This Phase I study of
MMI270, an p.o. administered
matrix metalloproteinase inhibitor, assessed toxicity, pharmacokinetics, and
tumor response data and 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,
bone resorption markers, direct targets of the inhibitor [
matrix metalloproteinase-2 (MMP-2), MMP-8, and
MMP-9], indirect targets [
tissue inhibitor of metalloproteinase-1 (TIMP-1),
TIMP-2,
basic fibroblast growth factor,
vascular endothelial growth factor,
vascular cell adhesion molecule-1, soluble
urokinase plasminogen activator receptor, and
cathepsins B and H] and for a
tumor necrosis factor-alpha cytokine release assay. Ninety-two patients were entered. There was no myelotoxicity. Eighteen patients developed a widespread maculopapular
rash, which increased in frequency and severity at doses > or = 300 mg bid. Thirty nine patients developed musculoskeletal side effects, which were related to
duration of treatment, not to dose level. Pharmacokinetics were linear, and
MMI270 was rapidly absorbed and eliminated with minimal accumulation on chronic dosing. Sustained plasma concentrations in excess of 4 x mean IC(50) for the target
enzymes were observed at dose levels > or = 150 mg bid. There were no
tumor regressions; however, 19 patients had stable disease for > or = 90 days. There was a dose-response increase 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 maximum tolerated dose of 300 mg bid and musculoskeletal side effects.
Biological marker data indicate
drug effects. The rise in
TIMP-1 suggests that a reflex rise in inhibitors could modify the effects of
MMI270. The recommended Phase II dose is 300 mg bid.