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.

Purpose: The purpose of this phase I clinical trial was to determine the maximum-tolerated dose and toxicity of CP-609,754 in patients with solid tumors refractory to standard therapies, to determine the cellular effects of CP-609,754 on its molecular target (farnesyltransferase), and to determine the recommended phase II dose (RP2D) of this agent.Experimental Design: Consenting patients with adequate bone marrow, liver, and renal function were enrolled with an accelerated dose strategy with single-patient parallel cohorts in whom the drug was given orally either once or twice daily. Once a dose-limiting toxicity was encountered or two patients developed Common Toxicity Criteria 2: grade 2 toxicities, a modified Fibonacci sequence was initiated. Blood samples were collected during cycle 1 for pharmacokinetic and pharmacodynamic analyses.Results: A total of 68 cycles of CP-609,754 was administered to 21 patients enrolled in this study. The dose escalation was from 20 mg once daily to 640 mg twice per day, and at the highest dose level, one of six patients developed a dose-limiting toxicity of grade 3 neuropathy. The drug was otherwise well tolerated, and the maximum-tolerated dose was not reached because of the large number of tablets that would have been required for additional dose escalation. Pharmacokinetic analyses showed a proportional increase in exposure with dose, rapid oral absorption, and a half-life of similar to3 hours. Pharmacodynamic results predict a 95% maximal inhibition of peripheral blood mononuclear cell farnesyltransferase activity 2 hours postdose, on average, with a dose of 400 mg twice per day of CP-609,754.Conclusions: On the basis of the safety findings and the pharmacokinetic and pharmacodynamic analyses, the RP2D of CP-609,754 is greater than or equal to640 mg twice per day.