A phase II, open label study for patients with renal cell carcinoma (RCC), the most common type of kidney cancer, is currently enrolling subjects at selected Hoosier Cancer Research Network sites. The HCRN GU17-289 study, led by researchers at the Indiana University Melvin and Bren Simon Cancer Center in Indianapolis, Ind., compares the positive and negative effects of using high-dose interleukin-2 (IL-2) and entinostat to using IL-2 alone. The study also assesses the safety and tolerability of IL-2 and entinostat.

IL-2, also known as aldesleukin, is a biological response modifier that boosts the immune system in cancer treatment and is made in a laboratory setting. The human body also produces IL-2, which is a protein that enhances the growth of cells to build the body’s immune system.

Entinostat is an investigational Class I selective histone deacetylase (HDAC) inhibitor that plays a vital role in regulating gene expression and inducing cell death, known as apoptosis, in cancer cells.

The National Cancer Institute estimates more than 65,000 new cases of kidney and renal pelvis cancer were diagnosed in 2018. Moreover, about one-third of patients with kidney cancer have advanced or metastatic disease at the time they are diagnosed.

People with RCC who are not in a study typically undergo a nephrectomy, or removal of the kidney and adjoining structures. Another treatment option for people with RCC is to undergo cytokine therapy, a protein therapy, with interferon alpha or high-dose IL-2 or anti-VEGF medications, such as sunitinib and sorafenib.

Roberto Pili, MD, sponsor-investigator of the research study and a medical oncologist at the Indiana University Melvin and Bren Simon Cancer Center, said this study is a continuation of previous phase I and phase II studies conducted through the Cancer Therapy Evaluation Program at the National Cancer Institute, part of the National Institutes of Health.

Results from the earlier study demonstrated a 37% overall response rate and a median progression-free survival of 13.8 months in patients with untreated RCC, when a combination of IL-2 and entinostat were used.

“Based on these initial results, we are now trying to confirm this hypothesis that entinostat may increase the clinical benefit of patients receiving high-dose interleukin-2,” Dr. Pili said. “This is based on preliminary data that suggest modulating the immune system with histone deacetylase inhibitors, we can increase the efficacy of immunotherapies not just in kidney cancer but also in other tumors.”

“This study hopefully will provide even more robust evidence that these combinations may be beneficial. And from a patient perspective, it may provide an additional regimen available in the future,” Dr. Pili said.

Participants in the HCRN GU17-289 study, “A Phase II Randomized, Open label Study of High Dose Interleukin 2 vs High Dose Interleukin 2 plus Entinostat in Advanced Renal Cell Carcinoma,” will be randomly grouped into two treatment arms. The first arm will receive high-dose IL-2 and entinostat and the second arm will receive IL-2 alone.

Dr. Pili warns because of the potential toxicity and side effects related to the use of IL-2, selected participants must be hospitalized during treatment intervals for close observation.

Subjects in both treatment arms will receive high-dose IL-2 intravenously every 8 hours for 5 days and again 9 days later.

Those assigned to the first arm also will receive entinostat, taken orally every 2 weeks, or until their disease worsens, they experience unacceptable side effects, or more than 2 doses of entinostat are missed.

Participants in the second arm will be scheduled for a clinic visit every 2 or 3 months to monitor their progress.

High-dose IL-2 is approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic renal cell carcinoma. 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.

Combining high-dose IL-2 and entinostat for the treatment of RCC has not been approved by the FDA and should be considered investigational.

Researchers will collect tissue samples for correlative studies to monitor how biomarkers and immune cells in subjects’ blood change while receiving treatment. The samples will also be used to study genetic information that will help researchers learn why a subject’s cancer responds the way it does to treatment. Previous biopsy tissue may also be used if available.

To qualify for the study, patients must be adults age 18 or older, have clear cell renal cell carcinoma that is metastatic or surgically unresectable, and have a life expectancy of greater than six months.

Up to 46 subjects will take part in this study — 23 subjects in each arm. The study is supported by Prometheus and Syndax and managed by Hoosier Cancer Research Network.

For more information about this research study, including full eligibility requirements, visit www.clinicaltrials.gov (study #NCT03501381).

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.