Image Guided Hypofractionated Radiation Therapy, Nelfinavir Mesylate, Pembrolizumab, Nivolumab and Atezolizumab in Treating Patients With Advanced Melanoma, Lung, or Kidney Cancer
Condition: Metastatic Kidney Carcinoma; Recurrent Lung Non-Small Cell Carcinoma; Stage IV Cutaneous Melanoma AJCC v6 and v7; Stage IV Renal Cell Cancer AJCC v7; Stage IV Lung Non-Small Cell Cancer AJCC v7
MeSH terms: Carcinoma; Melanoma; Carcinoma, Renal Cell; Carcinoma, Non-Small-Cell Lung; Kidney Neoplasms
Intervention: Atezolizumab; Hypofractionated Radiation Therapy; Laboratory Biomarker Analysis; Nelfinavir Mesylate; Nivolumab; Pembrolizumab
Intervention description: Given IV; Undergo hypofractionated radiation therapy; Correlative studies; Given PO; Given IV; Given IV
Intervention MeSH terms: Nelfinavir; Pembrolizumab; Nivolumab; Atezolizumab; Antibodies, Monoclonal
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 21.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Kidney; Lung; Melanoma, Skin

Summary:

      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.
    

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