MODERN Study: Immunotherapy After Surgery for Urothelial Cancer
This study, called MODERN, is looking at whether a blood test can help decide if you need immunotherapy after surgery for urothelial cancer (cancer of the bladder, kidney, ureter, or urethra). After surgery, some tumor cells can release their DNA (called circulating tumor DNA or ctDNA) into your bloodstream. This study will measure ctDNA in your blood to see if it can predict who might benefit from immunotherapy with nivolumab, or a combination of nivolumab and relatlimab, to prevent the cancer from returning. The study aims to see if these treatments improve how long people live or stay cancer-free. You may be eligible if you are 18 or older and have muscle-invasive urothelial cancer.
- Study design
- This is an interventional study with a planned enrollment of 992 participants. It is designed to compare different immunotherapy approaches based on ctDNA levels.
- What's involved
- You would undergo collection of tissue and blood, ctDNA surveillance, and imaging tests like CT scans, MRI, and cystoscopy.
- Compensation
- Not stated in the trial record.
- Follow-up
- Participants will be followed for overall survival and disease-free survival for up to 5 years after completing study treatment.
AI-generated from the public study record. Only the study team can confirm whether you're eligible — confirm details with them before making decisions.
NCT05987241
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
Recruiting
PHASE2Ages 18+InterventionalTreatmentNational Cancer Institute (NCI)Government-funded
~992 participants
Updated 2026-08-28 on ClinicalTrials.gov
What's tested:Biospecimen CollectioncfDNA or ctDNA MeasurementComputed TomographyCystoscopyMagnetic Resonance ImagingNivolumab
At a glance
Recruiting sites
453 of 500 listed sites are recruiting right now
RecruitingSuspended, closed, or not yet open
What they're measuring
Proportion of patients who are circulating tumor DNA negative (ctDNA[-]) (Cohort A Phase II)
Measured over At week 12 from treatment start date
+2 more outcomes measured
Conditions
Where it's being run
500 sites across 52 statesIllinois58
Michigan45
California42
Wisconsin29
Missouri22
North Carolina22
Connecticut20
Pennsylvania20
Study leadership
- Matthew D Galsky · PRINCIPAL_INVESTIGATOR · Alliance for Clinical Trials in Oncology
Who to contact
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Do you actually qualify for this trial?
Add a private profile and we'll compare every criterion below against your situation — and tell you which ones are met, uncertain, or excluding.
Eligibility criteria
Inclusion
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
PRE-REGISTRATION (STEP 0): No gross cancer at the surgical margins. Microscopic invasive urothelial carcinoma at the surgical margins (i.e., "positive margins") are allowed. Carcinoma in situ (CIS) at margins is considered negative margins
PRE-REGISTRATION (STEP 0): No evidence of residual cancer or metastasis after radical cystectomy or nephroureterectomy or ureterectomy (imaging is not required prior to pre-registration but is required prior to registration)
PRE-REGISTRATION (STEP 0): Have undergone a radical cystectomy nephroureterectomy, or ureterectomy with pathological evidence of urothelial carcinoma at high risk of recurrence as described in one of the two scenarios below (i or ii). The 7th edition of American Joint Committee on Cancer (AJCC) staging will be utilized.:
(i) Patients who have not received neoadjuvant systemic therapy: pT4N0 or pTanyN+ on radical surgery pathology specimen (i.e., cystectomy, nephroureterectomy, or ureterectomy) and are not eligible for adjuvant cisplatin chemotherapy
(i) Patients ineligible for cisplatin due to at least one of the following criteria and reason for ineligibility should be documented:
(i) Creatinine Clearance (using Cockcroft-Gault): \< 60 mL/min
(i) Common Terminology Criteria for Adverse Events (CTCAE) version 5, grade \>= 2 audiometric hearing loss
(i) CTCAE version 5, grade \>= 2 or above peripheral neuropathy
New York Heart Association Class III heart failure
(i) Eastern Cooperative Oncology Group (ECOG) performance status = 2
(i) Patients who are eligible for adjuvant cisplatin may be candidates if they refuse adjuvant cisplatin-based chemotherapy, despite being informed by the investigator about the treatment options. The patient's refusal must be documented.
(i) Patients with pT2N0 urothelial cancer on radical surgery specimen (without prior neoadjuvant systemic therapy) with ctDNA(+) Signatera results are eligible only if the result was obtained via commercial testing (central testing is not permitted for this population) (Note: this is distinct from patients with ypT2N0 who are eligible based on ii).
(ii) Patients who received neoadjuvant systemic therapy: ypT2-T4N0 or Nx or ypTanyN+ on radical surgery (i.e., cystectomy. , nephroureterectomy, or ureterectomy) pathology specimen. Neoadjuvant systemic therapy may have included cisplatin-based chemotherapy, cisplatin-based chemotherapy plus PD-1/PD-L1 blockade, or enfortumab vedotin plus PD-1/PD-L1 blockade
PRE-REGISTRATION (STEP 0): Patients are required to meet criteria for one of two criteria:
1\) Commercial Signatera pathway:
Available commercial Signatera testing result (i.e., ctDNA+ or ctDNA-) from blood sample obtained ≥ 3 weeks and ≤ 16 weeks from time of radical surgery performed as part of standard care
Sites are required to verify that the commercial Signatera report demonstrates a complete 16 target assay design and that the test was designed on exome. This verification is conducted at the site level during the eligibility review. OR
Central Signatera pathway:
Pre-registration samples are to be submitted after pre-registration, at ≥ 3 weeks but ≤ 12 weeks from the time of radical surgery
Ineligible patients for the commercial pathway must use the central Signatera pathway and provide tumor tissue as part of the A032103 study
For patients who have not had neoadjuvant chemotherapy, tumor tissue is preferred from the radical surgery specimen
For patients who have had neoadjuvant therapy, tissue is preferred from the pre-chemotherapy specimen diagnosing muscle-invasive disease (e.g., transurethral resection of bladder tumor specimen)
PRE-REGISTRATION (STEP 0): Age \>= 18 years
PRE-REGISTRATION (STEP 0): ECOG performance status 0-2
PRE-REGISTRATION (STEP 0): Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects
PRE-REGISTRATION (STEP 0): No postoperative adjuvant systemic therapy after radical surgery
PRE-REGISTRATION (STEP 0): No adjuvant radiation after radical surgery
PRE-REGISTRATION (STEP 0): No treatment with any other type of investigational agent =\< 4 weeks before pre-registration
PRE-REGISTRATION (STEP 0): No previous treatment with LAG-3 blockade therapy
PRE-REGISTRATION (STEP 0): Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
PRE-REGISTRATION (STEP 0): Absolute neutrophil count (ANC) \>= 1,200/mm\^3
PRE-REGISTRATION (STEP 0): Platelet count \>= 100,000/mm\^3
PRE-REGISTRATION (STEP 0): Hemoglobin \>= 8 g/dL
PRE-REGISTRATION (STEP 0): Creatinine =\< 1.5 x upper limit of normal (ULN) or calculated (calc.) creatinine clearance \> 30 mL/min (using either Cockcroft-Gault formula or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
PRE-REGISTRATION (STEP 0): Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =\< 3 x ULN
PRE-REGISTRATION (STEP 0): Total bilirubin =\< 1.5 x upper limit of normal (ULN) (except in patients with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL)
PRE-REGISTRATION (STEP 0): For women of childbearing potential only: A negative urine or serum pregnancy test done =\< 14 days prior to pre-registration is required
PRE-REGISTRATION (STEP 0): Not currently requiring hemodialysis
PRE-REGISTRATION (STEP 0): No current or prior history of myocarditis
PRE-REGISTRATION (STEP 0): No history of a grade ≥ 3 immune related adverse event with prior PD-1/PD-L1 blockade in the neoadjuvant setting
PRE-REGISTRATION (STEP 0): No active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens- Johnson syndrome, or phospholipid syndrome because of the risk of recurrence or exacerbation of disease.
PRE-REGISTRATION (STEP 0): Patients with vitiligo, endocrine deficiencies including type I diabetes mellitus, thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible.
PRE-REGISTRATION (STEP 0): Patients with rheumatoid arthritis and other arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.
PRE-REGISTRATION (STEP 0): No current pneumonitis or prior history of non-infectious pneumonitis that required steroids within the previous 5 years.
PRE-REGISTRATION (STEP 0): No known active hepatitis B (e.g., hepatitis B surface antigen \[HBsAg\] reactive) or hepatitis C (e.g., hepatitis C virus \[HCV\] ribonucleic acid \[RNA\] \[qualitative\] is detected).
PRE-REGISTRATION (STEP 0): For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
PRE-REGISTRATION (STEP 0): Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible.
PRE-REGISTRATION (STEP 0): No concurrent antineoplastic therapy including anti-hormonal treatments used for cancer therapy (e.g., leuprolide, antiandrogens)
PRE-REGISTRATION (STEP 0): No current immunosuppressive agents (except for corticosteroids as described below).
PRE-REGISTRATION (STEP 0): No condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of pre-registration (with the exception of steroid pre-medications for contrast allergies). Inhaled or topical steroids and adrenal replacement doses \< 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
REGISTRATION (STEP 1): Patient must have had radical cystectomy and lymph node dissection or nephroureterectomy or ureterectomy =\< 18 weeks prior to registration.
REGISTRATION (STEP 1): Must have evaluable ctDNA Signatera assay result (i.e., ctDNA+ or ctDNA-) based on either:
Commercial Signatera result OR
Central Signatera testing result (i.e. testing that was performed as part of A032103.)
REGISTRATION (STEP 1): All patients must have confirmed disease-free status defined as no measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or definitive non-measurable radiographic metastatic disease, within 60 days prior to registration. Patients with equivocal lymph nodes less than 15 mm in short axis, or \< 10 mm in long axis for non-lymph node lesions, not considered by the investigator to represent malignant disease will be eligible. Attempts should be made to resolve the etiology of equivocal lesions with complementary imaging (e.g., PET scan) or biopsy.
REGISTRATION (STEP 1): No major surgery =\< 3 weeks before registration.
REGISTRATION (STEP 1): No live vaccine within 30 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette- Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist \[registered trademark\]) are live attenuated vaccines and are not allowed. Coronavirus disease 2019 (COVID-19) vaccines are not live vaccines and are allowed
REGISTRATION (STEP 1): No change since Step 0 pre-registration in clinical condition and/or laboratory tests that would impact the safety of nivolumab +/- relatlimab administration in the opinion of the treating investigator
REGISTRATION (STEP 1): No evidence of high grade urothelial cancer in the bladder for patients with primary urothelial cancers of the upper urinary tract
RE-REGISTRATION (STEP 2) COHORT B, ARM 4 PATIENTS INITIATING NIVOLUMAB AFTER CONVERSION OF ctDNA ASSAY FROM ctDNA(-) to ctDNA (+):
Patient must have converted to ctDNA(+) during serial monitoring performed centrally as part of A032103
RE-REGISTRATION (STEP 2) COHORT B, ARM 4 PATIENTS INITIATING NIVOLUMAB AFTER CONVERSION OF ctDNA ASSAY FROM ctDNA(-) to ctDNA (+):
No evidence of metastatic disease on the most recent scheduled imaging assessment as outlined in the study calendar (no repeat imaging is necessary specifically at the time of the conversion from ctDNA\[-\] to ctDNA\[+\]).
RE-REGISTRATION (STEP 2) COHORT B, ARM 4 PATIENTS INITIATING NIVOLUMAB AFTER CONVERSION OF ctDNA ASSAY FROM ctDNA(-) to ctDNA (+):
In the opinion of the treating investigator, patient clinical condition and laboratory tests would not impact the safety of nivolumab administration in the opinion of the treating investigator
What this trial measures
- Proportion of patients who are circulating tumor DNA negative (ctDNA[-]) (Cohort A Phase II)At week 12 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(+). 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.
- Overall survival (OS) (Cohort A Phase III)From randomization until death due to any cause, assessed up to 5 years after completion of study treatment
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).
- Disease-Free Survival (DFS) (Cohort B)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
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.