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
- Conditions
- Stage II Bladder Urothelial Carcinoma AJCC v6 and v7Stage IV Bladder Urothelial Carcinoma AJCC v7Muscle Invasive Bladder Urothelial CarcinomaStage III Bladder Urothelial Carcinoma AJCC v6 and v7
- Interventions
- Procedure: Biospecimen CollectionProcedure: Computed TomographyOther: cfDNA or ctDNA MeasurementProcedure: Magnetic Resonance ImagingOther: Quality-of-Life AssessmentOther: Questionnaire Administration
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 1190
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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)
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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
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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
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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)
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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.:
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(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
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(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
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(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).
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(ii) Patients who received cisplatin-based neoadjuvant chemotherapy: ypT2-ypT4 or ypT0/x-pT4/N+ on cystectomy
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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
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PRE-REGISTRATION: Age >= 18 years
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PRE-REGISTRATION: ECOG Performance Status 0-2
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PRE-REGISTRATION: Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects
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PRE-REGISTRATION: No postoperative/adjuvant systemic therapy after cystectomy
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PRE-REGISTRATION: No adjuvant radiation after cystectomy
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PRE-REGISTRATION: No treatment with any other type of investigational agent =< 4 weeks before pre-registration
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PRE-REGISTRATION: Not have ever received prior treatment with PD-1/PD-L1 blockade.
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PRE-REGISTRATION: Not have ever received prior treatment with LAG-3 blockade.
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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
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PRE-REGISTRATION: Absolute Neutrophil Count (ANC) >= 1,200/mm^3
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PRE-REGISTRATION: Platelet count >= 100,000/mm^3
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PRE-REGISTRATION: Hemoglobin >= 8 g/dL
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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
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PRE-REGISTRATION: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN
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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)
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PRE-REGISTRATION: For women of childbearing potential only: A negative urine or serum pregnancy test done =< 14 days prior to pre-registration is required
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PRE-REGISTRATION: Not currently requiring hemodialysis
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PRE-REGISTRATION: No current or prior history of myocarditis
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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.
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PRE-REGISTRATION: Patients with vitiligo, endocrine deficiencies including type I diabetes mellitus, thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible.
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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.
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PRE-REGISTRATION: No current pneumonitis or prior history of non-infectious pneumonitis that required steroids within the previous 5 years.
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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).
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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.
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PRE-REGISTRATION: Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible.
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PRE-REGISTRATION: No concurrent antineoplastic therapy.
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PRE-REGISTRATION: No current immunosuppressive agents (with the exception of corticosteroids as described below).
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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.
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REGISTRATION: Patient must have had radical cystectomy and lymph node dissection =< 18 weeks prior to registration.
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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
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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.
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REGISTRATION: No major surgery =< 3 weeks before registration.
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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
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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
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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[+]).
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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
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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.
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