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

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.

Metronomic chemotherapy from rationale to clinical studies: A dream or reality?

“…The Netherlands phase I/II multi-center Study Trial NTR3085, currently ongoing, evaluates the combination of everolimus (5 mg daily) with the metronomic schedule of cyclophosphamide in patients with mRCC not amenable to, or progressive after a VEGF-receptor tyrosine kinase inhibitor containing regimen [87].…”

Chemotherapy in metastatic renal cell carcinoma today? A systematic review

“…In particular, a multicenter phase I/II trial is currently being conducted by Huijts and colleagues (available at: http:// www.clinicaltrial.gov, NCT01462214) to test the recommended dosing and the RR of metronomic cyclophosphamide in association with the selective mTOR inhibitor everolimus, which was recently shown to prolong PFS compared with placebo from 1.9 to 4.9 months (P < 0.001), providing an important additional therapeutic tool for patients with mRCC who progressed on VEGF receptor TKI therapy [14,111]. Also, another phase II randomized study is currently ongoing to determine the overall RR of combination therapy with gemcitabine and sunitinib in sarcomatoid and/or poor-risk mRCC patients as first-line therapy until PD (available at: http://www.clinicaltrial.gov, NCT00556049).…”

Activity and complexes of mTOR in diffuse large B-cell lymphomas—a tissue microarray study

“…[5][6][7][8] This study focuses on mTOR, a serine-threonine kinase, a regulator and integrator of many cellular functions, eg, survival, proliferation, protein translation and cellular metabolism. 9 mTOR can form two distinct complexes (mTORC1 and mTORC2), which can be activated by various stimuli (growth factors, hormones, metabolic stress, etc).…”