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

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.

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.

Eligibility Criteria:
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 or recurrent 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 to be irradiated. Prior checkpoint inhibitor immunotherapy or chemotherapy is allowed as long as the last dose was received \> 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 computed tomography (CT) or magnetic resonance imaging (MRI) within 2 months of study enrollment; by active brain metastases - we mean - actively symptomatic brain metastases requiring steroids
* 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

  * \*For a study regarding the safety and efficacy of high dose nelfinavir on patients with Kaposi's Sarcoma (KS), exclusion criteria included participants who were receiving any "strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 19 (2C19)"

Strong Inhibitors of CYP3A4:

* Antibiotics: clarithromycin, erythromycin, telithromycin, troleandomycin
* HIV: non-nucleoside reverse transcriptase inhibitors (delavirdine, nevirapine), protease inhibitors (ritonavir, indinavir, lopinavir/ritonavir, saquinavir), cobicistat-boosted antiretrovirals (e.g., elvitegravir); NOTE: Clinical trials have demonstrated that there are no clinically significant drug-drug interactions between nelfinavir and the following antiretrovirals: efavirenz (strong CYP3A4 inhibitor), etravirine (strong CYP3A4 inhibitor); therefore, these antiretrovirals will not be excluded. • Antifungals: itraconazole, ketoconazole, voriconazole, fluconazole, posaconazole
* Antidepressants: nefazodone
* Antidiuretic: conivaptan
* GI: cimetidine, aprepitant
* Hepatitis C: boceprevir, telaprevir
* Miscellaneous: seville oranges, grapefruit, or grapefruit juice and/or pomelos, star fruit, exotic citrus fruits, or grapefruit hybrids.

Strong Inducers of CYP3A4:

* Glucocorticoids: cortisone (\> 50 mg), hydrocortisone (\> 40 mg), prednisone (\> 10 mg), methylprednisolone (\> 8 mg), dexamethasone (\> 1.5 mg)
* Anticonvulsants: phenytoin, carbamazepine, primidone, phenobarbital and other enzyme inducing anti-convulsant drugs (EIACD)
* Antibiotics: rifampin (rifampicin), rifabutin, rifapentine
* Miscellaneous: St. John's Wort, modafinil

Strong Inhibitors of CYP2C9:

• Antifungals: fluconazole; lists including medications and substances known or with the potential to interact with the CYP3A or 2C19