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

Plain English Summary

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 is a Phase 3 clinical trial sponsored by National Cancer Institute (NCI) studying Muscle Invasive Bladder Urothelial Carcinoma, Muscle Invasive Renal Pelvis Urothelial Carcinoma, Muscle Invasive Ureter Urothelial Carcinoma, Muscle Invasive Urethral Urothelial Carcinoma, Stage II Bladder Urothelial Carcinoma AJCC v6 and v7, Stage III Bladder Urothelial Carcinoma AJCC v6 and v7, Stage IV Bladder Urothelial Carcinoma AJCC v7. This trial tests if a blood test can predict which patients need additional immunotherapy after surgery for urothelial cancer. It’s for patients who have had surgery to remove their bladder, kidney, ureter, or urethra for urothelial cancer. Participants will have blood drawn and undergo imaging tests to check for cancer recurrence and receive immunotherapy if needed. Alternatives include standard follow-up care without ctDNA testing. The trial aims to enroll 992 participants.

Official 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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Eligible patients must have had surgery for urothelial cancer and are at risk for recurrence. Patients must be 18 years or older and in good health. Those with other cancers or ongoing treatments are not eligible. Pregnant or nursing women are excluded. This trial is studying Muscle Invasive Bladder Urothelial Carcinoma, Muscle Invasive Renal Pelvis Urothelial Carcinoma, Muscle Invasive Ureter Urothelial Carcinoma, Muscle Invasive Urethral Urothelial Carcinoma, Stage II Bladder Urothelial Carcinoma AJCC v6 and v7, Stage III Bladder Urothelial Carcinoma AJCC v6 and v7, Stage IV Bladder Urothelial Carcinoma AJCC v7, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcome measures survival and disease-free survival, which means patients will know if the treatment helps them live longer and stay cancer-free. The specific primary outcome measures are: Proportion of patients who are circulating tumor DNA negative (ctDNA[-]) (Cohort A Phase II) (At week 12 from treatment start date); 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); 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). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial aims to fill a gap in treatment by using ctDNA to better identify patients who need additional immunotherapy. As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets Muscle Invasive Bladder Urothelial Carcinoma, Muscle Invasive Renal Pelvis Urothelial Carcinoma, Muscle Invasive Ureter Urothelial Carcinoma, Muscle Invasive Urethral Urothelial Carcinoma, Stage II Bladder Urothelial Carcinoma AJCC v6 and v7, Stage III Bladder Urothelial Carcinoma AJCC v6 and v7, Stage IV Bladder Urothelial Carcinoma AJCC v7, where improved treatment options are needed.

Investor Insight

The large market size and competitive landscape suggest a high approval probability for this innovative approach. Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage. The large enrollment target of 992 participants suggests significant investment in this program.

Is This Trial Right for Me?

Ask your doctor if you are a good candidate for this trial. Undergo blood draws and imaging tests as part of the study. This trial is currently recruiting participants. The trial is being conducted at 20 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 992 participants

Interventions

• 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

Primary Outcomes

• Proportion of patients who are circulating tumor DNA negative (ctDNA[-]) (Cohort A Phase II) (At week 12 from treatment start date)
• 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)
• 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)

Secondary Outcomes

• Proportion of patients who are ctDNA(-) (Cohort A Phase III) from treatment start date (At week 12)
• OS (Cohort A Phase II) (From randomization until death due to any cause, assessed up to 5 years after completion of study treatment)
• DFS (Cohort A Phase II or III) (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)
• Incidence of adverse events (Cohort A) (Up to 5 years after completion of study treatment)
• OS (Cohort B) (From randomization until death due to any cause, assessed up to 5 years after completion of study treatment)

Full Eligibility Criteria

Inclusion Criteria:

* 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 sy

Trial Locations

• Cancer Center at Saint Joseph's, Phoenix, Arizona, United States
• Mayo Clinic Hospital in Arizona, Phoenix, Arizona, United States
• University of Arizona Cancer Center-Orange Grove Campus, Tucson, Arizona, United States
• Banner University Medical Center - Tucson, Tucson, Arizona, United States
• University of Arizona Cancer Center-North Campus, Tucson, Arizona, United States
• Highlands Oncology Group - Fayetteville, Fayetteville, Arkansas, United States
• Highlands Oncology Group - Rogers, Rogers, Arkansas, United States
• Highlands Oncology Group, Springdale, Arkansas, United States
• Kaiser Permanente-Anaheim, Anaheim, California, United States
• Kaiser Permanente-Baldwin Park, Baldwin Park, California, United States
• ...and 10 more locations

Frequently Asked Questions

Related Conditions

• Bladder cancer, kidney cancer, ureter cancer, urethral cancer, and other urothelial cancers.

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