High-Dose Recombinant Interferon Alfa-2B, Ipilimumab, or Pembrolizumab in Treating Patients With Stage III-IV High Risk Melanoma That Has Been Removed by Surgery

Clinical Stage IV Cutaneous Melanoma AJCC v8 Clinical Trial

Official title:

A Phase III Randomized Trial Comparing Physician/Patient Choice of Either High Dose Interferon or Ipilimumab to MK-3475 (Pembrolizumab) in Patients With High Risk Resected Melanoma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02506153
• Other study ID #: NCI-2014-02676
• Secondary ID: NCI-2014-02676S1
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: November 10, 2015
• Est. completion date: January 23, 2025

Study information

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

Clinical Trial Summary

This randomized phase III trial studies how well high-dose recombinant interferon alfa-2B or ipilimumab works compared with pembrolizumab in treating patients with stage III-IV melanoma that has been removed by surgery but is likely to come back or spread. High-dose recombinant interferon alfa-2B may help shrink or slow the growth of melanoma. Immunotherapy with monoclonal antibodies, such as ipilimumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether high-dose recombinant interferon alfa-2B or ipilimumab is more effective than pembrolizumab in treating patients with melanoma.

Description:

PRIMARY OBJECTIVES: I. To compare overall survival (OS) of patients with resected stage III and IV melanoma treated with physician/patient choice of either high dose interferon recombinant interferon alfa-2b (alfa-2b) or ipilimumab versus MK-3475 (pembrolizumab). II. Among patients who are PD-L1 positive, to compare OS of patients with resected stage III and IV melanoma treated with physician/patient choice of either high dose interferon alfa-2b or ipilimumab versus MK-3475 (pembrolizumab). III. To compare relapse-free survival (RFS) of patients with resected stage III and IV melanoma treated with physician/patient choice of either high dose interferon alfa-2b or ipilimumab to MK-3475 (pembrolizumab). SECONDARY OBJECTIVES: I. To estimate OS and RFS for patients who are PD-L1 negative or PD-L1 indeterminate in this population. II. To compare OS and RFS of patients between the two arms within PD-L1 positive and negative subgroups and to look at the interaction between PD-L1 (positive versus negative) and treatment arm. III. To assess the safety and tolerability of the regimens. ADDITIONAL OBJECTIVES: I. To bank tissue and whole blood in anticipation of future correlative studies in this patient population. II. To evaluate PD-L1 expression through immunohistochemistry assay. III. To evaluate the effect of treatment-related side effects that may have an impact on the health-related domains of quality of life (QOL) using the Functional Assessment of Cancer Therapy (FACT)-Biological Response Modifiers (BRM), European Quality of Life Five Dimension Three Level Scale (EQ-5D-3L), and Functional Assessment of Chronic Illness Therapy Diarrhea (FACIT-D) between patients treated with physician/patient choice of either high-dose interferon alfa-2b or ipilimumab and MK-3475 (pembrolizumab). IV. Pharmacokinetic (PK) and anti-drug antibody (ADA) testing will be performed on all patients receiving MK-3475 (pembrolizumab). TRANSLATIONAL OBJECTIVES RELATED TO T-CELL RECEPTOR BETA CHAIN SEQUENCING: I. To evaluate the association between TCR beta variable gene (TRBV) haplotype and grade 3-4 immune-related adverse events (irAEs) among stage III melanoma patients treated with adjuvant ipilimumab or pembrolizumab. II. To describe the TRBV haplotype distribution among this cohort of patients studied. TRANSLATIONAL MEDICINAL OBJECTIVE RELATED TO ASSOCIATION OF CIRCULATING TUMOR DNA (ctDNA) WITH RELAPSE-FREE SURVIVAL IN HIGH-RISK, RESECTED MELANOMA PATIENTS. I. To evaluate associations between pretreatment ctDNA (present versus absent) and relapse within 2 years of randomization in a case-control analysis across treatment arms. II. To evaluate associations between pretreatment ctDNA (present versus absent) and relapse within 2 years of randomization in a case-control analysis across treatment arms. III. To evaluate associations between pretreatment ctDNA and relapse within 2 years of randomization in a case-control analysis within each treatment arm (after treatment arm data are unblinded to investigators). IV. To evaluate associations between "early-on treatment" ctDNA levels and relapse within 2 years of randomization. V. To describe ctDNA levels at end of therapy and time of relapse. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: INDUCTION THERAPY: Patients receive high-dose recombinant interferon alfa-2B intravenously (IV) over 20 minutes on days 1-5. Treatment repeats weekly for 4 weeks in the absence of disease progression or unacceptable toxicity. Or patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 3 weeks for a total of 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive high-dose recombinant interferon alfa-2B subcutaneously (SC) on days 1, 3, and 5. Treatment repeats every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity. Or patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 12 weeks for 3 years in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 52 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan, positron emission tomography (PET) scan, magnetic resonance imaging (MRI) and blood sample collection throughout the study. After completion of study treatment, patients are followed up at 30 days, 6 and 12 weeks, every 3 months for 2 years, every 6 months for 3 years, and then every 12 months for 5 years.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1345
• Est. completion date: January 23, 2025
• Est. primary completion date: September 15, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• STEP 1 REGISTRATION:
• Patients must have completely resected melanoma of cutaneous origin or of unknown primary in order to be eligible for this study; patients must be classified as stage IIIA (N2a), IIIB, IIIC, or stage IV melanoma; patients with non-ulcerated T1b N1a disease are not eligible; patients with melanoma of mucosal or other non-cutaneous origin are eligible; patients with melanoma of ocular origin are not eligible; patients with a history of brain metastases are ineligible
• Patients are eligible for this trial either at initial presentation of their melanoma or at the time of the first detected nodal, satellite/in-transit, distant metastases, or recurrent disease in prior lymphadenectomy basin or distant site; nodal, satellite/in-transit metastasis, distant metastases or disease in a prior complete lymphadenectomy basin must have been confirmed histologically by hematoxylin and eosin (H & E) stained slides
• Patients with multiple regional nodal basin involvement are eligible; gross or microscopic extracapsular nodal extension is permitted
• Patients at initial presentation of melanoma must undergo an adequate wide excision of the primary lesion, if present; patients with previously diagnosed melanoma must have had all current disease resected with pathologically negative margins and must have no evidence of disease at the primary site or must undergo re-resection of the primary site; a full lymphadenectomy meeting the criteria outlined is required for all node-positive patients including those with positive sentinel nodes; patients with recurrent disease who have had a prior complete lymphadenectomy fulfill this requirement as long as all recurrent disease has been resected; for all patients, all disease must have been resected with negative pathological margins and no clinical, radiologic, or pathological evidence of any incompletely resected melanoma; patients must be registered within 98 days of the last surgery performed to render the patient free of disease
• Patients must have available and be willing to submit a minimum of five unstained slides from primary, lymph node, or metastatic site to determine PD-L1 expression; the tumor tissue must be adequate for PD-L1 testing (defined as >= 100 tumor cells as confirmed by the treating institution's local pathologist); this must be documented by having a pathologist sign the S1404 Local Pathology Review form prior to step 1 registration; the specimens may come from an archived block but must be submitted within 20 days from cutting the slides
• Patients must be offered the opportunity to participate in specimen banking as outlined
• Patients must be willing to have blood draws for PK/ADA analysis as outlined, should the patient be randomized to the MK-3475 arm
• Patients may have received prior radiation therapy, including after the surgical resection; all adverse events associated with prior surgery and radiation therapy must have resolved to =< grade 1 prior to registration
• Patients must not have received neoadjuvant treatment for their melanoma; patients must not have had prior immunotherapy including, but not limited to ipilimumab, interferon alfa-2b, high dose IL-2, pegylated (PEG)-IFN, anti-PD-1, anti-PD-L1 intra-tumoral, or vaccine therapies; patients must not be planning to receive any of the prohibited therapies during the screening or treatment phases of the study
• Patients must not be planning to receive concomitant other biologic therapy, radiation therapy, hormonal therapy, other chemotherapy, surgery or other therapy after step 2 registration
• All patients must have disease-free status documented by a complete physical examination and imaging studies within 42 days prior to registration; imaging studies must include a total body positron emission tomography (PET)-computed tomography (CT) scan that is of diagnostic quality (with or without brain) or a CT of the chest, abdomen and pelvis; for patients with melanoma arising from the head and neck, dedicated neck imaging (CT with IV contrast or PET-CT through the region) is required; if the patient has had unknown primary with disease in the axilla, neck imaging is required to assure region is clear of cancer; CT imaging should be done with intravenous contrast if there are no contraindications for it; any other clinically-indicated imaging studies if performed (e.g. bone scan) must show no evidence of disease
• All patients must have a CT or magnetic resonance imaging (MRI) of the brain within 90 days prior to registration; the brain CT or MRI should be performed with intravenous contrast (unless contraindicated)
• Absolute neutrophil count (ANC) >= 1,500 microliter (mcL) (within 42 days prior to registration)
• Platelets >= 100,000 mcL (within 42 days prior to registration)
• Hemoglobin >= 10 g/dL (within 42 days prior to registration)
• Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (except Gilbert's syndrome, who must have a total bilirubin < 3.0 mg/dL) (within 42 days prior to registration)
• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2 x IULN (within 42 days prior to registration)
• Alkaline phosphatase =< 2 x IULN (within 42 days prior to registration)
• Serum creatinine =< IULN OR measured or calculated creatinine clearance >= 60 mL/min (within 42 days prior to registration)
• Patients must have lactate dehydrogenase (LDH) performed within 42 days prior to registration
• Patients must have Zubrod performance status =< 1
• Patients must have a baseline electrocardiogram (ECG) performed within 42 days of registration that is normal or considered not clinically significant by the site investigator
• Patients must not have a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Patients must not have an active infection requiring systemic therapy
• Patients must not have active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Patients must not have received live vaccines within 42 days prior to registration; examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, bacillus Calmette-Guerin (BCG), and typhoid (oral) vaccine; seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
• Patients known to be human immunodeficiency virus (HIV) positive are eligible if they meet the following criteria within 30 days prior to registration: stable and adequate cluster of differentiation 4 (CD4) counts (>= 350 mm^3), and serum HIV viral load of < 25,000 IU/ml; patients may be on or off anti-viral therapy so long as they meet the CD4 count criteria
• Patients must not have known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection prior to registration
• Patients must not have a history or current evidence of any condition, therapy or laboratory abnormality that might confound the trial results, interfere with the patient's participation for the full duration of the trial, or indicate that participation in the trial is not in the patient's best interests, in the opinion of the treating investigator
• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, lobular carcinoma of the breast in situ, atypical melanocytic hyperplasia or melanoma in situ, adequately treated stage I or II cancer (including multiple primary melanomas) from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years
• Women of childbearing potential must have a negative urine or serum pregnancy test within 28 days prior to registration; women/men of reproductive potential must have agreed to use an effective contraceptive method for the course of the study through 120 days after the last dose of study medication; 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; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy, or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures, he/she is responsible for beginning contraceptive measures; patients must not be pregnant or nursing due to unknown teratogenic side effects
• Patients who are able to complete questionnaires in English, Spanish or French must participate in the quality of life assessments; (those patients who cannot complete the quality of life questionnaires in English, Spanish or French can be registered to S1404 without contributing to the quality of life studies)
• Patients must be informed of the investigational nature of this study and must sign and give written informed consent for this protocol in accordance with institutional and federal guidelines
• As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
• STEP 2 REGISTRATION (RANDOMIZATION CRITERIA):
• Patients must not be registered until receiving confirmation from the Southwest Oncology Group (SWOG) Statistical Center that the patient's tissue specimen was adequate for PD-L1 testing; patients must be registered within 7 working days of receiving the e-mail notification
• Women of childbearing potential must plan to have a urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a negative serum pregnancy test will be required
• No tests or exams are required to be repeated for step 2 registration (randomization); however, patients who are known to have a change in eligibility status after step 1 registration are not eligible for step 2 registration; for example, ANC is not required to be repeated between step 1 and step 2 registration, but the most recent ANC performed before step 2 registration is required to be >= 1,500 mcL

Related Conditions & MeSH terms

• Clinical Stage III Cutaneous Melanoma AJCC v8
• Clinical Stage IV Cutaneous Melanoma AJCC v8
• Melanoma
• Metastatic Cutaneous Melanoma
• Metastatic Mucosal Melanoma
• Metastatic Non-Cutaneous Melanoma
• Non-Cutaneous Melanoma
• Recurrence
• Recurrent Cutaneous Melanoma
• Recurrent Mucosal Melanoma
• Recurrent Non-Cutaneous Melanoma
• Skin Neoplasms

Intervention

Procedure:
• Biospecimen Collection
Undergo blood sample collection
• Computed Tomography
Undergo CT scan

Biological:
• Ipilimumab
Given IV

Procedure:
• Magnetic Resonance Imaging
Undergo MRI

Biological:
• Pembrolizumab
Given IV

Procedure:
• Positron Emission Tomography
Undergo PET scan

Other:
• Quality-of-Life Assessment
Ancillary studies

Biological:
• Recombinant Interferon Alfa-2b
Given IV and SC

Locations

Country	Name	City	State
Canada	Royal Victoria Regional Health Centre	Barrie	Ontario
Canada	Juravinski Cancer Centre at Hamilton Health Sciences	Hamilton	Ontario
Canada	Kingston Health Sciences Centre	Kingston	Ontario
Canada	Grand River Regional Cancer Centre at Grand River Hospital	Kitchener	Ontario
Canada	Hopital de la Cite-de-la-Sante	Laval	Quebec
Canada	London Regional Cancer Program	London	Ontario
Canada	Trillium Health Partners - Credit Valley Hospital	Mississauga	Ontario
Canada	The Vitalite Health Network - Dr Leon Richard Oncology Centre	Moncton	New Brunswick
Canada	The Research Institute of the McGill University Health Centre (MUHC)	Montreal	Quebec
Canada	Lakeridge Health Oshawa	Oshawa	Ontario
Canada	Ottawa Hospital and Cancer Center-General Campus	Ottawa	Ontario
Canada	CHU de Quebec-L'Hotel-Dieu de Quebec (HDQ)	Quebec City	Quebec
Canada	Allan Blair Cancer Centre	Regina	Saskatchewan
Canada	Saskatoon Cancer Centre	Saskatoon	Saskatchewan
Canada	Algoma District Cancer Program Sault Area Hospital	Sault Ste Marie	Ontario
Canada	Centre Hospitalier Universitaire de Sherbrooke-Fleurimont	Sherbrooke	Quebec
Canada	Thunder Bay Regional Health Science Centre	Thunder Bay	Ontario
Canada	Odette Cancer Centre- Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	University Health Network-Princess Margaret Hospital	Toronto	Ontario
Canada	BCCA-Vancouver Cancer Centre	Vancouver	British Columbia
Canada	Windsor Regional Cancer Centre	Windsor	Ontario
Ireland	Saint Vincent's University Hospital	Dublin	Co Dublin
Ireland	University College Hospital Galway	Galway	Co Galway
Ireland	University Hospital Waterford	Waterford	Co Waterford
United States	Providence Regional Cancer System-Aberdeen	Aberdeen	Washington
United States	Jefferson Abington Hospital	Abington	Pennsylvania
United States	Lovelace Medical Center-Saint Joseph Square	Albuquerque	New Mexico
United States	Southwest Gynecologic Oncology Associates Inc	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	American Fork Hospital / Huntsman Intermountain Cancer Center	American Fork	Utah
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	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Langlade Hospital and Cancer Center	Antigo	Wisconsin
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	Northside Hospital	Atlanta	Georgia
United States	Hematology Oncology Associates of Central New York-Auburn	Auburn	New York
United States	Sutter Auburn Faith Hospital	Auburn	California
United States	Harold Alfond Center for Cancer Care	Augusta	Maine
United States	Rush - Copley Medical Center	Aurora	Illinois
United States	UCHealth University of Colorado Hospital	Aurora	Colorado
United States	Texas Oncology - Central Austin Cancer Center	Austin	Texas
United States	Kaiser Permanente-Baldwin Park	Baldwin Park	California
United States	MedStar Franklin Square Medical Center/Weinberg Cancer Institute	Baltimore	Maryland
United States	Mercy Medical Center	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Flaget Memorial Hospital	Bardstown	Kentucky
United States	Louisiana Hematology Oncology Associates LLC	Baton Rouge	Louisiana
United States	LSU Health Baton Rouge-North Clinic	Baton Rouge	Louisiana
United States	Mary Bird Perkins Cancer Center	Baton Rouge	Louisiana
United States	Our Lady of the Lake Physicians Group - Medical Oncology	Baton Rouge	Louisiana
United States	UHHS-Chagrin Highlands Medical Center	Beachwood	Ohio
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	Central Vermont Medical Center/National Life Cancer Treatment	Berlin	Vermont
United States	Saint Luke's University Hospital-Bethlehem Campus	Bethlehem	Pennsylvania
United States	Beverly Hospital	Beverly	Massachusetts
United States	Billings Clinic Cancer Center	Billings	Montana
United States	Saint Vincent Healthcare	Billings	Montana
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Parkland Health Center-Bonne Terre	Bonne Terre	Missouri
United States	McFarland Clinic - Boone	Boone	Iowa
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Boston Medical Center	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Bozeman Deaconess Hospital	Bozeman	Montana
United States	Lafayette Family Cancer Center-EMMC	Brewer	Maine
United States	United Hospital Center	Bridgeport	West Virginia
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Aurora Cancer Care-Southern Lakes VLCC	Burlington	Wisconsin
United States	Lahey Hospital and Medical Center	Burlington	Massachusetts
United States	University of Vermont and State Agricultural College	Burlington	Vermont
United States	University of Vermont Medical Center	Burlington	Vermont
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	Saint James Community Hospital and Cancer Treatment Center	Butte	Montana
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Southeast Cancer Center	Cape Girardeau	Missouri
United States	Sandra L Maxwell Cancer Center	Cedar City	Utah
United States	Physicians' Clinic of Iowa PC	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	Providence Regional Cancer System-Centralia	Centralia	Washington
United States	Cancer Center of Kansas - Chanute	Chanute	Kansas
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Bon Secours Saint Francis Hospital	Charleston	South Carolina
United States	Charleston Oncology - Roper	Charleston	South Carolina
United States	Charleston Oncology - Saint Francis	Charleston	South Carolina
United States	Lowcountry Hematology Oncology PA-North Charleston	Charleston	South Carolina
United States	Lowcountry Hematology Oncology PA-West Ashley	Charleston	South Carolina
United States	Roper Hospital	Charleston	South Carolina
United States	West Virginia University Charleston Division	Charleston	West Virginia
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Adena Regional Medical Center	Chillicothe	Ohio
United States	Marshfield Clinic-Chippewa Center	Chippewa Falls	Wisconsin
United States	University of Cincinnati Cancer Center-UC Medical Center	Cincinnati	Ohio
United States	Case Western Reserve University	Cleveland	Ohio
United States	Cleveland Clinic Cancer Center/Fairview Hospital	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	MetroHealth Medical Center	Cleveland	Ohio
United States	Southeastern Medical Oncology Center-Clinton	Clinton	North Carolina
United States	Medical Oncology and Hematology Associates-West Des Moines	Clive	Iowa
United States	Mercy Cancer Center-West Lakes	Clive	Iowa
United States	Big Horn Basin Cancer Center	Cody	Wyoming
United States	Billings Clinic-Cody	Cody	Wyoming
United States	Kootenai Health - Coeur d'Alene	Coeur d'Alene	Idaho
United States	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado
United States	UCHealth Memorial Hospital Central	Colorado Springs	Colorado
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	Mercy Hospital	Coon Rapids	Minnesota
United States	UC Irvine Health Cancer Center-Newport	Costa Mesa	California
United States	Northshore Oncology Associates-Covington	Covington	Louisiana
United States	Northside Hospital-Forsyth	Cumming	Georgia
United States	Baylor University Medical Center	Dallas	Texas
United States	Carle at The Riverfront	Danville	Illinois
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Dayton Physician LLC-Miami Valley Hospital North	Dayton	Ohio
United States	Good Samaritan Hospital - Dayton	Dayton	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	Miami Valley Hospital North	Dayton	Ohio
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Delaware Health Center-Grady Cancer Center	Delaware	Ohio
United States	Grady Memorial Hospital	Delaware	Ohio
United States	Kaiser Permanente-Franklin	Denver	Colorado
United States	Porter Adventist Hospital	Denver	Colorado
United States	SCL Health Saint Joseph Hospital	Denver	Colorado
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates-Des Moines	Des Moines	Iowa
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Mission Cancer and Blood - Laurel	Des Moines	Iowa
United States	Ascension Saint John Hospital	Detroit	Michigan
United States	Henry Ford Hospital	Detroit	Michigan
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Cancer Center of Kansas - Dodge City	Dodge City	Kansas
United States	Wentworth-Douglass Hospital	Dover	New Hampshire
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Essentia Health Cancer Center	Duluth	Minnesota
United States	Essentia Health Saint Mary's Medical Center	Duluth	Minnesota
United States	Miller-Dwan Hospital	Duluth	Minnesota
United States	Duke University Medical Center	Durham	North Carolina
United States	Great Lakes Cancer Management Specialists-Doctors Park	East China Township	Michigan
United States	Veterans Adminstration New Jersey Health Care System	East Orange	New Jersey
United States	Hematology Oncology Associates of Central New York-East Syracuse	East Syracuse	New York
United States	Marshfield Clinic Cancer Center at Sacred Heart	Eau Claire	Wisconsin
United States	Fairview Southdale Hospital	Edina	Minnesota
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Cancer Center of Kansas - El Dorado	El Dorado	Kansas
United States	Elmhurst Memorial Hospital	Elmhurst	Illinois
United States	Ephrata Cancer Center	Ephrata	Pennsylvania
United States	Ephrata Community Hospital	Ephrata	Pennsylvania
United States	UPMC Hillman Cancer Center Erie	Erie	Pennsylvania
United States	Green Bay Oncology - Escanaba	Escanaba	Michigan
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois
United States	Providence Regional Cancer Partnership	Everett	Washington
United States	Smilow Cancer Hospital Care Center-Fairfield	Fairfield	Connecticut
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Sanford Clinic North-Fargo	Fargo	North Dakota
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	Lake Region Healthcare Corporation-Cancer Care	Fergus Falls	Minnesota
United States	Armes Family Cancer Center	Findlay	Ohio
United States	Blanchard Valley Hospital	Findlay	Ohio
United States	Orion Cancer Care	Findlay	Ohio
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	Aurora Health Center-Fond du Lac	Fond Du Lac	Wisconsin
United States	Saint Agnes Hospital/Agnesian Cancer Center	Fond Du Lac	Wisconsin
United States	Kaiser Permanente-Fontana	Fontana	California
United States	Poudre Valley Hospital	Fort Collins	Colorado
United States	McFarland Clinic - Trinity Cancer Center	Fort Dodge	Iowa
United States	Frederick Memorial Hospital	Frederick	Maryland
United States	Kaiser Permanente-Fremont	Fremont	California
United States	Palo Alto Medical Foundation-Fremont	Fremont	California
United States	Kaiser Permanente-Fresno	Fresno	California
United States	Unity Hospital	Fridley	Minnesota
United States	Saint Luke's Cancer Institute - Fruitland	Fruitland	Idaho
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Saint Catherine Hospital	Garden City	Kansas
United States	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois
United States	Aurora Health Care Germantown Health Center	Germantown	Wisconsin
United States	The West Clinic - Wolf River	Germantown	Tennessee
United States	Adams Cancer Center	Gettysburg	Pennsylvania
United States	Glens Falls Hospital	Glens Falls	New York
United States	NorthShore University HealthSystem-Glenbrook Hospital	Glenview	Illinois
United States	Addison Gilbert Hospital	Gloucester	Massachusetts
United States	Southeastern Medical Oncology Center-Goldsboro	Goldsboro	North Carolina
United States	Wayne Memorial Hospital	Goldsboro	North Carolina
United States	Aurora Cancer Care-Grafton	Grafton	Wisconsin
United States	Altru Cancer Center	Grand Forks	North Dakota
United States	CHI Health Saint Francis	Grand Island	Nebraska
United States	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan
United States	Trinity Health Grand Rapids Hospital	Grand Rapids	Michigan
United States	Central Care Cancer Center - Great Bend	Great Bend	Kansas
United States	Saint Rose Ambulatory and Surgery Center	Great Bend	Kansas
United States	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana
United States	Great Falls Clinic	Great Falls	Montana
United States	North Colorado Medical Center	Greeley	Colorado
United States	Aurora BayCare Medical Center	Green Bay	Wisconsin
United States	Green Bay Oncology at Saint Vincent Hospital	Green Bay	Wisconsin
United States	Green Bay Oncology Limited at Saint Mary's Hospital	Green Bay	Wisconsin
United States	Saint Vincent Hospital Cancer Center at Saint Mary's	Green Bay	Wisconsin
United States	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin
United States	Saint Francis Cancer Center	Greenville	South Carolina
United States	Academic Hematology Oncology Specialists	Grosse Pointe Woods	Michigan
United States	Great Lakes Cancer Management Specialists-Van Elslander Cancer Center	Grosse Pointe Woods	Michigan
United States	Michigan Breast Specialists-Grosse Pointe Woods	Grosse Pointe Woods	Michigan
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Cherry Tree Cancer Center	Hanover	Pennsylvania
United States	Kaiser Permanente - Harbor City	Harbor City	California
United States	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut
United States	HaysMed University of Kansas Health System	Hays	Kansas
United States	Geisinger Medical Center-Cancer Center Hazleton	Hazleton	Pennsylvania
United States	Saint Peter's Community Hospital	Helena	Montana
United States	Cancer and Blood Specialists-Henderson	Henderson	Nevada
United States	Comprehensive Cancer Centers of Nevada - Henderson	Henderson	Nevada
United States	Comprehensive Cancer Centers of Nevada-Southeast Henderson	Henderson	Nevada
United States	GenesisCare USA - Henderson	Henderson	Nevada
United States	Las Vegas Cancer Center-Henderson	Henderson	Nevada
United States	Hendersonville Hematology and Oncology at Pardee	Hendersonville	North Carolina
United States	Margaret R Pardee Memorial Hospital	Hendersonville	North Carolina
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	NorthShore University HealthSystem-Highland Park Hospital	Highland Park	Illinois
United States	Hawaii Cancer Care Inc - Waterfront Plaza	Honolulu	Hawaii
United States	Hawaii Cancer Care Inc-Liliha	Honolulu	Hawaii
United States	Island Urology	Honolulu	Hawaii
United States	Queen's Cancer Cenrer - POB I	Honolulu	Hawaii
United States	Queen's Cancer Center - Kuakini	Honolulu	Hawaii
United States	Queen's Medical Center	Honolulu	Hawaii
United States	Straub Clinic and Hospital	Honolulu	Hawaii
United States	Tripler Army Medical Center	Honolulu	Hawaii
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	M D Anderson Cancer Center	Houston	Texas
United States	Centerpoint Medical Center LLC	Independence	Missouri
United States	Cleveland Clinic Cancer Center Independence	Independence	Ohio
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	Green Bay Oncology - Iron Mountain	Iron Mountain	Michigan
United States	Kaiser Permanente-Irvine	Irvine	California
United States	Allegiance Health	Jackson	Michigan
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Southeastern Medical Oncology Center-Jacksonville	Jacksonville	North Carolina
United States	McFarland Clinic - Jefferson	Jefferson	Iowa
United States	Capital Region Southwest Campus	Jefferson City	Missouri
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	Heartland Hematology and Oncology Associates Incorporated	Kansas City	Missouri
United States	Kansas City Veterans Affairs Medical Center	Kansas City	Missouri
United States	Research Medical Center	Kansas City	Missouri
United States	Saint Luke's Hospital of Kansas City	Kansas City	Missouri
United States	The University of Kansas Cancer Center-South	Kansas City	Missouri
United States	Truman Medical Centers	Kansas City	Missouri
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	University of Kansas Cancer Center - North	Kansas City	Missouri
United States	University of Kansas Cancer Center-West	Kansas City	Kansas
United States	Aurora Cancer Care-Kenosha South	Kenosha	Wisconsin
United States	Greater Dayton Cancer Center	Kettering	Ohio
United States	Kettering Medical Center	Kettering	Ohio
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	Providence Regional Cancer System-Lacey	Lacey	Washington
United States	Kaiser Permanente-Rock Creek	Lafayette	Colorado
United States	Lakeland Regional Health Hollis Cancer Center	Lakeland	Florida
United States	University of Michigan Health - Sparrow Lansing	Lansing	Michigan
United States	Ann M Wierman MD LTD	Las Vegas	Nevada
United States	Cancer Therapy and Integrative Medicine	Las Vegas	Nevada
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	Comprehensive Cancer Centers of Nevada - Central Valley	Las Vegas	Nevada
United States	Comprehensive Cancer Centers of Nevada - Northwest	Las Vegas	Nevada
United States	GenesisCare USA - Las Vegas	Las Vegas	Nevada
United States	Las Vegas Cancer Center-Medical Center	Las Vegas	Nevada
United States	OptumCare Cancer Care at Fort Apache	Las Vegas	Nevada
United States	University Cancer Center	Las Vegas	Nevada
United States	University Medical Center of Southern Nevada	Las Vegas	Nevada
United States	Lawrence Memorial Hospital	Lawrence	Kansas
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	Saint Luke's East - Lee's Summit	Lee's Summit	Missouri
United States	University of Kansas Cancer Center - Lee's Summit	Lee's Summit	Missouri
United States	Kansas Institute of Medicine Cancer and Blood Center	Lenexa	Kansas
United States	Minimally Invasive Surgery Hospital	Lenexa	Kansas
United States	Saint Joseph Hospital East	Lexington	Kentucky
United States	Saint Joseph Radiation Oncology Resource Center	Lexington	Kentucky
United States	Cancer Center of Kansas-Liberal	Liberal	Kansas
United States	Liberty Radiation Oncology Center	Liberty	Missouri
United States	Nebraska Hematology and Oncology	Lincoln	Nebraska
United States	Southeast Nebraska Cancer Center - 68th Street Place	Lincoln	Nebraska
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Littleton Adventist Hospital	Littleton	Colorado
United States	Saint Barnabas Medical Center	Livingston	New Jersey
United States	Logan Regional Hospital	Logan	Utah
United States	Kaiser Permanente-Lone Tree	Lone Tree	Colorado
United States	PeaceHealth Saint John Medical Center	Longview	Washington
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California
United States	Kaiser Permanente West Los Angeles	Los Angeles	California
United States	Los Angeles General Medical Center	Los Angeles	California
United States	UCLA / Jonsson Comprehensive Cancer Center	Los Angeles	California
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	Saints Mary and Elizabeth Hospital	Louisville	Kentucky
United States	UofL Health Medical Center Northeast	Louisville	Kentucky
United States	Centra Lynchburg Hematology-Oncology Clinic Inc	Lynchburg	Virginia
United States	Great Lakes Cancer Management Specialists-Macomb Medical Campus	Macomb	Michigan
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	Michigan Breast Specialists-Macomb Township	Macomb	Michigan
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Norris Cotton 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	Aurora Bay Area Medical Group-Marinette	Marinette	Wisconsin
United States	Bay Area Medical Center	Marinette	Wisconsin
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	Cancer Center of Kansas - McPherson	McPherson	Kansas
United States	The West Clinic - Mid-Town	Memphis	Tennessee
United States	University of Tennessee Health Science Center	Memphis	Tennessee
United States	Froedtert Menomonee Falls Hospital	Menomonee Falls	Wisconsin
United States	Saint Luke's Cancer Institute - Meridian	Meridian	Idaho
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Mount Sinai Medical Center	Miami Beach	Florida
United States	Ascension Southeast Wisconsin Hospital - Saint Joseph Campus	Milwaukee	Wisconsin
United States	Aurora Cancer Care-Milwaukee	Milwaukee	Wisconsin
United States	Aurora Saint Luke's Medical Center	Milwaukee	Wisconsin
United States	Aurora Sinai Medical Center	Milwaukee	Wisconsin
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	Community Medical Hospital	Missoula	Montana
United States	Saint Patrick Hospital - Community Hospital	Missoula	Montana
United States	Kaiser Permanente-Modesto	Modesto	California
United States	Memorial Medical Center	Modesto	California
United States	Ochsner LSU Health Monroe Medical Center	Monroe	Louisiana
United States	Franciscan Health Mooresville	Mooresville	Indiana
United States	West Virginia University Healthcare	Morgantown	West Virginia
United States	Lowcountry Hematology Oncology PA-Mount Pleasant	Mount Pleasant	South Carolina
United States	Knox Community Hospital	Mount Vernon	Ohio
United States	Palo Alto Medical Foundation-Camino Division	Mountain View	California
United States	Intermountain Medical Center	Murray	Utah
United States	Trinity Health Muskegon Hospital	Muskegon	Michigan
United States	Saint Luke's Cancer Institute - Nampa	Nampa	Idaho
United States	Edward Hospital/Cancer Center	Naperville	Illinois
United States	Dartmouth Cancer Center - Nashua	Nashua	New Hampshire
United States	Saint Joseph Hospital	Nashua	New Hampshire
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Yale University	New Haven	Connecticut
United States	UC Comprehensive Cancer Center at Silver Cross	New Lenox	Illinois
United States	Cancer Center of Western Wisconsin	New Richmond	Wisconsin
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Christiana Care Health System-Christiana Hospital	Newark	Delaware
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	Newport Hospital	Newport	Rhode Island
United States	USC Norris Oncology/Hematology-Newport Beach	Newport Beach	California
United States	Cancer Center of Kansas - Newton	Newton	Kansas
United States	Faith Regional Health Services Carson Cancer Center	Norfolk	Nebraska
United States	Sutter Cancer Research Consortium	Novato	California
United States	Cancer Care Center of O'Fallon	O'Fallon	Illinois
United States	Kaiser Permanente-Oakland	Oakland	California
United States	Saint Vincent Hospital Cancer Center at Oconto Falls	Oconto Falls	Wisconsin
United States	McKay-Dee Hospital Center	Ogden	Utah
United States	Mercy Hospital Oklahoma City	Oklahoma City	Oklahoma
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Olathe Health Cancer Center	Olathe	Kansas
United States	Alegent Health Bergan Mercy Medical Center	Omaha	Nebraska
United States	Alegent Health Immanuel Medical Center	Omaha	Nebraska
United States	Alegent Health Lakeside Hospital	Omaha	Nebraska
United States	Creighton University Medical Center	Omaha	Nebraska
United States	Nebraska Cancer Specialists - Omaha	Omaha	Nebraska
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	Saint Joseph Hospital - Orange	Orange	California
United States	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California
United States	University of Chicago Medicine-Orland Park	Orland Park	Illinois
United States	Orlando Health Cancer Institute	Orlando	Florida
United States	Vince Lombardi Cancer Clinic - Oshkosh	Oshkosh	Wisconsin
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	Menorah Medical Center	Overland Park	Kansas
United States	Saint Luke's South Hospital	Overland Park	Kansas
United States	University of Kansas Cancer Center-Overland Park	Overland Park	Kansas
United States	Owensboro Health Mitchell Memorial Cancer Center	Owensboro	Kentucky
United States	Palo Alto Medical Foundation Health Care	Palo Alto	California
United States	Stanford Cancer Institute Palo Alto	Palo Alto	California
United States	Kaiser Permanente - Panorama City	Panorama City	California
United States	Parker Adventist Hospital	Parker	Colorado
United States	Camden Clark Medical Center	Parkersburg	West Virginia
United States	University Hospitals Parma Medical Center	Parma	Ohio
United States	Cancer Center of Kansas - Parsons	Parsons	Kansas
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Cancer Center at Saint Joseph's	Phoenix	Arizona
United States	Ascension Via Christi - Pittsburg	Pittsburg	Kansas
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	Edward Hospital/Cancer Center?Plainfield	Plainfield	Illinois
United States	Kaiser Permanente Northwest	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Providence Portland 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	Geisinger Cancer Services-Pottsville	Pottsville	Pennsylvania
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Miriam Hospital	Providence	Rhode Island
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Utah Valley Regional Medical Center	Provo	Utah
United States	Aurora Cancer Care-Racine	Racine	Wisconsin
United States	Rapid City Regional Hospital	Rapid City	South Dakota
United States	Kaiser Permanente-Redwood City	Redwood City	California
United States	Corewell Health Reed City Hospital	Reed City	Michigan
United States	Beebe Health Campus	Rehoboth Beach	Delaware
United States	Lakeview Medical Center-Marshfield Clinic	Rice Lake	Wisconsin
United States	Marshfield Medical Center-Rice Lake	Rice Lake	Wisconsin
United States	Kaiser Permanente-Richmond	Richmond	California
United States	Reid Health	Richmond	Indiana
United States	Virginia Cancer Institute	Richmond	Virginia
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Kaiser Permanente-Riverside	Riverside	California
United States	Rochester General Hospital	Rochester	New York
United States	University of Rochester	Rochester	New York
United States	Great Lakes Cancer Management Specialists-Rochester Hills	Rochester Hills	Michigan
United States	SwedishAmerican Regional Cancer Center/ACT	Rockford	Illinois
United States	Highlands Oncology Group - Rogers	Rogers	Arkansas
United States	Kaiser Permanente-Roseville	Roseville	California
United States	Sutter Roseville Medical Center	Roseville	California
United States	Kaiser Permanente - Sacramento	Sacramento	California
United States	Kaiser Permanente-South Sacramento	Sacramento	California
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	Saint George Regional Medical Center	Saint George	Utah
United States	Heartland Regional Medical Center	Saint Joseph	Missouri
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Sainte Genevieve County Memorial Hospital	Sainte Genevieve	Missouri
United States	Cancer Center of Kansas - Salina	Salina	Kansas
United States	Salina Regional Health Center	Salina	Kansas
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	LDS Hospital	Salt Lake City	Utah
United States	Utah Cancer Specialists-Salt Lake City	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	California Pacific Medical Center-Pacific Campus	San Francisco	California
United States	Kaiser Permanente-San Francisco	San Francisco	California
United States	Kaiser Permanente-Santa Teresa-San Jose	San Jose	California
United States	Kaiser Permanente San Leandro	San Leandro	California
United States	Kaiser Permanente-San Marcos	San Marcos	California
United States	Kaiser Permanente-San Rafael	San Rafael	California
United States	Kootenai Cancer Clinic	Sandpoint	Idaho
United States	North Coast Cancer Care	Sandusky	Ohio
United States	UH Seidman Cancer Center at Firelands Regional Medical Center	Sandusky	Ohio
United States	Kaiser Permanente Medical Center - Santa Clara	Santa Clara	California
United States	Palo Alto Medical Foundation-Santa Cruz	Santa Cruz	California
United States	Kaiser Permanente-Santa Rosa	Santa Rosa	California
United States	Sutter Pacific Medical Foundation	Santa Rosa	California
United States	Lewis Cancer and Research Pavilion at Saint Joseph's/Candler	Savannah	Georgia
United States	Memorial Health University Medical Center	Savannah	Georgia
United States	Maine Center for Cancer Medicine-Scarborough	Scarborough	Maine
United States	Regional West Medical Center Cancer Center	Scottsbluff	Nebraska
United States	Virginia G Piper Cancer Care-Del Camino	Scottsdale	Arizona
United States	Kaiser Permanente Washington	Seattle	Washington
United States	Swedish Medical Center-First Hill	Seattle	Washington
United States	HSHS Saint Nicholas Hospital	Sheboygan	Wisconsin
United States	Vince Lombardi Cancer Clinic-Sheboygan	Sheboygan	Wisconsin
United States	Providence Regional Cancer System-Shelton	Shelton	Washington
United States	Welch Cancer Center	Sheridan	Wyoming
United States	LSU Health Sciences Center at Shreveport	Shreveport	Louisiana
United States	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	VCU Community Memorial Health Center	South Hill	Virginia
United States	South Jordan Health Center	South Jordan	Utah
United States	Kaiser Permanente-South San Francisco	South San Francisco	California
United States	Baystate Medical Center	Springfield	Massachusetts
United States	Central Illinois Hematology Oncology Center	Springfield	Illinois
United States	CoxHealth South Hospital	Springfield	Missouri
United States	Memorial Medical Center	Springfield	Illinois
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Springfield Clinic	Springfield	Illinois
United States	Stamford Hospital/Bennett Cancer Center	Stamford	Connecticut
United States	Ascension Saint Michael's Hospital	Stevens Point	Wisconsin
United States	Kaiser Permanente-Stockton	Stockton	California
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	Cleveland Clinic Cancer Center Strongsville	Strongsville	Ohio
United States	Green Bay Oncology - Sturgeon Bay	Sturgeon Bay	Wisconsin
United States	Saint Vincent Hospital Cancer Center at Sturgeon Bay	Sturgeon Bay	Wisconsin
United States	Missouri Baptist Sullivan Hospital	Sullivan	Missouri
United States	Aurora Medical Center in Summit	Summit	Wisconsin
United States	Palo Alto Medical Foundation-Sunnyvale	Sunnyvale	California
United States	ProMedica Flower Hospital	Sylvania	Ohio
United States	Hematology Oncology Associates of Central New York-Onondaga Hill	Syracuse	New York
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Moffitt Cancer Center	Tampa	Florida
United States	University of Toledo	Toledo	Ohio
United States	University of Kansas Health System Saint Francis Campus	Topeka	Kansas
United States	Munson Medical Center	Traverse City	Michigan
United States	Gene Upshaw Memorial Tahoe Forest Cancer Center	Truckee	California
United States	Smilow Cancer Hospital Care Center-Trumbull	Trumbull	Connecticut
United States	Banner University Medical Center - Tucson	Tucson	Arizona
United States	University of Arizona Cancer Center-North Campus	Tucson	Arizona
United States	Saint Luke's Cancer Institute - Twin Falls	Twin Falls	Idaho
United States	Vince Lombardi Cancer Clinic-Two Rivers	Two Rivers	Wisconsin
United States	Carle Cancer Center	Urbana	Illinois
United States	The Carle Foundation Hospital	Urbana	Illinois
United States	Kaiser Permanente Medical Center-Vacaville	Vacaville	California
United States	South Georgia Medical Center/Pearlman Cancer Center	Valdosta	Georgia
United States	Kaiser Permanente-Vallejo	Vallejo	California
United States	PeaceHealth Southwest Medical Center	Vancouver	Washington
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	Providence Saint Mary Regional Cancer Center	Walla Walla	Washington
United States	Kaiser Permanente-Walnut Creek	Walnut Creek	California
United States	Great Lakes Cancer Management Specialists-Macomb Professional Building	Warren	Michigan
United States	Saint John Macomb-Oakland Hospital	Warren	Michigan
United States	South Pointe Hospital	Warrensville Heights	Ohio
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	MedStar Washington Hospital Center	Washington	District of Columbia
United States	Aspirus Regional Cancer Center	Wausau	Wisconsin
United States	Marshfield Clinic-Wausau Center	Wausau	Wisconsin
United States	Aurora Cancer Care-Milwaukee West	Wauwatosa	Wisconsin
United States	Cancer Center of Kansas - Wellington	Wellington	Kansas
United States	Aurora West Allis Medical Center	West Allis	Wisconsin
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	Cleveland Clinic-Weston	Weston	Florida
United States	Marshfield Medical Center - Weston	Weston	Wisconsin
United States	Wexford Health and Wellness Pavilion	Wexford	Pennsylvania
United States	Ascension Via Christi Hospitals Wichita	Wichita	Kansas
United States	Cancer Center of Kansas - Wichita	Wichita	Kansas
United States	Cancer Center of Kansas-Wichita Medical Arts Tower	Wichita	Kansas
United States	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania
United States	UPMC Susquehanna	Williamsport	Pennsylvania
United States	Cancer Center of Kansas - Winfield	Winfield	Kansas
United States	Aspirus Cancer Care - Wisconsin Rapids	Wisconsin Rapids	Wisconsin
United States	Marshfield Clinic - Wisconsin Rapids Center	Wisconsin Rapids	Wisconsin
United States	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota
United States	Kaiser Permanente-Woodland Hills	Woodland Hills	California
United States	Cleveland Clinic Wooster Family Health and Surgery Center	Wooster	Ohio
United States	University of Michigan Health - West	Wyoming	Michigan
United States	Providence Regional Cancer System-Yelm	Yelm	Washington
United States	WellSpan Health-York Cancer Center	York	Pennsylvania
United States	WellSpan Health-York Hospital	York	Pennsylvania
United States	Rush-Copley Healthcare Center	Yorkville	Illinois
United States	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada,  Ireland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival (OS)	Cox regression models will be used to estimate hazard ratios and calculate confidence intervals to compare treatment arms in the PD-L1 negative subgroup. In addition, Cox regression models for OS will be used to estimate interaction terms between PD-L1 status and treatment arm. A restricted mean survival time analysis will be done as a supportive analysis.	From date of randomization to date of death due to any cause, assessed up to 5 years
Primary	Relapse-free survival (RFS)	Cox regression models will be used to estimate hazard ratios and calculate confidence intervals to compare treatment arms in the PD-L1 negative subgroup. In addition, Cox regression models for RFS will be used to estimate interaction terms between PD-L1 status and treatment arm. A restricted mean survival time analysis will be done as a supportive analysis.	From date of randomization to date of first documentation of progression or death due to any cause, assessed up to 5 years
Primary	PD-L1 status	Cox regression models will be used to estimate hazard ratios and calculate confidence intervals to compare treatment arms in the PD-L1 negative subgroup. In addition, Cox regression models for OS and RFS will be used to estimate interaction terms between PD-L1 status and treatment arm.	Baseline
Secondary	Incidence of toxicity	Will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (CTCAE version 5.0 beginning April 1, 2018). Toxicity rates will be estimated with a 95% confidence interval.	Up to 30 days after the last study drug administration
Secondary	Post-relapse therapy	Data on therapy after relapse will be collected for three years after relapse (or until 10 years after registration maximum). Therapies will be categorized into one of two categories: systemic or local. Specific therapies after relapse will be tabulated and summarized. Therapy after relapse will be analyzed as a time-dependent variable in Cox regression analyses for the endpoint of OS after relapse.	Up to 10 years
Secondary	BRAF mutation status	Pre-study BRAF mutation status on patients will be collected. BRAF mutation will be analyzed as a prognostic value as a covariate in Cox regression analyses and exponential-logistic cure regression models. In addition, BRAF mutation will be analyzed as a predictive factor by analyzing the interaction between mutation status and treatment in Cox regression models and in exponential-logistic cure regression model.	Baseline
Secondary	Long-term survival	Exponential-logistic cure regression models will be used to examine the association between known prognostic factors, including stage, and long-term survivor/cure status, and survival for patients who are not long-term survivors/cured.	Up to 10 years
Secondary	Change in quality of life	The European Quality of Life Five Dimension Three Level Scale, Functional Assessment of Cancer Therapy-Biological Response Modifiers, Functional Assessment of Chronic Illness Therapy Diarrhea, and Trial Outcome Index will be assessed at multiple time points. Longitudinal regression models (using mixed-effects models) will be used to evaluate changes over time.	Baseline to up to 5 years