A phase I, pharmacokinetic, and biological study of the farnesyltransferase inhibitor tipifarnib in combination with gemcitabine in patients with advanced malignancies

Clin Cancer Res. 2003 Oct 15;9(13):4761-71.


Purpose: To assess the feasibility of administering tipifarnib, an oral nonpeptidomimetic competitive inhibitor of farnesyltransferase, in combination with gemcitabine and recommend doses for disease-directed clinical trials. The study also sought to identify drug-drug pharmacokinetic interactions, evaluate effects on protein farnesylation, and seek preliminary evidence for clinical activity.

Experimental design: Patients with advanced solid malignancies were treated with tipifarnib at doses of 100, 200, and 300 mg twice daily continuously and 1000 mg/m(2) gemcitabine i.v. on days 1, 8, and 15 every 4 weeks. To identify pharmacokinetic interactions, the treatment and plasma sampling schemes were designed to permit comparisons of the pharmacokinetic behavior of each agent administered alone and together. The proportions of unfarnesylated and farnesylated HDJ2, a chaperone protein that undergoes farnesylation, were measured in peripheral blood mononuclear cells.

Results: Nineteen evaluable patients were treated with 74 courses of tipifarnib/gemcitabine (mg/mg/m(2)). Myelosuppression was the principal toxicity. Dose-limiting myelosuppression occurred in 2 of 5 patients at the 300/1000 dose level, whereas 2 of 11 evaluable patients at the 200/1000 dose level experienced dose-limiting toxicity. There was no evidence of clinically relevant pharmacokinetic interactions between tipifarnib and gemcitabine. Inhibition of farnesylation of HDJ2, a potential surrogate for Ras and/or other potentially relevant farnesylated proteins, was demonstrated in peripheral blood mononuclear cells at all dose levels. Partial responses were noted in patients with advanced pancreatic and nasopharyngeal carcinomas.

Conclusions: On the basis of the results of this study, the tipifarnib/gemcitabine dose level of 200/1000 is recommended for disease-directed studies. At this dose level, biologically relevant plasma concentrations of tipifarnib that consistently inhibit protein farnesylation in vitro are achieved and drug-induced inhibition of protein farnesylation is measured in most patients.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Antimetabolites, Antineoplastic / pharmacokinetics
  • Area Under Curve
  • Deoxycytidine / administration & dosage*
  • Deoxycytidine / analogs & derivatives*
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Inhibitors / pharmacokinetics*
  • Farnesyltranstransferase
  • Female
  • Humans
  • Leukocytes, Mononuclear / drug effects
  • Male
  • Middle Aged
  • Models, Chemical
  • Neoplasms / drug therapy*
  • Protein Prenylation
  • Quinolones / administration & dosage*
  • Time Factors
  • Treatment Outcome
  • ras Proteins / metabolism


  • Antimetabolites, Antineoplastic
  • Enzyme Inhibitors
  • Quinolones
  • Deoxycytidine
  • gemcitabine
  • Alkyl and Aryl Transferases
  • Farnesyltranstransferase
  • ras Proteins
  • tipifarnib