pooled Phase II analyses demonstrated a dose-dependent biological effect on tumor markers, with 58% response at doses >50 mg bid.
- Tumor marker effects correlated with increased survival.
- Demonstrated safety of combining Marimastat with cytotoxic chemotherapy.
Conclusions:
- Marimastat is a well-tolerated matrix metalloproteinase inhibitor with demonstrated biological activity in various cancers.
- Optimized dosing (10 mg bid) mitigates debilitating side effects.
- Marimastat shows potential as an anticancer agent, particularly when combined with chemotherapy, warranting further investigation in Phase III trials.