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

Charlotte M Huijts, Saskia J Santegoets, Alfons J van den Eertwegh, Laura S Pijpers, John B Haanen, Tanja D de Gruijl, Henk M Verheul, Hans J van der Vliet, Charlotte M Huijts, Saskia J Santegoets, Alfons J van den Eertwegh, Laura S Pijpers, John B Haanen, Tanja D de Gruijl, Henk M Verheul, Hans J van der Vliet

Abstract

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.

Figures

Figure 1
Figure 1
Trial design. Patients will be enrolled in cohorts of 5 per dose level. The first 5 patients enrolled will be assigned to dose level 0 in order to assess immune and anti-angiogenic effects of everolimus monotherapy. In subsequent dose levels the cyclophosphamide dose will be increased up to a maximum of 150 mg cyclophosphamide twice daily. The dose level showing the most selective depletion of Tregs will be selected for phase II. Endpoints for the phase I part are safety, immunologic and angiogenesis parameters, response rate and drug levels. In the phase II part of the study patients will receive 10 mg everolimus per day in combination with the optimal Treg depleting dose cyclophosphamide. Endpoints for the phase II part are progression free survival, safety, immunologic and angiogenesis parameters and response rate.

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Source: PubMed

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