A Phase I trial of the farnesyl protein transferase inhibitor R115777 in combination with gemcitabine and cisplatin in patients with advanced cancer.
OBJECTIVE
This Phase I study was undertaken to define the toxicity, pharmacodynamics, and maximum tolerated dose of the combination of R115777, a farnesyl transferase inhibitor, with gemcitabine and cisplatin in patients with advanced solid tumors.


METHODS
Thirty patients with solid tumors received a median of 2.5 cycles (range 1-30+) through five dose levels. R115777 was administered p.o. twice daily for 14 days. Gemcitabine was infused 15 min after the ingestion of R115777 on days 1 and 8. Cisplatin was administered starting 30 min after completion of the gemcitabine infusion on day 1. Cycles were repeated every 21 days. Toxicities were graded by the National Cancer Institute Common Toxicity Criteria and recorded as maximum grade per patient for each treatment cycle. At the maximum tolerated dose, accumulation of prelamin A in buccal mucosa cells of patients was evaluated as a marker of farnesyl transferase inhibition by R115777.


RESULTS
Neutropenia and thrombocytopenia were the most common toxicities. Dose-limiting toxicity in cycle 1 was myelosuppression with thrombocytopenia alone (4 patients), neutropenia alone (1 patient), or a combination of both (3 patients). Common nonhematologic toxicities were anorexia, rash, nausea, vomiting, and fatigue, none of which was dose limiting in the first cycle. At the maximum tolerated dose, defined as R115777 300 mg twice daily p.o., 1000 mg/m(2) gemcitabine, and 75 mg/m(2) cisplatin, inhibition of prelamin A farnesylation in buccal mucosa cells of patients was demonstrated, confirming that R115777 inhibits protein farnesylation in vivo. Nine objective responses (one complete response and eight partial responses) were documented in 27 evaluable patients.


CONCLUSIONS
The combination of R115777 with gemcitabine and cisplatin was well tolerated and showed evidence of antitumor activity. The maximum tolerated dose of R115777 successfully inhibits farnesyltransferase in patients in vivo. This combination warrants further evaluation in a number of tumor types.
Adjei
Alex A
AA
Mayo Clinic and Foundation, Departments of Oncology and Medicine, Rochester, Minnesota 55905, USA. adjei.alex@mayo.edu
Croghan
Gary A
GA
Erlichman
Charles
C
Marks
Randolph S
RS
Reid
Joel M
JM
Sloan
Jeff A
JA
Pitot
Henry C
HC
Alberts
Steven R
SR
Goldberg
Richard M
RM
Hanson
Lorelei J
LJ
Bruzek
Laura M
LM
Atherton
Pamela
P
Thibault
Alain
A
Palmer
Peter A
PA
Kaufmann
Scott H
SH
D000328:Adult; D000368:Aged; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage*; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D004573:Electrolytes; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051231:Farnesyltranstransferase; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009061:Mouth Mucosa / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy*; D015363:Quinolones / Q000008:administration & dosage* / Q000009:adverse effects; D013997:Time Factors; D000093542:Gemcitabine
D004573:Electrolytes; D004791:Enzyme Inhibitors; D015363:Quinolones; D003841:Deoxycytidine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C402769:tipifarnib; D002945:Cisplatin; D000093542:Gemcitabine