Phase I and pharmacological study of the oral matrix metalloproteinase inhibitor, MMI270 (CGS27023A), in patients with advanced solid cancer

This Phase I study of MMI270, an p.o. administered matrix metalloproteinase inhibitor, assessed toxicity, pharmacokinetics, and tumor response data an d investigated markers of biological activity to recommend a dose for Phase II studies. MMI270 was administered continuously at seven dose levels (50 mg once daily to 600 mg three times/day). Patients were evaluated for toxicity and tumor response, and blood and urine samples were taken for pharmacokinetics, bon e resorption markers, direct targets of the inhibitor [matrix metalloprotei nase-2 (MMP-2), MMP-8, and MMP-9], indirect targets [tissue inhibitor of me talloproteinase-1 (TIMP-1), TIMP-2, basic fibroblast growth factor, vascula r endothelial growth factor, vascular cell adhesion molecule-1, soluble uro kinase plasminogen activator receptor, and cathepsins B and H] and for a tu mor necrosis factor-alpha cytokine release assay. Ninety-two patients were entered. There was no myelotoxicity. Eighteen pati ents developed a widespread maculopapular rash, which increased in frequenc y and severity at doses greater than or equal to 300 mg bid. Thirty nine pa tients developed musculoskeletal side effects, which were related to durati on of treatment, not to dose level. Pharmacokinetics were linear, and MMI27 0 was rapidly absorbed and eliminated with minimal accumulation on chronic dosing. Sustained plasma concentrations in excess of 4 x mean IC50 for the target enzymes were observed at dose levels greater than or equal to 150 mg bid. There were no tumor regressions; however, 19 patients had stable dise ase for greater than or equal to 90 days. There was a dose-response increas e of MMP-2 and TIMP-1 with MMI270. Transient effects on the bone resorption markers were detected. MMI270 was generally well tolerated, with adequate plasma levels for target enzyme inhibition. The two main toxicities were rash, resulting in a maxim um tolerated dose of greater than or equal to 300 mg bid and musculoskeleta l side effects. Biological marker data indicate drug effects. The rise in T IMP-1 suggests that a reflex rise in inhibitors could modify the effects of MMI270. The recommended Phase II dose is 300 mg bid.