Image Guided Hypofractionated Radiation Therapy, Nelfinavir Mesylate, Pembrolizumab, Nivolumab and Atezolizumab in Treating Patients With Advanced Melanoma, Lung, or Kidney Cancer

PRIMARY OBJECTIVES:

I. Safety, tolerability and preliminary assessment of overall response rate (ORR) to
combination of hypofractionated radiotherapy with PD1/PDL1 immune checkpoint and nelfinavir
mesylate (nelfinavir).

SECONDARY OBJECTIVES:

I. Correlate overall response rate (ORR) with: 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.

II. Progression-free survival (PFS)-6 (systemic control): the proportion of patients who are
free from progression at 6 months.

III. Overall survival.

IV. The type and frequency of adverse events.

OUTLINE:

Beginning 7-14 days prior to start of pembrolizumab, nivolumab, or atezolizumab, patients
receive nelfinavir mesylate orally (PO) twice daily (BID) on days 1-14 up to 11-12 weeks.
Patients also receive pembrolizumab, nivolumab or atezolizumab intravenously (IV) over 30-60
minutes on day 1. Courses repeat every 14-21 days in the absence of disease progression or
unacceptable toxicity. Patients then undergo hypofractionated radiation therapy over 3-14
days starting after course 1 and before course 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.

Inclusion Criteria:

- Disease eligibility and stage

- Histologically confirmed diagnosis of melanoma, non-small cell lung cancer
(NSCLC), or renal carcinoma

- Previously treated or previously untreated stage IV melanoma, stage IV lung
cancer, and metastatic renal cancer by American Joint Committee on Cancer (AJCC)
staging criteria

- Presence of a lesion that is suitable for hypofractionated radiotherapy

- Subjects must have measurable disease by Response Evaluation Criteria in Solid Tumors
(RECIST) criteria independent of the lesion irradiated

- Prior immunotherapy or chemotherapy is allowed as long as > 14 days prior to
enrollment

- Eastern Cooperative Oncology Group (ECOG) 0-2

- Acceptable marrow function and hematologic indices for PD1/PDL1 immune checkpoint
inhibitor and nelfinavir as per standard of care

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Subjects who have had immunotherapy, chemotherapy, or radiation therapy within 14 days
(6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who
have not recovered from adverse events due to agents administered more than 4 weeks
earlier

- Subjects may not be receiving other investigational agents

- Patients with untreated/active brain metastases as documented by magnetic resonance
imaging (MRI) within 2 months of study enrollment

- Allergy or intolerance to nelfinavir or selected PD1/PDL1 immune checkpoint inhibitor

- Patients requiring steroids or other immunosuppressive therapy; low-dose or topical
steroids are allowable if being used as replacement therapy

- Patients receiving anti-retroviral therapy or other agents that are contra-indicated
with nelfinavir due to drug-drug interactions

- Pregnant or lactating patients

- Prior radiation that precludes delivery of hypofractionated radiotherapy