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Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor

The aims of this study were to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics of irinotecan given with oral R115777 (tipifarnib), a farnesyl protein transferase inhibitor. Patients were treated with escalating doses of irinotecan with interval-modulated dosing of...

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Autores principales: Sparreboom, A, Kehrer, D F S, Mathijssen, R H J, Xie, R, de Jonge, M J A, de Bruijn, P, Planting, A S T, Eskens, F A L M, Verheij, C, de Heus, G, Klaren, A, Zhang, S, Verhaeghe, T, Palmer, P A, Verweij, J
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2004
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409716/
https://www.ncbi.nlm.nih.gov/pubmed/15083177
http://dx.doi.org/10.1038/sj.bjc.6601732
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author Sparreboom, A
Kehrer, D F S
Mathijssen, R H J
Xie, R
de Jonge, M J A
de Bruijn, P
Planting, A S T
Eskens, F A L M
Verheij, C
de Heus, G
Klaren, A
Zhang, S
Verhaeghe, T
Palmer, P A
Verweij, J
author_facet Sparreboom, A
Kehrer, D F S
Mathijssen, R H J
Xie, R
de Jonge, M J A
de Bruijn, P
Planting, A S T
Eskens, F A L M
Verheij, C
de Heus, G
Klaren, A
Zhang, S
Verhaeghe, T
Palmer, P A
Verweij, J
author_sort Sparreboom, A
collection PubMed
description The aims of this study were to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics of irinotecan given with oral R115777 (tipifarnib), a farnesyl protein transferase inhibitor. Patients were treated with escalating doses of irinotecan with interval-modulated dosing of R115777 (continuously or on days 1–14, and repeated every 21 days). In total, 35 patients were entered onto the trial for a median duration of treatment of 43 days (range, 5–224 days). Neutropenia and thrombocytopenia were the dose-limiting toxicities; other side effects were mostly mild. The MTD was established at R115777 300 mg b.i.d. for 14 consecutive days with irinotecan 350 mg m(−2) given every 3 weeks starting on day 1. Three patients had a partial response and 14 had stable disease. In the continuous schedule, the area under the curves of irinotecan and its active metabolite SN-38 were 20.0% (P=0.004) and 38.0% (P<0.001) increased by R115777, respectively. Intermittent dosing of R115777 at a dose of 300 mg b.i.d. for 14 days every 3 weeks is the recommended dose of R115777 in combination with the recommended single-agent irinotecan dose of 350 mg m(−2).
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spelling pubmed-24097162009-09-10 Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor Sparreboom, A Kehrer, D F S Mathijssen, R H J Xie, R de Jonge, M J A de Bruijn, P Planting, A S T Eskens, F A L M Verheij, C de Heus, G Klaren, A Zhang, S Verhaeghe, T Palmer, P A Verweij, J Br J Cancer Clinical The aims of this study were to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics of irinotecan given with oral R115777 (tipifarnib), a farnesyl protein transferase inhibitor. Patients were treated with escalating doses of irinotecan with interval-modulated dosing of R115777 (continuously or on days 1–14, and repeated every 21 days). In total, 35 patients were entered onto the trial for a median duration of treatment of 43 days (range, 5–224 days). Neutropenia and thrombocytopenia were the dose-limiting toxicities; other side effects were mostly mild. The MTD was established at R115777 300 mg b.i.d. for 14 consecutive days with irinotecan 350 mg m(−2) given every 3 weeks starting on day 1. Three patients had a partial response and 14 had stable disease. In the continuous schedule, the area under the curves of irinotecan and its active metabolite SN-38 were 20.0% (P=0.004) and 38.0% (P<0.001) increased by R115777, respectively. Intermittent dosing of R115777 at a dose of 300 mg b.i.d. for 14 days every 3 weeks is the recommended dose of R115777 in combination with the recommended single-agent irinotecan dose of 350 mg m(−2). Nature Publishing Group 2004-04-19 2004-03-23 /pmc/articles/PMC2409716/ /pubmed/15083177 http://dx.doi.org/10.1038/sj.bjc.6601732 Text en Copyright © 2004 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.
spellingShingle Clinical
Sparreboom, A
Kehrer, D F S
Mathijssen, R H J
Xie, R
de Jonge, M J A
de Bruijn, P
Planting, A S T
Eskens, F A L M
Verheij, C
de Heus, G
Klaren, A
Zhang, S
Verhaeghe, T
Palmer, P A
Verweij, J
Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor
title Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor
title_full Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor
title_fullStr Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor
title_full_unstemmed Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor
title_short Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor
title_sort phase i and pharmacokinetic study of irinotecan in combination with r115777, a farnesyl protein transferase inhibitor
topic Clinical
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409716/
https://www.ncbi.nlm.nih.gov/pubmed/15083177
http://dx.doi.org/10.1038/sj.bjc.6601732
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