Testing the Role of DNA Released from Tumor Cells into the Blood in Guiding the Use of Immunotherapy after Surgical Removal of the Bladder for Bladder Cancer Treatment, MODERN Study

Summary

Objectives

PRIMARY OBJECTIVES:
I. To compare the ctDNA clearance proportion (i.e., ctDNA positive [+] --> ctDNA negative [-]) at 12 weeks in patients enrolled in Cohort A treated with adjuvant nivolumab versus nivolumab + relatlimab (phase 2 portion).
II. To compare overall survival in patients enrolled in Cohort A treated with adjuvant nivolumab versus nivolumab + relatlimab (phase 3 portion).
III. To compare disease-free survival in patients enrolled in Cohort B randomized to immediate treatment with nivolumab to those randomized to surveillance with subsequent treatment with nivolumab only upon converting to ctDNA(+)

SECONDARY OBJECTIVES:
I. To compare disease-free survival in patients enrolled in Cohort A treated with adjuvant nivolumab versus nivolumab + relatlimab.
II. To define the association between ctDNA clearance and disease-free survival and overall survival for Cohort A patients.
III. To compare overall survival in patients enrolled in Cohort B randomized to immediate treatment with nivolumab to those randomized to surveillance with subsequent treatment with nivolumab only upon converting to ctDNA(+).
IV. To determine the lead time from a ctDNA(+) assay to radiographic recurrence in patients initially ctDNA(-) post-definitive surgery enrolled in Cohort B.
V. To estimate the proportion of Cohort B patients on Arm 4 who become ctDNA(+) and receive nivolumab.
VI. To compare the cumulative incidence of Cohort B patients who become ctDNA(+) between Arms 3 and 4.
VII. To determine the safety of adjuvant nivolumab plus relatlimab.

EXPLORATORY OBJECTIVES:
I. To explore the kinetics of quantitative ctDNA levels (mean number of tumor molecules observed per mL of plasma or MTM/ml) over time and the association between ctDNA kinetics and time-to-event outcomes.
II. To estimate the costs and value of care in patients with a ctDNA(+) assay post-cystectomy treated with adjuvant nivolumab versus nivolumab + relatlimab.
III. To estimate the costs and value of care in patients with a ctDNA(-) assay post-cystectomy treated with adjuvant nivolumab versus surveillance with subsequent treatment with nivolumab at the time of conversion to ctDNA(+).

QUALITY OF LIFE OBJECTIVES:
I. Within each cohort, to compare quality-adjusted survival among randomized arms using European Quality of Life Five Dimension Five Level Scale (EQ-5D-5L).
II. Within Cohort B, to compare overall quality of life (QOL) as measured by the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) between baseline and 42 months (calculated as the area under the curve) among randomized arms.
III. Within each cohort, to compare overall QOL as measured by the EORTC QLQ-C30 at each time point among randomized arms.
IV. Within each cohort, to compare bladder cancer-specific QOL as measured by the EORTC Bladder Cancer Muscle-Invasive 30 Questionnaire (QLQ-BLM30) at each time point among randomized arms.
V. Within each cohort, to compare patient-reported fatigue as measured by Patient Reported Outcomes Measurement Information System (PROMIS)-Fatigue at each time point among randomized arms.

OUTLINE: Patients are assigned to 1 of 2 cohorts based on ctDNA results.

COHORT A: Patients who are ctDNA(+) are randomized to 1 of 2 arms:

ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of tissue during screening and collection of blood throughout the trial. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) scans throughout the trial.

ARM II: Patients receive nivolumab IV over 30 minutes and relatlimab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of tissue during screening and collection of blood throughout the trial. Patients also undergo CT or MRI scans throughout the trial.

COHORT B: Patients who are ctDNA(-) are randomized to 1 of 2 arms:

ARM III: Patients receive nivolumab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of tissue during screening and collection of blood throughout the trial. Patients also undergo CT or MRI scans throughout the trial.

ARM IV: Patients undergo ctDNA surveillance consisting of collection of tissue and blood during screening and collection of blood only on study and during follow up. Patients who convert to ctDNA(+) during surveillance then receive nivolumab IV over 30 minutes and relatlimab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI scans throughout the trial.

After completion of study treatment, patients are followed up at weeks 60, 72, 84, 96, 120, 144, 196, and 248.