A phase I and pharmacologic study of the matrix metalloproteinase inhibitor CP-471,358 in patients with advanced solid tumors

Abstract

Background: Matrix metalloproteinases play a role in the process of tissue invasion and metastasis by degrading the extracellular matrix. Inhibitors of matrix metalloproteinases are therefore of interest as anticancer drugs. CP-471,358 is a matrix metalloproteinase inhibitor that in vitro demonstrates strong inhibition of matrix metalloproteinases 2 and 9. The drug can be administered orally without food restriction.

Study design: An open-label phase I study was performed in patients with advanced solid tumors to assess the safety, tolerability, maximal tolerated dose (MTD) and pharmacokinetics of CP-471,358. The CP-471,358 doses studied were 50, 100 and 200 mg three times daily (TID) continuously, 50, 100 and 200 mg TID for 21 days followed by a 1-week treatment-free interval and 75 mg and 150 mg twice daily (BID) continuously.

Results: A total of 38 patients were treated in the study. The median number of cycles administered was two (range one to five). Myalgia and arthralgia were the most frequently observed adverse events (in 27 of 38 patients) and were observed at all dose levels and with all schedules except for the 150 mg BID continuous dosing level. In six patients National Cancer Institute (NCI) Common Toxicity Criteria (CTC) grade 3 myalgia/arthralgia was observed and this adverse event was considered to be the dose-limiting toxicity (DLT). Introduction of a 1-week treatment-free interval between cycles had no effect on the occurrence of myalgia/arthralgia. After cessation of treatment, arthralgia/myalgia was reversible in all patients. Other adverse events observed were fatigue and an increase of liver enzymes but these rarely exceeded CTC grade 2. Pharmacokinetic analysis showed that target efficacious concentrations were achieved throughout the morning dosing interval with 150 mg BID and 200 mg TID.

Conclusion: The DLT of CP-471,358 was myalgia and arthralgia, an adverse event observed during treatment with most matrix metalloproteinase inhibitors. A drug-free interval of 1 week was unable to prevent the occurrence of these adverse effects. Clearly this represents a limitation for potential long-term use of this compound.