Phase I clinical and pharmacologic study of chronic oral administration of the farnesyl protein transferase inhibitor R115777 in advanced cancer.
OBJECTIVE
To determine the maximum-tolerated dose, toxicities, and pharmacokinetics of R115777, a farnesyl transferase inhibitor, when administered continuously via the oral route.


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.


CONCLUSIONS
Continuous dosing of R115777 is feasible with an acceptable toxicity profile at a dose of 300 mg bid.
Crul
M
M
Netherlands Cancer Institute and Academic Medical Centre, Amsterdam, The Netherlands. apmcr@slz.nl
de Klerk
G J
GJ
Swart
M
M
van't Veer
L J
LJ
de Jong
D
D
Boerrigter
L
L
Palmer
P A
PA
Bol
C J
CJ
Tan
H
H
de Gast
G C
GC
Beijnen
J H
JH
Schellens
J H M
JH
D000284:Administration, Oral; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001711:Biotransformation; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D011905:Genes, ras / Q000187:drug effects; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009154:Mutation; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy*; D015363:Quinolones / Q000494:pharmacology*; D014839:Vomiting / Q000139:chemically induced
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C402769:tipifarnib