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

Charlotte M Huijts,Ruben S Goedegebuure,Carla M Van Herpen,Tanja D De Gruijl,Hans J Van Der Vliet,Inge M Werter,Paul Hamberg,For The Dutch Win-O Consortium ,John B Haanen,Sinéad M Lougheed,Henk M Verheul,Metin Tascilar

doi:10.1007/s00262-018-2248-3

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 registrationNCT01462214.

Highlights

Introduction administration ofCTX has been reported to result in Treg depletion, with possible beneficial effects on T- and NKcell functionality [25, 26]
When patients were treated for a longer period with the study drugs, more adverse events were reported
The two cohorts with the highest CTX dose showed slightly more adverse events compared to the lower cohorts

Summary

Introduction

Introduction administration ofCTX has been reported to result in Treg depletion, with possible beneficial effects on T- and NKcell functionality [25, 26]. We hypothesized that addition of metronomic CTX to therapy with everolimus in patients with mRCC might counteract the detrimental Treg expansion induced by everolimus and could thereby increase the antitumor efficacy. In this phase I study we aimed to determine the optimal dose of CTX that would result in the selective depletion of Tregs when combined with a fixed dose (10 mg) of everolimus, taking into account the safety and tolerability of the combination treatment. The most common tumor arising in the kidney is renal cell carcinoma (RCC). The combination of everolimus and the multi-target tyrosine kinase inhibitor lenvatinib improved progression-free survival (PFS) in patients with mRCC compared to everolimus alone following one prior anti-angiogenic therapy [8, 9]

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