xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT05987241</url>
    </required_header>
    <id_info>
      <org_study_id>NCI-2023-05980</org_study_id>
      <secondary_id>NCI-2023-05980</secondary_id>
      <secondary_id>A032103</secondary_id>
      <secondary_id>A032103</secondary_id>
      <secondary_id>U10CA180821</secondary_id>
      <nct_id>NCT05987241</nct_id>
    </id_info>
    <brief_title>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</brief_title>
    <official_title>MODERN: An Integrated Phase 2/3 and Phase 3 Trial of MRD-Based Optimization of ADjuvant ThErapy in URothelial CaNcer</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>National Cancer Institute (NCI)</agency>
        <agency_class>NIH</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>National Cancer Institute (NCI)</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        This phase II/III trial tests the role of DNA released from tumor cells into the blood in&#xD;
        guiding the use of immunotherapy (nivolumab alone or with relatlimab) after surgical removal&#xD;
        of the bladder for bladder cancer treatment. DNA is material found inside all of our cells&#xD;
        that acts as a blueprint for how cells function. Tumor cells often have abnormal DNA that&#xD;
        looks different than DNA in normal cells. A new test called Signatera has been developed that&#xD;
        can detect bladder cancer DNA in the blood which might indicate the presence of bladder tumor&#xD;
        cells somewhere in the body. Immunotherapy with monoclonal antibodies, such as nivolumab, may&#xD;
        help the body's immune system attack the cancer, and may interfere with the ability of tumor&#xD;
        cells to grow and spread. Relatlimab is a monoclonal antibody that may interfere with the&#xD;
        ability of tumor cells to grow and spread. This trial may help doctors determine if the&#xD;
        Signatera test can better identify which patients need an additional treatment with&#xD;
        immunotherapy to help prevent bladder cancer from coming back after surgery.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        PRIMARY OBJECTIVES:&#xD;
  &#xD;
        I. To compare the ctDNA clearance proportion (i.e., ctDNA positive [+] --&gt; ctDNA negative&#xD;
        [-]) at 12 weeks in patients enrolled in Cohort A treated with adjuvant nivolumab versus&#xD;
        nivolumab + relatlimab (phase 2 portion).&#xD;
  &#xD;
        II. To compare overall survival in patients enrolled in Cohort A treated with adjuvant&#xD;
        nivolumab versus nivolumab + relatlimab (phase 3 portion).&#xD;
  &#xD;
        III. To compare disease-free survival in patients enrolled in Cohort B randomized to&#xD;
        immediate treatment with nivolumab to those randomized to surveillance with subsequent&#xD;
        treatment with nivolumab only upon converting to ctDNA(+)&#xD;
  &#xD;
        SECONDARY OBJECTIVES:&#xD;
  &#xD;
        I. To compare disease-free survival in patients enrolled in Cohort A treated with adjuvant&#xD;
        nivolumab versus nivolumab + relatlimab.&#xD;
  &#xD;
        II. To define the association between ctDNA clearance and disease-free survival and overall&#xD;
        survival for Cohort A patients.&#xD;
  &#xD;
        III. To compare overall survival in patients enrolled in Cohort B randomized to immediate&#xD;
        treatment with nivolumab to those randomized to surveillance with subsequent treatment with&#xD;
        nivolumab only upon converting to ctDNA(+).&#xD;
  &#xD;
        IV. To determine the lead time from a ctDNA(+) assay to radiographic recurrence in patients&#xD;
        initially ctDNA(-) post-definitive surgery enrolled in Cohort B.&#xD;
  &#xD;
        V. To estimate the proportion of Cohort B patients on Arm 4 who become ctDNA(+) and receive&#xD;
        nivolumab.&#xD;
  &#xD;
        VI. To compare the cumulative incidence of Cohort B patients who become ctDNA(+) between Arms&#xD;
        3 and 4.&#xD;
  &#xD;
        VII. To determine the safety of adjuvant nivolumab plus relatlimab.&#xD;
  &#xD;
        EXPLORATORY OBJECTIVES:&#xD;
  &#xD;
        I. To explore the kinetics of quantitative ctDNA levels (mean number of tumor molecules&#xD;
        observed per mL of plasma or MTM/ml) over time and the association between ctDNA kinetics and&#xD;
        time-to-event outcomes.&#xD;
  &#xD;
        II. To estimate the costs and value of care in patients with a ctDNA(+) assay post-cystectomy&#xD;
        treated with adjuvant nivolumab versus nivolumab + relatlimab.&#xD;
  &#xD;
        III. To estimate the costs and value of care in patients with a ctDNA(-) assay&#xD;
        post-cystectomy treated with adjuvant nivolumab versus surveillance with subsequent treatment&#xD;
        with nivolumab at the time of conversion to ctDNA(+).&#xD;
  &#xD;
        QUALITY OF LIFE OBJECTIVES:&#xD;
  &#xD;
        I. Within each cohort, to compare quality-adjusted survival among randomized arms using&#xD;
        European Quality of Life Five Dimension Five Level Scale (EQ-5D-5L).&#xD;
  &#xD;
        II. Within Cohort B, to compare overall quality of life (QOL) as measured by the European&#xD;
        Organization for the Research and Treatment of Cancer (EORTC) Quality of Life&#xD;
        Questionnaire-Core 30 (QLQ-C30) between baseline and 42 months (calculated as the area under&#xD;
        the curve) among randomized arms.&#xD;
  &#xD;
        III. Within each cohort, to compare overall QOL as measured by the EORTC QLQ-C30 at each time&#xD;
        point among randomized arms.&#xD;
  &#xD;
        IV. Within each cohort, to compare bladder cancer-specific QOL as measured by the EORTC&#xD;
        Bladder Cancer Muscle-Invasive 30 Questionnaire (QLQ-BLM30) at each time point among&#xD;
        randomized arms.&#xD;
  &#xD;
        V. Within each cohort, to compare patient-reported fatigue as measured by Patient Reported&#xD;
        Outcomes Measurement Information System (PROMIS)-Fatigue at each time point among randomized&#xD;
        arms.&#xD;
  &#xD;
        OUTLINE: Patients are assigned to 1 of 2 cohorts based on ctDNA results.&#xD;
  &#xD;
        COHORT A: Patients who are ctDNA(+) are randomized to 1 of 2 arms:&#xD;
  &#xD;
        ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1 of each cycle.&#xD;
        Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or&#xD;
        unacceptable toxicity. Patients also undergo collection of tissue during screening and&#xD;
        collection of blood throughout the trial. Patients also undergo computed tomography (CT) or&#xD;
        magnetic resonance imaging (MRI) scans throughout the trial.&#xD;
  &#xD;
        ARM II: Patients receive nivolumab IV over 30 minutes and relatlimab IV over 30 minutes on&#xD;
        day 1 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of&#xD;
        disease progression or unacceptable toxicity. Patients also undergo collection of tissue&#xD;
        during screening and collection of blood throughout the trial. Patients also undergo CT or&#xD;
        MRI scans throughout the trial.&#xD;
  &#xD;
        COHORT B: Patients who are ctDNA(-) are randomized to 1 of 2 arms:&#xD;
  &#xD;
        ARM III: Patients receive nivolumab IV over 30 minutes on day 1 of each cycle. Treatment&#xD;
        repeats every 28 days for up to 12 cycles in the absence of disease progression or&#xD;
        unacceptable toxicity. Patients also undergo collection of tissue during screening and&#xD;
        collection of blood throughout the trial. Patients also undergo CT or MRI scans throughout&#xD;
        the trial.&#xD;
  &#xD;
        ARM IV: Patients undergo ctDNA surveillance consisting of collection of tissue and blood&#xD;
        during screening and collection of blood only on study and during follow up. Patients who&#xD;
        convert to ctDNA(+) during surveillance then receive nivolumab IV over 30 minutes and&#xD;
        relatlimab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 28 days for up&#xD;
        to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also&#xD;
        undergo CT or MRI scans throughout the trial.&#xD;
  &#xD;
        After completion of study treatment, patients are followed up at weeks 60, 72, 84, 96, 120,&#xD;
        144, 196, and 248.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">January 9, 2024</start_date>
    <completion_date type="Anticipated">April 11, 2026</completion_date>
    <primary_completion_date type="Anticipated">April 11, 2026</primary_completion_date>
    <phase>Phase 2/Phase 3</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Proportion of patients who are circulating tumor DNA negative (ctDNA[-]) (Cohort A Phase II)</measure>
      <time_frame>At week 12</time_frame>
      <description>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.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Overall survival (OS) (Cohort A Phase III)</measure>
      <time_frame>From randomization until death due to any cause, assessed up to 5 years after completion of study treatment</time_frame>
      <description>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).</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Disease-Free Survival (DFS) (Cohort B)</measure>
      <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</time_frame>
      <description>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% confidence interval (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.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Proportion of patients who are ctDNA(-) (Cohort A Phase III)</measure>
      <time_frame>At week 12</time_frame>
      <description>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(+).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>OS (Cohort A Phase II)</measure>
      <time_frame>From randomization until death due to any cause, assessed up to 5 years after completion of study treatment</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>DFS (Cohort A)</measure>
      <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</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence of adverse events (Cohort A)</measure>
      <time_frame>Up to 5 years after completion of study treatment</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>OS (Cohort B)</measure>
      <time_frame>From randomization until death due to any cause, assessed up to 5 years after completion of study treatment</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Cumulative incidence of ctDNA(+) conversion (Cohort B)</measure>
      <time_frame>From randomization until a patient becomes ctDNA(+), assessed up to 5 years after completion of study treatment</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Lead time for ctDNA(+) conversion (Cohort B)</measure>
      <time_frame>From when a patient becomes ctDNA(+) until a confirmed radiographic disease recurrence, assessed up to 5 years after completion of study treatment</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence of adverse events (Cohort B)</measure>
      <time_frame>Up to 5 years after completion of study treatment</time_frame>
      <description>Will be assessed using CTCAE v5.0. Adverse events 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.</description>
    </secondary_outcome>
    <number_of_arms>4</number_of_arms>
    <enrollment type="Anticipated">1190</enrollment>
    <condition>Muscle Invasive Bladder Urothelial Carcinoma</condition>
    <condition>Stage II Bladder Urothelial Carcinoma AJCC v6 and v7</condition>
    <condition>Stage III Bladder Urothelial Carcinoma AJCC v6 and v7</condition>
    <condition>Stage IV Bladder Urothelial Carcinoma AJCC v7</condition>
    <arm_group>
      <arm_group_label>Cohort A, Arm I (nivolumab)</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Patients in Cohort A, Arm I 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.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Cohort A, Arm II (nivolumab, relatlimab)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Patients in Cohort A, Arm II 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.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Cohort B, Arm III (nivolumab)</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Patients in Cohort B, Arm III 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.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Cohort B, Arm IV (ctDNA surveillance, nivolumab)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Patients in Cohort B, Arm IV 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.</description>
    </arm_group>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Biospecimen Collection</intervention_name>
      <description>Undergo collection of tissue and blood</description>
      <arm_group_label>Cohort A, Arm I (nivolumab)</arm_group_label>
      <arm_group_label>Cohort A, Arm II (nivolumab, relatlimab)</arm_group_label>
      <arm_group_label>Cohort B, Arm III (nivolumab)</arm_group_label>
      <arm_group_label>Cohort B, Arm IV (ctDNA surveillance, nivolumab)</arm_group_label>
      <other_name>Biological Sample Collection</other_name>
      <other_name>Biospecimen Collected</other_name>
      <other_name>Specimen Collection</other_name>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>cfDNA or ctDNA Measurement</intervention_name>
      <description>Undergo ctDNA surveillance</description>
      <arm_group_label>Cohort B, Arm IV (ctDNA surveillance, nivolumab)</arm_group_label>
      <other_name>Cell-Free DNA/Circulating Tumor DNA Measurement</other_name>
      <other_name>cfDNA/ctdDNA Measurement</other_name>
      <other_name>cfDNA/ctDNA</other_name>
      <other_name>cfDNA/ctDNA Measurement</other_name>
      <other_name>Circulating Cell-Free DNA/Circulating Tumor-Derived DNA Measurement</other_name>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Computed Tomography</intervention_name>
      <description>Undergo CT</description>
      <arm_group_label>Cohort A, Arm I (nivolumab)</arm_group_label>
      <arm_group_label>Cohort A, Arm II (nivolumab, relatlimab)</arm_group_label>
      <arm_group_label>Cohort B, Arm III (nivolumab)</arm_group_label>
      <arm_group_label>Cohort B, Arm IV (ctDNA surveillance, nivolumab)</arm_group_label>
      <other_name>CAT</other_name>
      <other_name>CAT Scan</other_name>
      <other_name>Computed Axial Tomography</other_name>
      <other_name>Computerized Axial Tomography</other_name>
      <other_name>Computerized axial tomography (procedure)</other_name>
      <other_name>Computerized Tomography</other_name>
      <other_name>CT</other_name>
      <other_name>CT Scan</other_name>
      <other_name>tomography</other_name>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Magnetic Resonance Imaging</intervention_name>
      <description>Undergo MRI</description>
      <arm_group_label>Cohort A, Arm I (nivolumab)</arm_group_label>
      <arm_group_label>Cohort A, Arm II (nivolumab, relatlimab)</arm_group_label>
      <arm_group_label>Cohort B, Arm III (nivolumab)</arm_group_label>
      <arm_group_label>Cohort B, Arm IV (ctDNA surveillance, nivolumab)</arm_group_label>
      <other_name>Magnetic Resonance</other_name>
      <other_name>Magnetic resonance imaging (procedure)</other_name>
      <other_name>Magnetic Resonance Imaging Scan</other_name>
      <other_name>Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance</other_name>
      <other_name>MR</other_name>
      <other_name>MR Imaging</other_name>
      <other_name>MRI</other_name>
      <other_name>MRI Scan</other_name>
      <other_name>NMR Imaging</other_name>
      <other_name>NMRI</other_name>
      <other_name>Nuclear Magnetic Resonance Imaging</other_name>
    </intervention>
    <intervention>
      <intervention_type>Biological</intervention_type>
      <intervention_name>Nivolumab</intervention_name>
      <description>Given IV</description>
      <arm_group_label>Cohort A, Arm I (nivolumab)</arm_group_label>
      <arm_group_label>Cohort A, Arm II (nivolumab, relatlimab)</arm_group_label>
      <arm_group_label>Cohort B, Arm III (nivolumab)</arm_group_label>
      <arm_group_label>Cohort B, Arm IV (ctDNA surveillance, nivolumab)</arm_group_label>
      <other_name>ABP 206</other_name>
      <other_name>BMS-936558</other_name>
      <other_name>CMAB819</other_name>
      <other_name>MDX-1106</other_name>
      <other_name>NIVO</other_name>
      <other_name>Nivolumab Biosimilar ABP 206</other_name>
      <other_name>Nivolumab Biosimilar CMAB819</other_name>
      <other_name>ONO-4538</other_name>
      <other_name>Opdivo</other_name>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Quality-of-Life Assessment</intervention_name>
      <description>Ancillary studies</description>
      <arm_group_label>Cohort A, Arm I (nivolumab)</arm_group_label>
      <arm_group_label>Cohort A, Arm II (nivolumab, relatlimab)</arm_group_label>
      <arm_group_label>Cohort B, Arm III (nivolumab)</arm_group_label>
      <arm_group_label>Cohort B, Arm IV (ctDNA surveillance, nivolumab)</arm_group_label>
      <other_name>Quality of Life Assessment</other_name>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Questionnaire Administration</intervention_name>
      <description>Ancillary studies</description>
      <arm_group_label>Cohort A, Arm I (nivolumab)</arm_group_label>
      <arm_group_label>Cohort A, Arm II (nivolumab, relatlimab)</arm_group_label>
      <arm_group_label>Cohort B, Arm III (nivolumab)</arm_group_label>
      <arm_group_label>Cohort B, Arm IV (ctDNA surveillance, nivolumab)</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Biological</intervention_type>
      <intervention_name>Relatlimab</intervention_name>
      <description>Given IV</description>
      <arm_group_label>Cohort A, Arm II (nivolumab, relatlimab)</arm_group_label>
      <other_name>BMS-986016</other_name>
      <other_name>BMS986016</other_name>
      <other_name>Immunoglobulin G4, Anti-(human Lymphocyte Activation Gene-3 Protein) (Human Heavy Chain), Disulfide with Human Light Chain, Dimer</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  PRE-REGISTRATION: Histologically confirmed muscle-invasive urothelial carcinoma of the&#xD;
               bladder. Variant histology, including neuroendocrine differentiation, is allowed if&#xD;
               urothelial cancer is predominant histology (any amount of squamous differentiation is&#xD;
               allowed provided the tumor is not a pure squamous cell cancer)&#xD;
  &#xD;
            -  PRE-REGISTRATION: Patient must have had radical cystectomy and lymph node dissection&#xD;
               &gt;= 3 weeks, but =&lt; 12 weeks prior to pre-registration. Patients who have had a partial&#xD;
               cystectomy as definitive therapy are not eligible&#xD;
  &#xD;
            -  PRE-REGISTRATION: No gross cancer at the surgical margins. Microscopic invasive&#xD;
               urothelial carcinoma at the surgical margins (i.e., &quot;positive margins&quot;) are allowed.&#xD;
               Carcinoma in situ (CIS) at margins is considered negative margins&#xD;
  &#xD;
            -  PRE-REGISTRATION: No evidence of residual cancer or metastasis after cystectomy&#xD;
               (imaging is not required prior to pre-registration but is required prior to&#xD;
               registration)&#xD;
  &#xD;
            -  PRE-REGISTRATION: Have undergone a radical cystectomy with pathological evidence of&#xD;
               urothelial carcinoma of the bladder at high risk of recurrence as described in one of&#xD;
               the two scenarios below (i or ii). The 7th edition of American Joint Committee on&#xD;
               Cancer (AJCC) staging will be utilized.:&#xD;
  &#xD;
                 -  (i) Patients who have not received neoadjuvant cisplatin-based chemotherapy:&#xD;
                    pT3-pT4* or pT0/x-pT4/N+ on cystectomy and are not eligible for adjuvant&#xD;
                    cisplatin chemotherapy&#xD;
  &#xD;
                      -  (i) Patients ineligible for cisplatin due to at least one of the following&#xD;
                         criteria and reason for ineligibility should be documented:&#xD;
  &#xD;
                           -  (i) Creatinine Clearance (using Cockcroft-Gault): &lt; 60 mL/min&#xD;
  &#xD;
                           -  (i) Common Terminology Criteria for Adverse Events (CTCAE) version 5,&#xD;
                              grade &gt;= 2 audiometric hearing loss&#xD;
  &#xD;
                           -  (i) CTCAE version 5, grade &gt;= 2 or above peripheral neuropathy&#xD;
  &#xD;
                           -  New York Heart Association Class III heart failure&#xD;
  &#xD;
                           -  (i) Eastern Cooperative Oncology Group (ECOG) performance status = 2&#xD;
  &#xD;
                      -  (i) Patients who are eligible for cisplatin may be candidates if they refuse&#xD;
                         available adjuvant chemotherapy, despite being informed by the investigator&#xD;
                         about the treatment options. The patient's refusal must be documented.&#xD;
  &#xD;
                           -  (i) Patients with pT2N0 urothelial cancer on cystectomy (without prior&#xD;
                              neoadjuvant chemotherapy) with ctDNA(+) Signatera results based on an&#xD;
                              assay performed post-cystectomy as part of routine care outside of the&#xD;
                              study may proceed with pre-registration but require confirmation of&#xD;
                              ctDNA(+) Signatera testing on repeat &quot;central testing&quot; in the context&#xD;
                              of A032103 testing. Patients with pT2N0 with central testing not&#xD;
                              confirming ctDNA(+) will not be eligible for A032103 (Note: this is&#xD;
                              distinct from patients with ypT2N0 who are eligible based on ii).&#xD;
  &#xD;
                 -  (ii) Patients who received cisplatin-based neoadjuvant chemotherapy: ypT2-ypT4 or&#xD;
                    ypT0/x-pT4/N+ on cystectomy&#xD;
  &#xD;
            -  PRE-REGISTRATION: Available tumor tissue for central Signatera testing to be submitted&#xD;
               after pre-registration. Central testing is defined as testing performed as part of the&#xD;
               A032103 study prior to registration and is provided by the study and not routine&#xD;
               standard commercial testing. Patients who have already had Signatera testing performed&#xD;
               as part of routine care will require repeat central testing as part of the A032103&#xD;
               study to be eligible for registration/randomization. Tumor tissue from the cystectomy&#xD;
               is preferred over tissue from prior transurethral resection&#xD;
  &#xD;
            -  PRE-REGISTRATION: Age &gt;= 18 years&#xD;
  &#xD;
            -  PRE-REGISTRATION: ECOG Performance Status 0-2&#xD;
  &#xD;
            -  PRE-REGISTRATION: Not pregnant and not nursing, because this study involves an agent&#xD;
               that has known genotoxic, mutagenic and teratogenic effects&#xD;
  &#xD;
            -  PRE-REGISTRATION: No postoperative/adjuvant systemic therapy after cystectomy&#xD;
  &#xD;
            -  PRE-REGISTRATION: No adjuvant radiation after cystectomy&#xD;
  &#xD;
            -  PRE-REGISTRATION: No treatment with any other type of investigational agent =&lt; 4 weeks&#xD;
               before pre-registration&#xD;
  &#xD;
            -  PRE-REGISTRATION: Not have ever received prior treatment with PD-1/PD-L1 blockade.&#xD;
  &#xD;
            -  PRE-REGISTRATION: Not have ever received prior treatment with LAG-3 blockade.&#xD;
  &#xD;
            -  PRE-REGISTRATION: Patients with a prior or concurrent malignancy whose natural history&#xD;
               or treatment does not have the potential to interfere with the safety or efficacy&#xD;
               assessment of the investigational regimen are eligible for this trial&#xD;
  &#xD;
            -  PRE-REGISTRATION: Absolute Neutrophil Count (ANC) &gt;= 1,200/mm^3&#xD;
  &#xD;
            -  PRE-REGISTRATION: Platelet count &gt;= 100,000/mm^3&#xD;
  &#xD;
            -  PRE-REGISTRATION: Hemoglobin &gt;= 8 g/dL&#xD;
  &#xD;
            -  PRE-REGISTRATION: Creatinine =&lt; 1.5 x upper limit of normal (ULN) or calculated&#xD;
               (calc.) creatinine clearance &gt; 30 mL/min (using either Cockcroft-Gault formula or&#xD;
               Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation&#xD;
  &#xD;
            -  PRE-REGISTRATION: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =&lt; 3&#xD;
               x ULN&#xD;
  &#xD;
            -  PRE-REGISTRATION: Total bilirubin =&lt; 1.5 x upper limit of normal (ULN) (except in&#xD;
               patients with Gilbert Syndrome, who can have total bilirubin &lt; 3.0 mg/dL)&#xD;
  &#xD;
            -  PRE-REGISTRATION: For women of childbearing potential only: A negative urine or serum&#xD;
               pregnancy test done =&lt; 14 days prior to pre-registration is required&#xD;
  &#xD;
            -  PRE-REGISTRATION: Not currently requiring hemodialysis&#xD;
  &#xD;
            -  PRE-REGISTRATION: No current or prior history of myocarditis&#xD;
  &#xD;
            -  PRE-REGISTRATION: No active autoimmune disease or history of autoimmune disease that&#xD;
               might recur, which may affect vital organ function or require immune suppressive&#xD;
               treatment including systemic corticosteroids. These include but are not limited to&#xD;
               patients with a history of immune related neurologic disease, multiple sclerosis,&#xD;
               autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis;&#xD;
               systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective&#xD;
               tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative&#xD;
               colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN),&#xD;
               Stevens- Johnson syndrome, or phospholipid syndrome because of the risk of recurrence&#xD;
               or exacerbation of disease.&#xD;
  &#xD;
            -  PRE-REGISTRATION: Patients with vitiligo, endocrine deficiencies including type I&#xD;
               diabetes mellitus, thyroiditis managed with replacement hormones including physiologic&#xD;
               corticosteroids are eligible.&#xD;
  &#xD;
            -  PRE-REGISTRATION: Patients with rheumatoid arthritis and other arthropathies,&#xD;
               Sjögren's syndrome and psoriasis controlled with topical medication and patients with&#xD;
               positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies&#xD;
               should be evaluated for the presence of target organ involvement and potential need&#xD;
               for systemic treatment but should otherwise be eligible.&#xD;
  &#xD;
            -  PRE-REGISTRATION: No current pneumonitis or prior history of non-infectious&#xD;
               pneumonitis that required steroids within the previous 5 years.&#xD;
  &#xD;
            -  PRE-REGISTRATION: No known active hepatitis B (e.g., hepatitis B surface antigen&#xD;
               [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA]&#xD;
               [qualitative] is detected).&#xD;
  &#xD;
            -  PRE-REGISTRATION: For patients with evidence of chronic hepatitis B virus (HBV)&#xD;
               infection, the HBV viral load must be undetectable on suppressive therapy, if&#xD;
               indicated. Patients with a history of hepatitis C virus (HCV) infection must have been&#xD;
               treated and cured. For patients with HCV infection who are currently on treatment,&#xD;
               they are eligible if they have an undetectable HCV viral load.&#xD;
  &#xD;
            -  PRE-REGISTRATION: Human immunodeficiency virus (HIV)-infected patients on effective&#xD;
               anti-retroviral therapy with undetectable viral load within 6 months are eligible.&#xD;
  &#xD;
            -  PRE-REGISTRATION: No concurrent antineoplastic therapy.&#xD;
  &#xD;
            -  PRE-REGISTRATION: No current immunosuppressive agents (with the exception of&#xD;
               corticosteroids as described below).&#xD;
  &#xD;
            -  PRE-REGISTRATION: No condition requiring systemic treatment with either&#xD;
               corticosteroids (&gt; 10 mg daily prednisone equivalents) or other immunosuppressive&#xD;
               medications within 14 days of pre-registration (with the exception of steroid&#xD;
               pre-medications for contrast allergies). Inhaled or topical steroids and adrenal&#xD;
               replacement doses &lt; 10 mg daily prednisone equivalents are permitted in the absence of&#xD;
               active autoimmune disease.&#xD;
  &#xD;
            -  REGISTRATION: Patient must have had radical cystectomy and lymph node dissection =&lt; 18&#xD;
               weeks prior to registration.&#xD;
  &#xD;
            -  REGISTRATION: Must have evaluable ctDNA Signatera assay result (i.e., ctDNA[+]or&#xD;
               ctDNA[-]) based on test performed as part of central testing after pre-registration to&#xD;
               A032103. Central testing is defined as testing performed as part of the A032103.&#xD;
               Local/commercial testing results may not be used for registration to A032103&#xD;
  &#xD;
                 -  Cisplatin-ineligible (or cisplatin-declining) patients with a pT2N0 urothelial&#xD;
                    cancer on cystectomy who were pre-registered based on routine standard care&#xD;
                    ctDNA(+) Signatera testing must have confirmed ctDNA(+) Signatera testing on&#xD;
                    central testing. If central Signatera testing yields a ctDNA(-) result, these&#xD;
                    patients are ineligible. NOTE: This is a distinct consideration from patients&#xD;
                    with ypT2-4 and/or ypN+ urothelial cancer (i.e., patients who had received&#xD;
                    neoadjuvant cisplatin-based chemotherapy) who are eligible with either ctDNA(+)&#xD;
                    or ctDNA(-) central Signatera testing&#xD;
  &#xD;
            -  REGISTRATION: All patients must have confirmed disease-free status defined as no&#xD;
               measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or&#xD;
               definitive non-measurable radiographic metastatic disease, within 60 days prior to&#xD;
               registration. Patients with equivocal nodes less than 15 mm in short axis, or &lt; 10 mm&#xD;
               in long axis for non-lymph node lesions, not considered by the investigator to&#xD;
               represent malignant disease will be eligible. Attempts should be made to resolve the&#xD;
               etiology of equivocal lesions with complementary imaging (e.g., PET scan) or biopsy.&#xD;
  &#xD;
            -  REGISTRATION: No major surgery =&lt; 3 weeks before registration.&#xD;
  &#xD;
            -  REGISTRATION: No live vaccine within 30 days prior to registration. Examples of live&#xD;
               vaccines include, but are not limited to, the following: measles, mumps, rubella,&#xD;
               varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette- Guerin (BCG),&#xD;
               and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed&#xD;
               virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist&#xD;
               [registered trademark]) are live attenuated vaccines and are not allowed. Coronavirus&#xD;
               disease 2019 (COVID-19) vaccines are not live vaccines and are allowed&#xD;
  &#xD;
            -  COHORT B, ARM 4 PATIENTS INITIATING NIVOLUMAB AFTER CONVERSION OF ctDNA ASSAY FROM&#xD;
               ctDNA(-) to ctDNA (+):&#xD;
  &#xD;
                 -  Patient must have converted to ctDNA(+) during serial monitoring performed&#xD;
                    centrally in the setting of the A032103 study&#xD;
  &#xD;
            -  COHORT B, ARM 4 PATIENTS INITIATING NIVOLUMAB AFTER CONVERSION OF ctDNA ASSAY FROM&#xD;
               ctDNA(-) to ctDNA (+):&#xD;
  &#xD;
                 -  No evidence of metastatic disease on the most recent scheduled imaging assessment&#xD;
                    as outlined in the study calendar (no repeat imaging is necessary specifically at&#xD;
                    the time of the conversion from ctDNA[-] to ctDNA[+]).&#xD;
  &#xD;
            -  COHORT B, ARM 4 PATIENTS INITIATING NIVOLUMAB AFTER CONVERSION OF ctDNA ASSAY FROM&#xD;
               ctDNA(-) to ctDNA (+):&#xD;
  &#xD;
                 -  No change in clinical condition and/or laboratory tests that would impact the&#xD;
                    safety of nivolumab in the opinion of the treating investigator&#xD;
  &#xD;
            -  COHORT B, ARM 4 PATIENTS INITIATING NIVOLUMAB AFTER CONVERSION OF ctDNA ASSAY FROM&#xD;
               ctDNA(-) to ctDNA (+):&#xD;
  &#xD;
                 -  =&lt; 6 weeks from reporting of ctDNA(+) result by Natera.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Matthew D Galsky</last_name>
      <role>Principal Investigator</role>
      <affiliation>Alliance for Clinical Trials in Oncology</affiliation>
    </overall_official>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 10, 2023</study_first_submitted>
    <study_first_submitted_qc>August 10, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 14, 2023</study_first_posted>
    <last_update_submitted>September 12, 2023</last_update_submitted>
    <last_update_submitted_qc>September 12, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 13, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Carcinoma</mesh_term>
      <mesh_term>Carcinoma, Transitional Cell</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Nivolumab</mesh_term>
      <mesh_term>Relatlimab</mesh_term>
      <mesh_term>Immunoglobulins</mesh_term>
      <mesh_term>Immunoglobulin G</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_description>NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.</ipd_description>
      <ipd_url>https://grants.nih.gov/policy/sharing.htm</ipd_url>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT05987241
  org study id: NCI-2023-05980
  secondary id: NCI-2023-05980
  secondary id: A032103
  secondary id: A032103
  secondary id: U10CA180821
  nct id: NCT05987241
  lead sponsor: 
  has dmc: No
  is fda regulated drug: Yes
  is fda regulated device: No
  This phase II/III trial tests the role of DNA released from tumor cells into the blood in
        guiding the use of immunotherapy (nivolumab alone or with relatlimab) after surgical removal
        of the bladder for bladder cancer treatment. DNA is material found inside all of our cells
        that acts as a blueprint for how cells function. Tumor cells often have abnormal DNA that
        looks different than DNA in normal cells. A new test called Signatera has been developed that
        can detect bladder cancer DNA in the blood which might indicate the presence of bladder tumor
        cells somewhere in the body. Immunotherapy with monoclonal antibodies, such as nivolumab, may
        help the body's immune system attack the cancer, and may interfere with the ability of tumor
        cells to grow and spread. Relatlimab is a monoclonal antibody that may interfere with the
        ability of tumor cells to grow and spread. This trial may help doctors determine if the
        Signatera test can better identify which patients need an additional treatment with
        immunotherapy to help prevent bladder cancer from coming back after surgery.
  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.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Proportion of patients who are circulating tumor DNA negative (ctDNA[-]) (Cohort A Phase II)
  time frame: At week 12
  description: 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.
  measure: Overall survival (OS) (Cohort A Phase III)
  time frame: From randomization until death due to any cause, assessed up to 5 years after completion of study treatment
  description: 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).
  measure: Disease-Free Survival (DFS) (Cohort B)
  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
  description: 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% confidence interval (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.
  measure: Proportion of patients who are ctDNA(-) (Cohort A Phase III)
  time frame: At week 12
  description: 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(+).
  measure: OS (Cohort A Phase II)
  time frame: From randomization until death due to any cause, assessed up to 5 years after completion of study treatment
  measure: DFS (Cohort A)
  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
  measure: Incidence of adverse events (Cohort A)
  time frame: Up to 5 years after completion of study treatment
  description: 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.
  measure: OS (Cohort B)
  time frame: From randomization until death due to any cause, assessed up to 5 years after completion of study treatment
  measure: Cumulative incidence of ctDNA(+) conversion (Cohort B)
  time frame: From randomization until a patient becomes ctDNA(+), assessed up to 5 years after completion of study treatment
  measure: Lead time for ctDNA(+) conversion (Cohort B)
  time frame: From when a patient becomes ctDNA(+) until a confirmed radiographic disease recurrence, assessed up to 5 years after completion of study treatment
  measure: Incidence of adverse events (Cohort B)
  time frame: Up to 5 years after completion of study treatment
  description: Will be assessed using CTCAE v5.0. Adverse events 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.
  arm group label: Cohort A, Arm I (nivolumab)
  arm group type: Active Comparator
  description: Patients in Cohort A, Arm I 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 group label: Cohort A, Arm II (nivolumab, relatlimab)
  arm group type: Experimental
  description: Patients in Cohort A, Arm II 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.
  arm group label: Cohort B, Arm III (nivolumab)
  arm group type: Active Comparator
  description: Patients in Cohort B, Arm III 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 group label: Cohort B, Arm IV (ctDNA surveillance, nivolumab)
  arm group type: Experimental
  description: Patients in Cohort B, Arm IV 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.
  intervention type: Procedure
  intervention name: Biospecimen Collection
  description: Undergo collection of tissue and blood
  arm group label: Cohort A, Arm I (nivolumab)
  arm group label: Cohort A, Arm II (nivolumab, relatlimab)
  arm group label: Cohort B, Arm III (nivolumab)
  arm group label: Cohort B, Arm IV (ctDNA surveillance, nivolumab)
  other name: Biological Sample Collection
  other name: Biospecimen Collected
  other name: Specimen Collection
  intervention type: Other
  intervention name: cfDNA or ctDNA Measurement
  description: Undergo ctDNA surveillance
  arm group label: Cohort B, Arm IV (ctDNA surveillance, nivolumab)
  other name: Cell-Free DNA/Circulating Tumor DNA Measurement
  other name: cfDNA/ctdDNA Measurement
  other name: cfDNA/ctDNA
  other name: cfDNA/ctDNA Measurement
  other name: Circulating Cell-Free DNA/Circulating Tumor-Derived DNA Measurement
  intervention type: Procedure
  intervention name: Computed Tomography
  description: Undergo CT
  arm group label: Cohort A, Arm I (nivolumab)
  arm group label: Cohort A, Arm II (nivolumab, relatlimab)
  arm group label: Cohort B, Arm III (nivolumab)
  arm group label: Cohort B, Arm IV (ctDNA surveillance, nivolumab)
  other name: CAT
  other name: CAT Scan
  other name: Computed Axial Tomography
  other name: Computerized Axial Tomography
  other name: Computerized axial tomography (procedure)
  other name: Computerized Tomography
  other name: CT
  other name: CT Scan
  other name: tomography
  intervention type: Procedure
  intervention name: Magnetic Resonance Imaging
  description: Undergo MRI
  arm group label: Cohort A, Arm I (nivolumab)
  arm group label: Cohort A, Arm II (nivolumab, relatlimab)
  arm group label: Cohort B, Arm III (nivolumab)
  arm group label: Cohort B, Arm IV (ctDNA surveillance, nivolumab)
  other name: Magnetic Resonance
  other name: Magnetic resonance imaging (procedure)
  other name: Magnetic Resonance Imaging Scan
  other name: Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  other name: MR
  other name: MR Imaging
  other name: MRI
  other name: MRI Scan
  other name: NMR Imaging
  other name: NMRI
  other name: Nuclear Magnetic Resonance Imaging
  intervention type: Biological
  intervention name: Nivolumab
  description: Given IV
  arm group label: Cohort A, Arm I (nivolumab)
  arm group label: Cohort A, Arm II (nivolumab, relatlimab)
  arm group label: Cohort B, Arm III (nivolumab)
  arm group label: Cohort B, Arm IV (ctDNA surveillance, nivolumab)
  other name: ABP 206
  other name: BMS-936558
  other name: CMAB819
  other name: MDX-1106
  other name: NIVO
  other name: Nivolumab Biosimilar ABP 206
  other name: Nivolumab Biosimilar CMAB819
  other name: ONO-4538
  other name: Opdivo
  intervention type: Other
  intervention name: Quality-of-Life Assessment
  description: Ancillary studies
  arm group label: Cohort A, Arm I (nivolumab)
  arm group label: Cohort A, Arm II (nivolumab, relatlimab)
  arm group label: Cohort B, Arm III (nivolumab)
  arm group label: Cohort B, Arm IV (ctDNA surveillance, nivolumab)
  other name: Quality of Life Assessment
  intervention type: Other
  intervention name: Questionnaire Administration
  description: Ancillary studies
  arm group label: Cohort A, Arm I (nivolumab)
  arm group label: Cohort A, Arm II (nivolumab, relatlimab)
  arm group label: Cohort B, Arm III (nivolumab)
  arm group label: Cohort B, Arm IV (ctDNA surveillance, nivolumab)
  intervention type: Biological
  intervention name: Relatlimab
  description: Given IV
  arm group label: Cohort A, Arm II (nivolumab, relatlimab)
  other name: BMS-986016
  other name: BMS986016
  other name: Immunoglobulin G4, Anti-(human Lymphocyte Activation Gene-3 Protein) (Human Heavy Chain), Disulfide with Human Light Chain, Dimer
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Matthew D Galsky
  role: Principal Investigator
  affiliation: Alliance for Clinical Trials in Oncology
  responsible party type: Sponsor
  mesh term: Carcinoma
  mesh term: Carcinoma, Transitional Cell
  mesh term: Nivolumab
  mesh term: Relatlimab
  mesh term: Immunoglobulins
  mesh term: Immunoglobulin G
  sharing ipd: Yes
  ipd description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
  ipd url: https://grants.nih.gov/policy/sharing.htm