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A dose-escalation study of indisulam in combination with capecitabine (Xeloda) in patients with solid tumours

This dose escalation study was designed to determine the recommended dose of the multi-targeted cell cycle inhibitor indisulam in combination with capecitabine in patients with solid tumours and to evaluate the pharmacokinetics of the combination. Thirty-five patients were treated with indisulam on...

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Autores principales: Siegel-Lakhai, W S, Zandvliet, A S, Huitema, A D R, Tibben, M M, Milano, G, Girre, V, Diéras, V, King, A, Richmond, E, Wanders, J, Beijnen, J H, Schellens, J H M
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361705/
https://www.ncbi.nlm.nih.gov/pubmed/18414469
http://dx.doi.org/10.1038/sj.bjc.6604300
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author Siegel-Lakhai, W S
Zandvliet, A S
Huitema, A D R
Tibben, M M
Milano, G
Girre, V
Diéras, V
King, A
Richmond, E
Wanders, J
Beijnen, J H
Schellens, J H M
author_facet Siegel-Lakhai, W S
Zandvliet, A S
Huitema, A D R
Tibben, M M
Milano, G
Girre, V
Diéras, V
King, A
Richmond, E
Wanders, J
Beijnen, J H
Schellens, J H M
author_sort Siegel-Lakhai, W S
collection PubMed
description This dose escalation study was designed to determine the recommended dose of the multi-targeted cell cycle inhibitor indisulam in combination with capecitabine in patients with solid tumours and to evaluate the pharmacokinetics of the combination. Thirty-five patients were treated with indisulam on day 1 of each 21-day cycle. Capecitabine was administered two times daily (BID) on days 1–14. Plasma concentrations of indisulam, capecitabine and its three metabolites were determined for pharmacokinetic analysis. The main dose-limiting toxicity was myelosuppression. Hand/foot syndrome and stomatitis were the major non-haematological toxicities. The recommended dose was initially established at indisulam 700 mg m(−2) and capecitabine 1250 mg m(−2) BID. However, during cycle 2 the recommended dose was poorly tolerated in three patients. A dose of indisulam 500 mg m(−2) and capecitabine 1250 mg m(−2) BID proved to be safe at cycle 1 and 2 in nine additional patients. Indisulam pharmacokinetics during cycle 1 were consistent with pharmacokinetic data from phase I mono-therapy studies. However, exposure to indisulam was remarkably increased at cycle 2 due to a drug–drug interaction between capecitabine and indisulam. Partial response was confirmed in two patients, one with colon carcinoma and the other with pancreatic carcinoma. Seventeen patients had stable disease. Indisulam (700 mg m(−2)) in combination with capecitabine (1250 mg m(−2) BID) was well tolerated during the first cycle. A dose of indisulam 500 mg m(−2) and capecitabine 1250 mg m(−2) BID was considered safe in multiple treatment cycles. The higher incidence of toxicities observed during cycle 2 can be explained by a time-dependent pharmacokinetic drug–drug interaction.
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spelling pubmed-23617052009-09-10 A dose-escalation study of indisulam in combination with capecitabine (Xeloda) in patients with solid tumours Siegel-Lakhai, W S Zandvliet, A S Huitema, A D R Tibben, M M Milano, G Girre, V Diéras, V King, A Richmond, E Wanders, J Beijnen, J H Schellens, J H M Br J Cancer Clinical Study This dose escalation study was designed to determine the recommended dose of the multi-targeted cell cycle inhibitor indisulam in combination with capecitabine in patients with solid tumours and to evaluate the pharmacokinetics of the combination. Thirty-five patients were treated with indisulam on day 1 of each 21-day cycle. Capecitabine was administered two times daily (BID) on days 1–14. Plasma concentrations of indisulam, capecitabine and its three metabolites were determined for pharmacokinetic analysis. The main dose-limiting toxicity was myelosuppression. Hand/foot syndrome and stomatitis were the major non-haematological toxicities. The recommended dose was initially established at indisulam 700 mg m(−2) and capecitabine 1250 mg m(−2) BID. However, during cycle 2 the recommended dose was poorly tolerated in three patients. A dose of indisulam 500 mg m(−2) and capecitabine 1250 mg m(−2) BID proved to be safe at cycle 1 and 2 in nine additional patients. Indisulam pharmacokinetics during cycle 1 were consistent with pharmacokinetic data from phase I mono-therapy studies. However, exposure to indisulam was remarkably increased at cycle 2 due to a drug–drug interaction between capecitabine and indisulam. Partial response was confirmed in two patients, one with colon carcinoma and the other with pancreatic carcinoma. Seventeen patients had stable disease. Indisulam (700 mg m(−2)) in combination with capecitabine (1250 mg m(−2) BID) was well tolerated during the first cycle. A dose of indisulam 500 mg m(−2) and capecitabine 1250 mg m(−2) BID was considered safe in multiple treatment cycles. The higher incidence of toxicities observed during cycle 2 can be explained by a time-dependent pharmacokinetic drug–drug interaction. Nature Publishing Group 2008-04-22 2008-04-15 /pmc/articles/PMC2361705/ /pubmed/18414469 http://dx.doi.org/10.1038/sj.bjc.6604300 Text en Copyright © 2008 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 Study
Siegel-Lakhai, W S
Zandvliet, A S
Huitema, A D R
Tibben, M M
Milano, G
Girre, V
Diéras, V
King, A
Richmond, E
Wanders, J
Beijnen, J H
Schellens, J H M
A dose-escalation study of indisulam in combination with capecitabine (Xeloda) in patients with solid tumours
title A dose-escalation study of indisulam in combination with capecitabine (Xeloda) in patients with solid tumours
title_full A dose-escalation study of indisulam in combination with capecitabine (Xeloda) in patients with solid tumours
title_fullStr A dose-escalation study of indisulam in combination with capecitabine (Xeloda) in patients with solid tumours
title_full_unstemmed A dose-escalation study of indisulam in combination with capecitabine (Xeloda) in patients with solid tumours
title_short A dose-escalation study of indisulam in combination with capecitabine (Xeloda) in patients with solid tumours
title_sort dose-escalation study of indisulam in combination with capecitabine (xeloda) in patients with solid tumours
topic Clinical Study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361705/
https://www.ncbi.nlm.nih.gov/pubmed/18414469
http://dx.doi.org/10.1038/sj.bjc.6604300
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