A phase I safety, pharmacological and biological study of the farnesyl protein transferase inhibitor, tipifarnib and capecitabine in advanced solid tumors.
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.
Gore
L
L
Department of Pediatrics, Medical Oncology, and Pharmacology, University of Colorado Cancer Center, Aurora, CO, USA. lia.gore@UCHSC.edu
Holden
S N
SN
Cohen
R B
RB
Morrow
M
M
Pierson
A S
AS
O'Bryant
C L
CL
Persky
M
M
Gustafson
D
D
Mikule
C
C
Zhang
S
S
Palmer
P A
PA
Eckhardt
S G
SG
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*
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