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Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer

BACKGROUND: For patients with metastatic renal cell cancer (mRCC) who progressed on vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor therapy, the orally administered mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to prolong progression free survi...

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Autores principales: Huijts, Charlotte M, Santegoets, Saskia J, van den Eertwegh, Alfons J, Pijpers, Laura S, Haanen, John B, de Gruijl, Tanja D, Verheul, Henk M, van der Vliet, Hans J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3305518/
https://www.ncbi.nlm.nih.gov/pubmed/22129044
http://dx.doi.org/10.1186/1471-2407-11-505
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author Huijts, Charlotte M
Santegoets, Saskia J
van den Eertwegh, Alfons J
Pijpers, Laura S
Haanen, John B
de Gruijl, Tanja D
Verheul, Henk M
van der Vliet, Hans J
author_facet Huijts, Charlotte M
Santegoets, Saskia J
van den Eertwegh, Alfons J
Pijpers, Laura S
Haanen, John B
de Gruijl, Tanja D
Verheul, Henk M
van der Vliet, Hans J
author_sort Huijts, Charlotte M
collection PubMed
description BACKGROUND: For patients with metastatic renal cell cancer (mRCC) who progressed on vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor therapy, the orally administered mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to prolong progression free survival. Intriguingly, inhibition of mTOR also promotes expansion of immunosuppressive regulatory T cells (Tregs) that can inhibit anti-tumor immune responses in a clinically relevant way in various tumor types including RCC. This study intends to investigate whether the antitumor efficacy of everolimus can be increased by preventing the detrimental everolimus induced expansion of Tregs using a metronomic schedule of cyclophosphamide. METHODS/DESIGN: This phase I-II trial is a national multi-center study of different doses and schedules of low-dose oral cyclophosphamide in combination with a fixed dose of everolimus in patients with mRCC not amenable to or progressive after a VEGF-receptor tyrosine kinase inhibitor containing treatment regimen. In the phase I part of the study the optimal Treg-depleting dose and schedule of metronomic oral cyclophosphamide when given in combination with everolimus will be determined. In the phase II part of the study we will evaluate whether the percentage of patients progression free at 4 months of everolimus treatment can be increased from 50% to 70% by adding metronomic cyclophosphamide (in the dose and schedule determined in the phase I part). In addition to efficacy, we will perform extensive immune monitoring with a focus on the number, phenotype and function of Tregs, evaluate the safety and feasibility of the combination of everolimus and cyclophosphamide, perform monitoring of selected angiogenesis parameters and analyze everolimus and cyclophosphamide drug levels. DISCUSSION: This phase I-II study is designed to determine whether metronomic cyclophosphamide can be used to counter the mTOR inhibitor everolimus induced Treg expansion in patients with metastatic renal cell carcinoma and increase the antitumor efficacy of everolimus. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01462214, EudraCT number 2010-024515-13, Netherlands Trial Register number NTR3085.
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spelling pubmed-33055182012-03-16 Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer Huijts, Charlotte M Santegoets, Saskia J van den Eertwegh, Alfons J Pijpers, Laura S Haanen, John B de Gruijl, Tanja D Verheul, Henk M van der Vliet, Hans J BMC Cancer Study Protocol BACKGROUND: For patients with metastatic renal cell cancer (mRCC) who progressed on vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor therapy, the orally administered mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to prolong progression free survival. Intriguingly, inhibition of mTOR also promotes expansion of immunosuppressive regulatory T cells (Tregs) that can inhibit anti-tumor immune responses in a clinically relevant way in various tumor types including RCC. This study intends to investigate whether the antitumor efficacy of everolimus can be increased by preventing the detrimental everolimus induced expansion of Tregs using a metronomic schedule of cyclophosphamide. METHODS/DESIGN: This phase I-II trial is a national multi-center study of different doses and schedules of low-dose oral cyclophosphamide in combination with a fixed dose of everolimus in patients with mRCC not amenable to or progressive after a VEGF-receptor tyrosine kinase inhibitor containing treatment regimen. In the phase I part of the study the optimal Treg-depleting dose and schedule of metronomic oral cyclophosphamide when given in combination with everolimus will be determined. In the phase II part of the study we will evaluate whether the percentage of patients progression free at 4 months of everolimus treatment can be increased from 50% to 70% by adding metronomic cyclophosphamide (in the dose and schedule determined in the phase I part). In addition to efficacy, we will perform extensive immune monitoring with a focus on the number, phenotype and function of Tregs, evaluate the safety and feasibility of the combination of everolimus and cyclophosphamide, perform monitoring of selected angiogenesis parameters and analyze everolimus and cyclophosphamide drug levels. DISCUSSION: This phase I-II study is designed to determine whether metronomic cyclophosphamide can be used to counter the mTOR inhibitor everolimus induced Treg expansion in patients with metastatic renal cell carcinoma and increase the antitumor efficacy of everolimus. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01462214, EudraCT number 2010-024515-13, Netherlands Trial Register number NTR3085. BioMed Central 2011-11-30 /pmc/articles/PMC3305518/ /pubmed/22129044 http://dx.doi.org/10.1186/1471-2407-11-505 Text en Copyright ©2011 Huijts et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Study Protocol
Huijts, Charlotte M
Santegoets, Saskia J
van den Eertwegh, Alfons J
Pijpers, Laura S
Haanen, John B
de Gruijl, Tanja D
Verheul, Henk M
van der Vliet, Hans J
Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer
title Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer
title_full Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer
title_fullStr Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer
title_full_unstemmed Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer
title_short Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer
title_sort phase i-ii study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer
topic Study Protocol
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3305518/
https://www.ncbi.nlm.nih.gov/pubmed/22129044
http://dx.doi.org/10.1186/1471-2407-11-505
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