This randomized phase III trial studies how well pembrolizumab works in treating patients with bladder cancer that has spread into the deep muscle of the bladder wall (muscle-invasive) or urothelial cancer that has spread from where it started to nearby tissue or lymph nodes (locally advanced). Monoclonal antibodies recognizing and blocking checkpoint molecules can enhance the patient's immune response and therefore help fight cancer. Pembrolizumab is one of the monoclonal antibodies that block the PD-1 axis and can interfere with the ability of tumor cells to grow.
DUAL PRIMARY OBJECTIVE:
I. To determine disease free survival (DFS) and overall survival (OS) in all patients with muscle-invasive bladder and upper-tract urothelial carcinoma treated with adjuvant pembrolizumab (MK-3475) versus (vs.) observation.
I. To determine DFS and OS in PD-L1 positive and negative patients with muscle-invasive bladder and upper-tract urothelial carcinoma treated with adjuvant MK-3475 (pembrolizumab) vs. observation.
II. To characterize the safety and tolerability of MK-3475 (pembrolizumab) when administered in the adjuvant setting in patients with muscle-invasive bladder and upper-tract urothelial carcinoma.
CORRELATIVE SCIENCE OBJECTIVES:
I. To determine if the 12 immune gene signatures are associated with OS and DFS.
II. To determine if tumor molecular subtype is associated with OS and DFS. III. To investigate whether the diversity of T-cell receptor (TCR) clonotypes is associated with OS and DFS.
IV. To investigate whether persistence of TCR clonotypes is associated with OS and DFS.
V. To determine if tumor burden and neoantigen burden are associated with OS and DFS.
VI. To determine if HLA subtypes are associated with OS and DFS. VII. To conduct exploratory analyses regarding the association of plasma HGF and VEGF levels with IL-10 and IL-17 and OS and DFS and between treated and untreated patients.
PHARMACOGENOMIC STUDY OBJECTIVES:
I. To investigate the effect of PDCD1 single-nucleotide polymorphism (SNP) rs11568821 on severe (grade 3 or higher) immune-related toxicity in the MK-3475 (pembrolizumab)-treated cohort.
II. To investigate whether other SNPs commonly polymorphic within or near PDCD1 associate with development of MK-3475 (pembrolizumab) toxicity in the treated cohort.
III. To identify novel germline genetic markers of treatment-related toxicity through genome-wide association analysis of pembrolizumab-treated patients.
IV. To identify novel germline genetic markers that are associated with DFS and OS through genome-wide association analysis.
QUALITY OF LIFE CORRELATIVE STUDY OBJECTIVES:
I. To compare health-related quality of life (HRQL) as assessed by the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-core (C)30 between patients randomized to MK-3475 (pembrolizumab) vs. observation.
II. To compare urinary symptoms as assessed by EORTC QLQ- muscle-invasive bladder cancer module (BLM)30 between patients randomized to MK-3475 (pembrolizumab) vs. observation.
III. To compare patient-reported fatigue, diarrhea, and pain between patients randomized to MK-3475 (pembrolizumab) vs. observation.
IV. To compare health utilities and quality-adjusted life year (QALYs) between patients randomized to MK-3475 (pembrolizumab) vs. observation.
V. To compare other scale scores of the EORTC QLQ-C30, EORTC QLQ-BLM30, and European Quality of Life 5 Dimensions 5 Levels (EQ5D-5L) between patients randomized to MK-3475 (pembrolizumab) vs. observation.
VI. To compare global quality of life, symptoms, health utilities, QALYs, and other scale scores of the three questionnaires between patients randomized to MK-3475 (pembrolizumab) vs. observation within subgroups defined by each of the stratification factors.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity.
ARM B: Patients undergo observation.
After completion of study treatment, patients are followed up every 12 weeks for up 2 years, and then annually for 3 years.
|Treatment||clinical observation, laboratory biomarker analysis, questionnaire administration, quality-of-life assessment, Pembrolizumab, pharmacological study|
|Clinical Study Identifier||NCT03244384|
|Sponsor||National Cancer Institute (NCI)|
|Last Modified on||25 November 2020|
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