Matrix Metalloproteinase Inhibitor COL-3 in the Treatment of AIDS-Related Kaposi’s Sarcoma: A Phase I AIDS Malignancy Consortium Study

Abstract

PURPOSE: Matrix metalloproteinases (MMPs) are involved in tumor invasion and metastasis and are overexpressed in Kaposi’s sarcoma (KS) cells. The primary aim was to define the safety and toxicity of the MMP inhibitor COL-3 in patients with AIDS-related KS. Secondary aims were to evaluate tumor response, pharmacokinetics, and changes in blood levels of MMP-2, MMP-9, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF). PATIENTS AND METHODS: COL-3 was administered orally once daily, and doses were escalated in cohorts of three to six subjects. Patients with symptomatic visceral KS or severe tumor-associated edema were excluded. Antiretroviral therapy was permitted but not required. Study end points were grade 3 or 4 toxicity or progressive KS. Serial blood specimens were obtained for pharmacokinetics and levels of MMP-2, MMP-9, VEGF, and bFGF. RESULTS: Eighteen patients received COL-3 in dosing cohorts of 25, 50, and 70 mg/m2/d. Prior KS therapy was reported by 17 patients (94%). COL-3–related grade 3 or 4 adverse events were reported by six patients and included photosensitivity, rash, and headache. There was one complete response and seven partial responses, for an overall response rate of 44%, with a median response duration of 25+ weeks. The median COL-3 half-life was 39.3 hours (range, 4.1 to 251.1 hours). There was a significant difference between responders and nonresponders with respect to the change in MMP-2 serum levels from baseline to minimum value on treatment (P = .037). CONCLUSION: COL-3 administered orally once daily to patients with AIDS-related KS is reasonably well tolerated. The most common adverse event was dose-related photosensitivity. Antitumor activity was noted. Further evaluation of COL-3 for the treatment of KS is warranted.

A Phase I and Pharmacokinetic Study of Col-3 (Metastat), an Oral Tetracycline Derivative with Potent Matrix Metalloproteinase and Antitumor Properties

“…The pharmacokinetic results of the present study suggest that Col-3 behaves in a dose-proportional manner, and pharmacokinetic parameters reflecting drug exposure were similar to those observed in other clinical trials to date (21,29). In addition, intraindividual variability was moderate; coefficients of variation in AUC 0 -24 values were 25% and 55% on days 1 and 29 at the MTD, respectively.…”

“…In a Phase I study performed at the NCI in patients with advanced solid malignancies, cutaneous photosensitivity reactions precluded treatment at Col-3 doses exceeding 70 and 36 mg/m 2 /day in patients who were and were not using prophylactic sunscreen, respectively, and the lower dose was recommended for subsequent disease-directed trials (21). An unacceptably high incidence of severe cutaneous photosensitivity reactions also precluded dose escalation of Col-3 Ͼ25 mg/m 2 /day in a Phase I study of Col-3 in patients with AIDS-related Kaposi's sarcoma performed by the AIDS Malignancy Consortium (29). For the most part, the toxicities in all three of the trials were nearly identical except for a constellation of manifestations that resembled drug-induced systemic lupus erythematosis in the National Cancer Institute study (21).…”

“…Nevertheless, the agent is the most potent photosensitizer among the tetracyclines. Photosensitivity skin reactions were determined to be the principal dose-limiting phenomena in two other Phase I studies of Col-3 administered on a similar schedule (21,29). In a Phase I study performed at the NCI in patients with advanced solid malignancies, cutaneous photosensitivity reactions precluded treatment at Col-3 doses exceeding 70 and 36 mg/m 2 /day in patients who were and were not using prophylactic sunscreen, respectively, and the lower dose was recommended for subsequent disease-directed trials (21).…”

Gelatinase-mediated migration and invasion of cancer cells

“…The tetracyclines act on two levels, they suppress the gelatinase expression (Seftor et al, 1998) and directly inhibit gelatinase activity trough a zinc-chelating effect (Sorsa et al, 1998). The tetracycline derivatives have entered clinical trials as MMP-inhibitors (Cianfrocca et al, 2002). Clodronate and other bisphosphonates have been developed to treat bone diseases due to their ability to inhibit bone resorption.…”

Kaposi sarcoma

“…Indeed, this was the rationale for phase 1 and 2 trials in KS patients using the MMP inhibitor known as COL-3 (6-demethyl-6-deoxy-4-dedimethylaminotetracycline), a chemically modified tetracycline. 16,17 In these trials, COL-3 was shown to be active and well tolerated in the treatment of AIDS-related KS. This may be partly related to the finding that COL-3 affects MMPs by multiple mechanisms, including inhibition of MMP activation and expression.…”