A single arm, phase II clinical trial for patients with metastatic renal cell carcinoma (RCC), the most common type of kidney cancer, is testing the histone deacetylase (HDAC) inhibitor entinostat in combination with ipilimumab and nivolumab in patients previously treated with nivolumab and ipilimumab or nivolumab alone. The study is open to accrual at Indiana University Melvin and Bren Simon Comprehensive Cancer Center in Indianapolis, Ind., and Georgetown University in Washington, D.C.

The study, HCRN-GU17-326, will test the safety and efficacy of this combination. Researchers will estimate the percentage of patients whose tumors shrink during the study, and how long it takes before their tumors start growing again.

Roberto Pili, MD, a professor of oncology at the Indiana University School of Medicine and a researcher at the IU Simon Cancer Center, is sponsor-investigator of the study. Dr. Pili said the combination of entinostat with nivolumab and ipilimumab has demonstrated significant activity for patients with RCC in early studies.

Nivolumab and ipilimumab are antibodies that stimulate the body’s immune system to fight cancer cells. Entinostat is a drug that interrupts cells from multiplying. It has been shown to block certain cells that suppress the immune system from fighting cancer. Blocking these cells may increase the body’s response to cancer cells.

“We recently published a paper in Clinical Cancer Research suggesting that entinostat may decrease the immunosuppression of the tumor micro-environment,” Dr. Pili said. “We inhibit the function of these cells called myeloid derived suppressor cells and we know that these cells infiltrating the tumor may in some way hamper the response to immunotherapies like PD-1 and CTLA4 inhibitors.”

Dr. Pili said this clinical trial will help to determine whether small molecules such as entinostat can restore sensitivity.

“The use of immune checkpoint inhibitors is really changing the way we treat patients with kidney cancer and other solid tumors,” Dr. Pili said. “We know that historically a small percentage of patients respond to this therapy, so there is indeed a need to increase the potential response to these therapies with other agents. We believe that using HDAC inhibitors, may be beneficial.”

Up to 53 people overall may take part in this study, which will run in two steps.

The first step will determine a safe dose for entinostat in combination with nivolumab and ipilimumab. Up to 18 people may participate in the first step. The second step will measure the percentage of patients whose tumor shrink after receiving entinostat with nivolumab and ipilimumab. About 41 people will participate in the second step.

Participants in the study will take entinostat orally once a week. Participants will receive nivolumab and ipilimumab intravenously every three weeks for the first three months. After three months, ipilimumab will be stopped and nivolumab will be given by itself every four weeks.

Study drugs may be taken until participants’ cancer worsens or side effects become severe. Participants may discontinue treatment at any time in consultation with their doctor.

Researchers will collect blood and tissue samples from participants for research purposes. The tissue will be used to study immune cells and a protein called PD-L1, to compare tissue results with how well the treatment worked. Samples may also be used for future unspecified research.

Nivolumab is approved by the U.S. Food and Drug Administration (FDA) to treat many cancers, including RCC. Ipilimumab is approved by the FDA to treat melanoma. Nivolumab in combination with ipilimumab is approved by the FDA to treat previously untreated RCC.

Entinostat is in development in combination with exemestane for advanced hormone receptor positive breast cancer (for which it has breakthrough therapy designation) and in combination with several approved PD-1/PD-L1 antagonists as a potential treatment for multiple solid tumors.

The combination of entinostat with nivolumab and ipilimumab is not FDA-approved and should be considered investigational.

Other drugs approved by the FDA are available to patients with disease progression after taking nivolumab and ipilimumab, but there currently is no standard of care for patients that progress after treatment with nivolumab and ipilimumab.

This study is supported by Bristol-Myers Squibb and Syndax.

To qualify, participants must be age 18 or older, with metastatic RCC that progressed after treatment with nivolumab and ipilimumab.

For more information about this research study, including full eligibility requirements, visit www.clinicaltrials.gov (study #NCT03552380).

About Hoosier Cancer Research Network:

Hoosier Cancer Research Network (formerly known as Hoosier Oncology Group) conducts innovative cancer research in collaboration with academic and community physicians and scientists across the United States. The organization provides comprehensive clinical trial management and support, from conception through publication. Created in 1984 as a program of the Walther Cancer Institute, Hoosier Cancer Research Network became an independent nonprofit clinical research organization in 2007. Since its founding, Hoosier Cancer Research Network has conducted more than 210 trials in a variety of cancer types and supportive care, resulting in more than 350 publications. More than 8,500 subjects have participated in Hoosier Cancer Research Network clinical trials.