Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer.
OBJECTIVE
To determine the maximum-tolerated dose, toxicities, and pharmacokinetic profile of the farnesyl protein transferase inhibitor R115777 when administered orally bid for 5 days every 2 weeks.


METHODS
Twenty-seven patients with a median age of 58 years received 85 cycles of R115777 using an intrapatient and interpatient dose escalation schema. Drug was administered orally at escalating doses as a solution (25 to 850 mg bid) or as pellet capsules (500 to 1300 mg bid). Pharmacokinetics were assessed after the first dose and the last dose administered during cycle 1.


RESULTS
Dose-limiting toxicity of grade 3 neuropathy was observed in one patient and grade 2 fatigue (decrease in two performance status levels) was seen in four of six patients treated with 1,300 mg bid. The most frequent clinical grade 2 or 3 adverse events in any cycle included nausea, vomiting, headache, fatigue, anemia, and hypotension. Myelosuppression was mild and infrequent. Peak plasma concentrations of R115777 were achieved within 0.5 to 4 hours after oral drug administration. The elimination of R115777 from plasma was biphasic, with sequential half-lives of about 5 hours and 16 hours. There was little drug accumulation after bid dosing, and steady-state concentrations were achieved within 2 to 3 days. The pharmacokinetics were dose proportional in the 25 to 325 mg/dose range for the oral solution. Urinary excretion of unchanged R115777 was less than 0.1% of the oral dose. One patient with metastatic colon cancer treated at the 500-mg bid dose had a 46% decrease in carcinoembryonic antigen levels, improvement in cough, and radiographically stable disease for 5 months.


CONCLUSIONS
R115777 is bioavailable after oral administration and has an acceptable toxicity profile. Based upon pharmacokinetic data, the recommended dose for phase II trials is 500 mg orally bid (total daily dose, 1, 000 mg) for 5 consecutive days followed by 9 days of rest. Studies of continuous dosing and studies of R115777 in combination with chemotherapy are ongoing.
Zujewski
J
J
Medicine Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD, USA.
Horak
I D
ID
Bol
C J
CJ
Woestenborghs
R
R
Bowden
C
C
End
D W
DW
Piotrovsky
V K
VK
Chiao
J
J
Belly
R T
RT
Todd
A
A
Kopp
W C
WC
Kohler
D R
DR
Chow
C
C
Noone
M
M
Hakim
F T
FT
Larkin
G
G
Gress
R E
RE
Nussenblatt
R B
RB
Kremer
A B
AB
Cowan
K H
KH
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000740:Anemia / Q000139:chemically induced; D001682:Biological Availability; D001853:Bone Marrow / Q000187:drug effects; D002214:Capsules; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051231:Farnesyltranstransferase; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006207:Half-Life; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D015363:Quinolones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012996:Solutions; D014839:Vomiting / Q000139:chemically induced
D002214:Capsules; D004791:Enzyme Inhibitors; D015363:Quinolones; D012996:Solutions; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C402769:tipifarnib