Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Urinary Bladder Neoplasms

Carcinoma, Transitional Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Transitional Cell Carcinoma

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Immunomodulating Agents

Nivolumab

Relatlimab

Immunoglobulins

Immunoglobulin G

Immunoglobulins, Intravenous

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Immunologic Factors

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.

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.

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.

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.

Biospecimen Collection

cfDNA or ctDNA Measurement

Computed Tomography

Magnetic Resonance Imaging

Quality-of-Life Assessment

Questionnaire Administration

Site Public Contact

Tyler Stewart

Sarmad Sadeghi

Mamta Parikh

Gregory A. Masters

Brian H. Ramnaraign

Bryan A. Faller

David VanderWeele

Natalie Reizine

Randy F. Sweis

Nicklas R. Pfanzelter

Melissa A. Reimers

Tareq Salous

Joseph J. Merchant

Joshua Lukenbill

Richard L. Deming

Brian T. Halbert

Sarah J. Sinclair

Brendan Connell

Elie G. Dib

Daniel Almquist

John C. Henegan

Kushal Naha

Jay W. Carlson

Harshraj Leuva

Douglas J. Weckstein

David H. Aggen

Robert S. Alter

Biren Saraiya

Matthew D Galsky

This phase II/III trial examines whether patients who have undergone surgical removal of bladder, but require an additional treatment called immunotherapy to help prevent their bladder 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 bladder cancer patients who have undergone surgical removal of their bladder.

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.

VI. Within each cohort, to compare patient-reported fear of cancer recurrence as measured by the Fear of Cancer Recurrence Inventory (FCRI)-Short Form 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.

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

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

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.

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.

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).

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.

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(+).

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

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.

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.

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.

National Cancer Institute (NCI)

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Urinary Bladder Diseases

Urologic Diseases

Male Urogenital Diseases

Daily adaptive radiation therapy delivered with Varian Ethos treatment system

Daily adaptive external beam radiation therapy delivered on Varian Ethos treatment system.

Daily Adaptive External Beam Radiation Therapy

Steve Kohlmyer, MS

Brian Baumann, MD

This trial is a single-arm, prospective, multi-center clinical trial designed to demonstrate that adaptive radiotherapy for muscle-invasive bladder cancer will translate into a decreased rate of acute (assessed weekly during chemo-radiotherapy) grade 3 or greater gastrointestinal/genitourinary toxicity compared with the historically reported rate for non-adaptive radiation therapy. The Common Terminology Criteria for Adverse Events (CTCAE) version 5 assessment tool will be utilized.

Daily Online Adaptive Short-Course Radiation Therapy and Concurrent Chemotherapy for Muscle-Invasive Bladder Cancer

Daily Online Adaptive Short-Course Radiation Therapy and Concurrent Chemotherapy for Muscle-Invasive Bladder Cancer: A Prospective Trial of an Individualized Approach for Reducing Bowel and Bladder Toxicity (ARTIA-Bladder)

To test the hypothesis that a biomarker driven genomic test, Decipher Bladder, performed on the TURBT specimen can be used as a prognostic/predictive biomarker for recurrence in patients treated with concurrent chemo-radiation therapy

Acute gastrointestinal and genitourinary CTCAE v5 grade 3 or higher toxicity

Loco-regional bladder tumor control at 2 years. Events include histologically proven presence of muscle-invasive disease or clinical evidence of nodal disease

Patient-reported quality of life changes during and after EBRT treatment using adaptive IMRT by the subscale EORTC QLQ-BLM30 and EPIC 26

Physician reported CTCAE V5 adverse events

Change in global function as measured with EuroQol 5 dimension 5 level (EQ-5D-5L) questionnaire. Higher scores for a given dimension indicate degraded function.

Disease-free survival at 2 years (events include histologically proven presence of muscle-invasive disease, clinical evidence of nodal or metastatic disease, or death due to any cause)

Bladder intact event-free survival at 2 years (events include histologically proven presence of muscle-invasive disease, clinical evidence of nodal or metastatic disease, radical cystectomy, or death due to any cause)

Bladder-cancer specific mortality at 2 years

Normal tissue complication probability (NTCP) model of acute GI toxicity for hypofractionated bladder RT based on true integrated daily dose to the bowel

Workflow feasibility of adaptive image guided EBRT for bladder cancer (including measuring time on table and frequency of using the adapted vs. original treatment plan for each fraction)

Improvement in target coverage and/or reduction in dose to critical organs at risk compared to the non-adaptive planned dosimetry

Acute grade 3 or higher GI/GU CTCAE v5 toxicity rate in subjects who received 75% or more of their fractions as adaptive treatments

Acute GI/GU CTCAE v5 grade 3 or higher toxicity (assessed weekly during chemo-radiotherapy) in the cohort treated with partial bladder boost to 55 Gy

Washington University School of Medicine

Varian, a Siemens Healthineers Company

Symptoms and General Pathology

Behaviors and Mental Disorders

Disease Progression

Leiomyosarcoma

Disease Attributes

Neoplasms, Connective and Soft Tissue

Sarcoma

Quality of Life

Soft Tissue Sarcoma

A radical cystectomy is an operation to remove the whole bladder

Radical Cystectomy

Francesco Montorsi, MD

Giusy Burgio, MSc

Observational study on the quality of life and pathological state of patients underwent radical cystectomy.

Each patient will be followed for approximately 10 years starting from the date of surgery. The patient may be contacted for yearly follow-up through one of the preferred methods indicated (phone call, email or home address) which will be carried out by the staff of the Urology Department. The data for each patient will then be transferred to the database itself. The data collected will be handled following the most strict GCPs and privacy norms.

The data entered will concern:

* period before hospitalization (symptoms, clinical data) and completion of a pre-surgery questionnaire
* hospitalization period with all its related data
* questionnaires relating to quality of life which will be administered to the patient once a year according to the preferred method expressed by the patient in the informed consent.

Study on the Quality of Life and Pathological State in Patients Who Underwent Radical Cystectomy

Bladder Archive: Observational Study on the Quality of Life and Pathological State in Patients Who Underwent Radical Cystectomy

All patients, before underwent radical cystectomy, receive a diary in which we ask a detailed clinical history of the patient with their symptoms, diagnosis and previous urological e non urological treatments performed before the operation. A detailed intraoperative, postoperative and follow-up clinical history.

Through the collection of a detailed clinical history of the patient in which themselves report symptoms, diagnosis and previous urological and non-urological treatments and also through the medical record.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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	NCT05987241	Muscle Invasive... Stage II Bladde... Stage III Bladd... Stage IV Bladde...	Biospecimen Col... cfDNA or ctDNA ... Computed Tomogr... Magnetic Resona... Nivolumab Quality-of-Life... Questionnaire A... Relatlimab	18 Years -	National Cancer Institute (NCI)
Daily Online Adaptive Short-Course Radiation Therapy and Concurrent Chemotherapy for Muscle-Invasive Bladder Cancer	NCT05700227	Muscle Invasive...	Daily Adaptive ...	18 Years -	Varian, a Siemens Healthineers Company
Study on the Quality of Life and Pathological State in Patients Who Underwent Radical Cystectomy	NCT06170177	Muscle-Invasive... Muscle Invasive... Bladder Cancer ... Bladder Cancer ... Bladder Cancer ... Bladder Cancer ... Bladder Leiomyo... Bladder Cancer Bladder Cancer ... Bladder Cancer ... Bladder Cancer ... Bladder Cancer ... Bladder Urothel... Progression, Di... Urinary Diversi... Neobladder Radical Cystect...	Radical Cystect...	18 Years -	IRCCS San Raffaele

Spots Global Cancer Trial Database for muscle invasive bladder urothelial carcinoma