Nivolumab in Treating Patients With Localized Kidney Cancer Undergoing Nephrectomy

• ClinicalTrials.gov Identifier: NCT03055013
• Recruitment Status: Recruiting
• First Posted: February 16, 2017
• Last Update Posted: March 5, 2021
• Sponsor: National Cancer Institute (NCI)
• Collaborator: Canadian Cancer Trials Group
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: February 15, 2017
• First Posted Date: February 16, 2017
• Last Update Posted Date: March 5, 2021
• Actual Study Start Date: February 2, 2017
• Estimated Primary Completion Date: November 30, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 19, 2020)

Event-free survival (EFS) [ Time Frame: Time from randomization to disease recurrence or death from any cause, assessed up to 10 years ]

Will be assessed among all randomized patients using a stratified log rank test, with nominal one-sided type I error of 2.5%. The type I error will be adjusted for interim analyses.

Original Primary Outcome Measures (submitted: February 15, 2017)

RFS [ Time Frame: Time from randomization to disease recurrence or death from any cause, assessed up to 10 years ]

Will be assessed among all randomized patients using a stratified log rank test, with nominal one-sided type I error of 2.5%. The type I error will be adjusted for interim analyses.

Current Secondary Outcome Measures (submitted: April 11, 2019)

• Overall survival [ Time Frame: Time from randomization to death from any cause, assessed up to 10 years ]
• RFS among patients with clear cell cancer [ Time Frame: Up to 10 years ]
  The stratified logrank test will be used.
• Incidence of toxicity [ Time Frame: Up to 10 years ]
  Graded per Common Criteria for Adverse Events (CTCAE) version (v)4.0. (Starting April 1, 2018, Cancer Therapy Evaluation Program Adverse Event Reporting System [CTEP-AERS] reporting will use CTCAE v5). Adverse events will be described separately for patients treated on each arm to evaluate safety and tolerability.

Original Secondary Outcome Measures (submitted: February 15, 2017)

• Incidence of toxicity using Common Criteria for Adverse Events version 4.0 [ Time Frame: Up to 10 years ]
  Adverse events will be described separately for patients treated on each arm to evaluate safety and tolerability.
• Overall survival [ Time Frame: Time from randomization to death from any cause, assessed up to 10 years ]
• RFS among patients with clear cell cancer [ Time Frame: Up to 10 years ]
  The stratified logrank test will be used.

Current Other Pre-specified Outcome Measures (submitted: August 19, 2020)

• Primary tumor's expression of PD-L1 [ Time Frame: Baseline to up to 10 years ]
  The percentage of cells exhibiting cell-surface staining for PD-L1 will be scored. PD-L1 positivity will be defined per specimen by a 5% expression threshold. Additional analyses will assess the 1% and 10% threshold levels. Information with respect to the relative abundance and location (peritumoral/intratumoral) of immune cell (macrophage and lymphocyte) PD-L1 staining will be captured. The expression-by-treatment interaction will be tested using a proportional hazards model. McNemar's Test will be used to explore categorical changes within each treatment group.
• Expression of PD-L1 on tumor tissue at recurrence [ Time Frame: Up to 10 years ]
• Pharmacokinetic analysis of nivolumab [ Time Frame: On day 1 of cycles 1-3, 5, 7 and the first 2 follow-up visits ]
  Serum concentration analyses for nivolumab will be performed by validated bio-analytical methods for nivolumab.
• Change in patient-reported symptoms and toxicities [ Time Frame: Baseline to up to 10 years ]
  Using the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy (NCCN/FACT) Kidney Symptom Index-19 (NFKSI-19) and items from the PRO-CTCAE pool of items measuring patient-reported toxicity. We will describe the severity, interference, and (as appropriate) frequency rates, along with response rates at each time point. Change in symptoms will be tested using a two-sided Wilcoxon rank sum test with Type I error of 3%. Change in physical function will be tested using a two-sided Wilcoxon rank sum test with Type I error of 1%. Changes in NFKSI-19 and PROMIS Physical Function scores from baseline to pre-nephrectomy among patients randomized to nivolumab and will be explored using a Wilcoxon signed rank test. Differences in scores post-nephrectomy between the arms will be described and tested using a Wilcoxon rank-sum test. Differences in the pattern of change over time in NFKSI-19 and PROMIS Physical Function scores will be examined using mixed effects models.
• Absolute T cell clonotype abundance [ Time Frame: Up to 10 years ]
  Will be determined by assessing the number of unique clonotypes identified. The data will be summarized descriptively and graphically.
• Change in T cell repertoire [ Time Frame: From diagnosis to on therapy or to time of recurrence, assessed up to 10 years ]
  Morisita's distance will be used as utilized by Cha and colleagues. Morisita's distance ranges from 0-1. Zero indicates minimal change in T cell repertoire (TCR) repertoire size (number of unique clonotypes) and 1 indicates maximal change after treatment.
• T cell receptor (TCR) diversity using change in repertoire size per patient [ Time Frame: Baseline to up to 10 years ]
  The top 25% of unique clonotypes will be identified by sorting for clone frequency. Fold change after recurrence will be measured and plotted on a logarithmic scale.
• Change in cytokine levels in patients randomized to the nivolumab arm [ Time Frame: Baseline to up to 10 years ]
  Differences in RFS between patients with and without robust CD8 infiltration will be explored. A Cox proportional hazards model will be used to test the interaction between treatment and cytokine changes.

Original Other Pre-specified Outcome Measures (submitted: February 15, 2017)

• Absolute T cell clonotype abundance [ Time Frame: Up to 10 years ]
  Will be determined by assessing the number of unique clonotypes identified. The data will be summarized descriptively and graphically.
• Change in cytokine levels in patients randomized to the nivolumab arm [ Time Frame: Baseline to up to 10 years ]
  Differences in RFS between patients with and without robust CD8 infiltration will be explored. A Cox proportional hazards model will be used to test the interaction between treatment and cytokine changes.
• Change in patient-reported symptoms and toxicities [ Time Frame: Baseline to up to 10 years ]
  Using the NCCN/FACT Kidney Symptom Index-19 (NFKSI-19), and a carefully selected subset of 5 questions from the PRO-CTCAE pool of items measuring patient-reported toxicity. Descriptive statistics will be used to summarize outcomes at each time point. The impact of nivolumab on symptoms can be assessed by considering the differences between arms in QOL at 18 and 36 weeks. To consider the overall impact of treatment, an area under the curve analysis comparing the entire period from randomization to one year will be used, based on the NFKSI-19 total score. Scoring of the NFKSI-19 will be done usi
• Change in T cell repertoire [ Time Frame: From diagnosis to on therapy or to time of recurrence, assessed up to 10 years ]
  Morisita's distance will be used as utilized by Cha and colleagues. Morisita's distance ranges from 0-1. Zero indicates minimal change in T cell repertoire (TCR) repertoire size (number of unique clonotypes) and 1 indicates maximal change after treatment.
• Expression of PD-L1 on tumor tissue at recurrence [ Time Frame: Up to 10 years ]
• Pharmacokinetic analysis of nivolumab [ Time Frame: Up to 10 years ]
  Serum concentration analyses for nivolumab will be performed by validated bio-analytical methods for nivolumab.
• Primary tumor's expression of PD-L1 [ Time Frame: Baseline to up to 10 years ]
  The percentage of cells exhibiting cell-surface staining for PD-L1 will be scored. PD-L1 positivity will be defined per specimen by a 5% expression threshold. Additional analyses will assess the 1% and 10% threshold levels. Information with respect to the relative abundance and location (peritumoral/intratumoral) of immune cell (macrophage and lymphocyte) PD-L1 staining will be captured. The expression-by-treatment interaction will be tested using a proportional hazards model. McNemar's Test will be used to explore categorical changes within each treatment group.
• TCR diversity using change in repertoire size per patient [ Time Frame: Baseline to up to 10 years ]
  The top 25% of unique clonotypes will be identified by sorting for clone frequency. Fold change after recurrence will be measured and plotted on a logarithmic scale.

Descriptive Information

• Brief Title: Nivolumab in Treating Patients With Localized Kidney Cancer Undergoing Nephrectomy
• Official Title: A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in Patients With Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC)
• Brief Summary: 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.

Detailed Description

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.

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

Condition

• Metastatic Renal Cell Carcinoma
• Sarcomatoid Renal Cell Carcinoma
• Stage II Renal Cell Cancer AJCC v7
• Stage III Renal Cell Cancer AJCC v7
• Unclassified Renal Cell Carcinoma

Intervention

• Procedure: Conventional Surgery
  Undergo nephrectomy
• Biological: Nivolumab
  Given IV
  Other Names:

  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo
• Other: Patient Observation
  Undergo observation
  Other Names:

  • Active Surveillance
  • deferred therapy
  • expectant management
  • Observation
  • Watchful Waiting
• Other: Quality-of-Life Assessment
  Ancillary studies
  Other Name: Quality of Life Assessment
• Other: Questionnaire Administration
  Ancillary studies

Study Arms

• Experimental: Arm I (nivolumab, nephrectomy)

  Patients receive nivolumab 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. Patients 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. Patient 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.

  Interventions:

  • Procedure: Conventional Surgery
  • Biological: Nivolumab
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
• Active Comparator: Arm II (nephrectomy)
  Patients undergo partial or radical nephrectomy within 8 weeks after registration followed by observation.
  Interventions:

  • Procedure: Conventional Surgery
  • Other: Patient Observation
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration

• Publications *: Marconi L, Sun M, Beisland C, Klatte T, Ljungberg B, Stewart GD, Dabestani S, Choueiri TK, Bex A. Prevalence, Disease-free, and Overall Survival of Contemporary Patients With Renal Cell Carcinoma Eligible for Adjuvant Checkpoint Inhibitor Trials. Clin Genitourin Cancer. 2021 Jan 7. pii: S1558-7673(21)00005-7. doi: 10.1016/j.clgc.2020.12.005. [Epub ahead of print]

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 15, 2017): 766
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: November 30, 2023
• Estimated Primary Completion Date: November 30, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• ELIGIBILITY CRITERIA FOR RANDOMIZATION:
• 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)

  • 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 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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: Canada, Israel, United States

Administrative Information

• NCT Number: NCT03055013
• Other Study ID Numbers: NCI-2016-00326; NCI-2016-00326 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); EA8143; EA8143 ( Other Identifier: ECOG-ACRIN Cancer Research Group ); EA8143 ( Other Identifier: CTEP ); U10CA180820 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: National Cancer Institute (NCI)
• Study Sponsor: National Cancer Institute (NCI)
• Collaborators: Canadian Cancer Trials Group

Investigators

• Principal Investigator: Lauren Harshman; ECOG-ACRIN Cancer Research Group

• PRS Account: National Cancer Institute (NCI)
• Verification Date: November 2020