Trials / Recruiting

RecruitingNCT05987241

Testing the Role of DNA Released From Tumor Cells Into the Blood in Guiding the Use of Immunotherapy After Surgical Removal of the Bladder, Kidney, Ureter, and Urethra for Urothelial Cancer Treatment, MODERN Study

MODERN: An Integrated Phase 2/3 and Phase 3 Trial of MRD-Based Optimization of ADjuvant ThErapy in URothelial CaNcer

Status: Recruiting
Phase: Phase 2 / Phase 3
Study type: Interventional
Enrollment: 992 (estimated)

Sponsor: National Cancer Institute (NCI) · NIH
Sex: All
Age: 18 Years
Healthy volunteers: Not accepted

Summary

This phase II/III trial examines whether patients who have undergone surgical removal of bladder, kidney, ureter or urethra, but require an additional treatment called immunotherapy to help prevent their urinary tract (urothelial) cancer from coming back, can be identified by a blood test. Many types of tumors tend to lose cells or release different types of cellular products including their DNA which is referred to as circulating tumor DNA (ctDNA) into the bloodstream before changes can be seen on scans. Health care providers can measure the level of ctDNA in blood or other bodily fluids to determine which patients are at higher risk for disease progression or relapse. In this study, a blood test is used to measure ctDNA and see if there is still cancer somewhere in the body after surgery and if giving a treatment will help eliminate the cancer. Immunotherapy with monoclonal antibodies, such as nivolumab and relatlimab, can help the body's immune system to attack the cancer, and can interfere with the ability of tumor cells to grow and spread. This trial may help doctors determine if ctDNA measurement in blood can better identify patients that need additional treatment, if treatment with nivolumab prolongs patients' life and whether the additional immunotherapy treatment with relatlimab extends time without disease progression or prolongs life of urothelial cancer patients who have undergone surgical removal of their bladder, kidney, ureter or urethra.

Detailed description

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. VIII. To compare disease-free survival and overall survival in patients enrolled in Cohort A treated with adjuvant nivolumab versus nivolumab + relatlimab according to receipt of neoadjuvant immune checkpoint blockade-containing therapy versus no neoadjuvant immune checkpoint blockade-containing therapy. IX. To compare disease-free survival and overall survival in patients enrolled in Cohort B treated with adjuvant nivolumab versus nivolumab + relatlimab according to receipt of neoadjuvant immune checkpoint blockade-containing therapy versus no neoadjuvant immune checkpoint blockade-containing therapy. 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-radical surgery treated with adjuvant nivolumab versus nivolumab + relatlimab. III. To estimate the costs and value of care in patients with a ctDNA(-) assay post-radical surgery 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) and may undergo cystoscopy 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 and may undergo cystoscopy 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 and may undergo cystoscopy 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 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 and may undergo cystoscopy throughout the trial. After completion of study treatment, patients are followed up at weeks 48, 60, 72, 84, 96, 120, 144, 196, and 248.

Conditions

Interventions

Type	Name	Description
PROCEDURE	Biospecimen Collection	Undergo collection of tissue and blood
OTHER	cfDNA or ctDNA Measurement	Undergo ctDNA surveillance
PROCEDURE	Computed Tomography	Undergo CT
PROCEDURE	Cystoscopy	Undergo cystoscopy
PROCEDURE	Magnetic Resonance Imaging	Undergo MRI
BIOLOGICAL	Nivolumab	Given IV
OTHER	Questionnaire Administration	Ancillary studies
BIOLOGICAL	Relatlimab	Given IV

Timeline

Start date: 2024-02-02
Primary completion: 2030-09-02
Completion: 2030-09-02
First posted: 2023-08-14
Last updated: 2026-04-20

Locations

494 sites across 2 countries: United States, Canada

Regulatory

FDA-regulated drug study

Source: ClinicalTrials.gov record NCT05987241. Inclusion in this directory is not an endorsement.