Nivolumab with or without Ipilimumab as Front Line Therapy in Treating Patients with Advanced Kidney Cancer

Inclusion Criteria

• INCLUSION CRITERIA - PART A
• Patients must have histologically confirmed advanced RCC (any histology); collecting duct tumors and tumors originating from the renal pelvis or upper urinary tract are considered of urothelial origin and are excluded from this protocol
• Patients must have at least one measurable site of disease, per RECIST 1.1, that has not been previously irradiated; if the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation
• Archival tissue of a metastatic lesion obtained within 1 year prior to study registration (within 4 weeks preferred) and tumor tissue from nephrectomy is required if available. In addition to archival tissue of a metastatic lesion and nephrectomy, patients must have at least one site of disease (not including bone metastases) accessible for biopsy. If biopsy/resection of a new lesion or primary tumor and slow freezing of fresh tissue for single cell RNAseq study (as specified in the Correlative Laboratory Manual [CLM]) is not feasible, the subject is not eligible for the study. All biopsies must be core needle or excisional. Fine needle aspirate is not acceptable. NOTE: The tissue collected from a surgical resection or multiple core biopsies of either a metastatic lesion or primary tumor for the slow freezing of fresh tissue after the patient has signed consent for the study could also be used for collecting the formalin-fixed paraffin-embedded (FFPE) specimens
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Have signed the current approved informed consent form
• White blood cell (WBC) >= 2000/uL (within 14 days prior to study entry)
• Absolute neutrophil count (ANC) >= 1500/uL (within 14 days prior to study entry)
• Platelets (Plt) >= 100 x 10^3/L (within 14 days prior to study entry)
• Hemoglobin (Hgb) > 9.0 g/dL (with or without transfusion) (within 14 days prior to study entry)
• Serum creatinine =< 1.5 x ULN (within 14 days prior to study entry)
• Calculated creatinine clearance >= 40 mL/min using Cockcroft-Gault formula (within 14 days prior to study entry)
• Bilirubin =< 1.5 x upper limit of normal (ULN); except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL (within 14 days prior to study entry)
• Aspartate aminotransferase (AST) =< 3 x ULN (within 14 days prior to study entry)
• Alanine aminotransferase (ALT) =< 3 x ULN (within 14 days prior to study entry)
• Patients should not have received prior systemic therapy for metastatic RCC; prior radiotherapy must have been completed at least 2 weeks prior to the administration of study drug; patients must be 2 weeks from prior major surgery and 1 week from pre-treatment biopsy; prior systemic adjuvant therapy (excluding with PD1 or CTLA4 pathway blockers) is allowed if treatment completed > 12 months previously
• Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception; WOCBP should use an adequate method to avoid pregnancy for 5 months after the last dose of study drug
• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) during screening for registration purposes; this pregnancy test should be repeated within 24 hours prior to the start of nivolumab; NOTE: “Women of childbearing potential” is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes; in addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/ml
• Women must not be breastfeeding
• Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year; men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational product Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception
• Be willing and able to comply with this protocol
• INCLUSION/EXCLUSION CRITERIA - PART B
• Must meet eligibility criteria for initiation of part A with the exception of being allowed to have prior nivolumab in part A of this protocol
• Must have evidence of either RECIST 1.1 defined disease progression or stable disease 1 year after initiating nivolumab therapy
• Tumor biopsy prior to combination treatment is mandatory. If a biopsy/resection of a new lesion or primary tumor and slow freezing of fresh tissue for single cell RNAseq study (as specified in the CLM) is not feasible, the subject is not eligible for the study. All biopsies must be core needle or excisional. Fine needle aspirate is not acceptable
• Must not have had a grade >= 3 immune related adverse event (irAE) on nivolumab monotherapy (excluding endocrine toxicity managed with replacement therapy)
• Must not have untreated brain metastases
• Must not have had major surgery or radiation therapy within 14 days of starting study treatment
• Must not have active autoimmune disease
• Must not have a concurrent medical condition requiring use of systemic corticosteroids with prednisone > 10 mg per day
• Must not have had prior systemic therapy for stage IV RCC (except for nivolumab as part of part A of this protocol)

Exclusion Criteria

• Patients are excluded if they have active brain metastases or leptomeningeal metastases; subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for 2 weeks of more after treatment is complete and within 28 days prior to the first dose of nivolumab administration; there must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration
• Patients with controlled brain metastases are allowed on protocol if they had brain metastases that were surgically resected without recurrence and/or up to 3 metastases treated with stereotactic radiosurgery (SRS) without progression on MRI obtained at least 2 weeks after completion of radiation and within 28 days prior to initiation of nivolumab
• Patients should be excluded if they have an active, known or suspected autoimmune disease; subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
• Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
• As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab-containing regimen
• Active infection requiring systemic therapy
• Has any other medical or personal condition that, in the opinion of the site investigator, may potentially compromise the safety or compliance of the patient, or may preclude the patient’s successful completion of the clinical trial
• Patients should be excluded if they are positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
• Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Allergies and adverse drug reaction * History of allergy to study drug components * History of severe hypersensitivity reaction to any monoclonal antibody
• Known additional malignancies within the past 3 years (excluding basal of squamous cell skin cancers, carcinoma in situ (CIS) or localized prostate cancer that has been treated or is being observed)
• Prior solid organ or stem cell transplant