Summary

This phase II trial studies how well nivolumab with or without ipilimumab as front line therapy work in treating patients with kidney cancer that has spread to other places in the body. Monoclonal antibodies, such as nivolumab and ipilimumab, may interfere with the ability of tumor cells to grow and spread.

Objectives

PRIMARY OBJECTIVE:
I. Determine the progression-free survival (PFS) rate at 1 year of nivolumab in patients with treatment naive clear cell renal cell cancer (ccRCC) based on tumor PD-L1 expression.

SECONDARY OBJECTIVES:
I. Determine the PFS rate at 1 year- by both Response Evaluation Criteria in Solid Tumors (RECIST) and immune related (ir)RECIST of nivolumab in patients with treatment naive ccRCC based on the PD1- blockade durable response predictive (PRP) biomarker model developed in the Dana–Farber/Harvard Cancer Center (DFHCC) Kidney Cancer Specialized Program in Research Excellence (SPORE).
II. Determine the objective response rate (complete response [CR]/partial response [PR]=objective response rate [ORR]), the ORR based on PDL1 expression and the PRP model, and duration of response for nivolumab in patients with treatment naive ccRCC.
III. Determine the response rate of combined nivolumab and ipilimumab therapy at the time of nivolumab failure (or lack of response at 1 year).
IV. Determine the clinical activity (CR, PR and stable disease [SD]) and PFS at 1 year of nivolumab in patients with treatment naive non-clear cell (ncc)RCC.
V. Assess the toxicity of nivolumab monotherapy in patients with treatment naive cc or nccRCC.

CORRELATIVE/EXPLORATORY OBJECTIVES:
I. Explore novel potential predictive biomarkers for patients with treatment naive ccRCC and nccRCC.
II. Explore the mechanisms of innate and acquired resistance to nivolumab therapy in treatment naive patients with ccRCC.
III. Identify biomarkers associated with response to nivolumab + ipilimumab in patients whose disease has not responded or progressed on nivolumab monotherapy.

OUTLINE: Patients are assigned to 1 of 2 parts.

PART A: Patients receive nivolumab intravenously (IV) over 60 minutes on days 1, 15, and 29. Treatment repeats every 42 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 60 minutes on days 1 and 22. Cycles repeat every 42 days for up to 96 weeks in the absence of disease progression or unacceptable toxicity. Patients with persistent progressive disease may be enrolled to Part B.

PART B: Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes on days 1 and 22. Treatment repeats every 42 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 60 minutes on days 1 and 22. Cycles repeat every 42 days for up to 48 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 3 years and then every 6 months for 2 years.

Eligibility

1. INCLUSION CRITERIA - PART A
2. 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
3. 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
4. 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
5. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
6. Have signed the current approved informed consent form
7. White blood cell (WBC) >= 2000/uL (within 14 days prior to study entry)
8. Absolute neutrophil count (ANC) >= 1500/uL (within 14 days prior to study entry)
9. Platelets (Plt) >= 100 x 10^3/L (within 14 days prior to study entry)
10. Hemoglobin (Hgb) > 9.0 g/dL (with or without transfusion) (within 14 days prior to study entry)
11. Serum creatinine =< 1.5 x ULN (within 14 days prior to study entry)
12. Calculated creatinine clearance >= 40 mL/min using Cockcroft-Gault formula (within 14 days prior to study entry)
13. 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)
14. Aspartate aminotransferase (AST) =< 3 x ULN (within 14 days prior to study entry)
15. Alanine aminotransferase (ALT) =< 3 x ULN (within 14 days prior to study entry)
16. 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
17. 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
18. 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
19. Women must not be breastfeeding
20. 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
21. Be willing and able to comply with this protocol
22. INCLUSION/EXCLUSION CRITERIA - PART B
23. 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
24. Must have evidence of either RECIST 1.1 defined disease progression or stable disease 1 year after initiating nivolumab therapy
25. 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
26. Must not have had a grade >= 3 immune related adverse event (irAE) on nivolumab monotherapy (excluding endocrine toxicity managed with replacement therapy)
27. Must not have untreated brain metastases
28. Must not have had major surgery or radiation therapy within 14 days of starting study treatment
29. Must not have active autoimmune disease
30. Must not have a concurrent medical condition requiring use of systemic corticosteroids with prednisone > 10 mg per day
31. Must not have had prior systemic therapy for stage IV RCC (except for nivolumab as part of part A of this protocol)

Treatment Sites in Georgia