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Randomized Phase II Trial of Matrix Metalloproteinase Inhibitor COL-3 in AIDS-Related Kaposi's Sarcoma: An AIDS Malignancy Consortium Study

Bruce J. Dezube, Susan E. Krown, Jeannette Y. Lee, Kenneth S. Bauer, David M. Aboulafia

From the Beth Israel Deaconess Medical Center, Boston, MA; Memorial Sloan-Kettering Cancer Center, New York, NY; Virginia Mason Cancer Center, Seattle, WA; School of Pharmacy, University of Maryland, Baltimore, MD; and AIDS Malignancy Consortium Operations Center, University of Alabama at Birmingham, Birmingham, AL

Address reprint requests to Bruce Dezube, MD, Beth Israel Deaconess Medical Center, 330 Brookline Ave, CC-913, Boston, MA 02215; e-mail: bdezube{at}bidmc.harvard.edu

PURPOSE: Matrix metalloproteinases (MMPs) are involved in tumor metastasis and are overexpressed in Kaposi's sarcoma (KS) cells. In a phase I trial of the MMP inhibitor COL-3 in patients with AIDS-related KS, the drug was well tolerated, KS regression was observed, and MMP-2 levels decreased significantly in responders compared with nonresponders. The aim of this trial was to extend these initial observations.

PATIENTS AND METHODS: This was a randomized, parallel-group, phase II study. COL-3 was administered orally once daily at one of two doses (group A received 50 mg and group B received 100 mg) to patients with AIDS-related KS. Antiretroviral therapy was permitted but not required. Serial tumor assessments and plasma levels of MMPs were obtained. Study end points were progressive KS and recurrent dose-limiting toxicity.

RESULTS: Seventy-five patients received COL-3: 37 in group A and 38 in group B. Fifty-seven patients (76%) had received prior KS therapy. Thirty-three patients (44%) had more than 50 KS lesions. The response rate in group A was 41%, which was significantly greater than the prespecified target rate of 20% (95% CI, 25% to 58%; P = .003); the response rate of group B was 29% (P = not significant). There were significant declines in MMP-2 and MMP-9 plasma levels from baseline to minimum value with treatment (MMP-2, P < .001; MMP-9, P = .001). The most common adverse events were photosensitivity and rash.

CONCLUSION: COL-3, when administered as 50 mg/d, is both active and well tolerated in the treatment of AIDS-related KS. COL-3 is a promising agent for the treatment of this opportunistic neoplasm of AIDS.

Supported by the National Cancer Institute Grants No. U01CA070019, U01CA070047, U01CA070054, U01CA70058, U01CA070062, U01CA070079, U01CA070072, U01CA070080, U01CA70081, U01CA071375, U01CA083118, U01CA083216, and U01CA083038; Cancer Therapy Evaluation Program/NCI; and CollaGenex Pharmaceuticals.

Presented in part at the International Conference on Malignancies in AIDS and Other Immune Deficiencies, April 29-30, 2004, Bethesda, MD.

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

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