Nivolumab in Treating Patients With Localized Kidney Cancer Undergoing Nephrectomy
Nivolumab in Treating Patients With Localized Kidney Cancer Undergoing Nephrectomy
This phase III trial compares nephrectomy (surgery to remove a kidney or part of a kidney)
 with nivolumab to the usual approach of nephrectomy followed by standard post-operative
 follow-up and monitoring, in treating patients with kidney cancer that is limited to a
 certain part of the body (localized). Nivolumab is a drug that may help stimulate the immune
 system to attack any cancer cells that may remain after surgery. The addition of nivolumab to
 the usual surgery could prevent the cancer from returning. It is not yet known whether
 nivolumab and nephrectomy is more effective than nephrectomy alone in treating patients with
 kidney cancer.
PRIMARY OBJECTIVE:

 I. To compare recurrence-free survival (RFS) between patients with 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 nephrectomy and recurrence with
 outcome.

 III. To archive images for potential 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 OBJECTIVE:

 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.

 II. To characterize the effects of nivolumab on bone metabolism and bone density.

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

 ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Treatment
 repeats every 14 days for 2 cycles. Patients then undergo partial or radical nephrectomy 7-28
 days later. Patient then receive nivolumab over 30 IV on day 1. Treatment repeats every 14
 days for 6 cycles, and then every 28 days for 6 cycles in the absence of disease progression
 or unacceptable toxicity.

 Patients enrolled after Amendment 4 receive nivolumab IV over 30 minutes on day 1. Patients
 then undergo partial or radical nephrectomy 7-28 days later. Patients then receive nivolumab
 IV over 30 minutes on day 1. Treatment repeats every 4 weeks for up to 9 cycles in the
 absence of disease progression or unacceptable toxicity.

 ARM II: Patients undergo partial or radical nephrectomy within 8 weeks after registration
 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 RANDOMIZATION:

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

 -  Patients must have no clinical or radiological evidence of distant metastases (M0)
 unless the presumed M1 disease is planned to 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)

 -  Liver, bone, or brain 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

 -  If histological confirmation of RCC has not been done within 12 months prior to
 randomization, patient must be willing to undergo a core biopsy for this purpose if
 randomized to Arm A

 -  NOTE: This histologic confirmation can be a (1) standard of care diagnostic
 biopsy or (2) a research biopsy or a planned metastasectomy. Tissue must be
 obtained with results available prior to the neoadjuvant dose

 -  Patients randomized to Arm A: core tumor biopsy must have demonstrated RCC
 of any histology, including sarcomatoid, unclassified, or "unknown
 histology" (if preoperative biopsy was uninformative) with exception below
 for non-diagnostic biopsies

 -  If the biopsy performed following randomization clearly demonstrates a
 benign condition, oncocytoma or a different type of cancer that is not RCC,
 the patient is not eligible and must come off study

 -  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

 -  Patient must not have any prior systemic or local anti-cancer therapy for the current
 RCC

 -  Patient must not have undergone a partial nephrectomy for the current RCC

 -  Patient must not have had a metastasectomy for the current RCC diagnosis unless
 performed to render patient NED (in addition to the planned nephrectomy) within 6
 months of the current diagnosis

 -  Patient must not have received current or past antineoplastic systemic therapies
 for RCC: i.e., chemotherapy, hormonal therapy, immunotherapy, or standard or
 investigational agents for treatment of RCC

 -  Patient must not have received 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

 -  Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0
 or 1

 -  Patient must not have a prior history of RCC that was treated 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 to be
 completely removed and subsequent hemodialysis will be required

 -  Permitted forms of local therapy for second tumor:

 -  Partial or radical nephrectomy

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

 -  Patients cannot 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 randomization 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

 -  Patient must not have active known or suspected autoimmune disease. The following
 autoimmune disorders are permitted: patients with vitiligo, type I diabetes mellitus,
 controlled/stable hypo or hyperthyroidism due to autoimmune or non-autoimmune
 conditions (hormone replacement is allowed), psoriasis not requiring systemic
 treatment, or other conditions not expected to recur

 -  Patient must not have any ongoing condition requiring systemic treatment with either
 corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive
 medications with the exceptions outlined below; patient must not have received any
 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

 -  Patient must not have uncontrolled adrenal insufficiency

 -  Patient must not have known evidence of chronic active liver disease or evidence of
 acute or chronic hepatitis B Virus (HBV) or hepatitis C (HCV); HBV and HCV testing
 must be completed within 8 weeks prior to randomization

 -  NOTE: If the patient has been treated and cured, and the HCV ribonucleic acid
 (RNA) is undetectable, the patient is eligible for this study

 -  Patient must not have any serious intercurrent illness, including ongoing or active
 infection requiring parenteral antibiotics

 -  Patient must not have known evidence of human immunodeficiency virus (HIV) infection,
 since the effects of nivolumab on anti-retroviral therapy have not been studied; HIV
 testing is only required if past or current history is suspected

 -  Patient must not have any 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

 -  Patient must not have had any major surgery within 28 days prior to randomization

 -  Patient must not be currently enrolled in other clinical trials testing a therapeutic
 intervention

 -  Patient must not have any history of severe hypersensitivity to a monoclonal antibody

 -  Patient must have the ability to understand and the willingness to sign a written
 informed consent document

 -  Women must not be pregnant or breast-feeding, as the effects of nivolumab on the
 developing human fetus or in the nursing infant are unknown; all females of
 childbearing potential must have a blood test or urine study within 2 weeks prior to
 randomization to rule out pregnancy; a female of childbearing potential is defined as
 any woman, regardless of sexual orientation or whether they have undergone tubal
 ligation, who meets the following criteria: 1) has achieved menarche at some point 2)
 has not undergone a hysterectomy or bilateral oophorectomy; or 3) 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)

 -  Women of childbearing potential (WOCBP) and males who are sexually active with WOCBP
 must use accepted and effective method(s) of contraception, as described in the
 Informed Consent Form (ICF), or abstain from sexual intercourse for the duration of
 their participation in the study; women of childbearing potential must use adequate
 methods to avoid pregnancy for 5 months after the last dose of nivolumab; sexually
 active males must use adequate methods to avoid pregnancy for 7 months after the last
 dose of nivolumab

 -  White blood cells >= 2000/uL (within 8 weeks prior to randomization)

 -  Absolute neutrophil count (ANC) >= 1,500/mm^3 (within 8 weeks prior to randomization)

 -  Platelet count >= 100,000/mm^3 (within 8 weeks prior to randomization)

 -  Hemoglobin >= 9.0 g/dL (within 8 weeks prior to randomization)

 -  Serum creatinine =< 1.5 x upper limit of normal (ULN) or calculated creatinine
 clearance (CrCl) >= 40mL/min (within 8 weeks prior to randomization)

 -  Total bilirubin =< 1.5 x ULN (except subjects with Gilbert syndrome, who can have
 total bilirubin < 3.0 x ULN) (within 8 weeks prior to randomization)

 -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
 (within 8 weeks prior to randomization)