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

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of investigational drugs to learn whether the drugs work in treating a
specific disease. "Investigational" means that the intervention is being studied.

Nivolumab and ipilimumab are antibodies (a type of human protein) that work to stimulate your
body's immune system to fight tumor cells. The FDA (the U.S. Food and Drug Administration)
has approved nivolumab as a treatment option for this disease; however, the FDA has not
approved the way nivolumab and ipilimumab are being administered in this study. Ipilimumab is
FDA approved for the treatment of melanoma (skin cancer) and has been previously studied in
renal cell cancer.

This study is being done to evaluate nivolumab treatment strategies based on each patients
individual response to treatment. In participants who have a response to treatment, nivolumab
will be stopped and participants will be closely monitored. In participants who do not have a
response to treatment,the investigators will investigate whether the addition of ipilimumab
improves a participant response to treatment. Participant blood and tissue samples will be
collected to learn about how certain biomarkers and genes relate to participant outcomes.

- 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.