J Clin Oncol  2002 Jun 1;20(11):2726-35 

Phase I clinical and pharmacologic study of chronic oral administration of the
farnesyl protein transferase inhibitor R115777 in advanced cancer.

Crul M, de Klerk GJ, Swart M, van't Veer LJ, de Jong D, Boerrigter L, Palmer PA,
Bol CJ, Tan H, de Gast GC, Beijnen JH, Schellens JH.

Netherlands Cancer Institute and Academic Medical Centre, Amsterdam, The
Netherlands. apmcr@slz.nl

PURPOSE: To determine the maximum-tolerated dose, toxicities, and
pharmacokinetics of R115777, a farnesyl transferase inhibitor, when administered
continuously via the oral route. PATIENTS AND METHODS: Patients with advanced
solid malignancies were treated with R115777 using an interpatient dose
escalation scheme starting at 50 mg bid. Pharmacokinetics were assessed on days
1, 28, and 56. RESULTS: Twenty-eight patients were entered onto the study and
the median duration of treatment was 55 days. The dose-limiting toxicities were
myelosuppression and neurotoxicity. At a dose of 400 mg bid, grade 4
leukocytopenia and neutropenia were seen in two of four patients. Neurotoxicity
grade 3 developed in one of five patients at 500 mg bid and in one of 13 at 300
mg bid after 8 weeks of treatment. Common nonhematologic toxicities were nausea,
vomiting, and fatigue. The recommended dose for phase II/III testing in this
scheme is 300 mg bid. The pharmacokinetic studies indicated dose
proportionality. Little accumulation occurred and steady-state levels were
reached within 2 to 3 days. Analyses of historic tumor material showed that five
of 15 of patients had a K-ras mutation in codon 12. Three patients with
pancreatic, colon, and cervix carcinomas had stable disease and one patient with
a colon carcinoma had a minor response accompanied by a more than 50% decrease
in carcinoembryonic antigen tumor marker. A fifth patient, with
platinum-refractory non-small-cell lung cancer, showed a partial response that
lasted for 5 months. CONCLUSION: Continuous dosing of R115777 is feasible with
an acceptable toxicity profile at a dose of 300 mg bid.

Publication Types:
Clinical Trial
Clinical Trial, Phase I

PMID: 12039935 [PubMed - indexed for MEDLINE]