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

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BMC Cancer

, 11:505

First Online: 30 November 2011Received: 24 November 2011Accepted: 30 November 2011DOI: 10.1186-1471-2407-11-505

Cite this article as: Huijts, C.M., Santegoets, S.J., van den Eertwegh, A.J. et al. BMC Cancer 2011 11: 505. doi:10.1186-1471-2407-11-505


BackgroundFor 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-designThis 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.

DiscussionThis 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 Identifier NCT01462214, EudraCT number 2010-024515-13, Netherlands Trial Register number NTR3085.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-11-505 contains supplementary material, which is available to authorized users.

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Autor: Charlotte M Huijts - Saskia J Santegoets - Alfons J van den Eertwegh - Laura S Pijpers - John B Haanen - Tanja D de Gr


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