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

Abstract

Purpose: The purpose of this research was to assess the feasibility of administering Col-3, an oral chemically modified tetracycline derivative with potent inhibitory effects on matrix metalloproteinase activity and production, and recommend a dose on an uninterrupted once-daily schedule. The study also sought to characterize the pharmacokinetic behavior of Col-3 and seek evidence of anticancer activity.Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of Col-3 with dose level assignment according to an accelerated titration scheme. Because photosensitivity skin reactions were being reported in concurrent trials of Col-3, patients were instructed to apply sunscreen rigorously throughout the trial. The maximum tolerated dose was defined as the highest dose at which <2 of the first 6 new patients experienced doselimiting toxicity. The pharmacokinetic behavior of Col-3 was characterized, and pharmacodynamic relationships were sought.Results: Thirty-three patients were treated with 73 courses of Col-3 at four dose levels ranging from 36 to 98 mg/m 2 /day. Unacceptably high incidences of photosensitivity skin reactions and malaise were noted in the first 28-day courses of patients treated with Col-3 at doses exceeding 50 mg/m 2 /day. At 50 mg/m 2 /day, severe toxicity occurred in 2 of 12 new patients in first courses, and no additional doselimiting toxicities were observed in subsequent courses. Other mild to modest adverse effects included nausea, vomiting, liver function tests abnormalities, diarrhea, mucositis, leukopenia, and thrombocytopenia. The pharmacokinetics of Col-3 were dose proportional, and mean trough concentrations at steady state were similar to biologically relevant concentrations in preclinical studies. Major responses did not occur, but durable disease stability was noted in 3 patients, one each with carcinosarcoma of the uterus, pancreas, and ovary, all of whom had experienced disease progression before Col-3 treatment.Conclusions: The recommended dose for Phase II studies of Col-3 administered once daily on an uninterrupted schedule is 50 mg/m 2 /day accompanied by efforts that promote adherence to the use of sunscreen and other photoprotective measures. Pharmacokinetic results indicate that plasma concentrations above biologically relevant concentrations are readily maintained at this dose, and additional disease-directed studies, particularly in patients with soft tissue sarcoma, should be considered.

Anti‐angiogenic drugs: from bench to clinical trials

“…316 Although no objective antitumor responses were observed, apparent clinical benefit in several patients with soft tissue sarcoma and with advanced solid malignancies that were unresponsive to standard therapy, as well as a 44% overall response rate in patients with AIDS-related Kaposi's sarcoma, suggest that COL-3 should undergo additional evaluation for the treatment of various types of sarcoma and other malignancies in which MMPs may play an important role in invasion, proliferation, and metastases. [316][317][318] This drug is being tested in phase I/II studies with astrocitoma/multiforme glioblastoma, and in phase II with Kaposi sarcoma patients, in collaboration with the NCI (www.clinicaltrials.gov).…”

Angiogenesis and tumor growth inhibition by a matrix metalloproteinase inhibitor targeting radiation-induced invasion

“…Metastat, or COL-3, is a chemically modified tetracycline (20) that is able to inhibit neutrophil gelatinase and MMP expression in colon, breast, or melanoma cancer models. The potential clinical interest of this drug was first suggested following the promising results of phase I/II clinical trials for Kaposi's sarcoma (21) and for patients with advanced solid malignancies (22,23).…”

A phase II and pharmacological study of the matrix metalloproteinase inhibitor (MMPI) COL-3 in patients with advanced soft tissue sarcomas

“…One asset from a toxicological perspective is that that they are devoid of gastrointestinal toxicity upon long-term administration. From a pharmacological standpoint, plasma concentrations exceeding IC 50 values for in vitro inhibition of MMPs can be readily achieved in the clinic and their pharmacokinetic characteristics and clearance rates render them conducive for daily oral administration [30][31][32]. Mechanistically, the modified tetracycline analogues inhibit both the activation and production of MMPs, particularly MMP-1, 2, 3, 9, and 13 and several other mechanistic advantages have been proposed [33,34].…”

“…Two results of two phase I trials of COL-3 administered on a daily continuous oral schedule to patients with advanced cancers have been reported [30,31]. The principal toxicity of COL-3 is photosensitivity, typified by rash and desquamatization in sun exposed areas.…”