Seleno-L Methionine (SLM)-Axitinib-Pembrolizumab

Inclusion Criteria:

To be eligible to participate in this study, an individual must meet all the following criteria:

* Written and voluntary informed consent.
* Histologically and radiologically confirmed locally advanced or metastatic ccRCC. Locally advanced is defined as non resectable in the opinion of the treating providers. Participants must be treatment naïve in metastatic setting. Prior immunotherapy treatment in adjuvant setting is allowed.
* \> 18 years of age
* At least one Response Evaluation Criteria in Solid Tumors (RECIST 1.1)-defined target lesion that has not been irradiated
* Eastern Cooperative Oncology Group performance status of 0 (fully active, able to carry on all pre-disease performance without restriction) or 1 (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, such as light housework or office work).
* Renal function (creatinine level within normal institutional limit, or creatinine clearance \>15 mL/min/1.73 m2 for patients with creatinine levels above institutional normal, calculated using the Cockcroft-Gault formula).
* Liver function (AST/ALT \<3.0 X institutional upper limit of normal OR \< 5 x institutional upper limit of normal in cases of liver metastases; Total bilirubin ≤ 1.5 times ULN.)
* Adequate hematological lab values including

  * Absolute Neutrophil Count (ANC) ≥ 1.0 x 109/L
  * Platelets ≥ 100 x 109/L
  * Hemoglobin ≥ 7.0 g/dL
* Has adequately controlled BP with or without antihypertensive medications, defined as BP ≤150/90 mm Hg with no change in antihypertensive medications within 1 week before randomization/allocation.
* Female subjects of childbearing potential and non-sterilized male subjects who intend to be sexually active during the study must agree to use a highly effective method of contraception from the time of screening, throughout the total duration of the drug treatment, and during the 6 month post-drug washout period. See section 5.6 for full details.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

* Patients with a prior or concurrent malignancy whose natural history or treatment may have the potential to interfere with the safety or efficacy assessment of the investigational regimen.
* Untreated metastases in the central nervous system.
* Pregnant or breastfeeding.
* Present use or anticipated need for cytochrome P450 (CYP) 3A4-inhibiting, CYP3A4-inducing drugs (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, phenobarbital, and St. John's wort, bosentan, efavirenz, etravirine, modafinil, and nafcillin).
* Myocardial infarction, uncontrolled angina, congestive heart failure, or cerebrovascular accident within previous 6 months. Participants with history of deep vein thrombosis or pulmonary embolism, at provider discretion.
* Major surgery within 4 weeks of starting study treatment.
* Patients with HIV infection with CD4+ T-cell (CD4+) counts \< 350 cells/uL
* Patients with HIV infection and a history of AIDS-defining opportunistic infections

No exclusions will be made based on sex, race, or ethnic background.