Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer

Purpose: To determine the maximum-tolerated dose, toxicities, and pharmacok inetic profile of the farnesyl protein transferase inhibitor R115777 when a dministered orally bid for 5 days every 2 weeks. Patients and Methods: Twenty-seven patients with a median age of 58 years r eceived 85 cycles of R115777 using an intrapatient and interpatient dose es calation schema. Drug was administered orally at escalating doses as a solu tion (25 to 850 mg bid) or as pellet capsules (500 to 1300 mg bid). Pharmac okinetics were assessed after the first dose and the last dose administered during cycle 1. Results: Dose-limiting toxicity of grade 3 neuropathy was observed in one p atient and grade 2 fatigue (decrease in two performance status levels) was seen in four of six patients treated with 1.300 mg bid. The most frequent c linical grade 2 or 3 adverse events in any cycle included nausea, vomiting, headache, fatigue, anemia, and hypotension. Myelosuppression was mild and infrequent. Peak plasma concentrations of R115777 were achieved within 0.5 to 4 hours after oral drug administration. The elimination of R115777 from plasma was biphasic, with sequential half-lives of about 5 hours and 16 hou rs. There was little drug accumulation after bid dosing, and steady-state c oncentrations were achieved within 2 to 3 days. The pharmacokinetics were d ose proportional in the 25 to 325 mg/dose range for the oral solution. Urin ary excretion of unchanged R115777 was less than 0.1% of the oral dose. One patient with metastatic colon cancer treated at the 500-mg bid dose had a 46% decrease in carcinoembryonic antigen levels, improvement in cough, and radiographically stable disease for 5 months. Conclusion: R115777 is bioavailable after oral administration and has an ac ceptable toxicity profile. Based upon pharmacokinetic data, the recommended dose for phase II trials is 500 mg orally bid (total daily dose, 1,000 mg) for 5 consecutive days followed by 9 days of rest. Studies of continuous d osing and studies of R115777 in combination with chemotherapy are ongoing. (C) 2000 by American Society of Clinical Oncology.