Study of Optimized Management of Nivolumab Based on Response in Patients With Advanced RCC (OMNIVORE Study)
Condition: Renal Cancer
MeSH terms: Kidney Neoplasms; Carcinoma, Renal Cell
Intervention: Ipilimumab; Nivolumab
Intervention description: YERVOY is thought to work with the body's immune system to increase the activity of T cells and cause the body to attack cancer cells; Nivolumab binds to and blocks the activation of PD-1, an Ig superfamily transmembrane protein, by its ligands programmed cell death ligand 1 (PD-L1), overexpressed on certain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on APCs
Intervention MeSH terms: Nivolumab; Ipilimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 85.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Renal Cancer

Summary:

      This research study is studying two drugs at different time points as a possible treatment
      for advanced renal cell cancer

      The drugs involved in this study are:

      Nivolumab Ipilimumab
    

Eligibility criteria:

        -  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.