Phase 1 study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell carcinoma

Abstract

mTOR inhibitors are frequently used in the treatment of metastatic renal cell cancer (mRCC). mTOR regulates cell growth, proliferation, angiogenesis, and survival, and additionally plays an important role in immune regulation. 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 mg 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 mg everolimus once daily, the optimal Treg depleting dose and schedule of CTX was 50 mg CTX once daily. 23 (59%) patients experienced one or more treatment-related ≥ grade 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 mg 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. Trial registration NCT01462214. Electronic supplementary material The online version of this article (10.1007/s00262-018-2248-3) contains supplementary material, which is available to authorized users.

T-Cell Infiltration and Adaptive Treg Resistance in Response to Androgen Deprivation With or Without Vaccination in Localized Prostate Cancer

“…One possibility is that the dosing regimen of cyclophosphamide used in this study was not optimal for Treg depletion. Since the completion of our study, emerging data showed that oral cyclophosphamide may be more effective for Treg depletion 35,36 . Given these limitations, future studies may be required to fully characterize the evolution of the immune TME over time and to optimize neoadjuvant immunotherapy in patients with prostate cancer.…”

The effect of everolimus and low-dose cyclophosphamide on immune cell subsets in patients with metastatic renal cell carcinoma: results from a phase I clinical trial

“…The trial was initiated by the department of medical oncology of the Amsterdam UMC, location VUmc and conducted within the context of the Netherlands Working Group on Immunotherapy of Oncology (WIN-O) with participation of 13 hospitals and enrollment of patients from January 2012 until August 2015. Clinical findings were reported separately [ 17 ].…”

“…Patients were treated in cohorts of five patients, with six different doses and schedules of CTX. Clinical results and results of changes in Treg frequencies in the various cohorts of this phase 1 trial were separately described [ 17 ]. Here, we report on the results of the extensive and comprehensive immune monitoring that was additionally performed in this phase 1 study, where patients were treated with either everolimus alone or the combination of everolimus and different CTX administration dosages and schedules.…”

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

“…Everolimus has also been tested in cervical cancer cell lines with a remarkable ability to inactivate efficiently the HPV16 E7 oncoprotein inhibiting cell proliferation (202). The capacity of everolimus-based combinations to inhibit cell proliferation from several cancer types has been reported for breast cancer (203,204), renal cell carcinoma (205,206), and thyroid cancer (207) in clinical trials.…”