This randomized phase III trial compares nephrectomy (surgery to remove a kidney or part of a
kidney) with or without nivolumab in treating patients with kidney cancer that is limited to
a certain part of the body (localized). Monoclonal antibodies, such as nivolumab, may
interfere with the ability of tumor cells to grow and spread. Giving nivolumab before
nephrectomy may make the tumor smaller and reduce the amount of normal tissue that needs to
be removed, and after nephrectomy to increase survival. It is not yet known whether nivolumab
and nephrectomy is more effective than nephrectomy alone in treating patients with kidney
cancer.
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 patients randomized to perioperative nivolumab in
addition to resection to patients randomized to primary tumor resection alone.
III. To describe the safety and tolerability of perioperative nivolumab.
TERTIARY 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. VII. To evaluate differences in change
from baseline in patient-reported symptoms and toxicities among patients randomized to
treatment with nivolumab compared to surgery alone.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive nivolumab intravenously (IV) over 60 minutes on day 1. Treatment
repeats every 14 days for 2 courses. Patients then undergo partial or radical nephrectomy.
Patient then receive nivolumab 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.
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):
- Preoperative biopsy for confirmation of renal cell carcinoma (RCC) must be performed
within four (4) months prior to randomization
- If biopsy was performed as part of patients standard care, and will not be
performed during step 0 proceed directly to randomization
- ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1):
- Patients with newly diagnosed higher risk RCC of any histology including sarcomatoid
or (if preoperative biopsy was uninformative) - "unknown" histology; RCC must have
been confirmed by biopsy within 4 months prior to randomization; if the biopsy clearly
demonstrated a benign condition or a different type of cancer, the patient is not
eligible to be randomized
- Clinical stage >= T2NxM0 or TanyN+ disease for which radical or partial nephrectomy is
planned
- Patients must have no clinical or radiological evidence of distant metastases (M0)
- No concurrent or prior systemic or local anti-cancer therapy for RCC is permitted;
examples of these prohibited therapies include:
- Radical or partial nephrectomy for prior RCC
- Metastectomy for RCC
- Radiation therapy to the renal bed or any distant metastatic sites
- 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-programmed cell death 1 (PD-1), anti-programmed cell
death-ligand 1 (PD-L1), anti-PD-L2, anti-cluster of differentiation (CD)137, or
anti-cytotoxic T-lymphocyte protein 4 (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 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)
- 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 must not have other current malignancies:
- Adequately treated basal cell or squamous cell skin cancer, in situ cervical
cancer, adequately treated stage I or II cancer from which the patient is
currently in complete remission, or any other cancer from which the patient has
been disease-free for 3 years prior to the time of registration and they are not
receiving any current treatment
- Prior or current prostate cancer is excluded
- A history of superficial Ta urothelial cancer is permitted (not being
currently treated) but T1 or greater disease is excluded
- No active known or suspected autoimmune disease; the following are permitted: patients
with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune or
non-autoimmune condition requiring hormone replacement, asymptomatic hypothyroidism
not requiring treatment, psoriasis not requiring systemic treatment, or conditions not
expected to recur
- No ongoing condition requiring systemic treatment with either corticosteroids (> 10 mg
daily prednisone equivalent) or other immunosuppressive medications; no treatment with
other immunosuppressive agents within 14 days prior to the first dose of study drug;
topical, ocular, intra-articular, intranasal, inhaled steroids and adrenal replacement
steroid doses > 10 mg daily prednisone 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: delayed-type hypersensitivity reaction caused
by a contact allergen) is permitted if > 14 days since last dose
- No uncontrolled adrenal insufficiency
- No known chronic active liver disease or evidence of acute or chronic hepatitis B
virus (HBV) or hepatitis C (HCV)
- Patients must not have a serious intercurrent illness, including ongoing or active
infection requiring parental antibiotics
- 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
- Patients currently enrolled in other clinical trials testing a therapeutic
intervention
- White blood cells >= 2000/uL, within 4 weeks of randomization
- Absolute granulocyte count (AGC) >= 1,500/mm^3, within 4 weeks of randomization
- Platelet count >= 100,000/mm^3, within 4 weeks of randomization
- Hemoglobin >= 9.0 g/dL, within 4 weeks of randomization
- Serum creatinine =< 1.5 x upper limit of normal (ULN) or calculated creatinine
clearance (CrCl) >= 40 mL/min, within 4 weeks of randomization
- 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 4 weeks of randomization
- No history of severe hypersensitivity to a monoclonal antibody
- Signed, dated informed consent
