Identifying Optimal Dose of Cyclophosphamide With Everolimus in Metastatic Kidney Cancer
Posted: Thursday, December 13, 2018
As in those with other types of cancer, in patients with metastatic renal cell carcinoma, increased levels of regulatory T cells (Tregs) are associated with poor survival. Treg expansion has been associated with inhibition of mammalian target of rapamycin (mTOR). On the other hand, mTOR inhibition, produced by such agents as everolimus, is associated with decreased growth, proliferation, and survival of tumor cells. In addition, metronomic administration of cyclophosphamide has been reported to result in Treg depletion.
Consequently, “we hypothesized that addition of metronomic cyclophosphamide to therapy with everolimus in patients with [metastatic renal cell carcinoma] might counteract the detrimental Treg expansion induced by everolimus and could thereby increase the antitumor efficacy,” explained a team headed by Charlotte M. Huijts, MD, of Vrije Universiteit Medical Center, Amsterdam, The Netherlands, in Cancer Immunology, Immunotherapy.
In their 39-patient phase I study, the investigators sought to determine the oral cyclophosphamide dose that would best result in the selective depletion of Tregs when combined with a fixed dose (10 mg) of everolimus, taking into account safety and tolerability. They succeeded: It was 50 mg, once daily. All toxicities that occurred were previously known to be associated with the agents.
Now the combination is being evaluated in a phase II trial, “to determine if the observed Treg depletion also results in an enhancement of the survival of patients with [metastatic renal cell carcinoma] when compared to everolimus alone,” wrote Dr. Huijts and colleagues.
“Recently everolimus was replaced by both nivolumab and cabozantinib as the standard second-line treatment for patients with [metastatic renal cell carcinoma],” they noted. However, if the phase II trial’s results indicate that the combination benefits survival, it “could still be implemented in a later treatment line.”