Combination Chemotherapy, Bevacizumab, and/or Atezolizumab in Treating Patients With Deficient DNA Mismatch Repair Metastatic Colorectal Cancer, the COMMIT Study

Metastatic Colorectal Adenocarcinoma Clinical Trial

Official title:

Colorectal Cancer Metastatic dMMR/MSI-H Immuno-Therapy (COMMIT) Study: A Randomized Phase III Study of mFOLFOX6/Bevacizumab/Atezolizumab Combination Versus Single Agent Atezolizumab in the First-Line Treatment of Patients With Deficient DNA Mismatch Repair (dMMR)/Microsatellite Instability-High (MSI-H) Metastatic Colorectal Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02997228
• Other study ID #: NCI-2016-01961
• Secondary ID: NCI-2016-01961NR
• Status: Recruiting
• Phase: Phase 3
• Start date: January 19, 2018
• Est. completion date: November 30, 2024

Study information

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

Clinical Trial Summary

This phase III trial studies how well combination chemotherapy, bevacizumab, and/or atezolizumab work in treating patients with deficient deoxyribonucleic acid (DNA) mismatch repair colorectal cancer that has spread from where it first started (primary site) to other places in the body (metastatic). Chemotherapy drugs, such as fluorouracil, oxaliplatin, and leucovorin calcium, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Bevacizumab may stop or slow colorectal cancer by blocking the growth of new blood vessels necessary for tumor growth. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving combination chemotherapy, bevacizumab, and atezolizumab may work better in treating patients with colorectal cancer.

Description:

PRIMARY OBJECTIVE:

I. To determine the efficacy, based on progression-free survival (PFS), of fluorouracil, oxaliplatin, and leucovorin calcium (modified [m]FOLFOX6)/bevacizumab plus atezolizumab (combination) as compared to single agent atezolizumab.

SECONDARY OBJECTIVES:

I. To compare the overall survival. II. To compare the objective response rates (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

III. To determine the safety profiles of single agent atezolizumab and the combination of mFOLFOX6/bevacizumab/atezolizumab in patients with mismatch-repair deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC).

IV. To determine the duration of response. V. To determine the duration of stable disease. VI. To determine the rate of progression-free survival (PFS) at 12 months. VII. To evaluate the disease control rate (complete response [CR] + partial response [PR] + stable disease [SD]) at 12 months.

TRANSLATIONAL OBJECTIVE:

I. To bank tissue and blood samples for other future correlative studies from patients enrolled on the study.

OUTLINE: Patients are randomized to 1 of 3 arms.

ARM I: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on day 1, oxaliplatin IV over 2 hours on day 1 of cycles 1-10, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1 and 2. Treatment with oxaliplatin repeats every 2 weeks for up to 10 cycles in the absence of disease progression or unacceptable toxicity. Treatment of bevacizumab, leucovorin calcium, and fluorouracil repeat every 2 weeks for up to 48 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) with or without positron emission tomography (PET) or magnetic resonance imaging (MRI) throughout the trial. Patients may also undergo collection of optional blood samples throughout the trial. (CLOSED TO ACCRUAL)

ARM II: Patients receive atezolizumab IV over 30-60 minutes on day 1. Treatment repeats every 2 weeks for up to 48 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT with or without PET or MRI throughout the trial. Patients may also undergo collection of optional blood samples throughout the trial.

ARM III: Patients receive atezolizumab IV over 30-60 minutes on day 1. Treatment repeats every 2 weeks for up to 48 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive bevacizumab IV over 30-90 minutes on day 1, oxaliplatin IV over 2 hours on day 1 cycles 1-10, leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on day 1. Treatment with oxaliplatin repeats every 2 weeks for up to 10 cycles in the absence of disease progression or unacceptable toxicity. Treatment of bevacizumab, leucovorin calcium, and fluorouracil repeat every 2 weeks for up to 48 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT with or without PET or MRI throughout the trial. Patients may also undergo collection of optional blood samples throughout the trial.

After completion of study treatment, patients are followed up every 8 weeks for 18 months, and then every 12 weeks for up to 5 years.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: November 30, 2024
• Est. primary completion date: November 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• The patient must have signed and dated an Institutional Review Board (IRB)-approved consent form that conforms to federal and institutional guidelines

• Age >= 18 years

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

• Diagnosis of metastatic adenocarcinoma of colon or rectum without previous chemotherapy or any other systemic therapy for metastatic colorectal cancer except for one cycle of FOLFOX or capecitabine and oxaliplatin (CAPOX), either with or without bevacizumab prior to enrollment. Upon enrollment, the preceding single cycle of FOLFOX or FOLFOX + bevacizumab, if the patient received one, will not count towards patients' assessments per protocol. Cycle 1 day 1 (C1D1) of atezolizumab or C1D1 of mFOLFOX6/bevacizumab + atezolizumab will correspond to the first day the patient received therapy on trial

• Tumor determined to be mismatch-repair deficient (dMMR) by Clinical Laboratory Improvement Act (CLIA)-certified immunohistochemical (IHC) assay with a panel of all four IHC markers, including MLH1, MSH2, PMS2, and MSH6; alternatively, MSI-H diagnosed by polymerase chain reaction (PCR)-based assessment of microsatellite alterations (either Bethesda markers or Pentaplex panel) or by next-generation sequencing (NGS) are eligible

• Documentation by PET/CT scan, CT scan, or MRI that the patient has measurable metastatic disease per RECIST 1.1

• No immediate need for surgical intervention for the primary tumor or palliative diversion/bypass

• Absolute neutrophil count (ANC) must be >= 1500/mm^3 (obtained within 28 days prior randomization)

• Platelet count must be >= 100,000/mm^3 (obtained within 28 days prior randomization)

• Hemoglobin must be >= 8 g/dL (obtained within 28 days prior randomization)

• Total bilirubin must be =< 4 x ULN (upper limit of normal) (obtained within 28 days prior randomization); and

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be =< 3 x ULN for the lab with the following exception: for patients with documented liver metastases, AST and ALT must be =< 5 x ULN (obtained within 28 days prior randomization)

• Calculated creatinine clearance >= 30 mL/min (obtained within 28 days prior randomization)

• A urine sample tested for proteinuria by either the dipstick method, urinalysis (UA), or a urine protein creatinine (UPC) ratio:

• The dipstick method must indicate 0-1+ protein; if dipstick reading is >= 2+, a 24-hour urine must be done and it must demonstrate < 1.0 g of protein per 24 hours or a UPC ratio < 1.0

• A urine protein creatinine (UPC) ratio must be < 1.0; if the UPC ratio is >= 1.0 a 24-hour urine must be done and it must demonstrate < 1.0 g of protein per 24 hours

• Urinalysis must indicate < 30 mg/dl. If urinalysis >= 30 mg/dl, a 24-hour urine must be done and it must demonstrate < 1.0 g of protein per 24 hours or a UPC ratio < 1.0

• International normalized ratio of prothrombin time (INR) and prothrombin time (PT) must be =< 1.5 x ULN for the lab within 28 days before randomization; patients who are therapeutically treated with an agent such as warfarin may participate if they are on a stable dose and no underlying abnormality in coagulation parameters exists per medical history, regardless of PT/INR results

• Pregnancy test done within 28 days prior randomization must be negative (for women of childbearing potential only); pregnancy testing should be performed according to institutional standards; administration of atezolizumab or mFOLFOX6/bevacizumab/atezolizumab may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

• Women of child-bearing potential and men must agree to use adequate contraception methods that result in a failure rate of < 1% per year during the treatment period (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 5 months (150 days) after the last dose of atezolizumab, 6 months after the last dose of bevacizumab, and 6 months after the last dose of mFOLFOX6; a woman is considered to be of childbearing potential if she is not postmenopausal, has not reached a postmenopausal state (>= 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus); examples of contraceptive methods with a failure rate of < 1% per year include: bilateral tubal ligation; male partner sterilization; intrauterine devices; the reliability of sexual abstinence should be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception; men must refrain from donating sperm during this same period

Exclusion Criteria:

• Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies, fluoropyrimidines, folic acid derivatives or oxaliplatin

• Uncontrolled high blood pressure defined as systolic blood pressure (BP) > 150 mmHg or diastolic BP > 100 mmHg with or without anti-hypertensive medication; patients with initial BP elevations are eligible if initiation or adjustment of BP medication lowers pressure to meet entry criteria

• Documented New York Heart Association (NYHA) class III or IV congestive heart failure

• Serious or non-healing wound, skin ulcer, or bone fracture

• History of inherited bleeding diathesis, gastrointestinal (GI) perforation, significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis or symptomatic peripheral ischemia, transient ischemic attack [TIA], cerebrovascular accident [CVA] or arterial thrombotic event), abdominal fistula, intra-abdominal abscess, or active GI bleeding (with cause not addressed) within 6 months prior to randomization, or other medical condition in the opinion of the treating oncologist that makes the risk of cardiovascular or bleeding complications with bevacizumab use unacceptably high

• Other malignancies are excluded unless the patient has completed therapy for the malignancy >= 12 months prior to randomization and is considered disease-free; patients with the following cancers are eligible if diagnosed and treated within the past 12 months: in situ carcinomas or basal cell and squamous cell carcinoma of the skin

• Known DPD (dihydro pyrimidine dehydrogenase) deficiency

• Symptomatic peripheral sensory neuropathy >= grade 2 (Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5.0)

• Prior treatment with oxaliplatin chemotherapy within 6 months prior to randomization

• History of grade 2 hemoptysis (defined as 2.5 mL of bright red blood per episode) within 1 month prior to screening

• Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents; patients who have received prior treatment with anti-CTLA-4 may be enrolled provided the following requirements are met:

• Minimum of 12 weeks from the first dose of anti-CTLA-4 and > 6 weeks from the last dose to randomization

• No history of severe immune-related adverse effects (CTCAE grade 3 and 4) from anti-CTLA-4

• Treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 14 days prior to randomization; however,

• Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea; or chronic daily treatment with corticosteroids with a dose of =< 10 mg/day methylprednisolone equivalent) may be enrolled

• The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed

• Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease; however,

• Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HbsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible if polymerase chain reaction (PCR) for hepatits B virus (HBV) ribonucleic acid (RNA) is negative per local guidelines

• Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA per local guidelines

• History or risk of autoimmune disease, including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis; however,

• Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible

• Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible

• Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:

• Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations

• Rash must cover less than 10% of body surface area (BSA)

• Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)

• No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)

• History of idiopathic pulmonary fibrosis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or active or recently active (within 90 days of randomization) pneumonitis (including drug induced) that required systemic immunosuppressive therapy (i.e. corticosteroids, etc.). History of radiation pneumonitis in the radiation field (fibrosis) is permitted

• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

• Patients with known active tuberculosis (TB) are excluded

• Severe infections within 28 days prior to randomization, including but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia

• Signs or symptoms of infection within 14 days prior to randomization

• Received oral or intravenous (IV) antibiotics within 14 days prior to randomization; patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible

• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization or anticipation of need for a major surgical procedure during the course of the study

• The administration of a live, attenuated vaccine within 28 days prior to randomization

• Pregnant women are excluded from this study because atezolizumab is an agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with atezolizumab, breastfeeding should be discontinued if the mother is treated with atezolizumab; these potential risks may also apply to other agents used in this study; (Note: pregnancy testing should be performed within 28 days prior to randomization according to institutional standards for women of childbearing potential)

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

• Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Adenocarcinoma
• Stage IV Colorectal Cancer AJCC v7

Intervention

Drug:
• Atezolizumab
Given IV

Biological:
• Bevacizumab
Given IV

Procedure:
• Biospecimen Collection
Undergo collection of blood samples
• Computed Tomography
Undergo CT or CT/PET

Drug:
• Fluorouracil
Given IV
• Leucovorin
Given IV

Procedure:
• Magnetic Resonance Imaging
Undergo MRI

Drug:
• Oxaliplatin
Given IV

Procedure:
• Positron Emission Tomography
Undergo CT/PET

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

Locations

Country	Name	City	State
United States	Avera Cancer Institute-Aberdeen	Aberdeen	South Dakota
United States	Cleveland Clinic Akron General	Akron	Ohio
United States	Phoebe Putney Memorial Hospital	Albany	Georgia
United States	Presbyterian Kaseman Hospital	Albuquerque	New Mexico
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania
United States	Saint Luke's Cancer Center - Allentown	Allentown	Pennsylvania
United States	The Don and Sybil Harrington Cancer Center	Amarillo	Texas
United States	Mary Greeley Medical Center	Ames	Iowa
United States	McFarland Clinic - Ames	Ames	Iowa
United States	Community Hospital of Anaconda	Anaconda	Montana
United States	Kaiser Permanente-Anaheim	Anaheim	California
United States	AnMed Health Cancer Center	Anderson	South Carolina
United States	Trinity Health Saint Joseph Mercy Hospital Ann Arbor	Ann Arbor	Michigan
United States	Langlade Hospital and Cancer Center	Antigo	Wisconsin
United States	Ascension Saint Elizabeth Hospital	Appleton	Wisconsin
United States	ThedaCare Regional Cancer Center	Appleton	Wisconsin
United States	Duluth Clinic Ashland	Ashland	Wisconsin
United States	University Cancer and Blood Center LLC	Athens	Georgia
United States	Augusta Oncology Associates PC-D'Antignac	Augusta	Georgia
United States	Augusta Oncology Associates PC-Wheeler	Augusta	Georgia
United States	Augusta University Medical Center	Augusta	Georgia
United States	Harold Alfond Center for Cancer Care	Augusta	Maine
United States	Rocky Mountain Cancer Centers-Aurora	Aurora	Colorado
United States	UCHealth University of Colorado Hospital	Aurora	Colorado
United States	Kaiser Permanente-Baldwin Park	Baldwin Park	California
United States	Saint Louis Cancer and Breast Institute-Ballwin	Ballwin	Missouri
United States	Kaiser Permanente-Woodlawn Medical Center	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Flaget Memorial Hospital	Bardstown	Kentucky
United States	McLaren Cancer Institute-Bay City	Bay City	Michigan
United States	Beaufort Memorial Hospital	Beaufort	South Carolina
United States	Baptist Hospitals of Southeast Texas Cancer Center	Beaumont	Texas
United States	Waldo County General Hospital	Belfast	Maine
United States	Kaiser Permanente-Bellflower	Bellflower	California
United States	Strecker Cancer Center-Belpre	Belpre	Ohio
United States	Sanford Joe Lueken Cancer Center	Bemidji	Minnesota
United States	Saint Charles Health System	Bend	Oregon
United States	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	Saint Luke's University Hospital-Bethlehem Campus	Bethlehem	Pennsylvania
United States	University of Iowa Healthcare Cancer Services Quad Cities	Bettendorf	Iowa
United States	MaineHealth/SMHC Cancer Care and Blood Disorders-Biddeford	Biddeford	Maine
United States	Billings Clinic Cancer Center	Billings	Montana
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	McLaren Cancer Institute-Bloomfield	Bloomfield	Michigan
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Prisma Health Cancer Institute - Spartanburg	Boiling Springs	South Carolina
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	McFarland Clinic - Boone	Boone	Iowa
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Boulder Community Hospital	Boulder	Colorado
United States	Rocky Mountain Cancer Centers-Boulder	Boulder	Colorado
United States	Bozeman Health Deaconess Hospital	Bozeman	Montana
United States	Lafayette Family Cancer Center-EMMC	Brewer	Maine
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Trinity Health Medical Center - Brighton	Brighton	Michigan
United States	Bristol Regional Medical Center	Bristol	Tennessee
United States	Wellmont Medical Associates-Bristol	Bristol	Virginia
United States	Ascension Southeast Wisconsin Hospital - Elmbrook Campus	Brookfield	Wisconsin
United States	Henry Ford Cancer Institute-Downriver	Brownstown	Michigan
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Kaiser Permanente-Burke Medical Center	Burke	Virginia
United States	Minnesota Oncology - Burnsville	Burnsville	Minnesota
United States	Saint Alphonsus Cancer Care Center-Caldwell	Caldwell	Idaho
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Trinity Health Medical Center - Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Illinois CancerCare-Carthage	Carthage	Illinois
United States	Mercy Hospital	Cedar Rapids	Iowa
United States	Oncology Associates at Mercy Medical Center	Cedar Rapids	Iowa
United States	Dayton Physicians LLC-Miami Valley South	Centerville	Ohio
United States	Miami Valley Hospital South	Centerville	Ohio
United States	Centralia Oncology Clinic	Centralia	Illinois
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	West Virginia University Charleston Division	Charleston	West Virginia
United States	Chelsea Hospital	Chelsea	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	Cheyenne Regional Medical Center-West	Cheyenne	Wyoming
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Adena Regional Medical Center	Chillicothe	Ohio
United States	University of Cincinnati Cancer Center-UC Medical Center	Cincinnati	Ohio
United States	Clackamas Radiation Oncology Center	Clackamas	Oregon
United States	Providence Cancer Institute Clackamas Clinic	Clackamas	Oregon
United States	Hematology Oncology Consultants-Clarkston	Clarkston	Michigan
United States	McLaren Cancer Institute-Clarkston	Clarkston	Michigan
United States	Newland Medical Associates-Clarkston	Clarkston	Michigan
United States	Cleveland Clinic Cancer Center/Fairview Hospital	Cleveland	Ohio
United States	Southeastern Medical Oncology Center-Clinton	Clinton	North Carolina
United States	Henry Ford Macomb Hospital-Clinton Township	Clinton Township	Michigan
United States	Mercy Cancer Center-West Lakes	Clive	Iowa
United States	Mission Cancer and Blood - West Des Moines	Clive	Iowa
United States	Billings Clinic-Cody	Cody	Wyoming
United States	Kootenai Health - Coeur d'Alene	Coeur d'Alene	Idaho
United States	Baptist Memorial Hospital and Cancer Center-Collierville	Collierville	Tennessee
United States	Memorial Hospital North	Colorado Springs	Colorado
United States	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado
United States	UCHealth Memorial Hospital Central	Colorado Springs	Colorado
United States	MU Health - University Hospital/Ellis Fischel Cancer Center	Columbia	Missouri
United States	Columbus Oncology and Hematology Associates Inc	Columbus	Ohio
United States	Doctors Hospital	Columbus	Ohio
United States	Grant Medical Center	Columbus	Ohio
United States	Mount Carmel East Hospital	Columbus	Ohio
United States	Mount Carmel Health Center West	Columbus	Ohio
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Riverside Methodist Hospital	Columbus	Ohio
United States	The Mark H Zangmeister Center	Columbus	Ohio
United States	John Muir Medical Center-Concord	Concord	California
United States	MD Anderson in The Woodlands	Conroe	Texas
United States	Cookeville Regional Medical Center	Cookeville	Tennessee
United States	Parkland Memorial Hospital	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Danbury Hospital	Danbury	Connecticut
United States	Carle at The Riverfront	Danville	Illinois
United States	Miami Valley Hospital	Dayton	Ohio
United States	Henry Ford Medical Center-Fairlane	Dearborn	Michigan
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Essentia Health - Deer River Clinic	Deer River	Minnesota
United States	Delaware Health Center-Grady Cancer Center	Delaware	Ohio
United States	Grady Memorial Hospital	Delaware	Ohio
United States	Denver Health Medical Center	Denver	Colorado
United States	National Jewish Health-Main Campus	Denver	Colorado
United States	Porter Adventist Hospital	Denver	Colorado
United States	Rocky Mountain Cancer Centers-Midtown	Denver	Colorado
United States	Rocky Mountain Cancer Centers-Rose	Denver	Colorado
United States	SCL Health Saint Joseph Hospital	Denver	Colorado
United States	Broadlawns Medical Center	Des Moines	Iowa
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Mission Cancer and Blood - Des Moines	Des Moines	Iowa
United States	Mission Cancer and Blood - Laurel	Des Moines	Iowa
United States	Henry Ford Hospital	Detroit	Michigan
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Illinois CancerCare-Dixon	Dixon	Illinois
United States	Essentia Health Cancer Center	Duluth	Minnesota
United States	Prisma Health Cancer Institute - Easley	Easley	South Carolina
United States	Saint Luke's Hospital-Anderson Campus	Easton	Pennsylvania
United States	University of Maryland Shore Medical Center at Easton	Easton	Maryland
United States	Marshfield Medical Center-EC Cancer Center	Eau Claire	Wisconsin
United States	STCC at DHR Health Institute for Research and Development	Edinburg	Texas
United States	Swedish Cancer Institute-Edmonds	Edmonds	Washington
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Arnot Ogden Medical Center/Falck Cancer Center	Elmira	New York
United States	Mountain Blue Cancer Care Center - Swedish	Englewood	Colorado
United States	Swedish Medical Center	Englewood	Colorado
United States	Saint Vincent Hospital	Erie	Pennsylvania
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	Weisberg Cancer Treatment Center	Farmington Hills	Michigan
United States	Augusta Health Center for Cancer and Blood Disorders	Fishersville	Virginia
United States	McLaren Cancer Institute-Flint	Flint	Michigan
United States	Singh and Arora Hematology Oncology PC	Flint	Michigan
United States	Kaiser Permanente-Fontana	Fontana	California
United States	Cancer Care and Hematology-Fort Collins	Fort Collins	Colorado
United States	Poudre Valley Hospital	Fort Collins	Colorado
United States	McFarland Clinic - Trinity Cancer Center	Fort Dodge	Iowa
United States	Trinity Regional Medical Center	Fort Dodge	Iowa
United States	Broward Health Medical Center	Fort Lauderdale	Florida
United States	Regional Cancer Center-Lee Memorial Health System	Fort Myers	Florida
United States	Beebe South Coastal Health Campus	Frankford	Delaware
United States	Ascension Saint Francis - Reiman Cancer Center	Franklin	Wisconsin
United States	Saint Luke's Cancer Institute - Fruitland	Fruitland	Idaho
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Kaiser Permanente-Gaithersburg Medical Center	Gaithersburg	Maryland
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	NorthShore University HealthSystem-Glenbrook Hospital	Glenview	Illinois
United States	National Jewish Health-Western Hematology Oncology	Golden	Colorado
United States	Southeastern Medical Oncology Center-Goldsboro	Goldsboro	North Carolina
United States	Altru Cancer Center	Grand Forks	North Dakota
United States	Corewell Health Grand Rapids Hospitals - Butterworth Hospital	Grand Rapids	Michigan
United States	Benefis Sletten Cancer Institute	Great Falls	Montana
United States	Great Falls Clinic	Great Falls	Montana
United States	Banner North Colorado Medical Center	Greeley	Colorado
United States	UCHealth Greeley Hospital	Greeley	Colorado
United States	Bellin Memorial Hospital	Green Bay	Wisconsin
United States	Prisma Health Cancer Institute - Butternut	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Eastside	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Faris	Greenville	South Carolina
United States	Saint Francis Cancer Center	Greenville	South Carolina
United States	Saint Francis Hospital	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Greer	Greer	South Carolina
United States	Baptist Cancer Center-Grenada	Grenada	Mississippi
United States	The Cancer Institute of New Jersey Hamilton	Hamilton	New Jersey
United States	Kaiser Permanente - Harbor City	Harbor City	California
United States	UPMC Pinnacle Cancer Center/Community Osteopathic Campus	Harrisburg	Pennsylvania
United States	Hartford Hospital	Hartford	Connecticut
United States	HaysMed	Hays	Kansas
United States	Saint Peter's Community Hospital	Helena	Montana
United States	OptumCare Cancer Care at Seven Hills	Henderson	Nevada
United States	Margaret R Pardee Memorial Hospital	Hendersonville	North Carolina
United States	Essentia Health Hibbing Clinic	Hibbing	Minnesota
United States	NorthShore University HealthSystem-Highland Park Hospital	Highland Park	Illinois
United States	Houston Methodist Hospital	Houston	Texas
United States	Lyndon Baines Johnson General Hospital	Houston	Texas
United States	M D Anderson Cancer Center	Houston	Texas
United States	MD Anderson West Houston	Houston	Texas
United States	Community Cancer Center East	Indianapolis	Indiana
United States	Community Cancer Center North	Indianapolis	Indiana
United States	Community Cancer Center South	Indianapolis	Indiana
United States	Franciscan Health Indianapolis	Indianapolis	Indiana
United States	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	Kaiser Permanente-Irvine	Irvine	California
United States	Swedish Cancer Institute-Issaquah	Issaquah	Washington
United States	Allegiance Health	Jackson	Michigan
United States	Baptist MD Anderson Cancer Center	Jacksonville	Florida
United States	Southeastern Medical Oncology Center-Jacksonville	Jacksonville	North Carolina
United States	Mercyhealth Hospital and Cancer Center - Janesville	Janesville	Wisconsin
United States	McFarland Clinic - Jefferson	Jefferson	Iowa
United States	Jefferson Hospital	Jefferson Hills	Pennsylvania
United States	Wellmont Medical Associates Oncology and Hematology-Johnson City	Johnson City	Tennessee
United States	University of Wisconsin Carbone Cancer Center - Johnson Creek	Johnson Creek	Wisconsin
United States	NEA Baptist Memorial Hospital and Fowler Family Cancer Center - Jonesboro	Jonesboro	Arkansas
United States	Freeman Health System	Joplin	Missouri
United States	Mercy Hospital Joplin	Joplin	Missouri
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	University Health Truman Medical Center	Kansas City	Missouri
United States	ECU Health Oncology Kenansville	Kenansville	North Carolina
United States	Ochsner Medical Center Kenner	Kenner	Louisiana
United States	Greater Dayton Cancer Center	Kettering	Ohio
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	Kingman Regional Medical Center	Kingman	Arizona
United States	Ballad Health Cancer Care - Kingsport	Kingsport	Tennessee
United States	Wellmont Holston Valley Hospital and Medical Center	Kingsport	Tennessee
United States	ECU Health Oncology Kinston	Kinston	North Carolina
United States	Community Howard Regional Health	Kokomo	Indiana
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	Franciscan Saint Elizabeth Health - Lafayette East	Lafayette	Indiana
United States	Northwell Health/Center for Advanced Medicine	Lake Success	New York
United States	Fairfield Medical Center	Lancaster	Ohio
United States	Karmanos Cancer Institute at McLaren Greater Lansing	Lansing	Michigan
United States	University of Michigan Health - Sparrow Lansing	Lansing	Michigan
United States	McLaren Cancer Institute-Lapeer Region	Lapeer	Michigan
United States	Kaiser Permanente - Largo Medical Center	Largo	Maryland
United States	Memorial Medical Center - Las Cruces	Las Cruces	New Mexico
United States	OptumCare Cancer Care at Charleston	Las Vegas	Nevada
United States	OptumCare Cancer Care at Fort Apache	Las Vegas	Nevada
United States	OptumCare Cancer Care at MountainView	Las Vegas	Nevada
United States	Lawrence Memorial Hospital	Lawrence	Kansas
United States	Cancer Centers of Southwest Oklahoma Research	Lawton	Oklahoma
United States	MD Anderson League City	League City	Texas
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	Baptist Health Lexington	Lexington	Kentucky
United States	Saint Joseph Hospital East	Lexington	Kentucky
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Rocky Mountain Cancer Centers-Littleton	Littleton	Colorado
United States	Hope Cancer Clinic	Livonia	Michigan
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Rocky Mountain Cancer Centers-Sky Ridge	Lone Tree	Colorado
United States	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California
United States	Kaiser Permanente West Los Angeles	Los Angeles	California
United States	Norton Audubon Hospital and Medical Campus	Louisville	Kentucky
United States	Norton Brownsboro Hospital and Medical Campus	Louisville	Kentucky
United States	Norton Hospital Pavilion and Medical Campus	Louisville	Kentucky
United States	Banner McKee Medical Center	Loveland	Colorado
United States	Medical Center of the Rockies	Loveland	Colorado
United States	Lowell General Hospital	Lowell	Massachusetts
United States	Kaiser Permanente Lutherville - Timonium Medical Center	Lutherville	Maryland
United States	Centra Alan B Pearson Regional Cancer Center	Lynchburg	Virginia
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	University of Wisconsin Carbone Cancer Center - University Hospital	Madison	Wisconsin
United States	Dartmouth Cancer Center - Manchester	Manchester	New Hampshire
United States	Cleveland Clinic Cancer Center Mansfield	Mansfield	Ohio
United States	OhioHealth Mansfield Hospital	Mansfield	Ohio
United States	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota
United States	Saint John's Hospital - Healtheast	Maplewood	Minnesota
United States	Marietta Memorial Hospital	Marietta	Ohio
United States	OhioHealth Marion General Hospital	Marion	Ohio
United States	McFarland Clinic - Marshalltown	Marshalltown	Iowa
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Fremont - Rideout Cancer Center	Marysville	California
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	Hillcrest Hospital Cancer Center	Mayfield Heights	Ohio
United States	Loyola University Medical Center	Maywood	Illinois
United States	Kaiser Permanente Tysons Corner Medical Center	McLean	Virginia
United States	Aspirus Medford Hospital	Medford	Wisconsin
United States	Baptist Memorial Hospital and Cancer Center-Memphis	Memphis	Tennessee
United States	Midstate Medical Center	Meriden	Connecticut
United States	Saint Luke's Cancer Institute - Meridian	Meridian	Idaho
United States	Woodland Cancer Care Center	Michigan City	Indiana
United States	Health Partners Inc	Minneapolis	Minnesota
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	Community Medical Center	Missoula	Montana
United States	Memorial Medical Center	Modesto	California
United States	Forbes Hospital	Monroeville	Pennsylvania
United States	Franciscan Health Mooresville	Mooresville	Indiana
United States	West Virginia University Healthcare	Morgantown	West Virginia
United States	Morristown Medical Center	Morristown	New Jersey
United States	McLaren Cancer Institute-Macomb	Mount Clemens	Michigan
United States	McLaren Cancer Institute-Central Michigan	Mount Pleasant	Michigan
United States	Good Samaritan Regional Health Center	Mount Vernon	Illinois
United States	Knox Community Hospital	Mount Vernon	Ohio
United States	ProHealth D N Greenwald Center	Mukwonago	Wisconsin
United States	Saint Alphonsus Cancer Care Center-Nampa	Nampa	Idaho
United States	Saint Luke's Cancer Institute - Nampa	Nampa	Idaho
United States	Dartmouth Cancer Center - Nashua	Nashua	New Hampshire
United States	Allegheny Valley Hospital	Natrona Heights	Pennsylvania
United States	Baptist Memorial Hospital and Cancer Center-Union County	New Albany	Mississippi
United States	The Hospital of Central Connecticut	New Britain	Connecticut
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	Cancer Center of Western Wisconsin	New Richmond	Wisconsin
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Licking Memorial Hospital	Newark	Ohio
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	Providence Newberg Medical Center	Newberg	Oregon
United States	CTCA at Southeastern Regional Medical Center	Newnan	Georgia
United States	Southwest VA Regional Cancer Center	Norton	Virginia
United States	William Backus Hospital	Norwich	Connecticut
United States	Henry Ford Medical Center-Columbus	Novi	Michigan
United States	Cancer Care Center of O'Fallon	O'Fallon	Illinois
United States	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Olathe Health Cancer Center	Olathe	Kansas
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	Kaiser Permanente-Ontario	Ontario	California
United States	Saint Alphonsus Cancer Care Center-Ontario	Ontario	Oregon
United States	Saint Joseph Hospital - Orange	Orange	California
United States	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California
United States	Providence Willamette Falls Medical Center	Oregon City	Oregon
United States	AdventHealth Orlando	Orlando	Florida
United States	Ascension Mercy Hospital	Oshkosh	Wisconsin
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	Baptist Memorial Hospital and Cancer Center-Oxford	Oxford	Mississippi
United States	Kaiser Permanente - Panorama City	Panorama City	California
United States	The Valley Hospital - Luckow Pavilion	Paramus	New Jersey
United States	Camden Clark Medical Center	Parkersburg	West Virginia
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	McLaren Cancer Institute-Northern Michigan	Petoskey	Michigan
United States	FirstHealth of the Carolinas-Moore Regional Hospital	Pinehurst	North Carolina
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	West Penn Hospital	Pittsburgh	Pennsylvania
United States	Newland Medical Associates-Pontiac	Pontiac	Michigan
United States	Trinity Health Saint Joseph Mercy Oakland Hospital	Pontiac	Michigan
United States	Baptist Regional Cancer Network-Cancer Center of Southeast Texas	Port Arthur	Texas
United States	McLaren-Port Huron	Port Huron	Michigan
United States	Jefferson Healthcare	Port Townsend	Washington
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	Southern Ohio Medical Center	Portsmouth	Ohio
United States	Kootenai Clinic Cancer Services - Post Falls	Post Falls	Idaho
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Saint Luke's Hospital-Quakertown Campus	Quakertown	Pennsylvania
United States	Ascension All Saints Hospital	Racine	Wisconsin
United States	Beebe Health Campus	Rehoboth Beach	Delaware
United States	Renown Regional Medical Center	Reno	Nevada
United States	Ascension Saint Mary's Hospital	Rhinelander	Wisconsin
United States	Marshfield Medical Center-Rice Lake	Rice Lake	Wisconsin
United States	ECU Health Oncology Richlands	Richlands	North Carolina
United States	VCU Massey Cancer Center at Stony Point	Richmond	Virginia
United States	Virginia Cancer Institute	Richmond	Virginia
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Valley Health System Ridgewood Campus	Ridgewood	New Jersey
United States	Presbyterian Rust Medical Center/Jorgensen Cancer Center	Rio Rancho	New Mexico
United States	Kaiser Permanente-Riverside	Riverside	California
United States	University of Rochester	Rochester	New York
United States	Penobscot Bay Medical Center	Rockport	Maine
United States	Sutter Medical Center Sacramento	Sacramento	California
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Ascension Saint Mary's Hospital	Saginaw	Michigan
United States	Oncology Hematology Associates of Saginaw Valley PC	Saginaw	Michigan
United States	Dartmouth Cancer Center - North	Saint Johnsbury	Vermont
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Saint Louis Cancer and Breast Institute-South City	Saint Louis	Missouri
United States	Regions Hospital	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Salina Regional Health Center	Salina	Kansas
United States	Salinas Valley Memorial	Salinas	California
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	Kaiser Permanente-San Diego Mission	San Diego	California
United States	Kaiser Permanente-San Diego Zion	San Diego	California
United States	Kaiser Permanente-San Marcos	San Marcos	California
United States	Kootenai Clinic Cancer Services - Sandpoint	Sandpoint	Idaho
United States	Essentia Health Sandstone	Sandstone	Minnesota
United States	North Coast Cancer Care	Sandusky	Ohio
United States	MaineHealth/SMHC Cancer Care and Blood Disorders-Sanford	Sanford	Maine
United States	Swedish Medical Center-First Hill	Seattle	Washington
United States	Prisma Health Cancer Institute - Seneca	Seneca	South Carolina
United States	Avera Cancer Institute	Sioux Falls	South Dakota
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	Robert Wood Johnson University Hospital Somerset	Somerville	New Jersey
United States	VCU Community Memorial Health Center	South Hill	Virginia
United States	Maine Medical Partners - South Portland	South Portland	Maine
United States	Baptist Memorial Hospital and Cancer Center-Desoto	Southhaven	Mississippi
United States	Spartanburg Medical Center	Spartanburg	South Carolina
United States	MultiCare Deaconess Cancer and Blood Specialty Center - Downtown	Spokane	Washington
United States	MultiCare Deaconess Cancer and Blood Specialty Center - North	Spokane	Washington
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Springfield Clinic	Springfield	Illinois
United States	Marshfield Medical Center-River Region at Stevens Point	Stevens Point	Wisconsin
United States	MD Anderson in Sugar Land	Sugar Land	Texas
United States	Overlook Hospital	Summit	New Jersey
United States	ProMedica Flower Hospital	Sylvania	Ohio
United States	Ascension Saint Joseph Hospital	Tawas City	Michigan
United States	Scott and White Memorial Hospital	Temple	Texas
United States	Union Hospital	Terre Haute	Indiana
United States	National Jewish Health-Northern Hematology Oncology	Thornton	Colorado
United States	University of Kansas Health System Saint Francis Campus	Topeka	Kansas
United States	Munson Medical Center	Traverse City	Michigan
United States	Cancer Treatment Centers of America	Tulsa	Oklahoma
United States	Oklahoma Cancer Specialists and Research Institute-Tulsa	Tulsa	Oklahoma
United States	Saint Luke's Cancer Institute - Twin Falls	Twin Falls	Idaho
United States	Carle Cancer Center	Urbana	Illinois
United States	Essentia Health Virginia Clinic	Virginia	Minnesota
United States	John Muir Medical Center-Walnut Creek	Walnut Creek	California
United States	South Pointe Hospital	Warrensville Heights	Ohio
United States	Illinois CancerCare - Washington	Washington	Illinois
United States	Kaiser Permanente-Capitol Hill Medical Center	Washington	District of Columbia
United States	ProHealth Waukesha Memorial Hospital	Waukesha	Wisconsin
United States	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin
United States	Aspirus Regional Cancer Center	Wausau	Wisconsin
United States	Ascension Medical Group Southeast Wisconsin - Mayfair Road	Wauwatosa	Wisconsin
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 Cincinnati Cancer Center-West Chester	West Chester	Ohio
United States	Mercy Medical Center-West Lakes	West Des Moines	Iowa
United States	Reading Hospital	West Reading	Pennsylvania
United States	Saint Ann's Hospital	Westerville	Ohio
United States	Marshfield Medical Center - Weston	Weston	Wisconsin
United States	University of Kansas Hospital-Westwood Cancer Center	Westwood	Kansas
United States	Wexford Health and Wellness Pavilion	Wexford	Pennsylvania
United States	SCL Health Lutheran Medical Center	Wheat Ridge	Colorado
United States	Dickstein Cancer Treatment Center	White Plains	New York
United States	Presbyterian Intercommunity Hospital	Whittier	California
United States	Cancer Center of Kansas - Wichita	Wichita	Kansas
United States	Cancer Center of Kansas-Wichita Medical Arts Tower	Wichita	Kansas
United States	Asplundh Cancer Pavilion	Willow Grove	Pennsylvania
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	Aspirus Cancer Care - Wisconsin Rapids	Wisconsin Rapids	Wisconsin
United States	Kaiser Permanente-Caton Hill Medical Center	Woodbridge	Virginia
United States	Kaiser Permanente-Woodland Hills	Woodland Hills	California
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan
United States	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)	NRG Oncology

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Severity of fatigue	Will use the ITT population. Measured by the Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue questionnaire. Will be compared between the control arm (Chemo-bevacizumab [Bev]) and the experimental arm by means of ordinal logistic regression with adjustment for the corresponding baseline measurement and stratification variables. The comparison will be performed at the significance level of 0.05 (two-sided) and the clinical meaningfulness of the comparison will be considered.	At 16 weeks
Other	Physical functioning	Will use the ITT population. Measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life questionnaire (QLQ)-C30 physical functioning scale. Will be compared between the control arm (Chemo-Bev) and the experimental arm by means of ordinal logistic regression with adjustment for the corresponding baseline measurement and stratification variables. The comparison will be performed at the significance level of 0.05 (two-sided) and the clinical meaningfulness of the comparison will be considered.	At 16 weeks
Other	Health utility scores	Will use the ITT population. Will be measured using the EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire.	Up to 5 years
Other	Proportion of patients reporting each response option at each assessment timepoint by treatment arm for item GP5 from the Functional Assessment of Cancer Therapy - General (FACT-G)	Will use the ITT population.	Up to 5 years
Other	Intratumoral lymphocyte PD-L1+ expression (>= 1 % is positive) by immunohistochemistry (IHC) as a predictive biomarker of efficacy	Will use the ITT population.	Up to 5 years
Other	Efficacy dependent on the number of somatic mutations	Will use the ITT population.	Up to 5 years
Other	Efficacy in tumors with MLH1 silencing	Will use the ITT population.	Up to 5 years
Other	Change in quantification of cell free deoxyribonucleic acid (cfDNA) mutations	Will use the ITT population.	Baseline up to 5 years
Other	Development of progression or relapse to treatment in cfDNA	Will use the ITT population.	Up to 5 years
Other	Changes in T-cell repertoire diversity as a predictive biomarker of efficacy	Will use the ITT population.	Baseline up to 5 years
Other	PFS of patients with high levels of diversity	Compared to patients with low levels of diversity. Will use the ITT population.	Up to 5 years
Other	Change in T-cell diversity	Will use the ITT population.	Baseline to first restaging between immunotherapy arms and the standard of care arm
Other	Mechanism of immune resistance to PD-1 blockade in mismatch repair deficient (dMMR)/microsatellite instability-high metastatic colorectal cancer (mCRC) by comparative analysis of tumor samples collected	Will use the ITT population.	Baseline up to 5 years
Primary	Progression free survival (PFS)	The analysis set is intent-to-treat (ITT). The experimental arms will be compared to the control arm by the log-rank test stratified by BRAF status (V600E mutation or not), metastatic disease: (liver-only, extra-hepatic), and prior adjuvant therapy for colon cancer (yes, no). Hazard ratios and associated confidence intervals from a stratified Cox regression model will also be reported along with estimates of the distributions of time to PFS event by the method of Kaplan and Meier. Sensitivity analyses accounting for 2 or more consecutively missed scheduled tumor imaging scans before progression/death will also be conducted.	From the time from randomization until first confirmed progression or death from any cause, assessed up to 5 years
Secondary	Overall survival (OS)	Will be analyzed using the stratified log rank test and the ITT population. Kaplan-Meier plots will illustrate the distribution of these endpoints by treatment. Stratified Cox regression models will be used to estimate hazard ratios and associated confidence intervals.	The time from randomization to death from any cause, assessed up to 5 years
Secondary	Objective response rate (ORR) (complete response [CR] or partial response [PR])	Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Will be analyzed by a logistic regression models that control for the stratification factors (BRAF status, liver involvement, and adjuvant chemotherapy [chemo]) using the ITT population. Observed proportions along with confidence intervals will be presented by treatment.	Up to 5 years
Secondary	Incidence of adverse events	Defined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The safety profile will be described by tabulating the maximum observed grade of adverse event for each individual adverse event, for each system organ class, and overall using the Safety population.	Up to 30 days after last cycle
Secondary	Rate of PFS		At 12 months
Secondary	Disease control rate (CR + PR + stable disease [SD])	Assessed by RECIST 1.1. Will be analyzed by a logistic regression models that control for the stratification factors (BRAF status, liver involvement, and adjuvant chemo) using the ITT population. Observed proportions along with confidence intervals will be presented by treatment.	At 12 months
Secondary	Duration of overall response (CR or PR)	Assessed by RECIST 1.1. Will be analyzed using the stratified log rank test and the ITT population. Kaplan-Meier plots will illustrate the distribution of these endpoints by treatment. Stratified Cox regression models will be used to estimate hazard ratios and associated confidence intervals.	From the time of first response to first confirmed progression by the study investigator or death from any cause, assessed up to 5 years
Secondary	Duration of SD	Assessed per RECIST 1.1. Will be analyzed using the stratified log rank test and the ITT population. Kaplan-Meier plots will illustrate the distribution of these endpoints by treatment. Stratified Cox regression models will be used to estimate hazard ratios and associated confidence intervals.	From the time of first on-study assessment of SD to first progression by the study investigator or death from any cause, assessed up to 5 years