Phase I study of the matrix metalloproteinase inhibitor, BAY 12-9566

Background: Matrix metalloproteinases (MMPs) are involved in tumor invasion and metastasis and have been implicated in breast, ovarian, colorectal, an d lung cancer growth. We undertook a phase I study of BAY 12-9566, an inhib itor of MMP-2, MMP-9, and MMP-3, in patients with solid tumors to determine its safety, pharmacokinetics, and effects on potential surrogate markers o f biologic activity. Patients and methods: BAY 12-9566 was orally administered daily at four dos e levels; 400 mg daily, 400 mg b.i.d., 400 mg t.i.d., and 800 mg b.i.d. Dru g disposition was determined on days 1 and 29 with weekly trough levels mea sured during the first four weeks. Plasma vascular endothelial growth facto r (VEGF), basic fibroblast growth factor (bFGF), and urinary pyridinoline a nd deoxypyridinoline crosslinks were determined at baseline, once weekly fo r four weeks, and then every four weeks. Results: Thirteen patients were entered on trial. BAY 12-9566 was well tole rated, with only one grade 3 headache, one grade 3 anemia, one grade 3 thro mbocytopenia, and no musculoskeletal effects. The median treatment duration was 57 days (range 7-560). Mean trough levels of BAY 12-9566 on day 28 ran ged from 80.5 to 108.6 mg/l. Plasma trough levels were 1500-42,000-fold abo ve the K-i's for MMP-2, MMP-3, and MMP-9 at the 800 mg p.o. b.i.d. dose lev el. There was no significant change in VEGF, bFGF, pyridinoline, and deoxyp yridinoline crosslinks with BAY 12-9566 administration. Conclusions: The recommended dose for further testing is 800 mg p.o. b.i.d.