British Biotech: Further results from Phase II trials of marimastat in the treatment of advanced cancer.

OXFORD, England--(BUSINESS WIRE)--Nov. 4, 1996--Five presentations on marimastat, British Biotech's oral anti-cancer drug, were made at the European Society for Medical Oncology (ESMO) medical congress in Vienna, Nov. 2-5 1996.

New data from the company's Phase II marimastat clinical trial program were presented, including an overall analysis of all six cancer antigen studies and results from separate studies in gastric, colorectal, ovarian and pancreatic cancer.

Background

Marimastat is an unlicensed drug with a new mechanism of action which is under investigation in Phase II and Phase III clinical trials in Europe and North America. The Phase II trial program comprised a series of open-label studies in different types of cancer using a 28-day treatment protocol. Patients were offered continued treatment beyond 28 days if they showed signs of clinical benefit. In a number of tumor types, namely ovarian, pancreatic, colorectal and prostatic cancer, cancer-specific antigens were used to monitor tumor progression during the test period. Antigen data are not intended to be used as the basis for any potential licensing submission. Proof of efficacy and safety must await the completion of randomized controlled Phase III trials which are now under way. Nevertheless, the additional results of Phase II patient studies presented at ESMO extend and strengthen the information currently available on the potential utility of marimastat in the treatment of malignant cancer.

Gastric Cancer 

Simon Parsons, Department of Surgery, Queen's Medical Center, Nottingham, presented the first results from a clinical trial of marimastat in gastric cancer. The patients all had advanced inoperable tumors of the stomach. The effect of marimastat was investigated by direct gastroscopic observation of the tumor at study entry and after seven and 28 days of treatment. In half of the 14 patients studied, there was evidence of response or static disease and in those seven patients marimastat was continued following the initial month's treatment. Four of the seven patients showed endoscopically observable and microscopically proven fibrosis of the tumor, consistent with the mode of action of marimastat in increasing tissue matrix formation. Musculo-skeletal side effects were experienced by the long term marimastat patients, but use of dosage reduction and drug holidays enabled long-term treatment to be safely carried out. This experience in advanced gastric cancer suggests a randomized, placebo-controlled clinical trial is warranted and a 300-patient trial is about to commence in gastric cancer.

Colorectal cancer 

Professor John Primrose, Department of Surgery, Southampton General Hospital, presented the results of a clinical trial conducted in 69 patients with advanced colorectal cancer in eight European cancer treatment centers. There was a significant reduction in the median rate of rise of the colorectal cancer specific antigen, CEA, in patients receiving 10, 25, and 50 mg of marimastat twice a day, but not in patients receiving 5 and 10 mg doses once a day. The data confirmed that twice a day dosing was more effective than once a day dosing. A positive correlation between the reduction in the rate of cancer antigen rise and survival was demonstrated.

Ovarian cancer 

Dr. Chris Poole of the CRC Institute for Cancer Studies, Queen Elizabeth Hospital, Birmingham, presented the results of a clinical trial of marimastat in 66 women with advanced ovarian cancer involving six European medical centers. All patients had received one or more prior courses of cytotoxic chemotherapy. Marimastat caused significant reductions in the rate of rise of CA 125, a specific antigen released by ovarian cancer cells. Plasma concentrations of marimastat increased in proportion to dose up to 25 mg twice a day. The number of patients showing musculo-skeleton side effects also increased with dose. However, this side effect is readily recognized by the patient and is reversible on interruption of marimastat treatment. Early evidence suggests that a dose of 10mg twice a day should be practical for longer treatment studies. A positive correlation between the reduction in rate of cancer antigen rise and survival was demonstrated. A safety study of marimastat in combination with carboplatin is now in progress prior to commencing a randomized, placebo-controlled trial of marimastat as an adjunct to carboplatin in ovarian cancer.

Pancreatic cancer

James Evans, Department of Surgery, Queen Elizabeth Hospital, Birmingham, presented the results of a Phase II trial of marimastat in 74 patients with advanced inoperable pancreatic cancer conducted at five UK hospitals. This is one of two Phase II studies of marimastat in pancreatic cancer, the other being a US study. The trial examined the effect of 28 days of treatment with marimastat on tumor progression measured by CT scan. Forty seven of the 74 patients also had measurable levels of the pancreatic specific cancer antigen, CA 19-9. However, unlike the US Phase II pancreatic cancer study, cancer antigens were not the primary endpoint in the UK study. Over the initial 28 day study period, CA 19-9 levels fell in 14 patients and rose in 33 patients. A greater proportion of patients with a fall in CA 19-9 had radiographically stable disease at day 28 and their median survival was significantly greater than that of patients with a rising CA 19-9. This difference in survival appeared to be independent of the major prognostic variable for this group, namely presence of metastases. Marimastat is currently being studied in a multicenter randomized comparison with gemcitabine in patients with histologically confirmed advanced pancreatic cancer.

Overall analysis of Phase II antigen trials

Dr. Andrew Millar, British Biotech's Director of Clinical Research, reported conclusions from a pooled analysis of 381 patients from six Phase II clinical trials (European and American ovarian cancer trials, European and American colorectal cancer trials, the American prostatic and pancreatic cancer trials). All patients had advanced cancer (predominately stage III or IV) and a majority had received previous chemotherapy. Patients were recruited into the trials only if they had a rising level (greater than 25 percent per month) of cancer specific antigens in their blood, measured during a 28 day screening period prior to the start of marimastat treatment.

Dose response

The effect of marimastat on cancer-specific antigens in this large group of patients confirms the results of earlier analyses. Patients given marimastat at doses of 10, 25 or 50 mg twice a day showed statistically significant reductions in the rates of rise of cancer antigens. These effects were significantly greater than those in patients, receiving lower doses, particularly once a day doses. A dose of 10mg twice a day was maximally effective, doses of 25mg and 50 mg twice a day not producing significantly greater effects on cancer antigens.

Survival

All patients in the trials were followed clinically and survival data collected. Since approximately 50 percent of patients continued on marimastat treatment for varying periods after the end of the 28-day study protocol, analyses of these survival data was considered of interest. Results were reported of four separate analyses.

i) An inverse relationship was demonstrated in these patients between the duration of survival and the cancer antigen rate of rise at screening. These data validate the rate of rise of cancer antigen as a prognostic marker of clinical outcome.

ii) There was a relationship between the size of the marimastat treatment effect on cancer antigens in the 28 day study period and the duration of survival. This treatment effect on survival was independent of the screening rate of rise.

iii) The median survival of patients who continued on marimastat after the initial 28-day period was significantly longer than that of patients who did not continue on treatment. Although patients were not allocated to these two categories on a randomized basis, retrospective analysis of the two groups showed continuers and discontinuers to be similar in terms of stage and type of tumor.

iv) Patients who were administered marimastat at the optimal dose selected for Phase III trials, 10 mg twice a day, had a significantly better survival outcome than patients given drug at the lower, less effective doses of 5, 10, or 25 mg once a day.

Taken together, these results are encouraging but should be interpreted with caution since the analyses were not defined prospectively nor protocolized.

Side effect profile

Marimastat is an unlicensed drug under investigation as a potential treatment for a range of solid tumors and its full side effect profile when used chronically over long periods has not been determined. Musculo-skeletal pain, mainly in the arm and shoulder, is the principal treatment-related side effect and has been reported by all of the investigators presenting data at the ESMO Congress. The rate and severity of onset increases with the dose of the marimastat administered. The side effects become more frequent at higher plasma levels such as those achieved at 25 mg twice a day and higher. At 10mg twice a day, the incidence is approximately 30% after three to five months. A clear relationship with trough plasma drug concentrations has been demonstrated. The symptoms are reversible on stopping treatment. Continuation with marimastat treatment is possible after a short dosing holiday (of one to three weeks) and this regimen is now being formally studied in patients who develop these musculo-skeletal side effects.

Regulatory status

Marimastat is an investigational new drug undergoing clinical trials in Europe and North America. Proof of safety and efficacy has not been determined by any drug regulatory authority. The current data from Phase II studies have enabled the company to undertake randomized controlled clinical trials which are suitable for the determination of safety and efficacy. Phase III pivotal trials of marimastat are now under way in pancreatic cancer (400 patients), small cell lung cancer (200 patients) and glioblastoma, a form of brain cancer (150 patients). Two further Phase III pivotal trials are also due to start in gastric (300 patients) and ovarian cancer (200 patients). Each trial will take approximately two years to complete.

CONTACT: British Biotech plc

(On Nov. 4, 1996: 011-44-171-253-2252)

(Thereafter:)

James Noble/Katie Arber

011-44-1865-781120/011-44-1865-781166

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British Biotech Inc.

Peter P. McCann, 410/266-7909

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G.A. Kraut Co., New York 

Gerard Coffey, 212/696-5600