Nivolumab in Treating Patients With Localized Kidney Cancer Undergoing Nephrectomy

PRIMARY OBJECTIVES:

I. To compare recurrence-free survival (RFS) between patients with locally advanced renal
cell carcinoma randomly assigned to perioperative nivolumab in conjunction with radical or
partial nephrectomy with patients randomized to surgery alone.

SECONDARY OBJECTIVES:

I. To evaluate for differences in recurrence-free survival associated with perioperative
nivolumab compared to surgery alone among the subset of patients with clear cell histology.

II. To compare the overall survival between the two arms. III. To describe the safety and
tolerability of perioperative nivolumab.

CORRELATIVE OBJECTIVES:

I. To correlate the primary tumor's expression of programmed cell death 1 ligand 1 (PD-L1)
with outcome.

II. To correlate the expression of PD-L1 on tumor tissue at recurrence with outcome.

III. To archive images for central confirmation of recurrence and for future correlative work
with American College of Radiology Imaging Network (ACRIN), including markers predicting
outcome or response.

IV. To prospectively collect tumor and biologic specimens (e.g., serum, peripheral blood
mononuclear cells [PBMCs]) for future correlative studies.

V. To characterize the pharmacokinetics of nivolumab and explore exposure response
relationships with respect to safety and efficacy.

VI. To characterize the immunogenicity of nivolumab.

QUALITY OF LIFE OBJECTIVES:

I. To evaluate differences in change from baseline in patient-reported symptoms and
toxicities among patients randomized to treatment with nivolumab compared to surgery alone.

OTHER EXPLORATORY OBJECTIVES:

I. To explore descriptively the efficacy of treatment with nivolumab in patients with
non-clear cell (including unclassified) histologies.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive nivolumab intravenously (IV) over 30-60 minutes on day 1. Treatment
repeats every 14 days for 2 courses. Patients then undergo partial or radical nephrectomy.
Patient then receive nivolumab over 30-60 IV on day 1. Treatment repeats every 14 days for 6
courses, and then every 28 days for 6 courses in the absence of disease progression or
unacceptable toxicity.

Patients enrolled after Amendment 4 receive nivolumab IV over 30-60 minutes on day 1..
Patients then undergo partial or radical nephrectomy. Patient then receive nivolumab IV over
30-60 minutes on day 1. Treatment repeats every 4 weeks for 9 courses in the absence of
disease progression or unacceptable toxicity.

ARM II: Patients undergo partial or radical nephrectomy followed by observation.

After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 3 years, and every 12 months for 5 years.

Inclusion Criteria:

- ELIGIBILITY CRITERIA FOR PREREGISTRATION (STEP 0):

- Patients with a renal mass consistent with a clinical stage >= T2Nx renal cell
carcinoma (RCC) or TanyN+ RCC for which radical or partial nephrectomy is planned

- If histological confirmation of RCC has not been done within 12 months prior to
pre-registration (Step 0), patient must be willing to undergo a core biopsy for this
purpose if randomized to Arm H

- NOTE: This can be a (1) standard of care diagnostic biopsy or (2) a research
biopsy following assignment to Arm H; if the biopsy performed following
pre-registration (Step 0) clearly demonstrates a benign condition or a different
type of cancer, the patient is not eligible for registration (Step 1); a
non-diagnostic biopsy is considered a good faith effort and does not need to be
repeated unless deemed clinically necessary by the treating investigator

- NOTE: Patients randomized to Arm O are permitted to register to Step 1 (Arm B)
immediately following pre-registration assignment to Arm O, regardless of if they
have had or have not had standard of care diagnostic biopsy

- Patients must have no clinical or radiological evidence of distant metastases (M0)
unless the presumed M1 disease can be resected/definitively treated (e.g., thermal
ablation, stereotactic radiation) at the same time or within a 12 week window from the
date of the initial procedure such that the patient is considered "no evidence of
disease" (M1 NED)

- Permitted sites of oligo-metastases: lung, adrenal, nodes, pancreas, soft tissue
or skin; liver or bone metastases are not permitted

- No more than 3 metastases are permitted and all must be able to be removed or
definitively treated within 12 weeks of the primary tumor resection

- No prior systemic or local anti-cancer therapy for the current RCC is permitted;
examples of these prohibited therapies include:

- Partial nephrectomy for prior RCC

- Mastectomy for RCC

- Radiation therapy to the renal bed or any distant metastatic sites

- Current or past antineoplastic systemic therapies for RCC: i.e., chemotherapy,
hormonal therapy, immunotherapy, or standard or investigational agents for
treatment of RCC

- Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell
co-stimulation or checkpoint pathways

- Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1

- Women of childbearing potential and sexually active males must be strongly advised to
use accepted and effective methods of contraception, as described in the informed
consent form (ICF), or to abstain from sexual intercourse for the duration of their
participation in the study; women of childbearing potential should use adequate
methods to avoid pregnancy for 23 weeks after the last dose of nivolumab; sexually
active males should use adequate methods to avoid pregnancy for 31 weeks after the
last dose of nivolumab

- Patient must have no prior history of RCC that was resected with curative intent
within the past 5 years

- Patients with a prior RCC that was treated > 5 years before, are eligible if the
current tumor is consistent with a new primary in the opinion of the treating
investigator

- Patients with bilateral synchronous RCCs are eligible if they can be resected or
definitively treated at the same time or within a 12 week window from time of
initial nephrectomy (partial or radical) or procedure and maintain adequate
residual renal function; the patient is not eligible if both kidneys are
completely removed and subsequent hemodialysis is required

- Permitted forms of local therapy for second tumor:

- Partial or radical nephrectomy

- If tumor is =< 3cm: thermal ablation (e.g., radiofrequency ablation,
cryoablation or stereotactic radiosurgery)

- Patients must not have concurrent malignancies, with the following exceptions:

- Adequately treated basal cell or squamous cell skin cancer

- In situ cervical cancer

- A history of superficial Ta urothelial cancer is permitted (as long as not
currently undergoing treatment) whereas T1 or greater disease is excluded if
< 3 years from diagnosis; concurrent persistent disease is not permitted

- Adequately treated Stage I or II cancer from which the patient is currently
in complete remission

- Any other cancer and stage from which the patient has been disease-free for
at least 3 years prior to the time of pre-registration and as long as they
are not receiving any current treatment (e.g. adjuvant or maintenance
systemic or local therapy)

- Concurrent low risk prostate cancer on active surveillance

- No active known or suspected autoimmune disease; the following autoimmune disorders
are permitted: patients with vitiligo, type I diabetes mellitus, controlled/stable
hypothyroidism due to autoimmune or non-autoimmune conditions (hormone replacement is
allowed), psoriasis not requiring systemic treatment, or other conditions not expected
to recur

- No ongoing condition requiring systemic treatment with either corticosteroids (> 10 mg
daily prednisone equivalent) or other immunosuppressive medications with the
exceptions outlined below; no treatment with other immunosuppressive agents within 14
days prior to the first dose of study drug with the following exceptions:

- Topical, ocular, intra-articular, intranasal, inhaled steroids and adrenal
replacement steroid doses > 10 mg daily prednisone or the equivalent are
permitted in the absence of active autoimmune disease

- A brief (less than 3 weeks) course of corticosteroids (any amount) for
prophylaxis (for example: contrast dye allergy) or for treatment of
non-autoimmune conditions (for example: nausea, delayed-type hypersensitivity
reaction caused by a contact allergen) is permitted

- No uncontrolled adrenal insufficiency

- No known chronic active liver disease or evidence of acute or chronic hepatitis B
virus (HBV) or hepatitis C virus (HCV)

- No serious intercurrent illness, including ongoing or active infection requiring
parenteral antibodies

- No known evidence of human immunodeficiency virus (HIV) infection

- No known medical condition (e.g. a condition associated with uncontrolled diarrhea
such as ulcerative colitis or acute diverticulitis) that, in the investigator's
opinion, would increase the risk associated with study participation or interfere with
the interpretation of safety results

- No major surgery within 28 days prior to randomization

- No patients currently enrolled in other clinical trials testing a therapeutic
intervention

- No history of severe hypersensitivity to a monoclonal antibody

- Signed, dated informed consent

- ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1):

- Patients must meet all Step 0 eligibility criteria at the time of their registration
to Step 1

- In patients randomized to Arm H, core tumor biopsy must demonstrate RCC of any
histology, including sarcomatoid, unclassified, or "unknown histology" (if
preoperative biopsy was uninformative)

- NOTE: A non-diagnostic biopsy is considered a good faith effort and does not need
to be repeated unless deemed clinically necessary by the treating investigator

- Women must not be pregnant or breast-feeding; all females of childbearing potential
must have a blood test or urine study within 2 weeks prior to registration to rule out
pregnancy; a female of childbearing potential is any woman, regardless of sexual
orientation or whether they have undergone tubal ligation, who meets the following
criteria:

- Has not undergone a hysterectomy or bilateral oophorectomy, or

- Has not been naturally postmenopausal for at least 24 consecutive months (i.e.,
has had menses at any time in the preceding 24 consecutive months)

- White blood cells >= 2000/uL, within 8 weeks of registration

- Absolute neutrophil count (ANC) >= 1,500/mm^3, within 8 weeks of registration

- Platelet count >= 100,000/mm^3, within 8 weeks of registration

- Hemoglobin >= 9.0 g/dL, within 8 weeks of registration

- Serum creatinine =< 1.5 x upper limit of normal (ULN) (except subjects with Gilbert
Syndrome, who can have total bilirubin < 3.0 x ULN), within 8 weeks of registration

- Total bilirubin =< 1.5 x ULN (except subjects with Gilbert syndrome, who can have
total bilirubin < 3.0 x ULN), within 4 weeks of randomization

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN,
within 8 weeks of registration