This phase III trial compares the usual treatment (treatment with ipilimumab and nivolumab followed by nivolumab alone) to treatment with ipilimumab and nivolumab, followed by nivolumab with cabozantinib in patients with untreated renal cell carcinoma that has spread to other parts of the body. The addition of cabozantinib to the usual treatment may make it work better. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known how well the combination of cabozantinib and nivolumab after initial treatment with ipilimumab and nivolumab works in treating patients with renal cell cancer that has spread to other parts of the body.
PRIMARY OBJECTIVE: I. To compare the overall survival (OS) in patients with metastatic renal cell cancer (RCC) treated with ipilimumab-nivolumab followed by either nivolumab versus cabozantinib-nivolumab. SECONDARY OBJECTIVES: I. To determine progression free survival (PFS) of patients treated with nivolumab versus nivolumab-cabozantinib. II. To evaluate the 12-month complete response rate in patients treated with ipilimumab-nivolumab followed by cabozantinib-nivolumab versus ipilimumab-nivolumab followed by nivolumab (patients who have complete response \[CR\] and relapse before 12 months will not be counted as a CR at 12-months). III. To evaluate the rates of discontinuing therapy at 1 year. IV. To compare objective response rates (ORR, assessed by Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1 and Immune Response Evaluation Criteria in Solid Tumors \[iRECIST\] criteria) for patients treated with ipilimumab-nivolumab followed by cabozantinib-nivolumab versus ipilimumab-nivolumab followed by nivolumab. V. To document the adverse event profile of ipilimumab-nivolumab followed by cabozantinib-nivolumab. BIOMARKER OBJECTIVES: I. To evaluate biomarkers associated with exceptional responses in both arms (exceptional responses defined as CRs with treatment discontinuation at 12 months or 24 months). II. To evaluate whether baseline IL-6 is predictive of outcome in patients treated with cabozantinib-containing regimen. QUALITY OF LIFE (QOL) OBJECTIVES: I. To compare health-related quality of life at 18 months post-registration as assessed by the Functional Assessment of Cancer Therapy (FACT)-Kidney Symptom Index 19 (FKSI-19) between patients randomized to nivolumab (nivo) versus (vs) cabozantinib (cabo)/nivo. II. To compare health-related quality of life as assessed by the FKSI-19 between patients randomized to nivo vs cabo/nivo at other time points. III. To compare patient-reported fatigue using Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue between patients randomized to nivo vs cabo/nivo. IV. To compare quality-adjusted survival (overall survival x utility score assessed by EuroQol five-dimensional questionnaire \[EQ5D-5L\]) between patients randomized to nivo vs cabo/nivo. OUTLINE: INDUCTION: Patients receive nivolumab intravenously (IV) over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. TREATMENT: Patients with unconfirmed but clinical progression of disease (iuPD) with clinical instability receive cabozantinib orally (PO) daily on days 1-28. Treatment repeats every 28 days until further disease progression or unacceptable toxicity. Patients with unconfirmed CR (iCR) receive nivolumab IV between 30-60 minutes on day 1. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients with non-CR/non-PD or iuPD with clinical stability are randomized to 1 of 2 arms. ARM A: Patients receive nivolumab IV between 30-60 minutes on day 1. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive nivolumab IV between 30-60 minutes on day 1 and cabozantinib PO daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI) and blood and urine sample collection, and may also undergo a bone scan as clinically indicated throughout the study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1,175
Undergo blood and urine sample collection
Undergo bone scan
Given PO
Undergo CT scan
Given IV
Undergo MRI
Given IV
Ancillary studies
Ancillary studies
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Overall survival (OS)
OS of patients who achieve complete response (CR) and progressive disease (PD) from ipilimumab-nivolumab induction phase will be summarized. The stratified log-rank statistic will be the primary analysis to compare the hypothesis on OS with the stratification factors (presence of bone metastases and IMDC risk criteria). The Kaplan-Meier product-limit estimator will be used to estimate the OS. A stratified proportional hazards model will be used to generate estimates for the OS hazard ratio. For the randomized patients, OS will be calculated and compared from the time of randomization until the time of an OS event or time of last-follow-up, whatever occurs first. For the patients who were initially CR or PD, OS will be measured from the time of study registration. A comparison of OS will be made across the patient groups (randomized patients, patients initially CR, and patients initially PD).
Time frame: From registration to date of death from any cause for non-randomized patients, from time of randomization until death from any cause for randomized patients, assessed up to 5 years
Progression-free survival (PFS)
Progression will be defined using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. PFS of patients who achieve CR and PD from ipilimumab-nivolumab induction phase will be summarized (secondary analysis). The Kaplan-Meier product-limit estimator will be used to estimate the PFS distribution. A stratified proportional hazards model will be used to generate estimates for the PFS hazard ratio. For the randomized patients, PFS will be calculated and compared from the time of randomization until the time of a PFS event or time of last-follow-up, whatever occurs first. For the patients who were initially CR or PD, PFS will be measured from the time of study registration. A comparison of PFS will be made across the patient groups (randomized patients, patients initially CR, and patients initially PD). For this comparison, PFS will be measured from time of study registration all the patients, regardless of whether they were randomized or not.
Time frame: From date of registration to date of progression (or disease recurrence) or death due to any cause, whichever occurs first, assessed up to 5 years
Complete response (CR) (randomized patients)
Patients who had a CR prior to 12 months but have experienced a disease recurrence prior to 12 months, will not be considered to be a CR at 12 months. The Cochran-Mantel-Haenszel test will be used to compare the two arms on the proportion of patients who have a 12-month CR adjusting on the stratification factors.
Time frame: At 12 months from date of randomization
Objective response
Defined as the best response observed that has been confirmed by a scan performed 4 or more weeks after the observation of the initial response. The objective response will be confirmed using RECIST 1.1. In addition, objective responses will also be confirmed using Immune Response Evaluation Criteria in Solid Tumors (iRECIST).
Time frame: Up to 5 years
Proportion of patients who discontinue protocol-directed treatment prior to 1 year from date of study registration
Patients who stop their protocol directed treatment for any reason prior to one year from study registration will be considered to have discontinued their treatment. The Cochran-Mantel-Haenszel test will also be used to compare the proportion of patients who discontinue their treatment prior to one-year after study registration.
Time frame: Up to 5 years
Incidence of adverse events
Assessed with National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. A Fisher's exact test will be used to compare the two treatment arms on the proportion of patient with a grade 3 or higher adverse event.
Time frame: Up to 5 years
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