Phase I and Pharmacologic Study of the Specific Matrix Metalloproteinase Inhibitor BAY 12-9566 on a Protracted Oral Daily Dosing Schedule in Patients With Solid Malignancies

PURPOSE: To evaluate the feasibility of administering BAY 12-9566, a matrix metalloproteinase (MMP) inhibitor with relative specificity against MMP-2, MMP-3, and MMP-9, on a protracted oral daily dosing schedule in patients with advanced solid malignancies. The study also sought to determine the principal toxicities of BAY 12-9566, whether plasma BAY 12-9566 steady state concentrations (Css) of biologic relevance could be sustained for prolonged periods, and whether BAY 12-9566 affected plasma concentrations of MMP-2, MMP-9, and tissue inhibitor of MMP-2 (TIMP-2). PATIENTS AND METHODS: Patients with solid malignancies were treated with BAY 12-9566 at daily oral doses ranging from 100 to 1,600 mg. BAY 12-9566 dose schedules included 100 mg once daily, 400 mg once daily, 400 mg twice daily, 400 mg three times daily, 400 mg four times daily, and 800 mg twice daily. Plasma was collected to study the range of BAY 12-9566 Css values achieved, and exploratory studies were performed to assess the effects of BAY 1...