Spotlight on Clinical Trials: A phase II study of nivolumab combined with ipilimumab for patients with advanced rare genitourinary tumors

March, 2018

A trial is now enrolling at two DF/HCC member institutions (Beth Israel Deaconess Medical Center and Dana-Farber Cancer Institute/Brigham and Women’s Hospital), led by Bradley A McGregor, MD (DFCI), that will evaluate combination therapy with two checkpoint inhibitors, nivolumab and ipilimumab, in a Phase II open-label study in patients with rare genitourinary cancers.

“There are several rare histologies in genitourinary cancers,” said McGregor, who is the Clinical Director for the Lank Center of Genitourinary Oncology and a medical oncologist specializing in genitourinary malignancies at Dana-Farber Cancer Institute. “Because they are so rare, patients with these tumors are almost always excluded from clinical trials. These patients have limited treatment options.”

Combination Therapy Provided Survival Benefit in Other GU Cancer Trial
McGregor seized on the idea to investigate nivolumab and ipilimumab in these patients based on studies of the combination therapy in other cancers, particularly in kidney and non-variant bladder cancers. “This kind of immunotherapy is really a tumor-agnostic treatment,” he said. “It spans all tumor types.” Several studies have shown efficacy against non-small cell lung cancer, head and neck cancers, and Hodgkin lymphoma.

The nivolumab/ipilimumab combination therapy is already approved for advanced melanoma, with a different dosing schedule. Alternative dosing schedules have been explored with hopes of reducing side effects but still maintaining efficacy.

To this end, results of the Phase III Checkmate 214 clinical trial of the combination with higher dose nivolumab and lower dose ipilimumab in renal cell carcinoma were announced at the European Society for Medical Oncology (ESMO) Congress in fall 2017. This treatment regimen improved overall response rates, progression-free survival, and overall survival in intermediate- and poor-risk patients with kidney cancer compared to treatment with the gold standard, sunitinib. “Given the efficacy of the combination at this dose, we hope patients with rare GU cancers could potentially benefit from this same immunotherapy. While individually rare, by grouping into one trial, we could offer this treatment to our patients” McGregor explained.

Checkpoint Inhibitors Act in Tandem
Both nivolumab and ipilimumab are checkpoint inhibitors that act synergistically on T-cells, allowing them to recognize and attack cancer cells. Nivolumab is an antibody that binds to and inhibits the programmed cell death-1 (PD-1) receptor on the surface of T cells. PD-1 is a checkpoint protein that normally helps keep the T cells from attacking other cells in the body. Cancer cells use this natural immune pathway mechanism to evade destruction from the immune system. When nivolumab binds to the PD-1 receptor, it boosts the body’s T-cell immune response against cancer cells.

The ipilimumab antibody blocks the action of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), another molecule that normally prevents T-cells from attacking normal cells and cancer cells in the body.

Study Design
Patients will receive nivolumab and ipilimumab intravenously every 3 weeks for a total of 4 maximum doses. After combination therapy, nivolumab will be administered as monotherapy. The primary outcome is objective response as measured by response evaluation criteria in solid tumors (RECIST). Secondary outcomes include immune-related overall response, duration of response, progression-free and overall survival, as well as safety and tolerability.

The trial will enroll approximately 60 patients in the US, including patients with adrenocortical carcinoma, non-urothelial bladder, non-urothelial upper tract penile cancer, non-adenocarcinoma prostate cancer, and refractory germ-cell tumors. The trial is enrolling now at DFCI and BIDMC with plans to open in other centers nationwide.

“When patients come to the DF/HCC institutions, they are coming to see if there is something new,” said McGregor. “This is a trial that any patient with these rare genitourinary cancers can participate in regardless where they are in treatment, first-line or beyond.”

Phase II Trial
A Phase II Study of nivolumab combined with ipilimumab for Patients with Advanced Genitourinary Tumors
Principal Investigator: Bradley A McGregor, MD (DFCI)
NIH Trial Number: NCT03333616
DF/HCC Protocol Number: 17-423

The trial is actively recruiting patients. Find more information at ClinicalTrials.gov.

— By Alice McCarthy