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
- 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.
