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Cohen SJ, Gallo J, Lewis NL, Alpaugh RK, Gentner L, Rogatko A, Yeslow G, Schol J, Verhaeghe T, Zannikos P, Palmer PA, Weiner LM, Meropol NJ
Phase I and pharmacokinetic study of the farnesyltransferase inhibitor R115777 in combination with irinotecan in patients with advanced cancer
Cancer Chemotherapy and Pharmacology (2004) 53:513-518.
Abstract
Purpose. 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. Patients and 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 recei! ved 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.
Note
Publication Date: 2004-06-01.
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