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

Phase 2

Recruiting

• Conditions: Stage II Bladder Urothelial Carcinoma AJCC v6 and v7; Stage IV Bladder Urothelial Carcinoma AJCC v7; Muscle Invasive Bladder Urothelial Carcinoma; Stage III Bladder Urothelial Carcinoma AJCC v6 and v7
• Interventions: Procedure: Biospecimen Collection; Procedure: Computed Tomography; Other: cfDNA or ctDNA Measurement; Procedure: Magnetic Resonance Imaging; Biological: Nivolumab; Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Biological: Relatlimab

• Registration Number: NCT05987241
• Lead Sponsor: National Cancer Institute (NCI)

Brief 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.

Detailed 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.

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.

Study Timeline

• Study First Submitted: 2023-08-10
• Study First Submitted QC: 2023-08-10
• Study First Posted: 2023-08-14
• Study Start: 2024-02-02
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-20
• Last Update Posted: 2025-05-21
• Primary Completion: 2030-09-02
• Study Completion: 2030-09-02

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1190

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, Sjögren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.

• PRE-REGISTRATION: 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.

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort A, Arm I (nivolumab)	Computed Tomography	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.
Cohort B, Arm III (nivolumab)	Biospecimen Collection	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.
Cohort B, Arm IV (ctDNA surveillance, nivolumab)	Quality-of-Life Assessment	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.
Cohort A, Arm I (nivolumab)	Magnetic Resonance Imaging	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.
Cohort A, Arm II (nivolumab, relatlimab)	Magnetic Resonance Imaging	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.
Cohort B, Arm IV (ctDNA surveillance, nivolumab)	cfDNA or ctDNA Measurement	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.
Cohort A, Arm I (nivolumab)	Biospecimen Collection	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.
Cohort A, Arm II (nivolumab, relatlimab)	Biospecimen Collection	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.
Cohort A, Arm II (nivolumab, relatlimab)	Computed Tomography	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.
Cohort B, Arm III (nivolumab)	Questionnaire Administration	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.
Cohort A, Arm I (nivolumab)	Quality-of-Life Assessment	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.
Cohort A, Arm I (nivolumab)	Questionnaire Administration	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.
Cohort A, Arm II (nivolumab, relatlimab)	Questionnaire Administration	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.
Cohort B, Arm III (nivolumab)	Computed Tomography	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.
Cohort B, Arm IV (ctDNA surveillance, nivolumab)	Magnetic Resonance Imaging	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.
Cohort A, Arm II (nivolumab, relatlimab)	Quality-of-Life Assessment	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.
Cohort B, Arm III (nivolumab)	Quality-of-Life Assessment	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.
Cohort B, Arm IV (ctDNA surveillance, nivolumab)	Questionnaire Administration	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.
Cohort B, Arm III (nivolumab)	Magnetic Resonance Imaging	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.
Cohort B, Arm IV (ctDNA surveillance, nivolumab)	Biospecimen Collection	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.
Cohort B, Arm IV (ctDNA surveillance, nivolumab)	Computed Tomography	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.
Cohort A, Arm I (nivolumab)	Nivolumab	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.
Cohort A, Arm II (nivolumab, relatlimab)	Nivolumab	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.
Cohort B, Arm III (nivolumab)	Nivolumab	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.
Cohort B, Arm IV (ctDNA surveillance, nivolumab)	Nivolumab	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.
Cohort A, Arm II (nivolumab, relatlimab)	Relatlimab	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.

Primary Outcome Measures

Name	Time	Method
Overall survival (OS) (Cohort A Phase III)	From randomization until death due to any cause, assessed up to 5 years after completion of study treatment	The analysis will be performed using a stratified log-rank test that uses the specified stratification variables. An additional analysis will be perform using a stratified Cox regression model to generate the point estimate and 90% confidence interval for the hazard ratio (HR) (comparing Arm 2 to Arm 1).
Proportion of patients who are circulating tumor DNA negative (ctDNA[-]) (Cohort A Phase II)	At week 12 from treatment start date	Will be determined for each treatment arm as the number of patients who are ctDNA(-) after 12 weeks of treatment divided by the total number of patients on the treatment arm. Patients who do not have a 12-week ctDNA result will be deemed to be ctDNA(+). The comparison of the proportions of patients who are ctDNA(-) after 12 weeks of treatment between the two arms will be performed with a chi-square test.
Disease-Free Survival (DFS) (Cohort B)	From randomization until confirmed disease recurrence as assessed by the treating physician or death due to any cause, assessed up to 5 years after completion of study treatment	A stratified Cox model (using the randomization stratification variables will be used to generate a 90% confidence interval (CI) for the HR. If the 90% 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.

Secondary Outcome Measures

Name	Time	Method
OS (Cohort B)	From randomization until death due to any cause, assessed up to 5 years after completion of study treatment
Cumulative incidence of ctDNA(+) conversion (Cohort B)	From randomization until a patient becomes ctDNA(+), assessed up to 5 years after completion of study treatment
Proportion of patients who are ctDNA(-) (Cohort A Phase III) from treatment start date	At week 12	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(+).
OS (Cohort A Phase II)	From randomization until death due to any cause, assessed up to 5 years after completion of study treatment	If the trial does not continue to phase III, OS will be a secondary endpoint.
Incidence of adverse events (Cohort A)	Up to 5 years after completion of study treatment	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.
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
DFS (Cohort A Phase II or III)	From randomization until confirmed disease recurrence as assessed by the treating physician or death due to any cause, assessed up to 5 years after completion of study treatment	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.
Incidence of adverse events (Cohort B)	Up to 5 years after completion of study treatment	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.

Trial Locations

Locations (391)

Cancer Center at Saint Joseph's; 🇺🇸 Phoenix, Arizona, United States

University of Arizona Cancer Center-Orange Grove Campus; 🇺🇸 Tucson, Arizona, United States

Banner University Medical Center - Tucson; 🇺🇸 Tucson, Arizona, United States

University of Arizona Cancer Center-North Campus; 🇺🇸 Tucson, Arizona, United States

Highlands Oncology Group - Fayetteville; 🇺🇸 Fayetteville, Arkansas, United States

Highlands Oncology Group - Rogers; 🇺🇸 Rogers, Arkansas, United States

Highlands Oncology Group; 🇺🇸 Springdale, Arkansas, United States

Kaiser Permanente-Anaheim; 🇺🇸 Anaheim, California, United States

Kaiser Permanente-Baldwin Park; 🇺🇸 Baldwin Park, California, United States

Kaiser Permanente-Bellflower; 🇺🇸 Bellflower, California, United States

Kaiser Permanente-Fontana; 🇺🇸 Fontana, California, United States

Kaiser Permanente South Bay; 🇺🇸 Harbor City, California, United States

Kaiser Permanente-Irvine; 🇺🇸 Irvine, California, United States

UC San Diego Moores Cancer Center; 🇺🇸 La Jolla, California, United States

Keck Medicine of USC Koreatown; 🇺🇸 Los Angeles, California, United States

Kaiser Permanente Los Angeles Medical Center; 🇺🇸 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

Kaiser Permanente West Los Angeles; 🇺🇸 Los Angeles, California, United States

USC Norris Oncology/Hematology-Newport Beach; 🇺🇸 Newport Beach, California, United States

Kaiser Permanente-Ontario; 🇺🇸 Ontario, California, United States

Stanford Cancer Institute Palo Alto; 🇺🇸 Palo Alto, California, United States

Kaiser Permanente - Panorama City; 🇺🇸 Panorama City, California, United States

Kaiser Permanente-Riverside; 🇺🇸 Riverside, California, United States

University of California Davis Comprehensive Cancer Center; 🇺🇸 Sacramento, California, United States

Kaiser Permanente-San Diego Zion; 🇺🇸 San Diego, California, United States

Kaiser Permanente-San Marcos; 🇺🇸 San Marcos, California, United States

Kaiser Permanente-Woodland Hills; 🇺🇸 Woodland Hills, California, United States

UCHealth University of Colorado Hospital; 🇺🇸 Aurora, Colorado, United States

Kaiser Permanente-Franklin; 🇺🇸 Denver, Colorado, United States

Poudre Valley Hospital; 🇺🇸 Fort Collins, Colorado, United States

Cancer Care and Hematology-Fort Collins; 🇺🇸 Fort Collins, Colorado, United States

UCHealth Greeley Hospital; 🇺🇸 Greeley, Colorado, United States

UCHealth Highlands Ranch Hospital; 🇺🇸 Highlands Ranch, Colorado, United States

Kaiser Permanente-Rock Creek; 🇺🇸 Lafayette, Colorado, United States

Kaiser Permanente-Lone Tree; 🇺🇸 Lone Tree, Colorado, United States

UCHealth Lone Tree Health Center; 🇺🇸 Lone Tree, Colorado, United States

Medical Center of the Rockies; 🇺🇸 Loveland, Colorado, United States

Smilow Cancer Hospital-Derby Care Center; 🇺🇸 Derby, Connecticut, United States

Smilow Cancer Hospital Care Center-Fairfield; 🇺🇸 Fairfield, Connecticut, United States

Smilow Cancer Hospital Care Center at Glastonbury; 🇺🇸 Glastonbury, Connecticut, United States

Smilow Cancer Hospital Care Center at Greenwich; 🇺🇸 Greenwich, Connecticut, United States

Smilow Cancer Hospital Care Center - Guilford; 🇺🇸 Guilford, Connecticut, United States

Smilow Cancer Hospital Care Center at Saint Francis; 🇺🇸 Hartford, Connecticut, United States

Yale University; 🇺🇸 New Haven, Connecticut, United States

Yale-New Haven Hospital North Haven Medical Center; 🇺🇸 North Haven, Connecticut, United States

Smilow Cancer Hospital Care Center at Long Ridge; 🇺🇸 Stamford, Connecticut, United States

Smilow Cancer Hospital-Torrington Care Center; 🇺🇸 Torrington, Connecticut, United States

Smilow Cancer Hospital Care Center-Trumbull; 🇺🇸 Trumbull, Connecticut, United States

Smilow Cancer Hospital-Waterbury Care Center; 🇺🇸 Waterbury, Connecticut, United States

Smilow Cancer Hospital Care Center - Waterford; 🇺🇸 Waterford, Connecticut, United States

Helen F Graham Cancer Center; 🇺🇸 Newark, Delaware, United States

Medical Oncology Hematology Consultants PA; 🇺🇸 Newark, Delaware, United States

MedStar Georgetown University Hospital; 🇺🇸 Washington, District of Columbia, United States

MedStar Washington Hospital Center; 🇺🇸 Washington, District of Columbia, United States

Mount Sinai Comprehensive Cancer Center at Aventura; 🇺🇸 Aventura, Florida, United States

UM Sylvester Comprehensive Cancer Center at Aventura; 🇺🇸 Aventura, Florida, United States

UM Sylvester Comprehensive Cancer Center at Coral Gables; 🇺🇸 Coral Gables, Florida, United States

UM Sylvester Comprehensive Cancer Center at Deerfield Beach; 🇺🇸 Deerfield Beach, Florida, United States

Malcom Randall Veterans Administration Medical Center; 🇺🇸 Gainesville, Florida, United States

University of Florida Health Science Center - Gainesville; 🇺🇸 Gainesville, Florida, United States

Mount Sinai Medical Center; 🇺🇸 Miami Beach, Florida, United States

University of Miami Miller School of Medicine-Sylvester Cancer Center; 🇺🇸 Miami, Florida, United States

Miami Cancer Institute; 🇺🇸 Miami, Florida, United States

UM Sylvester Comprehensive Cancer Center at Kendall; 🇺🇸 Miami, Florida, United States

AdventHealth Orlando; 🇺🇸 Orlando, Florida, United States

UM Sylvester Comprehensive Cancer Center at Plantation; 🇺🇸 Plantation, Florida, United States

Emory University Hospital Midtown; 🇺🇸 Atlanta, Georgia, United States

Emory University Hospital/Winship Cancer Institute; 🇺🇸 Atlanta, Georgia, United States

Emory Saint Joseph's Hospital; 🇺🇸 Atlanta, Georgia, United States

Northside Hospital; 🇺🇸 Atlanta, Georgia, United States

Northside Hospital - Duluth; 🇺🇸 Duluth, Georgia, United States

Emory Johns Creek Hospital; 🇺🇸 Johns Creek, Georgia, United States

Northside Hospital - Gwinnett; 🇺🇸 Lawrenceville, Georgia, United States

Saint Alphonsus Cancer Care Center-Boise; 🇺🇸 Boise, Idaho, United States

Saint Alphonsus Cancer Care Center-Caldwell; 🇺🇸 Caldwell, Idaho, United States

Kootenai Health - Coeur d'Alene; 🇺🇸 Coeur d'Alene, Idaho, United States

Saint Alphonsus Cancer Care Center-Nampa; 🇺🇸 Nampa, Idaho, United States

Kootenai Clinic Cancer Services - Post Falls; 🇺🇸 Post Falls, Idaho, United States

Kootenai Clinic Cancer Services - Sandpoint; 🇺🇸 Sandpoint, Idaho, United States

Advocate Good Shepherd Hospital; 🇺🇸 Barrington, Illinois, United States

Illinois CancerCare-Bloomington; 🇺🇸 Bloomington, Illinois, United States

Illinois CancerCare-Canton; 🇺🇸 Canton, Illinois, United States

Illinois CancerCare-Carthage; 🇺🇸 Carthage, Illinois, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States

University of Illinois; 🇺🇸 Chicago, Illinois, United States

Swedish Covenant Hospital; 🇺🇸 Chicago, Illinois, United States

University of Chicago Comprehensive Cancer Center; 🇺🇸 Chicago, Illinois, United States

Advocate Illinois Masonic Medical Center; 🇺🇸 Chicago, Illinois, United States

AMG Crystal Lake - Oncology; 🇺🇸 Crystal Lake, Illinois, United States

Carle at The Riverfront; 🇺🇸 Danville, Illinois, 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

Illinois CancerCare-Dixon; 🇺🇸 Dixon, Illinois, United States

Advocate Good Samaritan Hospital; 🇺🇸 Downers Grove, Illinois, United States

Carle Physician Group-Effingham; 🇺🇸 Effingham, Illinois, United States

Crossroads Cancer Center; 🇺🇸 Effingham, Illinois, United States

Advocate Sherman Hospital; 🇺🇸 Elgin, Illinois, United States

Elmhurst Memorial Hospital; 🇺🇸 Elmhurst, Illinois, United States

Illinois CancerCare-Eureka; 🇺🇸 Eureka, Illinois, United States

NorthShore University HealthSystem-Evanston Hospital; 🇺🇸 Evanston, Illinois, United States

Illinois CancerCare-Galesburg; 🇺🇸 Galesburg, Illinois, United States

Northwestern Medicine Cancer Center Delnor; 🇺🇸 Geneva, Illinois, United States

NorthShore University HealthSystem-Glenbrook Hospital; 🇺🇸 Glenview, Illinois, United States

Northwestern Medicine Glenview Outpatient Center; 🇺🇸 Glenview, Illinois, United States

Northwestern Medicine Grayslake Outpatient Center; 🇺🇸 Grayslake, Illinois, United States

Ingalls Memorial Hospital; 🇺🇸 Harvey, Illinois, United States

NorthShore University HealthSystem-Highland Park Hospital; 🇺🇸 Highland Park, Illinois, United States

Illinois CancerCare-Kewanee Clinic; 🇺🇸 Kewanee, Illinois, United States

Northwestern Medicine Lake Forest Hospital; 🇺🇸 Lake Forest, Illinois, United States

AMG Libertyville - Oncology; 🇺🇸 Libertyville, Illinois, United States

Condell Memorial Hospital; 🇺🇸 Libertyville, Illinois, United States

Illinois CancerCare-Macomb; 🇺🇸 Macomb, Illinois, United States

Carle Physician Group-Mattoon/Charleston; 🇺🇸 Mattoon, Illinois, United States

Edward Hospital/Cancer Center; 🇺🇸 Naperville, Illinois, United States

UC Comprehensive Cancer Center at Silver Cross; 🇺🇸 New Lenox, Illinois, United States

Cancer Care Center of O'Fallon; 🇺🇸 O'Fallon, Illinois, United States

Northwestern Medicine Oak Brook; 🇺🇸 Oak Brook, Illinois, United States

Advocate Christ Medical Center; 🇺🇸 Oak Lawn, Illinois, 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

Advocate Lutheran General Hospital; 🇺🇸 Park Ridge, Illinois, United States

Illinois CancerCare-Pekin; 🇺🇸 Pekin, Illinois, United States

Illinois CancerCare-Peoria; 🇺🇸 Peoria, Illinois, United States

Illinois CancerCare-Peru; 🇺🇸 Peru, Illinois, United States

Edward Hospital/Cancer Center?Plainfield; 🇺🇸 Plainfield, Illinois, United States

Illinois CancerCare-Princeton; 🇺🇸 Princeton, Illinois, United States

UW Health Carbone Cancer Center Rockford; 🇺🇸 Rockford, Illinois, United States

Memorial Hospital East; 🇺🇸 Shiloh, Illinois, United States

Southern Illinois University School of Medicine; 🇺🇸 Springfield, Illinois, United States

Springfield Clinic; 🇺🇸 Springfield, Illinois, United States

Springfield Memorial Hospital; 🇺🇸 Springfield, Illinois, United States

Carle Cancer Center; 🇺🇸 Urbana, Illinois, United States

Northwestern Medicine Cancer Center Warrenville; 🇺🇸 Warrenville, Illinois, United States

Illinois CancerCare - Washington; 🇺🇸 Washington, Illinois, United States

Indiana University/Melvin and Bren Simon Cancer Center; 🇺🇸 Indianapolis, Indiana, United States

Mary Greeley Medical Center; 🇺🇸 Ames, Iowa, United States

McFarland Clinic - Ames; 🇺🇸 Ames, Iowa, United States

UI Health Care Mission Cancer and Blood - Ankeny Clinic; 🇺🇸 Ankeny, Iowa, United States

McFarland Clinic - Boone; 🇺🇸 Boone, Iowa, United States

UI Health Care Mission Cancer and Blood - West Des Moines Clinic; 🇺🇸 Clive, Iowa, United States

Iowa Methodist Medical Center; 🇺🇸 Des Moines, Iowa, United States

UI Health Care Mission Cancer and Blood - Des Moines Clinic; 🇺🇸 Des Moines, Iowa, United States

Mercy Medical Center - Des Moines; 🇺🇸 Des Moines, Iowa, United States

UI Health Care Mission Cancer and Blood - Laurel Clinic; 🇺🇸 Des Moines, Iowa, United States

McFarland Clinic - Trinity Cancer Center; 🇺🇸 Fort Dodge, Iowa, United States

McFarland Clinic - Jefferson; 🇺🇸 Jefferson, Iowa, United States

McFarland Clinic - Marshalltown; 🇺🇸 Marshalltown, Iowa, United States

UI Health Care Mission Cancer and Blood - Waukee Clinic; 🇺🇸 Waukee, Iowa, United States

HaysMed; 🇺🇸 Hays, Kansas, United States

University of Kansas Cancer Center; 🇺🇸 Kansas City, Kansas, United States

Lawrence Memorial Hospital; 🇺🇸 Lawrence, Kansas, United States

The University of Kansas Cancer Center - Olathe; 🇺🇸 Olathe, Kansas, United States

University of Kansas Cancer Center-Overland Park; 🇺🇸 Overland Park, Kansas, United States

Salina Regional Health Center; 🇺🇸 Salina, Kansas, United States

University of Kansas Health System Saint Francis Campus; 🇺🇸 Topeka, Kansas, United States

University of Kansas Hospital-Westwood Cancer Center; 🇺🇸 Westwood, Kansas, United States

University of Kentucky/Markey Cancer Center; 🇺🇸 Lexington, Kentucky, United States

Baptist Health Louisville; 🇺🇸 Louisville, Kentucky, United States

Ochsner Medical Center Jefferson; 🇺🇸 New Orleans, Louisiana, United States

Lafayette Family Cancer Center-EMMC; 🇺🇸 Brewer, Maine, United States

University of Maryland/Greenebaum Cancer Center; 🇺🇸 Baltimore, Maryland, United States

Johns Hopkins University/Sidney Kimmel Cancer Center; 🇺🇸 Baltimore, Maryland, United States

UPMC Western Maryland; 🇺🇸 Cumberland, Maryland, United States

Beverly Hospital; 🇺🇸 Beverly, Massachusetts, United States

Beth Israel Deaconess Medical Center; 🇺🇸 Boston, Massachusetts, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Steward Saint Elizabeth's Medical Center; 🇺🇸 Brighton, Massachusetts, United States

Lahey Hospital and Medical Center; 🇺🇸 Burlington, Massachusetts, United States

Dana-Farber Cancer Institute at Foxborough; 🇺🇸 Foxboro, Massachusetts, United States

Addison Gilbert Hospital; 🇺🇸 Gloucester, Massachusetts, United States

Lahey Medical Center-Peabody; 🇺🇸 Peabody, Massachusetts, United States

Dana-Farber/Brigham and Women's Cancer Center at South Shore; 🇺🇸 South Weymouth, Massachusetts, United States

Beth Israel Deaconess Medical Center/Winchester Center for Cancer Care; 🇺🇸 Winchester, Massachusetts, United States

Trinity Health Saint Joseph Mercy Hospital Ann Arbor; 🇺🇸 Ann Arbor, Michigan, United States

University of Michigan Comprehensive Cancer Center; 🇺🇸 Ann Arbor, Michigan, United States

Bronson Battle Creek; 🇺🇸 Battle Creek, Michigan, United States

McLaren Cancer Institute-Bay City; 🇺🇸 Bay City, Michigan, United States

Trinity Health IHA Medical Group Hematology Oncology - Brighton; 🇺🇸 Brighton, Michigan, United States

University of Michigan - Brighton Center for Specialty Care; 🇺🇸 Brighton, Michigan, United States

Trinity Health IHA Medical Group Hematology Oncology - Canton; 🇺🇸 Canton, Michigan, United States

Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital; 🇺🇸 Chelsea, Michigan, United States

Henry Ford Macomb Hospital-Clinton Township; 🇺🇸 Clinton Township, Michigan, United States

Wayne State University/Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

Henry Ford Hospital; 🇺🇸 Detroit, Michigan, United States

OSF Saint Francis Hospital and Medical Group; 🇺🇸 Escanaba, Michigan, United States

Weisberg Cancer Treatment Center; 🇺🇸 Farmington Hills, Michigan, United States

Cancer Hematology Centers - Flint; 🇺🇸 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

Corewell Health Grand Rapids Hospitals - Butterworth Hospital; 🇺🇸 Grand Rapids, Michigan, United States

Trinity Health Grand Rapids Hospital; 🇺🇸 Grand Rapids, Michigan, United States

Bronson Methodist Hospital; 🇺🇸 Kalamazoo, Michigan, United States

West Michigan Cancer Center; 🇺🇸 Kalamazoo, Michigan, United States

Karmanos Cancer Institute at McLaren Greater Lansing; 🇺🇸 Lansing, Michigan, United States

University of Michigan Health - Sparrow Lansing; 🇺🇸 Lansing, Michigan, United States

Trinity Health Saint Mary Mercy Livonia Hospital; 🇺🇸 Livonia, Michigan, United States

Trinity Health Muskegon Hospital; 🇺🇸 Muskegon, Michigan, United States

Corewell Health Lakeland Hospitals - Niles Hospital; 🇺🇸 Niles, Michigan, United States

Cancer and Hematology Centers of Western Michigan - Norton Shores; 🇺🇸 Norton Shores, Michigan, United States

Henry Ford Medical Center-Columbus; 🇺🇸 Novi, Michigan, United States

McLaren Cancer Institute-Northern Michigan; 🇺🇸 Petoskey, Michigan, United States

Corewell Health Reed City Hospital; 🇺🇸 Reed City, Michigan, United States

MyMichigan Medical Center Saginaw; 🇺🇸 Saginaw, Michigan, United States

Oncology Hematology Associates of Saginaw Valley PC; 🇺🇸 Saginaw, Michigan, United States

Corewell Health Lakeland Hospitals - Marie Yeager Cancer Center; 🇺🇸 Saint Joseph, Michigan, United States

Corewell Health Lakeland Hospitals - Saint Joseph Hospital; 🇺🇸 Saint Joseph, Michigan, United States

MyMichigan Medical Center Tawas; 🇺🇸 Tawas City, Michigan, United States

Munson Medical Center; 🇺🇸 Traverse City, Michigan, United States

Henry Ford West Bloomfield Hospital; 🇺🇸 West Bloomfield, Michigan, United States

Saint Mary's Oncology/Hematology Associates of West Branch; 🇺🇸 West Branch, Michigan, United States

University of Michigan Health - West; 🇺🇸 Wyoming, Michigan, United States

Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus; 🇺🇸 Ypsilanti, Michigan, United States

Sanford Joe Lueken Cancer Center; 🇺🇸 Bemidji, Minnesota, United States

Mercy Hospital; 🇺🇸 Coon Rapids, Minnesota, United States

Fairview Southdale Hospital; 🇺🇸 Edina, Minnesota, United States

Abbott-Northwestern Hospital; 🇺🇸 Minneapolis, Minnesota, United States

United Hospital; 🇺🇸 Saint Paul, Minnesota, United States

University of Mississippi Medical Center; 🇺🇸 Jackson, Mississippi, United States

Saint Francis Medical Center; 🇺🇸 Cape Girardeau, Missouri, United States

MU Health - University Hospital/Ellis Fischel Cancer Center; 🇺🇸 Columbia, Missouri, United States

Siteman Cancer Center at West County Hospital; 🇺🇸 Creve Coeur, Missouri, United States

Parkland Health Center - Farmington; 🇺🇸 Farmington, Missouri, United States

MU Health Care Goldschmidt Cancer Center; 🇺🇸 Jefferson City, Missouri, United States

University Health Truman Medical Center; 🇺🇸 Kansas City, Missouri, United States

Kansas City Veterans Affairs Medical Center; 🇺🇸 Kansas City, Missouri, United States

University of Kansas Cancer Center - North; 🇺🇸 Kansas City, Missouri, United States

University of Kansas Cancer Center - Lee's Summit; 🇺🇸 Lee's Summit, Missouri, United States

University of Kansas Cancer Center at North Kansas City Hospital; 🇺🇸 North Kansas City, Missouri, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

Veteran's Affairs Medical Center - Saint Louis; 🇺🇸 Saint Louis, Missouri, United States

Mercy Hospital South; 🇺🇸 Saint Louis, Missouri, United States

Siteman Cancer Center-South County; 🇺🇸 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

Mercy Hospital Saint Louis; 🇺🇸 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

Missouri Baptist Sullivan Hospital; 🇺🇸 Sullivan, Missouri, United States

BJC Outpatient Center at Sunset Hills; 🇺🇸 Sunset Hills, Missouri, United States

Community Hospital of Anaconda; 🇺🇸 Anaconda, Montana, United States

Billings Clinic Cancer Center; 🇺🇸 Billings, Montana, United States

Bozeman Health Deaconess Hospital; 🇺🇸 Bozeman, Montana, United States

Benefis Sletten Cancer Institute; 🇺🇸 Great Falls, Montana, United States

Logan Health Medical Center; 🇺🇸 Kalispell, Montana, United States

Community Medical Center; 🇺🇸 Toms River, New Jersey, United States

Nebraska Medicine-Bellevue; 🇺🇸 Bellevue, Nebraska, United States

Nebraska Medicine-Village Pointe; 🇺🇸 Omaha, Nebraska, United States

University of Nebraska Medical Center; 🇺🇸 Omaha, Nebraska, United States

OptumCare Cancer Care at Seven Hills; 🇺🇸 Henderson, Nevada, United States

OptumCare Cancer Care at Charleston; 🇺🇸 Las Vegas, Nevada, United States

OptumCare Cancer Care at Fort Apache; 🇺🇸 Las Vegas, Nevada, United States

New Hampshire Oncology Hematology PA-Concord; 🇺🇸 Concord, New Hampshire, United States

Solinsky Center for Cancer Care; 🇺🇸 Manchester, New Hampshire, United States

Memorial Sloan Kettering Basking Ridge; 🇺🇸 Basking Ridge, New Jersey, United States

Jefferson Cherry Hill Hospital; 🇺🇸 Cherry Hill, New Jersey, United States

Hackensack University Medical Center; 🇺🇸 Hackensack, New Jersey, United States

Monmouth Medical Center Southern Campus; 🇺🇸 Lakewood, New Jersey, United States

Monmouth Medical Center; 🇺🇸 Long Branch, New Jersey, United States

Southern Ocean County Medical Center; 🇺🇸 Manahawkin, New Jersey, United States

Memorial Sloan Kettering Monmouth; 🇺🇸 Middletown, New Jersey, United States

Memorial Sloan Kettering Bergen; 🇺🇸 Montvale, New Jersey, United States

Rutgers Cancer Institute of New Jersey; 🇺🇸 New Brunswick, New Jersey, United States

Sidney Kimmel Cancer Center Washington Township; 🇺🇸 Sewell, New Jersey, United States

University of New Mexico Cancer Center; 🇺🇸 Albuquerque, New Mexico, United States

Presbyterian Kaseman Hospital; 🇺🇸 Albuquerque, New Mexico, United States

Presbyterian Rust Medical Center/Jorgensen Cancer Center; 🇺🇸 Rio Rancho, New Mexico, United States

Montefiore Medical Center-Einstein Campus; 🇺🇸 Bronx, New York, United States

Maimonides Medical Center; 🇺🇸 Brooklyn, New York, United States

Roswell Park Cancer Institute; 🇺🇸 Buffalo, New York, United States

Memorial Sloan Kettering Commack; 🇺🇸 Commack, New York, United States

Glens Falls Hospital; 🇺🇸 Glens Falls, New York, United States

Memorial Sloan Kettering Westchester; 🇺🇸 Harrison, New York, United States

NYU Langone Hospital - Long Island; 🇺🇸 Mineola, New York, United States

Mount Sinai Chelsea; 🇺🇸 New York, New York, United States

Laura and Isaac Perlmutter Cancer Center at NYU Langone; 🇺🇸 New York, New York, United States

Duke Cancer Center Raleigh; 🇺🇸 Raleigh, North Carolina, United States

Mount Sinai Hospital; 🇺🇸 New York, New York, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

Rochester General Hospital; 🇺🇸 Rochester, New York, United States

Unity Park Ridge Campus; 🇺🇸 Rochester, New York, United States

University of Rochester; 🇺🇸 Rochester, New York, United States

Memorial Sloan Kettering Nassau; 🇺🇸 Uniondale, New York, United States

Wilmot Cancer Institute at Webster; 🇺🇸 Webster, New York, United States

Duke Cancer Center Cary; 🇺🇸 Cary, North Carolina, United States

UNC Lineberger Comprehensive Cancer Center; 🇺🇸 Chapel Hill, North Carolina, United States

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States

FirstHealth of the Carolinas-Moore Regional Hospital; 🇺🇸 Pinehurst, North Carolina, United States

Wake Forest University Health Sciences; 🇺🇸 Winston-Salem, North Carolina, United States

Sanford Bismarck Medical Center; 🇺🇸 Bismarck, North Dakota, United States

Sanford Broadway Medical Center; 🇺🇸 Fargo, North Dakota, United States

Sanford Roger Maris Cancer Center; 🇺🇸 Fargo, North Dakota, United States

University of Cincinnati Cancer Center-UC Medical Center; 🇺🇸 Cincinnati, Ohio, United States

Ohio State University Comprehensive Cancer Center; 🇺🇸 Columbus, Ohio, United States

Columbus Oncology and Hematology Associates Inc; 🇺🇸 Columbus, Ohio, United States

Riverside Methodist Hospital; 🇺🇸 Columbus, Ohio, United States

Grant Medical Center; 🇺🇸 Columbus, Ohio, United States

Doctors Hospital; 🇺🇸 Columbus, Ohio, United States

Delaware Health Center-Grady Cancer Center; 🇺🇸 Delaware, Ohio, United States

Columbus Oncology and Hematology Associates; 🇺🇸 Dublin, Ohio, United States

Dublin Methodist Hospital; 🇺🇸 Dublin, Ohio, United States

OhioHealth Mansfield Hospital; 🇺🇸 Mansfield, Ohio, United States

OhioHealth Marion General Hospital; 🇺🇸 Marion, Ohio, United States

OhioHealth Pickerington Methodist Hospital; 🇺🇸 Pickerington, Ohio, United States

ProMedica Flower Hospital; 🇺🇸 Sylvania, Ohio, United States

University of Cincinnati Cancer Center-West Chester; 🇺🇸 West Chester, Ohio, United States

OhioHealth Westerville Medical Campus/Westerville Cancer Center; 🇺🇸 Westerville, Ohio, United States

Cancer Centers of Southwest Oklahoma Research; 🇺🇸 Lawton, Oklahoma, United States

University of Oklahoma Health Sciences Center; 🇺🇸 Oklahoma City, Oklahoma, United States

Oklahoma Cancer Specialists and Research Institute-Tulsa; 🇺🇸 Tulsa, Oklahoma, United States

Saint Alphonsus Cancer Care Center-Ontario; 🇺🇸 Ontario, Oregon, United States

Providence Willamette Falls Medical Center; 🇺🇸 Oregon City, Oregon, United States

Providence Portland Medical Center; 🇺🇸 Portland, Oregon, United States

Providence Saint Vincent Medical Center; 🇺🇸 Portland, Oregon, United States

Oregon Health and Science University; 🇺🇸 Portland, Oregon, United States

Lehigh Valley Hospital-Cedar Crest; 🇺🇸 Allentown, Pennsylvania, United States

UPMC Altoona; 🇺🇸 Altoona, Pennsylvania, United States

Lehigh Valley Hospital - Muhlenberg; 🇺🇸 Bethlehem, Pennsylvania, United States

Pocono Medical Center; 🇺🇸 East Stroudsburg, Pennsylvania, United States

UPMC Hillman Cancer Center Erie; 🇺🇸 Erie, Pennsylvania, United States

UPMC Cancer Centers - Arnold Palmer Pavilion; 🇺🇸 Greensburg, Pennsylvania, United States

UPMC Pinnacle Cancer Center/Community Osteopathic Campus; 🇺🇸 Harrisburg, Pennsylvania, United States

UPMC Hillman Cancer Center at Rocco And Nancy Ortenzio Cancer Pavilion; 🇺🇸 Mechanicsburg, Pennsylvania, United States

UPMC Hillman Cancer Center - Monroeville; 🇺🇸 Monroeville, Pennsylvania, United States

University of Pennsylvania/Abramson Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

Thomas Jefferson University Hospital; 🇺🇸 Philadelphia, Pennsylvania, United States

Jefferson Torresdale Hospital; 🇺🇸 Philadelphia, Pennsylvania, United States

UPMC-Saint Margaret; 🇺🇸 Pittsburgh, Pennsylvania, 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

Reading Hospital; 🇺🇸 West Reading, Pennsylvania, United States

Asplundh Cancer Pavilion; 🇺🇸 Willow Grove, Pennsylvania, United States

Smilow Cancer Hospital Care Center - Westerly; 🇺🇸 Westerly, Rhode Island, United States

Prisma Health Cancer Institute - Spartanburg; 🇺🇸 Boiling Springs, South Carolina, United States

Medical University of South Carolina; 🇺🇸 Charleston, South Carolina, United States

Prisma Health Cancer Institute - Easley; 🇺🇸 Easley, South Carolina, United States

Prisma Health Cancer Institute - Butternut; 🇺🇸 Greenville, South Carolina, United States

Prisma Health Cancer Institute - Faris; 🇺🇸 Greenville, South Carolina, United States

Prisma Health Greenville Memorial Hospital; 🇺🇸 Greenville, South Carolina, United States

Prisma Health Cancer Institute - Eastside; 🇺🇸 Greenville, South Carolina, United States

Ben Taub General Hospital; 🇺🇸 Houston, Texas, United States

Michael E DeBakey VA Medical Center; 🇺🇸 Houston, Texas, United States

Prisma Health Cancer Institute - Greer; 🇺🇸 Greer, South Carolina, United States

Prisma Health Cancer Institute - Seneca; 🇺🇸 Seneca, South Carolina, 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

The West Clinic - Wolf River; 🇺🇸 Germantown, Tennessee, United States

Vanderbilt University/Ingram Cancer Center; 🇺🇸 Nashville, Tennessee, United States

UT Southwestern Simmons Cancer Center - RedBird; 🇺🇸 Dallas, Texas, United States

UT Southwestern/Simmons Cancer Center-Dallas; 🇺🇸 Dallas, Texas, United States

UT Southwestern/Simmons Cancer Center-Fort Worth; 🇺🇸 Fort Worth, Texas, United States

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center; 🇺🇸 Houston, Texas, United States

UT Southwestern Clinical Center at Richardson/Plano; 🇺🇸 Richardson, Texas, United States

Central Vermont Medical Center/National Life Cancer Treatment; 🇺🇸 Berlin, Vermont, United States

University of Vermont Medical Center; 🇺🇸 Burlington, Vermont, United States

University of Vermont and State Agricultural College; 🇺🇸 Burlington, Vermont, United States

University of Virginia Cancer Center; 🇺🇸 Charlottesville, Virginia, United States

Virginia Commonwealth University/Massey Cancer Center; 🇺🇸 Richmond, Virginia, United States

VCU Community Memorial Health Center; 🇺🇸 South Hill, Virginia, United States

Virginia Mason Medical Center; 🇺🇸 Seattle, Washington, United States

West Virginia University Charleston Division; 🇺🇸 Charleston, West Virginia, United States

Aurora Saint Luke's South Shore; 🇺🇸 Cudahy, Wisconsin, United States

Aurora Cancer Care-Grafton; 🇺🇸 Grafton, Wisconsin, United States

VCU Massey Cancer Center at Stony Point; 🇺🇸 Richmond, Virginia, United States

Saint Vincent Hospital Cancer Center Green Bay; 🇺🇸 Green Bay, Wisconsin, United States

Saint Vincent Hospital Cancer Center at Saint Mary's; 🇺🇸 Green Bay, Wisconsin, United States

Aurora BayCare Medical Center; 🇺🇸 Green Bay, Wisconsin, United States

University of Wisconsin Carbone Cancer Center - Eastpark Medical Center; 🇺🇸 Madison, Wisconsin, United States

University of Wisconsin Carbone Cancer Center - University Hospital; 🇺🇸 Madison, Wisconsin, United States

Aurora Bay Area Medical Group-Marinette; 🇺🇸 Marinette, Wisconsin, United States

Aurora Saint Luke's Medical Center; 🇺🇸 Milwaukee, Wisconsin, United States

Medical College of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States

Aurora Sinai Medical Center; 🇺🇸 Milwaukee, Wisconsin, United States

ProHealth D N Greenwald Center; 🇺🇸 Mukwonago, Wisconsin, United States

ProHealth Oconomowoc Memorial Hospital; 🇺🇸 Oconomowoc, Wisconsin, United States

Saint Vincent Hospital Cancer Center at Oconto Falls; 🇺🇸 Oconto Falls, Wisconsin, United States

Vince Lombardi Cancer Clinic - Oshkosh; 🇺🇸 Oshkosh, Wisconsin, United States

Saint Vincent Hospital Cancer Center at Sheboygan; 🇺🇸 Sheboygan, Wisconsin, United States

Vince Lombardi Cancer Clinic-Sheboygan; 🇺🇸 Sheboygan, Wisconsin, United States

Saint Vincent Hospital Cancer Center at Sturgeon Bay; 🇺🇸 Sturgeon Bay, Wisconsin, United States

Aurora Medical Center in Summit; 🇺🇸 Summit, Wisconsin, United States

Vince Lombardi Cancer Clinic-Two Rivers; 🇺🇸 Two Rivers, Wisconsin, United States

ProHealth Waukesha Memorial Hospital; 🇺🇸 Waukesha, Wisconsin, United States

UW Cancer Center at ProHealth Care; 🇺🇸 Waukesha, Wisconsin, United States

Aurora Cancer Care-Milwaukee West; 🇺🇸 Wauwatosa, Wisconsin, United States

Aurora West Allis Medical Center; 🇺🇸 West Allis, Wisconsin, United States

BCCA-Vancouver Cancer Centre; 🇨🇦 Vancouver, British Columbia, Canada