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

Stage III Bladder Urothelial Carcinoma AJCC v6 and v7 Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05987241
• Other study ID #: NCI-2023-05980
• Secondary ID: NCI-2023-05980A0
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: February 2, 2024
• Est. completion date: April 11, 2026

Study information

• Verified date: March 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1190
• Est. completion date: April 11, 2026
• Est. primary completion date: April 11, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• PRE-REGISTRATION: Histologically confirmed muscle-invasive urothelial carcinoma of the bladder. Variant histology, including neuroendocrine differentiation, 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: Patient must have had radical cystectomy and lymph node dissection >= 3 weeks, but =< 12 weeks prior to pre-registration. Patients who have had a partial cystectomy as definitive therapy are not eligible

• PRE-REGISTRATION: 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: No evidence of residual cancer or metastasis after cystectomy (imaging is not required prior to pre-registration but is required prior to registration)

• PRE-REGISTRATION: Have undergone a radical cystectomy with pathological evidence of urothelial carcinoma of the bladder 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 cisplatin-based chemotherapy:

pT3-pT4* or pT0/x-pT4/N+ on cystectomy 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 cisplatin may be candidates if they refuse available adjuvant 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 cystectomy (without prior neoadjuvant chemotherapy) with ctDNA(+) Signatera results based on an assay performed post-cystectomy as part of routine care outside of the study may proceed with pre-registration but require confirmation of ctDNA(+) Signatera testing on repeat "central testing" in the context of A032103 testing. Patients with pT2N0 with central testing not confirming ctDNA(+) will not be eligible for A032103 (Note: this is distinct from patients with ypT2N0 who are eligible based on ii).

• (ii) Patients who received cisplatin-based neoadjuvant chemotherapy: ypT2-ypT4 or ypT0/x-pT4/N+ on cystectomy

• PRE-REGISTRATION: Available tumor tissue for central Signatera testing to be submitted after pre-registration. Central testing is defined as testing performed as part of the A032103 study prior to registration and is provided by the study and not routine standard commercial testing. Patients who have already had Signatera testing performed as part of routine care will require repeat central testing as part of the A032103 study to be eligible for registration/randomization. Tumor tissue from the cystectomy is preferred over tissue from prior transurethral resection

• PRE-REGISTRATION: Age >= 18 years

• PRE-REGISTRATION: ECOG Performance Status 0-2

• PRE-REGISTRATION: Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects

• PRE-REGISTRATION: No postoperative/adjuvant systemic therapy after cystectomy

• PRE-REGISTRATION: No adjuvant radiation after cystectomy

• PRE-REGISTRATION: No treatment with any other type of investigational agent =< 4 weeks before pre-registration

• PRE-REGISTRATION: Not have ever received prior treatment with PD-1/PD-L1 blockade.

• PRE-REGISTRATION: Not have ever received prior treatment with LAG-3 blockade.

• PRE-REGISTRATION: Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• PRE-REGISTRATION: Absolute Neutrophil Count (ANC) >= 1,200/mm^3

• PRE-REGISTRATION: Platelet count >= 100,000/mm^3

• PRE-REGISTRATION: Hemoglobin >= 8 g/dL

• PRE-REGISTRATION: Creatinine =< 1.5 x upper limit of normal (ULN) or calculated (calc.) creatinine clearance > 30 mL/min (using either Cockcroft-Gault formula or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation

• PRE-REGISTRATION: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN

• PRE-REGISTRATION: Total bilirubin =< 1.5 x upper limit of normal (ULN) (except in patients with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)

• PRE-REGISTRATION: For women of childbearing potential only: A negative urine or serum pregnancy test done =< 14 days prior to pre-registration is required

• PRE-REGISTRATION: Not currently requiring hemodialysis

• PRE-REGISTRATION: No current or prior history of myocarditis

• PRE-REGISTRATION: No active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens- Johnson syndrome, or phospholipid syndrome because of the risk of recurrence or exacerbation of disease.

• PRE-REGISTRATION: Patients with vitiligo, endocrine deficiencies including type I diabetes mellitus, thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible.

• PRE-REGISTRATION: Patients with rheumatoid arthritis and other arthropathies, Sjo¨gren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.

• PRE-REGISTRATION: No current pneumonitis or prior history of non-infectious pneumonitis that required steroids within the previous 5 years.

• PRE-REGISTRATION: No known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected).

• PRE-REGISTRATION: For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

• PRE-REGISTRATION: Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible.

• PRE-REGISTRATION: No concurrent antineoplastic therapy.

• PRE-REGISTRATION: No current immunosuppressive agents (with the exception of corticosteroids as described below).

• PRE-REGISTRATION: No condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of pre-registration (with the exception of steroid pre-medications for contrast allergies). Inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.

• REGISTRATION: Patient must have had radical cystectomy and lymph node dissection =< 18 weeks prior to registration.

• REGISTRATION: Must have evaluable ctDNA Signatera assay result (i.e., ctDNA[+]or ctDNA[-]) based on test performed as part of central testing after pre-registration to A032103. Central testing is defined as testing performed as part of the A032103. Local/commercial testing results may not be used for registration to A032103

• Cisplatin-ineligible (or cisplatin-declining) patients with a pT2N0 urothelial cancer on cystectomy who were pre-registered based on routine standard care ctDNA(+) Signatera testing must have confirmed ctDNA(+) Signatera testing on central testing. If central Signatera testing yields a ctDNA(-) result, these patients are ineligible. NOTE: This is a distinct consideration from patients with ypT2-4 and/or ypN+ urothelial cancer (i.e., patients who had received neoadjuvant cisplatin-based chemotherapy) who are eligible with either ctDNA(+) or ctDNA(-) central Signatera testing

• REGISTRATION: All patients must have confirmed disease-free status defined as no measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or definitive non-measurable radiographic metastatic disease, within 60 days prior to registration. Patients with equivocal nodes less than 15 mm in short axis, or < 10 mm in long axis for non-lymph node lesions, not considered by the investigator to represent malignant disease will be eligible. Attempts should be made to resolve the etiology of equivocal lesions with complementary imaging (e.g., PET scan) or biopsy.

• REGISTRATION: No major surgery =< 3 weeks before registration.

• REGISTRATION: No live vaccine within 30 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette- Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist [registered trademark]) are live attenuated vaccines and are not allowed. Coronavirus disease 2019 (COVID-19) vaccines are not live vaccines and are allowed

• COHORT B, ARM 4 PATIENTS INITIATING NIVOLUMAB AFTER CONVERSION OF ctDNA ASSAY FROM ctDNA(-) to ctDNA (+):

• Patient must have converted to ctDNA(+) during serial monitoring performed centrally in the setting of the A032103 study

• COHORT B, ARM 4 PATIENTS INITIATING NIVOLUMAB AFTER CONVERSION OF ctDNA ASSAY FROM ctDNA(-) to ctDNA (+):

• No evidence of metastatic disease on the most recent scheduled imaging assessment as outlined in the study calendar (no repeat imaging is necessary specifically at the time of the conversion from ctDNA[-] to ctDNA[+]).

• COHORT B, ARM 4 PATIENTS INITIATING NIVOLUMAB AFTER CONVERSION OF ctDNA ASSAY FROM ctDNA(-) to ctDNA (+):

• No change in clinical condition and/or laboratory tests that would impact the safety of nivolumab in the opinion of the treating investigator

• COHORT B, ARM 4 PATIENTS INITIATING NIVOLUMAB AFTER CONVERSION OF ctDNA ASSAY FROM ctDNA(-) to ctDNA (+):

• =< 6 weeks from reporting of ctDNA(+) result by Natera.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Transitional Cell
• 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

Intervention

Procedure:
• Biospecimen Collection
Undergo collection of tissue and blood

Other:
• cfDNA or ctDNA Measurement
Undergo ctDNA surveillance

Procedure:
• Computed Tomography
Undergo CT
• Magnetic Resonance Imaging
Undergo MRI

Biological:
• Nivolumab
Given IV

Other:
• Quality-of-Life Assessment
Ancillary studies
• Questionnaire Administration
Ancillary studies

Biological:
• Relatlimab
Given IV

Locations

Country	Name	City	State
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania
United States	UPMC Altoona	Altoona	Pennsylvania
United States	Mary Greeley Medical Center	Ames	Iowa
United States	McFarland Clinic - Ames	Ames	Iowa
United States	Mission Cancer and Blood - Ankeny	Ankeny	Iowa
United States	Trinity Health Saint Joseph Mercy Hospital Ann Arbor	Ann Arbor	Michigan
United States	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey
United States	Nebraska Medicine-Bellevue	Bellevue	Nebraska
United States	Sanford Joe Lueken Cancer Center	Bemidji	Minnesota
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	Beverly Hospital	Beverly	Massachusetts
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Prisma Health Cancer Institute - Spartanburg	Boiling Springs	South Carolina
United States	McFarland Clinic - Boone	Boone	Iowa
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Lafayette Family Cancer Center-EMMC	Brewer	Maine
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Lahey Hospital and Medical Center	Burlington	Massachusetts
United States	University of Vermont and State Agricultural College	Burlington	Vermont
United States	University of Vermont Medical Center	Burlington	Vermont
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Illinois CancerCare-Carthage	Carthage	Illinois
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Mission Cancer and Blood - West Des Moines	Clive	Iowa
United States	MU Health - University Hospital/Ellis Fischel Cancer Center	Columbia	Missouri
United States	Memorial Sloan Kettering Commack	Commack	New York
United States	New Hampshire Oncology Hematology PA-Concord	Concord	New Hampshire
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	UPMC Western Maryland	Cumberland	Maryland
United States	UT Southwestern Simmons Cancer Center - RedBird	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Northwestern Medicine Cancer Center Kishwaukee	DeKalb	Illinois
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Mission Cancer and Blood - Des Moines	Des Moines	Iowa
United States	Mission Cancer and Blood - Laurel	Des Moines	Iowa
United States	Illinois CancerCare-Dixon	Dixon	Illinois
United States	Prisma Health Cancer Institute - Easley	Easley	South Carolina
United States	Pocono Medical Center	East Stroudsburg	Pennsylvania
United States	Crossroads Cancer Center	Effingham	Illinois
United States	UPMC Hillman Cancer Center Erie	Erie	Pennsylvania
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	Parkland Health Center - Farmington	Farmington	Missouri
United States	Genesee Cancer and Blood Disease Treatment Center	Flint	Michigan
United States	Genesee Hematology Oncology PC	Flint	Michigan
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	McFarland Clinic - Trinity Cancer Center	Fort Dodge	Iowa
United States	UT Southwestern/Simmons Cancer Center-Fort Worth	Fort Worth	Texas
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois
United States	The West Clinic - Wolf River	Germantown	Tennessee
United States	Glens Falls Hospital	Glens Falls	New York
United States	NorthShore University HealthSystem-Glenbrook Hospital	Glenview	Illinois
United States	Northwestern Medicine Glenview Outpatient Center	Glenview	Illinois
United States	Addison Gilbert Hospital	Gloucester	Massachusetts
United States	Northwestern Medicine Grayslake Outpatient Center	Grayslake	Illinois
United States	UPMC Cancer Centers - Arnold Palmer Pavilion	Greensburg	Pennsylvania
United States	Prisma Health Cancer Institute - Butternut	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Eastside	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Faris	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Greer	Greer	South Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	UPMC Pinnacle Cancer Center/Community Osteopathic Campus	Harrisburg	Pennsylvania
United States	Memorial Sloan Kettering Westchester	Harrison	New York
United States	NorthShore University HealthSystem-Highland Park Hospital	Highland Park	Illinois
United States	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	McFarland Clinic - Jefferson	Jefferson	Iowa
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	University of Kansas Cancer Center - North	Kansas City	Missouri
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	Northwestern Medicine Lake Forest Hospital	Lake Forest	Illinois
United States	Monmouth Medical Center Southern Campus	Lakewood	New Jersey
United States	University of Michigan Health - Sparrow Lansing	Lansing	Michigan
United States	Cancer Centers of Southwest Oklahoma Research	Lawton	Oklahoma
United States	University of Kansas Cancer Center - Lee's Summit	Lee's Summit	Missouri
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Monmouth Medical Center	Long Branch	New Jersey
United States	Keck Medicine of USC Koreatown	Los Angeles	California
United States	Los Angeles General Medical Center	Los Angeles	California
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	University of Wisconsin Carbone Cancer Center - University Hospital	Madison	Wisconsin
United States	Solinsky Center for Cancer Care	Manchester	New Hampshire
United States	McFarland Clinic - Marshalltown	Marshalltown	Iowa
United States	UPMC Hillman Cancer Center at Rocco And Nancy Ortenzio Cancer Pavilion	Mechanicsburg	Pennsylvania
United States	Memorial Sloan Kettering Monmouth	Middletown	New Jersey
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	UPMC Hillman Cancer Center - Monroeville	Monroeville	Pennsylvania
United States	Memorial Sloan Kettering Bergen	Montvale	New Jersey
United States	ProHealth D N Greenwald Center	Mukwonago	Wisconsin
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	UC Comprehensive Cancer Center at Silver Cross	New Lenox	Illinois
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Mount Sinai Chelsea	New York	New York
United States	Mount Sinai Hospital	New York	New York
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	USC Norris Oncology/Hematology-Newport Beach	Newport Beach	California
United States	University of Kansas Cancer Center at North Kansas City Hospital	North Kansas City	Missouri
United States	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Olathe Health Cancer Center	Olathe	Kansas
United States	Nebraska Medicine-Village Pointe	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Providence Willamette Falls Medical Center	Oregon City	Oregon
United States	Northwestern Medicine Orland Park	Orland Park	Illinois
United States	University of Chicago Medicine-Orland Park	Orland Park	Illinois
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	University of Kansas Cancer Center-Overland Park	Overland Park	Kansas
United States	Lahey Medical Center-Peabody	Peabody	Massachusetts
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	UPMC-Passavant Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Saint Clair Hospital Cancer Center	Pittsburgh	Pennsylvania
United States	UPMC-Saint Margaret	Pittsburgh	Pennsylvania
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	UT Southwestern Clinical Center at Richardson/Plano	Richardson	Texas
United States	VCU Massey Cancer Center at Stony Point	Richmond	Virginia
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
United States	Siteman Cancer Center at Christian Hospital	Saint Louis	Missouri
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	Sainte Genevieve County Memorial Hospital	Sainte Genevieve	Missouri
United States	Salina Regional Health Center	Salina	Kansas
United States	Prisma Health Cancer Institute - Seneca	Seneca	South Carolina
United States	Memorial Hospital East	Shiloh	Illinois
United States	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	VCU Community Memorial Health Center	South Hill	Virginia
United States	Memorial Medical Center	Springfield	Illinois
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Springfield Clinic	Springfield	Illinois
United States	Missouri Baptist Sullivan Hospital	Sullivan	Missouri
United States	BJC Outpatient Center at Sunset Hills	Sunset Hills	Missouri
United States	ProMedica Flower Hospital	Sylvania	Ohio
United States	Community Medical Center	Toms River	New Jersey
United States	University of Kansas Health System Saint Francis Campus	Topeka	Kansas
United States	Oklahoma Cancer Specialists and Research Institute-Tulsa	Tulsa	Oklahoma
United States	Memorial Sloan Kettering Nassau	Uniondale	New York
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	Illinois CancerCare - Washington	Washington	Illinois
United States	ProHealth Waukesha Memorial Hospital	Waukesha	Wisconsin
United States	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin
United States	University of Kansas Hospital-Westwood Cancer Center	Westwood	Kansas
United States	Winchester Hospital	Winchester	Massachusetts
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of patients who are circulating tumor DNA negative (ctDNA[-]) (Cohort A Phase II)	Will be determined for each treatment arm as the number of patients who are ctDNA(-) after 12 weeks of treatment divided by the total number of patients on the treatment arm. Patients who do not have a 12-week ctDNA result will be deemed to be ctDNA(+). The comparison of the proportions of patients who are ctDNA(-) after 12 weeks of treatment between the two arms will be performed with a chi-square test.	At week 12 from treatment start date
Primary	Overall survival (OS) (Cohort A Phase III)	The analysis will be performed using a stratified log-rank test that uses the specified stratification variables. An additional analysis will be perform using a stratified Cox regression model to generate the point estimate and 90% confidence interval for the hazard ratio (HR) (comparing Arm 2 to Arm 1).	From randomization until death due to any cause, assessed up to 5 years after completion of study treatment
Primary	Disease-Free Survival (DFS) (Cohort B)	A stratified Cox model (using the randomization stratification variables will be used to generate a 90% confidence interval (CI) for the HR. If the 90% 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.	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	Proportion of patients who are ctDNA(-) (Cohort A Phase III) from treatment start date	Will be determined for each treatment arm as the number of patients who are ctDNA(-) after 12 weeks of treatment divided by the total number of patients on the treatment arm. Patients who do not have a 12-week ctDNA result will be deemed to be ctDNA(+).	At week 12
Secondary	OS (Cohort A Phase II)	If the trial does not continue to phase III, OS will be a secondary endpoint.	From randomization until death due to any cause, assessed up to 5 years after completion of study treatment
Secondary	DFS (Cohort A Phase II or III)	This will be a secondary endpoint for the phase III trial, if completed, or for the phase II trial if the phase III trial is not performed.	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	Incidence of adverse events (Cohort A)	Will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. Adverse events (AEs) will be summarized with frequencies and relative frequencies. The maximum grade for an AE will be recorded for each patient by treatment arm. The number (percent) of patients that experience each observed adverse event will be summarized by treatment arm. In addition, the proportion of patients that experience a grade 3+, grade 4+, and grade 5 adverse event will be summarized as the number and percent of patients by treatment arm. The primary summary will be regardless of attribution.	Up to 5 years after completion of study treatment
Secondary	OS (Cohort B)		From randomization until death due to any cause, assessed up to 5 years after completion of study treatment
Secondary	Cumulative incidence of ctDNA(+) conversion (Cohort B)		From randomization until a patient becomes ctDNA(+), assessed up to 5 years after completion of study treatment
Secondary	Lead time for ctDNA(+) conversion (Cohort B)		From when a patient becomes ctDNA(+) until a confirmed radiographic disease recurrence, assessed up to 5 years after completion of study treatment
Secondary	Incidence of adverse events (Cohort B)	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.	Up to 5 years after completion of study treatment