title: A phase I safety, pharmacological and biological study of the farnesyl protein transferase inhibitor, tipifarnib and capecitabine in advanced solid tumors.
abstract: BACKGROUND
  To evaluate the toxicity and pharmacological and biological properties of the farnesyl protein transferase (FPTase) inhibitor, tipifarnib (R115777, ZARNESTRAtrade mark) and capecitabine administered for 14 days every 3 weeks.
  
  
  METHODS
  Patients with advanced cancers received twice daily tipifarnib (100-500 mg) and capecitabine (1000-1125 mg/m(2)) for 14 days every 3 weeks. Pharmacokinetics of tipifarnib, capecitabine and 5-fluorouracil (5-FU) were determined. Peripheral blood mononuclear cells were analyzed for farnesylation of the HDJ2 chaperone protein and FPTase activity.
  
  
  RESULTS
  Forty-one patients received 185 courses of treatment. Diarrhea and palmar-plantar erythrodysesthesia were dose limiting at 300 mg tipifarnib/1125 mg/m(2) capecitabine b.i.d. When the capecitabine dose was fixed at 1000 mg/m(2) b.i.d., neutropenia was dose limiting at 400 and 500 mg b.i.d. of tipifarnib. Capecitabine did not affect the pharmacology of tipifarnib at 100-300 mg b.i.d., although tipifarnib significantly increased the C(max) of 5-FU at 400 mg b.i.d. HDJ2 farnesylation and FPTase activity decreased between 200 and 400 mg b.i.d. doses of tipifarnib, without a dose-response relationship. Five patients demonstrated partial remissions and 11 patients maintained prolonged stable disease.
  
  
  CONCLUSIONS
  Tipifarnib and capecitabine are well tolerated at 300 mg/1000 mg/m(2) b.i.d., respectively, resulting in biologically relevant plasma concentrations and antitumor activity. The recommended dose for further disease-focused studies is 300 mg b.i.d. tipifarnib and 1000 mg/m(2) b.i.d. capecitabine, given for 14 days every 3 weeks.
authors.affiliation: Department of Pediatrics, Medical Oncology, and Pharmacology, University of Colorado Cancer Center, Aurora, CO, USA. lia.gore@UCHSC.edu
authors.forename: L
authors.initials: L
authors.lastname: Gore
authors.forename: S N
authors.initials: SN
authors.lastname: Holden
authors.forename: R B
authors.initials: RB
authors.lastname: Cohen
authors.forename: M
authors.initials: M
authors.lastname: Morrow
authors.forename: A S
authors.initials: AS
authors.lastname: Pierson
authors.forename: C L
authors.initials: CL
authors.lastname: O'Bryant
authors.forename: M
authors.initials: M
authors.lastname: Persky
authors.forename: D
authors.initials: D
authors.lastname: Gustafson
authors.forename: C
authors.initials: C
authors.lastname: Mikule
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.forename: P A
authors.initials: PA
authors.lastname: Palmer
authors.forename: S G
authors.initials: SG
authors.lastname: Eckhardt
mesh_terms: D000328:Adult; D000368:Aged; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy*; D017368:Protein Prenylation / Q000187:drug effects; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000964:Antimetabolites, Antineoplastic; C107481:DNAJA1 protein, human; D050956:HSP40 Heat-Shock Proteins; D015363:Quinolones; D003841:Deoxycytidine; D000069287:Capecitabine; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; C402769:tipifarnib; D005472:Fluorouracil