This phase Ib/II trial investigates the safety and effect of low-dose-rate brachytherapy and immune checkpoint inhibition in treating patients with stage III-IV cutaneous melanoma, stage IV renal cell cancer, and stage IV urothelial cancer. Brachytherapy, also known as internal radiation therapy, uses radioactive material placed directly into or near a tumor to kill tumor cells. Immunotherapy with monoclonal antibodies, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving low-dose-rate brachytherapy and immunotherapy may kill more tumor cells.
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04620603.
PRIMARY OBJECTIVES:
I. Evaluate the effect of combining low dose rate brachytherapy (LDR) with immune checkpoint inhibition in stage III and IV cutaneous melanoma, stage IV renal cell cancer, and stage IV urothelial cancer.
II. Determine safety and feasibility of combining LDR with immunotherapy.
SECONDARY OBJECTIVES:
I. To generate a toxicity profile for this novel combination of brachytherapy and immunotherapy (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0).
II. To evaluate the overall response (OR) from first day of treatment to end of treatment (EOT).
III. To assess overall survival (OS), will be assessed every 3 months via phone call.
CORRELATIVE OBJECTIVES:
I. To determine whether clinical response after LDR in combination with checkpoint blockade is associated with a gene expression signature characterized by low expression of TREX1 and elevated levels of IFN-beta and its associated genes.
II. To evaluate the clinical response, overall response, and Trex1 association with clinical effect.
III. To demonstrate that LDR more effectively stimulates circulating tumor deoxyribonucleic acid (ctDNA) release and may enhance the sensitivity and specificity of non-invasive detection of tumor derived nucleic acid.
IV. To correlate ctDNA with response to immunotherapy.
V. To determine if LDR will enhance cytotoxic T cell infiltration in poorly immunogenic tumors.
VI. To evaluate the relationship between circulating myeloid-derived suppressor cells (MDSC) levels and radiation response.
VII. To determine the impact of reduced Trex1 levels on the secretion of IFN-beta.
VIII. To determine if mutations of CCR2 inhibit post-therapy tumor infiltrations of MDSCs and improve efficacy of radiation via germline sequencing.
OUTLINE:
Patients undergo LDR on day 1. After a minimum of 7 days but no more than 30 days patients receive standard of care (SOC) immunotherapy. Treatment with SOC immunotherapy cycles continue per standard cycle length for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection and may undergo computed tomography (CT) scan with biopsy on study.
After completion of study treatment, patients are followed up every 3 months.
Lead OrganizationCase Comprehensive Cancer Center
Principal InvestigatorJay Phillip Ciezki
