Purpose

This 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). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and 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.

Conditions

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Criteria


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

- 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

- 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 or a planned metastasectomy before or after
randomization; if the biopsy performed following pre-registration (Step 0)
clearly demonstrates a benign condition, oncocytoma or a different type of cancer
that is not RCC, 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 (Observation) are permitted to register to
Step 1 (Arm B) immediately following pre-registration assignment to Arm O,
regardless of whether or not they have had a standard of care diagnostic biopsy

- No prior systemic or local anti-cancer therapy for the current RCC is permitted

- Partial nephrectomy for prior RCC

- Metastasectomy for the current RCC diagnosis is not allowed unless performed to
render patient NED (in addition to the planned nephrectomy) within 6 months of
the current diagnosis

- Radiation therapyto the bilateral kidney or any distant metastatic sites, is not
allowed unless administered to render patient NED within 6 months of the current
diagnosis

- Current or past antineoplastic systemic therapies for RCC are not allowed: 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

- 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 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 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, since the effects
of nivolumab on anti-retroviral therapy have not been studied

- 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

- Ability to understand and the willingness to sign a written informed consent document

- 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, 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
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: 1) has achieved menarche at some point 2) has not
undergone a hysterectomy or bilateral oophorectomy; or 2) 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, or to 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 23 weeks after
the last dose of nivolumab; sexually active males must use adequate methods to avoid
pregnancy for 31 weeks after the last dose of nivolumab

- 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 8 weeks of registration)

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

Study Design

Phase
Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
Single (Outcomes Assessor)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Arm I (nivolumab, nephrectomy)
Patients receive nivolumab IV over 30-60 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 30-60 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 30-60 minutes on day 1. Patients then undergo partial or radical nephrectomy 7-28 days later. Patient then receive nivolumab IV over 30-60 minutes on day 1. Treatment repeats every 4 weeks for 9 cycles in the absence of disease progression or unacceptable toxicity.
  • Procedure: Conventional Surgery
    Undergo nephrectomy
  • Biological: Nivolumab
    Given IV
    Other names:
    • BMS-936558
    • MDX-1106
    • NIVO
    • ONO-4538
    • Opdivo
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other names:
    • Quality of Life Assessment
  • Other: Questionnaire Administration
    Ancillary studies
Active Comparator
Arm II (nephrectomy)
ARM II: Patients undergo partial or radical nephrectomy within 8 weeks after registration followed by observation.
  • Procedure: Conventional Surgery
    Undergo nephrectomy
  • Other: Patient Observation
    Undergo observation
    Other names:
    • Active Surveillance
    • deferred therapy
    • expectant management
    • observation
    • Watchful Waiting
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other names:
    • Quality of Life Assessment
  • Other: Questionnaire Administration
    Ancillary studies

Recruiting Locations

Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee 37232
Contact:
Site Public Contact
800-811-8480

More Details

NCT ID
NCT03055013
Status
Recruiting
Sponsor
National Cancer Institute (NCI)

Study Contact

Detailed Description

PRIMARY OBJECTIVES:

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 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.

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 30-60 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 30-60 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 30-60 minutes on day 1. Patients then undergo partial or radical nephrectomy 7-28 days later. Patient then receive nivolumab IV over 30-60 minutes on day 1. Treatment repeats every 4 weeks for 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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.