Phase I Pharmacokinetic and Pharmacodynamic Study of Weekly 1-Hour and 24-Hour Infusion BMS-214662, a Farnesyltransferase Inhibitor, in Patients With Advanced Solid Tumors

Abstract

Purpose BMS-214662 is a potent, nonpeptide, small molecule inhibitor of human farnesyltransferase (FT). We have conducted a phase I pharmacokinetic (PK) and pharmacodynamic study of BMS-214662 administered intravenously weekly with 1- and 24-hour infusions. The objectives were to determine the dose-limiting toxicities and the recommended dose (RD), to describe PKs, and to evaluate the relationships between BMS-214662 exposure, FT inhibition, downstream signaling, and induction of apoptosis in tumor samples. Patients and Methods Patients with advanced solid tumors and adequate organ function were eligible. The dose was escalated according to a modified Fibonacci schedule. Results BMS-214662 was escalated from 56 to 278 mg/m2 in 37 patients in the 1-hour schedule, and from 84 to 492 mg/m2 in 31 patients in the 24-hour schedule. Dose-limiting toxicities included gastrointestinal and renal events. The RDs were 209 mg/m2 and 275 mg/m2 in the 1- and 24-hour schedules, respectively. Five patients (three with breast, one with gastric, and one with renal cell cancer) had clinical benefit from treatment. BMS-214662 exhibited linear PKs with area under the concentration-time curves at the RDs of 27 and 32 μM × h in the 1- and 24-hour schedules, respectively. The pattern of FT inhibition in peripheral-blood mononuclear cells at the RDs was different in the two schedules: high (> 80%) but short-lived (≤ 6 hours) in the 1-hour infusion and moderate (> 40%) but long-lived (24 hours) in the 24-hour infusion. BMS-214662 induced apoptosis in tumors but did not inhibit MAPK signaling. Conclusion BMS-214662 can be safely delivered in both the 1-hour and 24-hour infusions at biologically active doses, with the preclinical, PK, and pharmacodynamic profiles favoring the 24-hour schedule.