Introduction: Metastatic renal cell cancer (mRCC) patients have a median overall survival (mOS) of approximately 28 months. Until recently, mammalian target of rapamycin (mTOR) inhibition with everolimus was the standard second-line treatment regimen for mRCC patients, improving median progression-free survival (mPFS). Treatment with everolimus supports the expansion of immunosuppressive regulatory T cells (Tregs), which exert a negative effect on antitumor immune responses. In a phase 1 dose-escalation study, we have recently demonstrated that a low dose of 50 mg oral cyclophosphamide once daily can be safely combined with everolimus in mRCC patients and prevents the everolimus-induced increase in Tregs. Materials and methods: In a multicenter phase 2 study, performed in patients with mRCC not amenable to or progressive on a vascular endothelial growth factor (VEGF)-receptor tyrosine kinase inhibitor (TKI) containing treatment regimen, we assessed whether the addition of this metronomic dosing schedule of cyclophosphamide to therapy with everolimus could result in an improvement of progression-free survival (PFS) after 4 months of treatment. Results: Though results from this study confirmed that combination treatment effectively lowered circulating levels of Tregs, addition of cyclophosphamide did not improve the PFS rate at 4 months. For this reason, the study was abrogated at the predefined interim analysis. Conclusion: Although the comprehensive immunomonitoring analysis performed in this study provides relevant information for the design of future immunotherapeutic approaches, the addition of metronomic cyclophosphamide to mRCC patients receiving everolimus cannot be recommended.