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Annals of Oncology 13:1220-1224, 2002
© 2002 European Society for Medical Oncology

Original Paper

A randomized phase II pilot trial of adjuvant marimastat in patients with early-stage breast cancer

K. D. Miller1,+, W. Gradishar2, L. Schuchter3, J. A. Sparano4, M. Cobleigh5, N. Robert6, H. Rasmussen7 and G. W. Sledge1

1 Indiana University, Indianapolis, IN; 2 Northwestern University, Chicago, IL; 3 University of Pennsylvania, Philadelphia, PA; 4 Montefiore Medical Center, New York, NY; 5 Rush-Presbyterian Medical Center, Chicago, IL; 6 Fairfax Hospital, Fairfax, VA; 7 British Biotech, Annapolis, MD, USA

Received 26 September 2001; revised 10 December 2001; accepted 9 January 2002

Background:

This pilot trial was performed to evaluate the safety, toxicity and pharmacokinetics of chronic therapy with the matrix metalloproteinase inhibitor marimastat in the adjuvant treatment of breast cancer.

Patients and methods:

Patients with high-risk node negative or node positive breast cancer received marimastat either 5 or 10 mg p.o. b.i.d. for 12 months. Marimastat was given either as a single agent following completion of adjuvant chemotherapy or concurrently with tamoxifen.

Results:

Sixty-three patients were enrolled from June 1997 to May 1998. All patients have completed 12 months of treatment or have discontinued therapy due to toxicity, relapse or intercurrent illness. Moderate (WHO criteria) arthralgia/arthritis was reported by 34% of patients receiving 5 mg b.i.d. and 45% of patients receiving 10 mg b.i.d.; severe arthralgia/arthritis was reported by 6% and 23% of patients, respectively. Six patients (19%) receiving 5 mg b.i.d. and 11 (35%) receiving 10 mg b.i.d. discontinued marimastat therapy due to toxicity. Trough plasma levels were rarely within the target range for biological activity (40–200 ng/ml) with mean concentration for patients receiving: 5 mg b.i.d. = 7.5; 5 mg b.i.d. plus tamoxifen = 6.9; 10 mg b.i.d. = 11.9; 10 mg b.i.d. plus tamoxifen = 12.8.

Conclusions:

A randomized adjuvant trial with marimastat is not warranted as chronic administration cannot maintain plasma levels with the target range.

Key words: angiogenesis, breast cancer, metalloproteinase, metalloproteinase inhibitor


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