This phase II trial studies how well image guided hypofractionated radiation therapy works with nelfinavir mesylate, pembrolizumab, nivolumab, and atezolizumab in treating patients with melanoma, lung cancer, or kidney cancer that has spread (advanced). Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Nelfinavir mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, nivolumab and atezolizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving hypofractionated radiation therapy, nelfinavir mesylate, pembrolizumab, nivolumab and atezolizumab may work better in treating patients with melanoma, lung, or kidney cancer.
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03050060.
PRIMARY OBJECTIVES:
I. To evaluate the response rate (complete [CR] or partial [PR] response, confirmed and unconfirmed) by immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) 1.1 in:
Ia. Patients with: non-small cell lung cancer, melanoma, or renal cell carcinoma that is either naive or refractory to anti-PD-L1 or PD-L1 therapy;
Ib. Who are treated with: Hypofractionated radiotherapy, anti-PD1/PD-L1 therapy and nelfinavir.
SECONDARY OBJECTIVES:
I. To assess the safety and tolerability of the regimen as determined by the rate of grade 4 hepatoxicity.
II. To evaluate the frequency and severity of toxicities by Common Terminology Criteria for Adverse Events (CTCAE) 5.0 attributed to treatment.
III. To evaluate progression-free survival within each disease and prior treatment cohort.
IV. To evaluate overall survival within each disease and prior treatment cohort
V. To evaluate the association between response and smoking status, underlying genetic mutations if known (e.g.: Kras, BRAF) circulating cell-free deoxyribonucleic acid (cfDNA), circulating tumor cells, PDL-1 expression in tumor and peripheral blood T cell receptor repertoire by sequencing within each disease and prior treatment cohort.
OUTLINE:
Beginning 7-14 days prior to start of pembrolizumab, nivolumab, or atezolizumab, patients receive nelfinavir mesylate orally (PO) twice daily (BID) on days 1-7 or 1-14 (dependent upon when treatment is started) up to 11-12 weeks. Patients also receive pembrolizumab, nivolumab or atezolizumab intravenously (IV) over 30-60 minutes on day 1. Cycles repeat every 21-28 days in the absence of disease progression or unacceptable toxicity. Patients then undergo hypofractionated radiation therapy over 3-14 days starting after cycle 1 and before cycle 3 of pembrolizumab, nivolumab or atezolizumab.
After completion of study treatment, patients are followed up at 30 days and then every 6 months for up to 2 years.
Lead OrganizationFred Hutch/University of Washington/Seattle Children's Cancer Consortium
Principal InvestigatorRamesh Rengan
