Abstract
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 RegistrationClinicalTrials.gov Identifier NCT01462214, EudraCT number 2010-024515-13, Netherlands Trial Register number NTR3085.
Highlights
For patients with metastatic renal cell cancer who progressed on vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor therapy, the orally administered mammalian target of rapamycin inhibitor everolimus has been shown to prolong progression free survival
For patients with metastatic renal cell cancer (mRCC) that progressed on VEGF receptor tyrosine kinase inhibitor therapy, the orally administered mammalian target of rapamycin (mTOR) inhibitor everolimus was recently shown to prolong progression free survival relative to placebo from 1.9 months to 4.9 months (p < 0.001), providing an important additional therapeutic tool for this patient category [6,7]
As a derivative of rapamycin, everolimus acts as a signal transduction inhibitor that is selective for mTOR. mTOR is a key protein kinase present in all cells which regulates cell growth, proliferation, angiogenesis, and survival
Summary
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. Renal cell carcinoma (RCC) is the most common primary tumor arising in the kidney and can be classified into four histological subtypes, i.e. The treatment of metastatic RCC (mRCC) has considerably changed over the last 5 years due to the antitumor efficacy of two groups of targeted agents, namely agents that inhibit vascular endothelial growth factor (VEGF)-signaling pathways and those that inhibit mammalian target of rapamycin (mTOR) [4]. It critically controls homeostasis and the balance between effector T cells and regulatory T cells [8,9,10,11]; inhibition of mTOR has been shown to result in expansion of immunosuppressive regulatory T cells in vitro and in vivo [12,13,14]
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