A phase I pharmacokinetic and pharmacodynamic study of s-3304, a novel matrix metalloproteinase inhibitor, in patients with advanced and refractory solid tumors.

PURPOSE: Matrix metalloproteinases (MMP) play a fundamental role in cancer development and progression. S-3304 is a potent, orally active, noncytotoxic inhibitor of MMPs, primarily MMP-2 and MMP-9, that prolongs survival in mice xenografts and is well tolerated in healthy volunteers. EXPERIMENTAL DESIGN: The aims of this phase I clinical trial were to determine the maximum tolerated dose, dose-limiting toxicities, pharmacokinetic profile, and intratumoral MMP inhibitory activity of single-agent S-3304 in advanced and refractory solid tumors. MMP activity was determined by film in situ zymography (FIZ). Patients had tumor biopsies before and after S-3304 administration and were also evaluated for response and survival. RESULTS: Four dose levels were explored [DL1-DL4 or 800, 1,600, 2,400, and 3200 mg twice daily (BID), respectively], and 32 patients were enrolled. Toxicities were mostly gastrointestinal. The maximum tolerated dose was not reached, but dose escalations beyond DL4 were impractical (number of capsules needed). S-3304 steady-state concentrations were reached by day 8, and day 1 mean C(max) and AUC(0-8) increases were less than dose proportional. After S-3304 administration, 17 of 18 patients experienced inhibition of MMP activity by FIZ. Strong mean inhibition of MMP activity was observed in DL1 to DL3. The negative mean inhibitory activity calculated for DL4 was due to one patient with a 397% MMP activity increase. CONCLUSION: S-3304 is safe, well tolerated, and achieves plasma concentrations above those required to inhibit MMP-2 and MMP-9. Its intratumoral MMP inhibitory activity has been shown using FIZ, which is useful as a biomarker with this and other MMP inhibitors.

Pharmacokinetics and safety assessments of high-dose and 4-week treatment with S-3304, a novel matrix metalloproteinase inhibitor, in healthy volunteers.

AIMS: To investigate the tolerability, safety and pharmacokinetics of S-3304 in healthy volunteers treated with high doses of S-3304 for 28 days. METHODS: Thirty-two healthy volunteers were recruited. Four male and four female subjects were allocated to one of four doses (800 mg, 1600 mg, 2400 mg and 3200 mg). At each dose six volunteers took active medication and two volunteers took placebo in a double-blind fashion. Volunteers took a single dose on days 1 and 28 for pharmacokinetic purposes, and took twice daily doses from day 3-27. The pharmacokinetics of S-3304 and its hydroxy metabolites were evaluated. Tolerance was based on subjective adverse events, clinical examination, vital signs, ECG and laboratory tests including haematology and biochemistry profiles using CTC grading. RESULTS: Doses up to 2400 mg twice daily were generally well tolerated. At 3200 mg twice daily, five volunteers including one randomized to placebo were withdrawn from treatment mainly due to alanine aminotransferase (ALT) elevation. C(max) of S-3304 on day 1, whose geometric mean and 95% confidence interval were 66.3 microg ml(-1) (48.8, 90.0) for 800 mg, 82.6 microg ml(-1) (69.3, 98.6) for 1600 mg, 89.5 microg ml(-1) (79.5, 100.7) for 2400 mg, and 110.5 microg ml(-1) (88.9, 137.7) for 3200 mg, respectively, was correlated with the log-transformed peak ALT (P < 0.0001 for male and P = 0.048 for female volunteers). CONCLUSIONS: In healthy volunteers the maximum tolerated dose of S-3304 was 2400 mg twice daily. ALT elevation was the most frequent dose-limiting factor and was correlated with C(max) on day 1.