Health Trials

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

ConditionsMuscle Invasive Bladder Urothelial CarcinomaMuscle Invasive Renal Pelvis Urothelial CarcinomaMuscle Invasive Ureter Urothelial CarcinomaMuscle Invasive Urethral Urothelial CarcinomaStage II Bladder Urothelial Carcinoma AJCC v6 and v7Stage III Bladder Urothelial Carcinoma AJCC v6 and v7Stage IV Bladder Urothelial Carcinoma AJCC v7
Trial statusRecruiting
Trial phasePhase 2, Phase 3
Trial typeInterventional
Biological sexAll
Age18+
SponsorNational Cancer Institute (NCI)

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

PRE-REGISTRATION (STEP 0): Histologically confirmed muscle-invasive urothelial carcinoma of the urethra, bladder, ureter or renal pelvis

PRE-REGISTRATION (STEP 0): Variant histology, including neuroendocrine differentiation, sarcomatoid, micropapillary, glandular, trophoblastic, Mullerian, is allowed if urothelial cancer is predominant histology (any amount of squamous differentiation is allowed provided the tumor is not a pure squamous cell cancer)

PRE-REGISTRATION (STEP 0): Radical surgery (cystectomy with lymph node dissection or nephroureterectomy or ureterectomy) must be ≥ 3 weeks and ≤ 12 weeks (central Signatera pathway) or ≤ 16 weeks (commercial Signatera pathwary) prior to pre-registration. Patients who have had a partial cystectomy as definitive therapy are not eligible

PRE-REGISTRATION (STEP 0): Patients who have had a partial cystectomy as definitive therapy are not eligible

Disqualifiers

None

Trial design

Design model

Parallel

Treatments tested in this trial

  • Biospecimen Collection

    Procedure/Surgery

    Undergo collection of tissue and blood

  • cfDNA or ctDNA Measurement

    Other intervention

    Undergo ctDNA surveillance

  • Computed Tomography

    Procedure/Surgery

    Undergo CT

  • Cystoscopy

    Procedure/Surgery

    Undergo cystoscopy

  • Magnetic Resonance Imaging

    Procedure/Surgery

    Undergo MRI

  • Nivolumab

    Biological/Vaccine

    Given IV

  • Questionnaire Administration

    Other intervention

    Ancillary studies

  • Relatlimab

    Biological/Vaccine

    Given IV

Treatment groups

992 Participants
are divided into 4 treatment groups
Group A: Cohort A, Arm I (nivolumab)Active comparator 6 interventions
Group B: Cohort A, Arm II (nivolumab, relatlimab)Experimental treatment 7 interventions
Group C: Cohort B, Arm III (nivolumab)Active comparator 5 interventions
Group D: Cohort B, Arm IV (ctDNA surveillance, nivolumab)Experimental treatment 7 interventions

Trial outcomes

Primary outcomes

1

Proportion of patients who are circulating tumor DNA negative (ctDNA[-]) (Cohort A Phase II)

Will be determined for each treatment arm as the number of patients who are ctDNA(-) after 12 weeks of treatment divided by the total number of patients on the treatment arm. Patients who do not have a 12-week ctDNA result will be deemed to be ctDNA(+). The comparison of the proportions of patients who are ctDNA(-) after 12 weeks of treatment between the two arms will be performed with a chi-square test.

Time frame
At week 12 from treatment start date
2

Overall survival (OS) (Cohort A Phase III)

The analysis will be performed using a stratified log-rank test that uses the specified stratification variables. An additional analysis will be perform using a stratified Cox regression model to generate the point estimate and 90% confidence interval for the hazard ratio (HR) (comparing Arm 2 to Arm 1).

Time frame
From randomization until death due to any cause, assessed up to 5 years after completion of study treatment
3

Disease-Free Survival (DFS) (Cohort B)

A stratified Cox model (using the randomization stratification variables will be used to generate a 90% confidence interval (CI) for the HR. If the 90% CI does not contain 1.39, Arm 4 (surveillance with ctDNA serial testing to determine whether patient is treated with nivolumab) will be deemed to be non-inferior to treating patients immediately with nivolumab.

Time frame
From randomization until confirmed disease recurrence as assessed by the treating physician or death due to any cause, assessed up to 5 years after completion of study treatment

Secondary outcomes

1

Proportion of patients who are ctDNA(-) (Cohort A Phase III) from treatment start date

Will be determined for each treatment arm as the number of patients who are ctDNA(-) after 12 weeks of treatment divided by the total number of patients on the treatment arm. Patients who do not have a 12-week ctDNA result will be deemed to be ctDNA(+).

Time frame
At week 12
2

OS (Cohort A Phase II)

If the trial does not continue to phase III, OS will be a secondary endpoint.

Time frame
From randomization until death due to any cause, assessed up to 5 years after completion of study treatment
3

DFS (Cohort A Phase II or III)

This will be a secondary endpoint for the phase III trial, if completed, or for the phase II trial if the phase III trial is not performed.

Time frame
From randomization until confirmed disease recurrence as assessed by the treating physician or death due to any cause, assessed up to 5 years after completion of study treatment
4

Incidence of adverse events (Cohort A)

Will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. Adverse events (AEs) 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.

Time frame
Up to 5 years after completion of study treatment

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

National Cancer Institute (NCI)

Lead sponsor

Source ClinicalTrials.gov
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