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Randomized Phase III Trial of Marimastat Versus Placebo in Patients With Metastatic Breast Cancer Who Have Responding or Stable Disease After First-Line Chemotherapy: Eastern Cooperative Oncology Group Trial E2196

From the Albert Einstein Cancer Center, Montefiore Medical Center, Bronx; State University Hospital of New York, Stony Brook, NY; Dana-Farber Cancer Institute, Boston, MA; Northwestern University, Chicago, IL; Mayo Clinic, Rochester, MN; and the Johns Hopkins University, Baltimore, MD

Address reprint requests to Joseph A. Sparano, MD, Albert Einstein Cancer Center, Montefiore Medical Center, Weiler Division, 1825 Eastchester Rd, 2 South, Rm 47-48, Bronx, NY 10461; e-mail: Sparano{at}jimmy.harvard.edu

PURPOSE: To determine whether a matrix metalloproteinase inhibitor improves progression-free survival (PFS) in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy.

PATIENTS AND METHODS: One hundred seventy-nine eligible patients were randomly assigned to receive oral marimastat (10 mg bid; n = 114) or a placebo (n = 65) within 3 to 6 weeks of completing six to eight cycles of first-line doxorubicin- and/or taxane-containing chemotherapy for metastatic disease. Patients were evaluated every 3 months until disease progression.

RESULTS: When comparing placebo with marimastat, there was no significant difference in PFS (median, 3.1 months v 4.7 months, respectively; hazard ratio, 1.26; 95% CI, 0.91 to 1.74; P = .16) or overall survival (median, 26.6 months v 24.7 months, respectively; hazard ratio, 1.03; 95% CI, 0.73 to 1.46; P = .86). Patients treated with marimastat were more likely to develop grade 2 or 3 musculoskeletal toxicity (MST), a known complication of the drug indicative of achieving a biologic effect, compared with patients administered placebo (63% v 22%, respectively; P < .0001). Patients with grade 2 or 3 MST had significantly inferior survival compared with patients who had grade 0 or 1 MST (median, 22.5 months v 28.2 months; P = .04). In addition, patients who had a marimastat plasma concentration of at least 10 ng/mL at month 1 and/or 3 were significantly more likely to have grade 2 to 3 MST (P < .0001).

CONCLUSION: Marimastat does not prolong PFS when used after first-line chemotherapy for metastatic breast cancer. Patients with higher marimastat levels exhibited MST, and MST was associated with inferior survival.

Conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, MD, Chair) and supported in part by Public Health Service grant Nos. CA23318, CA66636, CA21115, CA14958, CA17145, CA13650, and CA16116, and the National Cancer Institute, National Institutes of Health; and Department of Health and Human Services, Bethesda, MD.

Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002, and at the American Society of Clinical Oncology Molecular Therapeutics Symposium, San Diego, CA, November 8-10, 2002.

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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