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

Abstract

This phase II study evaluated the antitumor activity of the tetracycline analog COL-3, a potent inhibitor of metalloproteinases (MMPs), particularly MMP-2 and MMP-9, on a continuous oral schedule at a dose of 50 mg/m2 daily in patients with advanced and/or metastatic soft tissue sarcoma (STS). The principal endpoints were the rate of objective tumor regression and the proportion of patients who did not experience disease progression during the first 8 weeks of treatment. Other study objectives included an assessment of pharmacology of COL-3, time to progression (TTP), and overall survival. A Simon two-stage design with multinomial stopping rule was employed, with 15 patients enrolled during the first stage of the study. Although COL-3 was generally well-tolerated, there were no objective responses and 5(33%) patients experienced disease progression during the first 8 weeks of treatment, which exceeded the criteria established a priori with regard to pursuing further evaluations of COL-3 in STS. The median values for TTP and survival were 109 and 279 days, respectively. Based on these results, further studies of COL-3 on this administration schedule in patients with STS are not warranted.

Matrix metalloproteinases in the brain and blood–brain barrier: Versatile breakers and makers

“…In addition, clinical trials testing more than 50 MMP inhibitors for the treatment of cancer have all failed. [310][311][312][313][314][315][316][317][318][319][320][321][322] Vandenbrouke and Libert 319 summarized the reasons for failure, which included the complexity of MMP biology and lack of MMP knowledge. The authors also listed suboptimal trial design, inadequate clinical endpoints, use of metabolically unstable MMP inhibitors, poor oral bioavailability, no effect, toxic adverse effects, and discrepancies between preclinical animal models and human patients.…”

Matrix metalloproteinases in the pathophysiology and progression of gynecological malignancies: could their inhibition be an effective therapeutic approach?

“…Most MMPIs bind reversibly at the active site of the MMP in a stereospecific manner and chelate the zinc ion on the enzyme activation site [137]. MMPIs can be categorized as peptidomimetic (most common, hydroxamate derivatives), nonpeptidic, biphosphonates and tetracycline derivatives [138,139].…”

A novel and selective membrane type-1 matrix metalloproteinase (MT1-MMP) inhibitor reduces cancer cell motility and tumor growth

“…10 The trend to develop MMPIs with more limited spectrum can be clearly seen in recent or ongoing Phase I and II clinical trials while some of them are focusing on other somatic diseases than cancer. [36][37][38][39][40] Still, most of the MMPIs used in these trials have to be considered rather unselective. In this regard, peptides such as CTT1, CTT2 and the here reported PG are selective and effective MMP inhibitors.…”