Study of Optimized Management of Nivolumab Based on Response in Patients With Advanced RCC (OMNIVORE Study)

* Age ≥ 18 years at the time of consent. * ECOG Performance Status of ≤ 2 within 28 days prior to registration. * Unresectable advanced or metastatic RCC to include both clear cell and non-clear histologies. oPatients who have suspected metastatic RCC, which has not yet been pathologically proven, may be enrolled if they plan to undergo a cytoreductive nephrectomy, metastectomy, or biopsy. Fresh tissue from one of these procedures can be used for the clinical trial requirements (eligibility #4) as well as serve as pathologic confirmation of RCC. The pathologic confirmation must be documented prior to C1D1. * Availability at the study site of formalin-fixed, paraffin-embedded (FFPE) archival tumor specimens, when available, and willingness of the subject to undergo mandatory fresh tumor biopsy prior to treatment initiation unless determined medically unsafe or not feasible. If a target lesion is biopsied at screening, this lesion must be followed as non-target lesion after the biopsy unless it is the patient's only target lesion. If there is only one target lesion, it should be followed as a target lesion regardless. * The archival specimen must contain adequate viable tumor tissue. * The specimen may consist of a tissue block (preferred and should contain the highest grade of tumor) or at least 30 unstained serial sections. Fine-needle aspiration, brushings, cell pellet from pleural effusion, bone marrow aspirate/biopsy are not acceptable. * Previously untreated or treated subjects with no limit on prior lines of systemic therapies are allowed. Patient may have received prior adjuvant therapy. * Measurable disease as defined by Response Evaluation Criteria In Solid Tumors RECIST 1.1 within 28 days prior to registration. * Demonstrate adequate organ function as defined in the table below. All screening labs to be obtained within 28 days prior to first study treatment. System Laboratory Value * Hematological * White blood cell (WBC) ≥ 2500 cells/µL * Absolute Neutrophil Count (ANC) ≥ 1500 cells/µL * Platelet count (plt) ≥ 100,000/ µL * Hemoglobin (Hgb) ≥ 9 g/dL (transfusions allowed) * Absolute lymphocyte count ≥ 500 cells/µL * Renal --Serum creatinine OR Calculated creatinine clearance ≤ 1.5 x ULN ≥ 40 mL/min * Cockcroft-Gault formula will be used to calculate creatinine clearance * Hepatic and Other * Bilirubin ≤ 1.5 × upper limit of normal (ULN) * Aspartate aminotransferase (AST) ≤ 2.5 × ULN * Alanine aminotransferase (ALT) ≤ 2.5 × ULN * Alkaline Phosphatase ≤ 2.5 × ULN * Subjects with documented liver metastases should have AST and ALT ≤ 5 x ULN. Subjects with documented liver or bone metastases should have alkaline phosphatase ≤ 5 x ULN * Subjects with known Gilbert's disease should have a serum bilirubin ≤ 3 x ULN. --Albumin \> 2.5 g/dL * Coagulation * International Normalized Ratio (INR) or Prothrombin Time (PT) * Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 × ULN (unless on prophylactic or therapeutic dosing with low molecular weight heparin) * Females of childbearing potential must have a negative serum pregnancy test within 28 days prior to registration. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. * Females of childbearing potential and males must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 120 days after treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method. * As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study. Exclusion Criteria * Subjects meeting any of the criteria below may not participate in the study: * Prior use of systemic checkpoint inhibitors for the management of metastatic RCC is excluded. Prior IFN-α or IL-2 is allowed. * Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitors) within 2 weeks of enrollment or receipt of any anti-cancer therapy (including investigational therapy, monoclonal antibodies, cytokine therapy) within 4 weeks of enrollment. * Treatment with systemic immunosuppressive medications including but not limited to: * prednisone, dexamethasone, cyclosporin, azathioprine, methotrexate, thalidomide, anti- tumor necrosis factor (TNF) agents within 2 weeks of first study dose. * Subjects who have received acute, low-dose systemic immunosuppressant medications may be enrolled (such as steroids for acute nausea or cancer-related pain ≤ 10 mg prednisone) may be enrolled sooner than 2 weeks of first study dose. * Subjects with adrenal insufficiency on physiologic replacement doses of steroids may be enrolled (≤ 10 mg prednisone). * The use of inhaled, topical, ocular or intra-articular corticosteroids and mineralocorticoids are allowed. * Treatment with a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor (e.g. denosumab) within 2 weeks of first study dose. * Radiotherapy for RCC within 14 days of first study treatment with the exception of a single fraction of radiation administered for palliation of symptoms. * Known active metastases to the brain, spinal cord or leptomeninges unless adequately treated with radiotherapy, radiosurgery, or surgery and stable for at least 4 weeks of first study treatment as documented by magnetic resonance imaging (MRI) or computerized tomography (CT) imaging and having no ongoing requirement for steroids. * Malignancies other than RCC within 5 years of first study treatment with the exception of those with negligible risk of metastases or death and/or treated with expected curative outcome (carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, ductal carcinoma in situ of the breast, non-muscle invasive urothelial carcinoma). * History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion protein. * Known hypersensitivity to any component of the nivolumab or ipilimumab product. * Any active or recent history (within 6 months of first study dose) of autoimmune disease or syndrome that requires systemic corticosteroids (\>10 mg daily prednisone equivalent) or immunosuppressive medications including but not limited to: myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, Wegner's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Subjects with vitiligo, controlled type I diabetes mellitus, hypo- or hyperthyroid disease, or surgical adrenal insufficiency requiring hormone replacement therapy are permitted to enroll. * Any condition requiring treatment with corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medication within 14 days of the first dose of study drug. Inhaled, topical, ocular or intra-articular steroids and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. * Uncontrolled adrenal insufficiency. * History of idiopathic pulmonary fibrosis, organized pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening imaging CT of the chest. History of radiation pneumonitis in the radiation field is permitted. * Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome. * Known active or chronic hepatitis B infection (defined as having a positive hepatitis B surface antigen (HBsAg) test at screening). Subject with past or resolved hepatitis B infection (defined as having a negative HBsAg test and positive antibody to hepatitis B core antigen test) are eligible. Hepatitis B viral DNA must be obtained in subjects with positive hepatitis B core antibody prior to first treatment start. * Active hepatitis C infection. Subjects positive hepatitis C antibody test are eligible if PCR is negative for hepatitis C viral DNA. * Severe infections within 4 weeks of first study treatment including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia. * Receipt of therapeutic oral or IV antibiotics within 2 weeks of first study treatment. Subjects receiving routine antibiotic prophylaxis (for dental extractions/procedures) are eligible. * Significant cardiovascular disease such as New York Heart Association (NYHA) class III or greater, myocardial infarction within the previous 3 months, unstable arrhythmias, unstable angina. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction \< 45% must be on a stable regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist when appropriate. * Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on screening EKG \> 500 msec. * History of abdominal or tracheoesophageal fistula or GI perforation within 6 months of first study treatment. * Clinical signs or symptoms of GI obstruction or requirement of routine parenteral nutrition. * Evidence of abdominal free air not explained by paracentesis or recent surgical procedure. * Serious, non-healing or dehiscing wound or active ulcer * Major surgical procedure within 4 weeks of first study treatment. * Presence of any toxicities attributed to prior anti-cancer therapy that are not resolved to grade 1 (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0) or baseline before administration of study drug. * Prior allogenic stem cell or solid organ transplant. * Administration of a live, attenuated vaccine within 4 weeks for first study treatment.