This phase III trial compares the effect of adding tivozanib to standard therapy pembrolizumab versus pembrolizumab alone for the treatment of patients with high-risk renal cell carcinoma (RCC). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Tivozanib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that signals tumor cells to multiply. This helps stop the spread of tumor cells. Giving pembrolizumab and tivozanib together may work better than pembrolizumab alone in treating patients with RCC.
PRIMARY OBJECTIVE: I. To compare disease free survival (DFS) as assessed by the investigator for high-risk renal cell carcinoma patients treated with adjuvant pembrolizumab and tivozanib versus those receiving pembrolizumab alone. SECONDARY OBJECTIVES: I. To compare overall survival (OS) for patients treated with adjuvant pembrolizumab and tivozanib versus those receiving pembrolizumab alone. II. To assess adverse events in each study arm by Common Terminology Criteria for Adverse Events (CTCAE) 5.0. BIOBANKING OBJECTIVE: I. To bank specimens for future unspecified research. QUALITY OF LIFE (QOL) OBJECTIVES: I. To compare global quality of life (QOL) for patients treated with pembrolizumab and tivozanib versus those receiving pembrolizumab alone. II. To compare patient-reported fatigue for patients treated with pembrolizumab and tivozanib versus those receiving pembrolizumab alone. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive pembrolizumab intravenously (IV) on days 1 and 43 of each cycle, or on days 1, 22, 43 and 64 of each cycle. Cycles repeat every 12 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and magnetic resonance imaging (MRI) or computed tomography (CT) throughout the trial and may undergo tissue biopsy on study. ARM II: Patients receive pembrolizumab IV on days 1 and 43 of each cycle and tivozanib orally (PO) once daily (QD) on days 1-21, days 29-49, and days 57-77 of each cycle for up to 6 months. Cycles repeat every 12 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and MRI or CT throughout the trial and may undergo tissue biopsy on study. After completion of study treatment, patients are followed up every 4 months for 2 years, then every 6 months for 3 years, then every subsequent year for 5 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1,040
Given intravenously
Given orally
Undergo blood sample collection
Undergo MRI
Undergo CT scan
Undergo biopsy
Ancillary studies
Cancer Center at Saint Joseph's
Phoenix, Arizona, United States
RECRUITINGBanner University Medical Center - Tucson
Tucson, Arizona, United States
RECRUITINGUniversity of Arizona Cancer Center-North Campus
Tucson, Arizona, United States
RECRUITINGNEA Baptist Memorial Hospital and Fowler Family Cancer Center - Jonesboro
Jonesboro, Arkansas, United States
Disease-free survival (DFS)
The primary analysis will be a comparison of DFS between the two study arms using a stratified log-rank test. The treatment effect will be estimated with a hazard ratio (HR) and corresponding 95% confidence interval obtained from a stratified Cox model with treatment group (experimental group versus control group) as the explanatory variable. Interim analyses: There will be several futility analyses for the trial. These analyses will employ the linear 20% method proposed by Freidlin, Korn and Gray. Based on the current design parameters, the first analysis would be performed at 37% information (99 DFS events), and the trial would be stopped for futility if the observed hazard ratio (experimental versus \[vs.\] control) were worse than 1. Additional analyses will be performed at 50% (133 DFS events), 60% (159 DFS events), and 70% information (186 DFS events), the trial would be stopped for futility if the observed HR were worse than 0.983, 0.971 and 0.959, respectively.
Time frame: From time of randomization until disease recurrence or death, assessed up to 10 years
Overall survival (OS)
The OS will be compared between the two treatment arms using a stratified log-rank test. An estimate of the OS difference between the arms will be made with a HR generated by a stratified Cox model. A point estimate and 95% confidence interval will be generated. If there are clinically meaningful imbalances between the treatment arms, a secondary analysis for DFS will be performed with a multivariable Cox model that includes the stratification variable and all baseline variables with meaningful differences. A similar analysis will be done for the OS endpoint. Key subgroup analyses will be performed to determine whether there is evidence that the treatment effect differs among subgroups that correspond to key prognostic variables. This includes the stratification variable.
Time frame: From time of randomization until death, assessed up to 10 years
Incidence of adverse events (AEs)
These will be assessed using Common Terminology Criteria for Adverse Events version 5.0. Adverse events will be summarized with frequencies and relative frequencies. The maximum grade for an AE will be recorded for each patient by treatment arm. The number (percent) of patients that experience each observed adverse event will be summarized by treatment arm. In addition, the proportion of patients that experience a grade 3+, grade 4+, and grade 5 adverse event will be summarized as the number and percent of patients by treatment arm. The primary summary will be regardless of attribution. Will also have an analogous summary for the adverse events that were deemed at least possibly related to treatment.
Time frame: From baseline to 10 years after registration
Proportion of patients that tolerate pembrolizumab and tivozanib
Tolerability will be defined as the ability of a patient to receive at least half the planned doses of tivozanib in combination with pembrolizumab if they have not had a DFS event. This will be determined as the number of patients on arm 2 who received at least one dose of tivozanib, who have not had a DFS within 6 months, and who received at half of the planned doses tivozanib divided by the number of patients on arm 2 who received at least one dose of tivozanib and who have not had a DFS within 6 months. The proportion of patients who tolerated tivozanib in combination with pembrolizumab will be estimated with a binomial point estimate and 95% binomial confidence interval.
Time frame: From day 1 to 6 months
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University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
RECRUITINGSutter Auburn Faith Hospital
Auburn, California, United States
RECRUITINGTower Cancer Research Foundation
Beverly Hills, California, United States
SUSPENDEDCity of Hope Comprehensive Cancer Center
Duarte, California, United States
RECRUITINGUCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, United States
RECRUITINGCity of Hope at Irvine Lennar
Irvine, California, United States
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