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

Abstract

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.

• Authors: M Crul, G J de Klerk, M Swart, L J van't Veer, D de Jong, L Boerrigter, P A Palmer, C J Bol, H Tan, G C de Gast, J H Beijnen, J H M Schellens
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 20 Issue 11 Pg. 2726-35 (Jun 01 2002) ISSN: 0732-183X [Print] United States
• PMID: 12039935 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Quinolones
• Alkyl and Aryl Transferases
• Farnesyltranstransferase
• tipifarnib

Topics

• Administration, Oral
• Alkyl and Aryl Transferases (antagonists & inhibitors)
• Antineoplastic Agents (pharmacology)
• Biotransformation
• Drug Administration Schedule
• Enzyme Inhibitors (pharmacology)
• Farnesyltranstransferase
• Fatigue (chemically induced)
• Female
• Genes, ras (drug effects)
• Hematologic Diseases (chemically induced)
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Mutation
• Nausea (chemically induced)
• Neoplasms (drug therapy)
• Quinolones (pharmacology)
• Vomiting (chemically induced)