title: Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer.
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
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier NCT01462214, EudraCT number 2010-024515-13, Netherlands Trial Register number NTR3085.
authors: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Charlotte M
authors: CM
authors: Huijts
authors: Saskia J
authors: SJ
authors: Santegoets
authors: Alfons J
authors: AJ
authors: van den Eertwegh
authors: Laura S
authors: LS
authors: Pijpers
authors: John B
authors: JB
authors: Haanen
authors: Tanja D
authors: TD
authors: de Gruijl
authors: Henk M
authors: HM
authors: Verheul
authors: Hans J
authors: HJ
authors: van der Vliet
mesh_terms: D000284:Administration, Oral; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary*; D003520:Cyclophosphamide / Q000008:administration & dosage*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination / Q000379:methods; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D009426:Netherlands; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus