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Since mTOR inhibitors were shown to benefit immunosuppressive regulatory T-cell (Treg) expansion, this might suppress antitumor immune responses. Metronomic cyclophosphamide (CTX) was shown to selectively deplete Tregs. This study was, therefore, designed to determine the optimal dosage and schedule of CTX when combined with everolimus to prevent this potentially detrimental Treg expansion. In this national multi-center phase I study, patients with mRCC progressive on first line anti-angiogenic therapy received 10\u00a0mg everolimus once daily and were enrolled into cohorts with different CTX dosages and schedules. Besides immune monitoring, adverse events and survival data were monitored. 40 patients, 39 evaluable, were treated with different doses and schedules of CTX. Combined with 10\u00a0mg everolimus once daily, the optimal Treg depleting dose and schedule of CTX was 50\u00a0mg CTX once daily. 23 (59%) patients experienced one or more treatment-related\u2009\u2265\u2009grade 3 toxicity, mostly fatigue, laboratory abnormalities and pneumonitis. The majority of the patients achieved stable disease, two patients a partial response. Median PFS of all cohorts was 3.5 months. In conclusion, the optimal Treg depleting dose and schedule of CTX, when combined with everolimus, is 50\u00a0mg once daily. This combination leads to acceptable adverse events in comparison with everolimus alone. Currently, the here selected combination is being evaluated in a phase II clinical trial.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>NCT01462214.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00262-018-2248-3","type":"journal-article","created":{"date-parts":[[2018,11,9]],"date-time":"2018-11-09T08:12:48Z","timestamp":1541751168000},"page":"319-329","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Phase 1 study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell carcinoma"],"prefix":"10.1007","volume":"68","clinical-trial-number":[{"clinical-trial-number":"nct01462214","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Charlotte M.","family":"Huijts","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inge M.","family":"Werter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sin\u00e9ad M.","family":"Lougheed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruben S.","family":"Goedegebuure","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla M.","family":"van Herpen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Hamberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Metin","family":"Tascilar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John B.","family":"Haanen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henk M.","family":"Verheul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja D.","family":"de Gruijl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans J.","family":"van der Vliet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Dutch WIN-O Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,11,9]]},"reference":[{"key":"2248_CR1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21387","volume":"67","author":"RL Siegel","year":"2017","unstructured":"Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. 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