A Phase 3 Randomized Study Comparing Perioperative Nivolumab vs. Observation in Patients With Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC)
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.
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.
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.
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 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 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 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.
18 Years and up
Accepting Healthy Volunteers?
- ELIGIBILITY CRITERIA FOR RANDOMIZATION (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 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)
- 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 randomization (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 randomization (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 randomization assignment to Arm O, regardless of whether or not they have had a standard of care diagnostic biopsy
- Patient must not have any 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 therapy to 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 are not allowed
- 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 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 will be required
- Permitted forms of local therapy for second tumor:
- Partial or radical nephrectomy
- If 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 (Step 0) 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 virus (HCV). For patient randomized to Arm H, HBV and HCV testing must be completed within 8 weeks prior to registration Step 1.
- 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
- No known evidence of human immunodeficiency virus (HIV) infection, since the effects of nivolumab on anti-retroviral therapy have not been studied; HIV testing is not required as long as no 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
- ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1):
- Patients must meet all Step 0 eligibility criteria at the time of their registration to Step 1
- Patients randomized to Arm H: 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
- 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, 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 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) or calculated creatinine clearance (CrCl) >= 40mL/min (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)
- Patient randomized to Arm H must have the following laboratory tests performed within 8 weeks prior to registration to Step 1 to ensure the patient does not have known chronic active liver disease or evidence of acute or chronic hepatitis B virus (HBV) or hepatitis C (HCV)
- Hepatitis B virus (HBV)
- Hepatitis C virus (HCV)
- NOTE: For patients that are positive for hepatitis (Hep) B core antibody, hepatitis B surface antigen (HBsAg) must be negative; for patients that are positive for Hep C antibody, polymerase chain reaction (PCR) must be negative
- Renal Cancer