Phase I and pharmacokinetic study of the farnesyltransferase inhibitor R115777 in combination with irinotecan in patients with advanced cancer.
OBJECTIVE
R115777 is a selective, nonpeptidomimetic inhibitor of farnesyltransferase (FTase), an enzyme responsible for the post-translational modification of several proteins, including Ras. Given the high frequency of K-Ras mutations in malignancies commonly treated with irinotecan, the broad preclinical antiproliferative activity of R115777 and its largely non-overlapping toxicity profile with irinotecan, this phase I study of the combination of R115777 and irinotecan in patients with advanced cancer was undertaken.


METHODS
Enrolled onto the study were 14 patients (eight male, six female; median age 63 years, range 48-72 years). Five patients had an ECOG performance status (PS) of 0, eight patients PS 1, and one patient PS 2. The patients were treated with R115777 orally twice daily for 28 days and irinotecan 100 mg/m(2) as an intravenous infusion on days 1, 8, 15, and 22 of each 42-day cycle. Seven patients received R115777 100 mg twice daily and seven received R115777 200 mg twice daily.


RESULTS
Dose-limiting toxicity (DLT) was experienced by one of seven patients treated with R115777 100 mg (grade 3 fatigue), and two of seven patients treated with R115777 200 mg (grade 3 diarrhea, grade 4 neutropenia lasting >5 days). The maximum tolerated dose (MTD) was R115777 100 mg twice daily and irinotecan 100 mg/m(2) weekly. Non-DLTs were primarily rash, fatigue, diarrhea, and neutropenia. R115777 demonstrated linear pharmacokinetics without interaction with irinotecan and achieved serum levels required for antitumor activity in vitro.


CONCLUSIONS
Serum levels of R115777 exceeded those necessary for FTase inhibition in vitro without evidence of interaction with irinotecan. However, the MTD of R115777 in this study was lower than that obtained with an alternate schedule. Thus, further development of this schedule is not recommended.
Cohen
Steven J
SJ
Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA. S_Cohen@fccc.edu
Gallo
James
J
Lewis
Nancy L
NL
Alpaugh
R Katherine
RK
Gentner
Louis
L
Rogatko
André
A
Yeslow
Gwen
G
Schol
Jessie
J
Verhaeghe
Tom
T
Zannikos
Peter
P
Palmer
Peter A
PA
Weiner
Louis M
LM
Meropol
Neal J
NJ
D000284:Administration, Oral; D000368:Aged; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003967:Diarrhea / Q000139:chemically induced / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D051231:Farnesyltranstransferase; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015363:Quinolones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D015363:Quinolones; D000077146:Irinotecan; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C402769:tipifarnib; D002166:Camptothecin