Phase I and pharmacokinetic study of the ovally administered farnesyl transferase inhibitor R115777 in patients with advanced solid tumors

R115777 is a novel selective inhibitor of farnesyl transferase, an enzyme t hat is involved in the proliferation of the malignant cell type. This study was designed to determine the toxicity, maximal tolerated dose and pharmac okinetics of R115777 when given orally b.i.d. for 28 days followed by 1-2 w eeks of rest. Patients with advanced solid tumors for whom no standard ther apy was available could enter the study. The starting dose of R115777 was 2 00 mg/dose and inter- as well as intra-patient dose escalations were perfor med with increments of 100 mg/dose, Nine patients entered the study and rec eived in total 23 treatment cycles. A dose of 300 mg b.i.d. proved feasible with grade 4 neutropenia occurring in one of six patients who completed th e first treatment cycle. Other toxicities were infrequent. Pharmacokinetic analysis demonstrated that peak plasma concentrations of 881 +/- 393 ng/ml were reached within 1-5 h. No accumulation of R115777 was observed over a 2 8-day period. The study was terminated based on these results together with the observation from a related phase I study in which higher doses of R115 777 were associated with the frequent occurrence of grade 3-4 myelosuppress ion. We conclude that the recommended dose of R115777 given for 28 days fol lowed by 1-2 weeks of rest is 300 mg b.i.d, Myelosuppression is the dose-li miting toxicity, [(C) 2001 Lippincott Williams & Wilkins].