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Marimastat: the clinical development of a matrix metalloproteinase inhibitor
1Department of Oncology, Leicester Royal Infirmary, Leicester, LE1 5WW, UK. wsteward@uhl.trent.nhs.uk
Abstract:
Marimastat (BB-2516) is the first orally bioavailable matrix metalloproteinase inhibitor to have entered clinical trials in the field of oncology. It has excellent bioavailability and has completed Phase I, II and some Phase III trials. In Phase I studies, which recruited patients with various malignancies, the main toxicity observed was mild to severe joint and muscle pain seen in > 60% of patients receiving a dose of marimastat > 50 mg b.i.d. The symptoms were reversible on discontinuation of the drug and their incidence has been reduced by using marimastat 10 mg b.i.d. In a number of Phase II studies in a variety of tumours, serum tumour markers were used as surrogate determinants of efficacy. Results were interpreted as indicating activity, but this has not yet translated into improved survival in the Phase III studies, which have been completed in pancreatic or gastric carcinoma and glioma. It is likely that these drugs will be most effective in the setting of minimal tumour volume such as in adjuvant treatment or maintenance therapy following response to standard cytotoxics. Therefore, the analysis of Phase III studies in small cell lung cancer (SCLC) where this hypothesis has been tested is awaited with interest. Marimastat can be safely co-administered with conventional cytotoxics and radiotherapy and Phase III studies using these approaches are currently ongoing.
Insights
Marimastat, an orally bioavailable matrix metalloproteinase inhibitor, showed promise in early oncology trials but did not improve survival in Phase III studies. Further research is needed to determine its optimal use in cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Drug Development
Background:
- Marimastat (BB-2516) is the first orally bioavailable matrix metalloproteinase inhibitor investigated in oncology.
- It has demonstrated excellent bioavailability and completed Phase I, II, and some Phase III clinical trials.
Purpose of the Study:
- To evaluate the efficacy and safety of marimastat in patients with various malignancies.
- To explore the potential of marimastat as an adjuvant or maintenance therapy in oncology.
Main Methods:
- Phase I, II, and III clinical trials were conducted in patients with various solid tumors.
- Toxicity was assessed, and serum tumor markers were used as surrogate endpoints in Phase II studies.
- Phase III studies evaluated marimastat in pancreatic carcinoma, gastric carcinoma, and glioma.
Main Results:
- The primary toxicity observed was dose-dependent musculoskeletal pain, which was reversible upon drug discontinuation.
- While Phase II studies suggested potential activity, Phase III trials did not demonstrate improved survival in pancreatic, gastric, or glioma patients.
- Marimastat can be safely co-administered with conventional chemotherapy and radiotherapy.
Conclusions:
- Marimastat's clinical efficacy in improving survival has not been established in completed Phase III trials.
- Its potential utility may lie in settings with minimal tumor burden, such as adjuvant or maintenance therapy.
- Ongoing Phase III studies investigating combination approaches are of significant interest.
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