This phase II trial studies how well nivolumab works with radiation therapy in treating patients with urothelial bladder cancer that has spread from its original site of growth to nearby tissues or lymph nodes and are ineligible for chemotherapy. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving nivolumab and radiation therapy may work better in treating patients with urothelial bladder cancer.
PRIMARY OBJECTIVES: I. To compare the 12-month rate of progression-free survival (PFS) achieved with the combination of nivolumab, a programmed death (PD-1) inhibitor, and radiation therapy in localized/locally advanced urothelial cancer patients, who are chemotherapy ineligible, to a historical control reference 12-month PFS rate. SECONDARY OBJECTIVES: I. To assess the toxicity of concurrent nivolumab and radiation therapy in urothelial cancer. II. To determine overall response rate (ORR). III. To determine metastasis-free survival (MFS). IV. To determine overall survival (OS). V. To evaluate the quality of life and bladder functioning during and after the therapy. VI. To explore the relationships of PD-1 expression, PDL-1 expression, and the Th1/Th2 cytokine ratio to clinical outcomes (response, PFS, MFS, and OS). OUTLINE: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 14 days (2 weeks) for up to 14 courses (6 months) in the absence of disease progression or unacceptable toxicity. Beginning 3 days of course 1, patients undergo radiation therapy over 32-35 on weeks 1, 3, 5, 7 and 9. After completion of study treatment, patients are followed up every 3 months for 12 months.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
20
Patients receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 14 days (2 weeks) for up to 14 courses (6 months) in the absence of disease progression or unacceptable toxicity. Beginning 3 days of course 1, patients undergo radiation therapy over 32-35 on weeks 1, 3, 5, 7 and 9.
Beginning 3 days of course 1, patients undergo radiation therapy over 32-35 on weeks 1, 3, 5, 7 and 9.
Barbara Ann Karmanos Cancer Institute
Detroit, Michigan, United States
Roswell Park Cancer Institute
Buffalo, New York, United States
Progression-free Survival (PFS)
PFS distribution will be summarized with the Kaplan-Meier (K-M) survivorship estimate. A graph of the K-M curve for PFS will be generated along with the Hall-Wellner 90% confidence band, and a display of the number of patients at risk at several time points, below the X-axis. Summary statistics (12-month PFS rate, median PFS, etc.) will be calculated from the K-M life table, each one with its respective 90% confidence interval (CI).
Time frame: From date of registration to date of first documented disease relapse/progression, or death from urothelial cancer whichever occurs first, assessed up to 12 months
Overall Response Rate (ORR)
ORR will be estimated among all patients. Frequency distributions of best response will be generated. The point estimate of the ORR will be computed, along with its 95% (Wilson type) CI.
Time frame: Up to 12 months
Metastasis-free Survival (MFS)
MFS will be calculated as a rate at 1 year with a 90% confidence interval from the K-M life tables.
Time frame: From registration to the appearance of metastases or cancer related death, assessed up to 12 months
Overall Survival (OS)
Summary statistics of OS will be calculated from the K-M life tables. K-M graphs of the censored OS distributions will also be generated.
Time frame: From date of registration to death or last follow up, assessed up to 36 months
Quality of Life (QOL) and Bladder Functioning Questionnaires Assessment
The QOL score will be measured pre therapy, during therapy and after therapy to compare the changes.
Time frame: Up to 12 months
PD-1 and PDL-1 Expression Analysis Using Immunohistochemistry (IHC)
PD-1 status will be checked on pre-therapy tumor tissue and will be correlated with the primary endpoint. Also, the PDL-1 status will be checked on pre-therapy tumor tissue and will be correlated with the primary endpoint.
Time frame: Up to 12 months
Th1/Th2 Cytokine Ratio Analysis
The continuous markers (e.g., tumor infiltrating lymphocyte \[TIL\]s, Th1/Th2 cytokine ratio, etc.) will be summarized with standard descriptive statistics. These descriptive analyses of the serum markers will be performed for each time point at which the each marker is determined. Response (CR/PR vs not) will be modeled as a function of a dichotomized version of pre-study the continuous (ungrouped) markers (e.g., TILs from tissue, and the Th1/Th2 cytokine ratio from serum). The statistical goal of these exploratory analyses is to obtain the point and 95% CI estimates of the OR, and to simply determine the direction and approximate magnitude of these associations for use in planning a subsequent study. Censored PFS will be modeled as a function of a dichotomized version of the continuous (ungrouped) markers (e.g., TILs from tissue, and the Th1/Th2 cytokine ratio using Cox modelling strategy.
Time frame: Up to 12 months
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