Phase I and pharmacologic study of the specific matrix metalloproteinase inhibitor BAY 12-9566 on a protracted oral daily dosing schedule in patientswith 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 w ith advanced solid malignancies. The study also sought to determine the pri ncipal toxicities of BAY 12-9566, whether plasma BAY 12-9566 steady state c oncentrations (C-ss) of biologic relevance could be sustained for prolonged periods, and whether BAY 12-9566 affected plasma concentrations of MMP-5, MMP-9, and tissue inhibitor of MMP-5 (TIMP-2). Patients and Methods: Patients with solid malignanciesere 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 C-ss values achiev ed, and exploratory studies were performed to assess the effects of BAY 12- 9566 on plasma concentrations of MMP-2, MMP-9, and TIMP-2. Results: Twenty-one patients were treated with 47 28-day courses of BAY 12- 9566. The most common side effects were headache, nausea, vomiting, abnorma lities in hepatic functions, and thrombocytopenia, which were rarely clinic ally significant. BAY 12-9566 was well tolerated on all dose schedules, and there was no consistent dose-limiting toxicity that precluded treatment in the range of dose schedules evaluated. Instead, dose escalation was termin ated because BAY 12-9566 plasma C-ss values increased less than proportiona tely and plateaued as the daily dose was increased within the dose range of 100 to 1,600 mg/d, suggesting saturable drug absorption. Mean plasma C-ss values achieved with all dose schedules exceeded BAY 12-9566 concentrations required to inhibit MMPs in vitro and in vascular invasion and tumor proli feration in vivo models. There were no consistent effects of BAY 12-9566 on the plasma concentrations of MMP-2 and MMP-9 over the continuous dosing pe riod at any dose schedule level. However, plasma levels of TIMP-2 seemed to increase in a dose-dependent manner (r(2) = .50, P = .046). Conclusions: The recommended dose of BAY 12-9566 for subsequent disease dir ected studies is 800 mg twice daily, which resulted in biologically relevan t plasma C-ss values and an acceptable toxicity profile. Although explorato ry studies of MMPs in plasma were not revealing, it is conceivable that som e tumor types and disease settings are more likely to produce more readily quantifiable levels of activated MMPs than others. Therefore, attempts to i dentify and quantify surrogate markers of MMP inhibitory effects should con tinue to be performed in disease-directed studies in more homogenous patien t populations. (C) 2000 by American Society of Clinical Oncology.