S1403, Afatinib Dimaleate With or Without Cetuximab in Treating Patients With Newly Diagnosed Stage IV or Recurrent, EGFR Mutation Positive Non-small Cell Lung Cancer

Stage IV Non-Small Cell Lung Cancer Clinical Trial

Official title:

A Randomized Phase II/III Trial of Afatinib Plus Cetuximab Versus Afatinib Alone in Treatment-Naive Patients With Advanced, EGFR Mutation Positive Non-small Cell Lung Cancer (NSCLC)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02438722
• Other study ID #: S1403
• Secondary ID: NCI-2014-02405BI
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: May 7, 2015
• Est. completion date: December 15, 2024

Study information

• Verified date: February 2024
• Source: SWOG Cancer Research Network
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized phase II/III trial studies how well afatinib dimaleate with cetuximab works and compares it with afatinib dimaleate alone in treating patients with newly diagnosed stage IV or recurrent (has come back), epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer. Afatinib dimaleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, may block tumor growth in different ways by targeting certain cells. It is not yet known whether afatinib dimaleate is more effective when given alone or with cetuximab in treating patients with non-small cell lung cancer.

Description:

PRIMARY OBJECTIVES:

I. To evaluate if there is sufficient evidence to continue to the phase III component by comparing progression-free survival (PFS) between patients randomized to afatinib (afatinib dimaleate) in combination with cetuximab versus afatinib alone in the first-line treatment of patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). (Phase II) II. To determine the efficacy of the combination of afatinib and cetuximab compared to afatinib alone as measured by overall survival (OS) in the first-line treatment of patients with advanced EGFR-mutant NSCLC. (Phase III)

SECONDARY OBJECTIVES:

I. To evaluate the overall response rate (confirmed and unconfirmed, complete and partial responses) in the subset of patients with measurable disease treated with afatinib plus cetuximab compared to afatinib alone.

II. To assess the safety of each treatment arm when used in the first-line setting.

III. To compare time to treatment failure and time to treatment discontinuation between randomized to afatinib in combination with cetuximab versus afatinib alone.

TERTIARY OBJECTIVES:

I. To investigate the molecular mechanisms that confer benefit from afatinib and afatinib plus cetuximab by evaluating whether the presence of de novo EGFR T790M mutation or other molecular alterations in the pre-treatment tumor influence the clinical outcomes.

II. To quantitatively assess whether the ratio of sensitizing EGFR (EGFRs) mutation to EGFR T790M influences outcome and is altered during treatment.

III. To evaluate the frequency of known mechanisms of resistance to EGFR-directed therapies in the context of afatinib plus cetuximab and afatinib alone treatment.

IV. To identify potential novel predictors of benefit to afatinib plus cetuximab.

V. To identify potential new mechanisms of resistance to EGFR-directed therapies.

VI. To establish patient-derived xenografts (PDXs) from a subset of patients by re-biopsy at the time of progressive disease for drug testing and genomic analysis.

VII. To assess whether circulating tumor markers can be used as indicators of sensitivity and resistance to afatinib plus cetuximab and afatinib alone.

VIII. To determine whether the levels of EGFR protein by immunohistochemistry predict for benefit to afatinib plus cetuximab and afatinib alone.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive afatinib dimaleate orally (PO) once daily (QD) on days 1-28 and cetuximab intravenously (IV) over 2 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive afatinib dimaleate as in Arm I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 3 years.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 174
• Est. completion date: December 15, 2024
• Est. primary completion date: September 25, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed stage IV (American Joint Committee on Cancer [AJCC] 7th Edition) or recurrent non-small cell lung cancer (NSCLC)

• Patients must have documented presence of an EGFR exon 19 deltion or exon 21 (L858R) substitution mutation; T790M mutation or other molecular abnormality will be allowed as long as it accompanies one of the mutations listed above; EGFR testing must be performed using a Food and Drug Administration (FDA)-approved test or in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.

• Patients must have tissue available and must agree to submission of tissue and blood; one to two paraffin-embedded tissue blocks or 15-20 unstained slides are requested (a minimum of 12 slides is required); cytology (i.e. fine-needle aspirations, pleural effusion specimens) is acceptable if a cell block or sufficient unstained slides are available; tumor material must be reviewed by a local pathologist who must confirm that at least 100 viable tumor cells are present in the sample and sign the S1403 Pathology Review Form; patients must also be willing to submit blood samples for correlative research at baseline, during treatment and at progression

• Patients enrolled at sites participating in the Repeat Biopsy Study must agree to submission of tissue obtained by a repeat biopsy performed at the time of disease progression

• Patients must not have received any prior systemic anticancer therapy for advanced or metastatic disease including chemotherapy or EGFR tyrosine kinase inhibitor therapy (including gefitinib, erlotinib, afatinib, or any experimental EGFR tyrosine kinase inhibitors [TKI] agents); prior chemotherapy for non-metastatic disease (i.e. adjuvant therapy or concurrent chemo-radiotherapy) is allowed as long as > 12 months has passed since completion of therapy; adjuvant EGFR-directed therapy is not allowed; local therapy (i.e. palliative radiotherapy) is allowed as long as a period of 7 days has passed since the last dose was received and the patient has recovered from any associated toxicity at the time of registration

• Patients may have measurable or non-measurable disease documented by computed tomography (CT) or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic quality; laboratory parameters are not acceptable as the only evidence of disease; in order to qualify as measurable, measurable disease must be outside previous radiation field; all disease must be assessed and documented on the Baseline Tumor Assessment Form (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1)

• Patients must have a CT or MRI scan of the brain to evaluate for central nervous system (CNS) disease within 42 days prior to registration; patient must not have symptomatic brain metastases or evidence of leptomeningeal carcinomatosis; patients with asymptomatic brain metastases are eligible if off of steroids for at least 7 days prior to registration without development of symptoms

• Patients must not have any known clinically active interstitial lung disease

• Absolute neutrophil count (ANC) >= 1,500/mcL

• Platelets >= 75,000/mcL

• Hemoglobin >= 9 g/dL

• Total bilirubin =< 1.5 x institutional upper limit of normal (IULN)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or =< 5 x IULN for patients with known liver metastases)

• Serum creatinine =< 1.5 x IULN OR measured or calculated creatinine clearance >= 60 mL/min

• Patients must not have significant gastrointestinal disorders with diarrhea as a major symptom (e.g. Crohn's disease, malabsorption, etc)

• Patients must be able to swallow medication by oral route

• Patients must not have a history of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia or myocardial infarction within 6 months prior to registration; if clinically indicated, echocardiogram or multigated acquisition (MUGA) must be performed and cardiac ejection fraction must be >= 50%

• Patients must not have had major surgery within 28 days prior to registration or be scheduled for surgery during the projected course of protocol treatment; tumor biopsy is allowed

• Patients must not have a known history of active hepatitis B infection (defined as presence of hepatitis B surface antigen [Hep B sAg] and/ or Hep B deoxyribonucleic acid [DNA]), active hepatitis C infection (defined as presence of hepatitis C [Hep C] ribonucleic acid [RNA]) and/or known human immunodeficiency virus (HIV) seropositive

• Patients must not have any other concomitant serious illness or organ system dysfunction which in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the study drug

• Patients must not be planning to receive any other investigational agents during the course of protocol treatment

• Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to afatinib and/or cetuximab

• Prestudy history and physical must be obtained with 28 days prior to registration

• Patients must have Zubrod performance status of 0 - 2

• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years

• Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; 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 outlined in the protocol, he/she is responsible for beginning contraceptive measures

• Patients must be informed of the investigational nature of this study and must sign and give written informed consent 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

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Recurrent Non-Small Cell Lung Carcinoma
• Stage IV Non-Small Cell Lung Cancer

Intervention

Drug:
• Afatinib Dimaleate
Given PO

Biological:
• Cetuximab
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies

Locations

Country	Name	City	State
United States	Hawaii Oncology Inc-Pali Momi	'Aiea	Hawaii
United States	Pali Momi Medical Center	'Aiea	Hawaii
United States	The Cancer Center of Hawaii-Pali Momi	'Aiea	Hawaii
United States	Akron General Medical Center	Akron	Ohio
United States	Lovelace Medical Center-Saint Joseph Square	Albuquerque	New Mexico
United States	New Mexico Oncology Hematology Consultants	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	Mary Greeley Medical Center	Ames	Iowa
United States	McFarland Clinic PC-William R Bliss Cancer Center	Ames	Iowa
United States	Kaiser Permanente-Anaheim	Anaheim	California
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Langlade Hospital and Cancer Center	Antigo	Wisconsin
United States	PCR Oncology	Arroyo Grande	California
United States	Asheville Hematology-Oncology Associates	Asheville	North Carolina
United States	Cancer Care of Western North Carolina	Asheville	North Carolina
United States	Mission Hospital-Memorial Campus	Asheville	North Carolina
United States	Sutter Auburn Faith Hospital	Auburn	California
United States	Sutter Cancer Centers Radiation Oncology Services-Auburn	Auburn	California
United States	Harold Alfond Center for Cancer Care	Augusta	Maine
United States	Rush - Copley Medical Center	Aurora	Illinois
United States	Saint Alphonsus Medical Center-Baker City	Baker City	Oregon
United States	AIS Cancer Center at San Joaquin Community Hospital	Bakersfield	California
United States	Kaiser Permanente-Baldwin Park	Baldwin Park	California
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Flaget Memorial Hospital	Bardstown	Kentucky
United States	Boston Baskin Cancer Center-Bartlett	Bartlett	Tennessee
United States	Bronson Battle Creek	Battle Creek	Michigan
United States	UPMC-Heritage Valley Health System Beaver	Beaver	Pennsylvania
United States	Indu and Raj Soin Medical Center	Beavercreek	Ohio
United States	Kaiser Permanente-Bellflower	Bellflower	California
United States	Strecker Cancer Center-Belpre	Belpre	Ohio
United States	Sanford Clinic North-Bemidgi	Bemidji	Minnesota
United States	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	Constantinou, Costas L MD (UIA Investigator)	Bettendorf	Iowa
United States	Beverly Hospital	Beverly	Massachusetts
United States	Billings Clinic Cancer Center	Billings	Montana
United States	Saint Vincent Healthcare	Billings	Montana
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Saint Joseph Medical Center	Bloomington	Illinois
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Central Care Cancer Center - Bolivar	Bolivar	Missouri
United States	Parkland Health Center-Bonne Terre	Bonne Terre	Missouri
United States	McFarland Clinic PC-Boone	Boone	Iowa
United States	Bozeman Deaconess Hospital	Bozeman	Montana
United States	Cox Cancer Center Branson	Branson	Missouri
United States	Harrison HealthPartners Hematology and Oncology-Bremerton	Bremerton	Washington
United States	Harrison Medical Center	Bremerton	Washington
United States	Lafayette Family Cancer Center-EMMC	Brewer	Maine
United States	IHA Hematology Oncology Consultants-Brighton	Brighton	Michigan
United States	Saint Joseph Mercy Brighton	Brighton	Michigan
United States	Saint Joseph Regional Cancer Center	Bryan	Texas
United States	Highline Medical Center-Main Campus	Burien	Washington
United States	Mills-Peninsula Medical Center	Burlingame	California
United States	Aurora Cancer Care-Southern Lakes VLCC	Burlington	Wisconsin
United States	Lahey Hospital and Medical Center	Burlington	Massachusetts
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	Saint James Community Hospital and Cancer Treatment Center	Butte	Montana
United States	Saint Alphonsus Cancer Care Center-Caldwell	Caldwell	Idaho
United States	Sutter Cancer Centers Radiation Oncology Services-Cameron Park	Cameron Park	California
United States	IHA Hematology Oncology Consultants-Canton	Canton	Michigan
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Mercy Medical Center	Canton	Ohio
United States	Saint Joseph Mercy Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Southeast Cancer Center	Cape Girardeau	Missouri
United States	Memorial Hospital of Carbondale	Carbondale	Illinois
United States	Caro Cancer Center	Caro	Michigan
United States	Carson Tahoe Regional Medical Center	Carson City	Nevada
United States	SIH Cancer Institute	Carterville	Illinois
United States	Illinois CancerCare-Carthage	Carthage	Illinois
United States	Eden Hospital Medical Center	Castro Valley	California
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	Christiana Care Health System-Concord Health Center	Chadds Ford	Pennsylvania
United States	Cancer Center of Kansas - Chanute	Chanute	Kansas
United States	Memorial Hospital	Chattanooga	Tennessee
United States	IHA Hematology Oncology Consultants-Chelsea	Chelsea	Michigan
United States	Saint Joseph Mercy Chelsea	Chelsea	Michigan
United States	Adena Regional Medical Center	Chillicothe	Ohio
United States	Marshfield Clinic-Chippewa Center	Chippewa Falls	Wisconsin
United States	Bethesda North Hospital	Cincinnati	Ohio
United States	Good Samaritan Hospital - Cincinnati	Cincinnati	Ohio
United States	Oncology Hematology Care Inc - Anderson	Cincinnati	Ohio
United States	Oncology Hematology Care Inc-Blue Ash	Cincinnati	Ohio
United States	Oncology Hematology Care Inc-Eden Park	Cincinnati	Ohio
United States	Oncology Hematology Care Inc-Kenwood	Cincinnati	Ohio
United States	Oncology Hematology Care Inc-Mercy West	Cincinnati	Ohio
United States	TriHealth Cancer Institute-Anderson	Cincinnati	Ohio
United States	TriHealth Cancer Institute-Westside	Cincinnati	Ohio
United States	Hematology Oncology Consultants-Clarkston	Clarkston	Michigan
United States	Newland Medical Associates-Clarkston	Clarkston	Michigan
United States	Sampson Radiation Oncology	Clinton	North Carolina
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 Medical Center	Coeur d'Alene	Idaho
United States	Coffeyville Regional Medical Center	Coffeyville	Kansas
United States	Integrity Oncology PLLC-Collierville	Collierville	Tennessee
United States	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado
United States	Rocky Mountain Cancer Centers-Penrose	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 Health Center West	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	Commonwealth Cancer Center-Corbin	Corbin	Kentucky
United States	Alegent Health Mercy Hospital	Council Bluffs	Iowa
United States	Greater Regional Medical Center	Creston	Iowa
United States	Oncology Hematology Care Inc-Crestview	Crestview Hills	Kentucky
United States	Carle on Vermilion	Danville	Illinois
United States	Sutter Davis Hospital	Davis	California
United States	Dayton Physicians LLC-Samaritan North	Dayton	Ohio
United States	Good Samaritan Hospital - Dayton	Dayton	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	Samaritan North Health Center	Dayton	Ohio
United States	Beaumont Hospital-Dearborn	Dearborn	Michigan
United States	Cancer Care Specialists of Central Illinois	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Delaware Health Center-Grady Cancer Center	Delaware	Ohio
United States	Delaware Radiation Oncology	Delaware	Ohio
United States	Grady Memorial Hospital	Delaware	Ohio
United States	Porter Adventist Hospital	Denver	Colorado
United States	Smilow Cancer Hospital-Derby Care Center	Derby	Connecticut
United States	Medical Oncology and Hematology Associates-Laurel	Des Moines	Iowa
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Saint John Hospital and Medical Center	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	Mercy Medical Center	Durango	Colorado
United States	Southwest Oncology PC	Durango	Colorado
United States	Greenville Health System Cancer Institute-Easley	Easley	South Carolina
United States	Great Lakes Cancer Management Specialists-Doctors Park	East China Township	Michigan
United States	Marshfield Clinic Cancer Center - Eau Claire	Eau Claire	Wisconsin
United States	Marshfield Clinic Cancer Center at Sacred Heart	Eau Claire	Wisconsin
United States	Sacred Heart Hospital	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	Walter Knox Memorial Hospital	Emmett	Idaho
United States	Englewood Hospital and Medical Center	Englewood	New Jersey
United States	Saint Elizabeth Hospital	Enumclaw	Washington
United States	Ephrata Cancer Center	Ephrata	Pennsylvania
United States	Ephrata Community Hospital	Ephrata	Pennsylvania
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	Deaconess Clinic Downtown	Evansville	Indiana
United States	Oncology Hematology Care Inc-Healthplex	Fairfield	Ohio
United States	Smilow Cancer Hospital Care Center-Fairfield	Fairfield	Connecticut
United States	Roger Maris Cancer Center	Fargo	North Dakota
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Sanford Clinic North-Fargo	Fargo	North Dakota
United States	Weisberg Cancer Treatment Center	Farmington Hills	Michigan
United States	Saint Francis Hospital	Federal Way	Washington
United States	Armes Family Cancer Center	Findlay	Ohio
United States	Blanchard Valley Hospital	Findlay	Ohio
United States	Orion Cancer Care	Findlay	Ohio
United States	Genesee Cancer and Blood Disease Treatment Center	Flint	Michigan
United States	Genesee Hematology Oncology PC	Flint	Michigan
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	McLeod Regional Medical Center	Florence	South Carolina
United States	Aurora Health Center-Fond du Lac	Fond Du Lac	Wisconsin
United States	Kaiser Permanente-Fontana	Fontana	California
United States	McFarland Clinic PC-Trinity Cancer Center	Fort Dodge	Iowa
United States	Cancer Center of Kansas - Fort Scott	Fort Scott	Kansas
United States	Mercy Hospital Fort Smith	Fort Smith	Arkansas
United States	Parkview Hospital Randallia	Fort Wayne	Indiana
United States	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio
United States	Dayton Physicians LLC-Atrium	Franklin	Ohio
United States	Vanderbilt-Ingram Cancer Center Cool Springs	Franklin	Tennessee
United States	Palo Alto Medical Foundation-Fremont	Fremont	California
United States	Unity Hospital	Fridley	Minnesota
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Western Illinois Cancer Treatment Center	Galesburg	Illinois
United States	Saint Catherine Hospital	Garden City	Kansas
United States	Aurora Health Care Germantown Health Center	Germantown	Wisconsin
United States	Adams Cancer Center	Gettysburg	Pennsylvania
United States	Addison Gilbert Hospital	Gloucester	Massachusetts
United States	Mountain Blue Cancer Care Center	Golden	Colorado
United States	Southeastern Medical Oncology Center-Goldsboro	Goldsboro	North Carolina
United States	Wayne Memorial Hospital	Goldsboro	North Carolina
United States	Wayne Radiation Oncology	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	Mercy Health Saint Mary's	Grand Rapids	Michigan
United States	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan
United States	Three Rivers Community Hospital	Grants Pass	Oregon
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	Aurora BayCare Medical Center	Green Bay	Wisconsin
United States	UPMC Cancer Centers - Arnold Palmer Pavilion	Greensburg	Pennsylvania
United States	Dayton Physicians LLC-Wayne	Greenville	Ohio
United States	Greenville Health System Cancer Institute-Butternut	Greenville	South Carolina
United States	Greenville Health System Cancer Institute-Eastside	Greenville	South Carolina
United States	Greenville Health System Cancer Institute-Faris	Greenville	South Carolina
United States	Greenville Memorial Hospital	Greenville	South Carolina
United States	Saint Francis Cancer Center	Greenville	South Carolina
United States	Saint Francis Hospital	Greenville	South Carolina
United States	Wayne Hospital	Greenville	Ohio
United States	Greenville Health System Cancer Institute-Greer	Greer	South Carolina
United States	Great Lakes Cancer Management Specialists-Van Elslander Cancer Center	Grosse Pointe Woods	Michigan
United States	Lymphoma Clinic of Michigan	Grosse Pointe Woods	Michigan
United States	Michigan Breast Specialists-Grosse Pointe Woods	Grosse Pointe Woods	Michigan
United States	Yale-New Haven Shoreline Medical Center	Guilford	Connecticut
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	Hays Medical Center	Hays	Kansas
United States	Saint Peter's Community Hospital	Helena	Montana
United States	21st Century Oncology-Henderson	Henderson	Nevada
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-Horizon Ridge	Henderson	Nevada
United States	Comprehensive Cancer Centers of Nevada-Southeast 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	Park Ridge Hospital Breast Health Center	Hendersonville	North Carolina
United States	Pulmonary Medicine Center of Chattanooga-Hixson	Hixson	Tennessee
United States	Hawaii Cancer Care Inc-Liliha	Honolulu	Hawaii
United States	Hawaii Cancer Care Inc-POB II	Honolulu	Hawaii
United States	Hawaii Oncology Inc-Kuakini	Honolulu	Hawaii
United States	Hawaii Oncology Inc-POB I	Honolulu	Hawaii
United States	Island Urology	Honolulu	Hawaii
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	Kuakini Medical Center	Honolulu	Hawaii
United States	Queen's Medical Center	Honolulu	Hawaii
United States	Straub Clinic and Hospital	Honolulu	Hawaii
United States	The Cancer Center of Hawaii-Liliha	Honolulu	Hawaii
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	CHI Saint Vincent Cancer Center Hot Springs	Hot Springs	Arkansas
United States	Saint Mary's Medical Center	Huntington	West Virginia
United States	Cancer Center of Kansas-Independence	Independence	Kansas
United States	Centerpoint Medical Center LLC	Independence	Missouri
United States	Kaiser Permanente-Irvine	Irvine	California
United States	Allegiance Health	Jackson	Michigan
United States	Baptist MD Anderson Cancer Center	Jacksonville	Florida
United States	Onslow Memorial Hospital	Jacksonville	North Carolina
United States	Southeastern Medical Oncology Center-Jacksonville	Jacksonville	North Carolina
United States	McFarland Clinic PC-Jefferson	Jefferson	Iowa
United States	Capital Region Medical Center-Goldschmidt Cancer Center	Jefferson City	Missouri
United States	UPMC-Johnstown/John P. Murtha Regional Cancer Center	Johnstown	Pennsylvania
United States	Fowler Family Center for Cancer Care	Jonesboro	Arkansas
United States	Freeman Health System	Joplin	Missouri
United States	Mercy Hospital Joplin	Joplin	Missouri
United States	Borgess Medical Center	Kalamazoo	Michigan
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
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-North	Kansas City	Missouri
United States	The University of Kansas Cancer Center-South	Kansas City	Missouri
United States	Truman Medical Center	Kansas City	Missouri
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	University of Kansas Cancer Center-West	Kansas City	Kansas
United States	CHI Health Good Samaritan	Kearney	Nebraska
United States	Heartland Hematology and Oncology	Kearney	Nebraska
United States	Aurora Cancer Care-Kenosha South	Kenosha	Wisconsin
United States	First Dayton Cancer Care	Kettering	Ohio
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	Cancer Center of Kansas-Kingman	Kingman	Kansas
United States	Kinston Medical Specialists PA	Kinston	North Carolina
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	Marshfield Clinic - Ladysmith Center	Ladysmith	Wisconsin
United States	Rocky Mountain Cancer Centers-Lakewood	Lakewood	Colorado
United States	Saint Anthony Hospital	Lakewood	Colorado
United States	Saint Clare Hospital	Lakewood	Washington
United States	Fairfield Medical Center	Lancaster	Ohio
United States	Sparrow Hospital	Lansing	Michigan
United States	Memorial Medical Center - Las Cruces	Las Cruces	New Mexico
United States	21st Century Oncology	Las Vegas	Nevada
United States	21st Century Oncology-Fort Apache	Las Vegas	Nevada
United States	21st Century Oncology-Vegas Tenaya	Las Vegas	Nevada
United States	Ann M Wierman MD LTD	Las Vegas	Nevada
United States	Cancer and Blood Specialists-Shadow	Las Vegas	Nevada
United States	Cancer and Blood Specialists-Tenaya	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	Comprehensive Cancer Centers of Nevada-Summerlin	Las Vegas	Nevada
United States	HealthCare Partners Medical Group Oncology/Hematology-Centennial Hills	Las Vegas	Nevada
United States	HealthCare Partners Medical Group Oncology/Hematology-Maryland Parkway	Las Vegas	Nevada
United States	HealthCare Partners Medical Group Oncology/Hematology-San Martin	Las Vegas	Nevada
United States	HealthCare Partners Medical Group Oncology/Hematology-Tenaya	Las Vegas	Nevada
United States	Las Vegas Cancer Center-Medical Center	Las Vegas	Nevada
United States	Nevada Cancer Specialists-Fort Apache	Las Vegas	Nevada
United States	Radiation Oncology Centers of Nevada Central	Las Vegas	Nevada
United States	Radiation Oncology Centers of Nevada Southeast	Las Vegas	Nevada
United States	Summerlin Hospital Medical Center	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	Lebanon	New Hampshire
United States	Sechler Family Cancer Center	Lebanon	Pennsylvania
United States	Saint Luke's East - Lee's Summit	Lee's Summit	Missouri
United States	The 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	Beebe Medical Center	Lewes	Delaware
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	Wilcox Memorial Hospital and Kauai Medical Clinic	Lihue	Hawaii
United States	Nebraska Cancer Research Center	Lincoln	Nebraska
United States	Nebraska Hematology and Oncology	Lincoln	Nebraska
United States	Saint Elizabeth Regional Medical Center	Lincoln	Nebraska
United States	Southeast Nebraska Cancer Center	Lincoln	Nebraska
United States	Littleton Adventist Hospital	Littleton	Colorado
United States	Hope Cancer Clinic	Livonia	Michigan
United States	Saint Mary Mercy Hospital	Livonia	Michigan
United States	Longmont United Hospital	Longmont	Colorado
United States	Rocky Mountain Cancer Centers-Longmont	Longmont	Colorado
United States	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California
United States	Kaiser Permanente-Cadillac	Los Angeles	California
United States	Jewish Hospital	Louisville	Kentucky
United States	Jewish Hospital Medical Center Northeast	Louisville	Kentucky
United States	Saints Mary and Elizabeth Hospital	Louisville	Kentucky
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	Central Georgia Gynecologic Oncology	Macon	Georgia
United States	Medical Center of Central Georgia	Macon	Georgia
United States	Norris Cotton Cancer Center-Manchester	Manchester	New Hampshire
United States	Cancer Center of Kansas-Manhattan	Manhattan	Kansas
United States	Fairview Maple Grove Medical Center	Maple Grove	Minnesota
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	Vince Lombardi Cancer Clinic-Marinette	Marinette	Wisconsin
United States	Saint Mary's Oncology/Hematology Associates of Marlette	Marlette	Michigan
United States	UP Health System Hematology Oncology Marquette	Marquette	Michigan
United States	UP Health System Marquette	Marquette	Michigan
United States	McFarland Clinic PC-Marshalltown	Marshalltown	Iowa
United States	Marshfield Clinic	Marshfield	Wisconsin
United States	Marshfield Medical Center	Marshfield	Wisconsin
United States	Fremont - Rideout Cancer Center	Marysville	California
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	Loyola University Medical Center	Maywood	Illinois
United States	UPMC Cancer Center at UPMC McKeesport	McKeesport	Pennsylvania
United States	Cancer Center of Kansas - McPherson	McPherson	Kansas
United States	Providence Medford Medical Center	Medford	Oregon
United States	Rogue Valley Medical Center	Medford	Oregon
United States	Baptist Memorial Hospital and Cancer Center-Memphis	Memphis	Tennessee
United States	Baptist Memorial Hospital for Women	Memphis	Tennessee
United States	Family Cancer Center-Memphis	Memphis	Tennessee
United States	Columbia Saint Mary's Hospital - Ozaukee	Mequon	Wisconsin
United States	Mercy UC Davis Cancer Center	Merced	California
United States	Idaho Urologic Institute-Meridian	Meridian	Idaho
United States	Franciscan Saint Anthony Health-Michigan City	Michigan City	Indiana
United States	Woodland Cancer Care Center	Michigan City	Indiana
United States	Dayton Physicians LLC-Signal Point	Middletown	Ohio
United States	Middlesex Hospital	Middletown	Connecticut
United States	Orange Regional Medical Center	Middletown	New York
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	Columbia Saint Mary's Water Tower Medical Commons	Milwaukee	Wisconsin
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
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	Trinity Cancer Care Center	Minot	North Dakota
United States	Community Medical Hospital	Missoula	Montana
United States	Saint Patrick Hospital - Community Hospital	Missoula	Montana
United States	Memorial Medical Center	Modesto	California
United States	Garneau, Stewart C MD (UIA Investigator)	Moline	Illinois
United States	Spector, David MD (UIA Investigator)	Moline	Illinois
United States	Trinity Medical Center	Moline	Illinois
United States	Monroe Cancer Center	Monroe	Michigan
United States	UPMC-Coraopolis/Heritage Valley Radiation Oncology	Moon	Pennsylvania
United States	Good Samaritan Regional Health Center	Mount Vernon	Illinois
United States	Knox Community Hospital	Mount Vernon	Ohio
United States	Palo Alto Medical Foundation-Camino Division	Mountain View	California
United States	Palo Alto Medical Foundation-Gynecologic Oncology	Mountain View	California
United States	Mercy Health Mercy Campus	Muskegon	Michigan
United States	Saint Alphonsus Medical Center-Nampa	Nampa	Idaho
United States	Edward Hospital/Cancer Center	Naperville	Illinois
United States	Norris Cotton Cancer Center-Nashua	Nashua	New Hampshire
United States	Vanderbilt Breast Center at One Hundred Oaks	Nashville	Tennessee
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Baptist Memorial Hospital and Cancer Center-Union County	New Albany	Mississippi
United States	Yale University	New Haven	Connecticut
United States	Cancer Center of Western Wisconsin	New Richmond	Wisconsin
United States	New Ulm Medical Center	New Ulm	Minnesota
United States	Christiana Care Health System-Christiana Hospital	Newark	Delaware
United States	Delaware Clinical and Laboratory Physicians PA	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	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Newark Radiation Oncology	Newark	Ohio
United States	Regional Hematology and Oncology PA	Newark	Delaware
United States	Chancellor Center for Oncology	Newburgh	Indiana
United States	Cancer Center of Kansas - Newton	Newton	Kansas
United States	Lakeland Community Hospital	Niles	Michigan
United States	Faith Regional Health Services Carson Cancer Center	Norfolk	Nebraska
United States	Yale-New Haven Hospital North Haven Medical Center	North Haven	Connecticut
United States	Great Plains Health Callahan Cancer Center	North Platte	Nebraska
United States	Sutter Cancer Research Consortium	Novato	California
United States	Mercy Hospital Oklahoma City	Oklahoma City	Oklahoma
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Olathe Medical 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	Hematology and Oncology Consultants PC	Omaha	Nebraska
United States	Nebraska Cancer Specialists - Omaha	Omaha	Nebraska
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	Oncology Hematology West PC	Omaha	Nebraska
United States	Saint Alphonsus Medical Center-Ontario	Ontario	Oregon
United States	Memorial GYN Plus	Ooltewah	Tennessee
United States	Smilow Cancer Hospital-Orange Care Center	Orange	Connecticut
United States	Vince Lombardi Cancer Clinic - Oshkosh	Oshkosh	Wisconsin
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	Radiation Oncology of Northern Illinois	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	Baptist Memorial Hospital and Cancer Center-Oxford	Oxford	Mississippi
United States	Hope Cancer Care of Nevada-Pahrump	Pahrump	Nevada
United States	Palo Alto Medical Foundation Health Care	Palo Alto	California
United States	Kaiser Permanente - Panorama City	Panorama City	California
United States	Midlands Community Hospital	Papillion	Nebraska
United States	Parker Adventist Hospital	Parker	Colorado
United States	Rocky Mountain Cancer Centers-Parker	Parker	Colorado
United States	Cancer Center of Kansas - Parsons	Parsons	Kansas
United States	Singing River Hospital	Pascagoula	Mississippi
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	OSF Saint Francis Radiation Oncology at Pekin Cancer Treatment Center	Pekin	Illinois
United States	Sacred Heart Hospital	Pensacola	Florida
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	OSF Saint Francis Radiation Oncology at Peoria Cancer Center	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	Valley Radiation Oncology	Peru	Illinois
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	Via Christi Hospital-Pittsburg	Pittsburg	Kansas
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	UPMC-Magee Womens Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Passavant Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Presbyterian Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Saint Clair Hospital Cancer Center	Pittsburgh	Pennsylvania
United States	UPMC-Saint Margaret	Pittsburgh	Pennsylvania
United States	UPMC-Shadyside Hospital	Pittsburgh	Pennsylvania
United States	Edward Hospital/Cancer Center?Plainfield	Plainfield	Illinois
United States	21st Century Oncology-Pontiac	Pontiac	Michigan
United States	Hope Cancer Center	Pontiac	Michigan
United States	Newland Medical Associates-Pontiac	Pontiac	Michigan
United States	Saint Joseph Mercy Oakland	Pontiac	Michigan
United States	Huron Medical Center PC	Port Huron	Michigan
United States	Lake Huron Medical Center	Port Huron	Michigan
United States	Kaiser Permanente Northwest	Portland	Oregon
United States	Southern Ohio Medical Center	Portsmouth	Ohio
United States	Kootenai Cancer Center	Post Falls	Idaho
United States	Harrison HealthPartners Hematology and Oncology-Poulsbo	Poulsbo	Washington
United States	Kansas City NCI Community Oncology Research Program	Prairie Village	Kansas
United States	Cancer Center of Kansas - Pratt	Pratt	Kansas
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Rocky Mountain Cancer Centers - Pueblo	Pueblo	Colorado
United States	Saint Mary Corwin Medical Center	Pueblo	Colorado
United States	Aurora Cancer Care-Racine	Racine	Wisconsin
United States	Eisenhower Medical Center	Rancho Mirage	California
United States	Penn State Health Saint Joseph Medical Center	Reading	Pennsylvania
United States	Spectrum Health Reed City Hospital	Reed City	Michigan
United States	Beebe Health Campus	Rehoboth Beach	Delaware
United States	Radiation Oncology Associates	Reno	Nevada
United States	Renown Regional Medical Center	Reno	Nevada
United States	Saint Mary's Regional Medical Center	Reno	Nevada
United States	Lakeview Medical Center-Marshfield Clinic	Rice Lake	Wisconsin
United States	Marshfield Clinic-Rice Lake Center	Rice Lake	Wisconsin
United States	Reid Health	Richmond	Indiana
United States	Kaiser Permanente-Riverside	Riverside	California
United States	North Memorial Medical Health Center	Robbinsdale	Minnesota
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	Penobscot Bay Medical Center	Rockport	Maine
United States	Delbert Day Cancer Institute at PCRMC	Rolla	Missouri
United States	Mercy Clinic-Rolla-Cancer and Hematology	Rolla	Missouri
United States	Sutter Cancer Centers Radiation Oncology Services-Roseville	Roseville	California
United States	Sutter Roseville Medical Center	Roseville	California
United States	Sutter Medical Center Sacramento	Sacramento	California
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Oncology Hematology Associates of Saginaw Valley PC	Saginaw	Michigan
United States	Saint Mary's of Michigan	Saginaw	Michigan
United States	Norris Cotton Cancer Center-North	Saint Johnsbury	Vermont
United States	Heartland Regional Medical Center	Saint Joseph	Missouri
United States	Lakeland Hospital	Saint Joseph	Michigan
United States	Marie Yeager Cancer Center	Saint Joseph	Michigan
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
United States	Saint Louis Cancer and Breast Institute-South City	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	University of Texas Health Science Center at San Antonio	San Antonio	Texas
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 Marcos	San Marcos	California
United States	Kootenai Cancer Clinic	Sandpoint	Idaho
United States	Palo Alto Medical Foundation-Santa Cruz	Santa Cruz	California
United States	Christus Saint Vincent Regional Cancer Center	Santa Fe	New Mexico
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	Low Country Cancer Care Associates PC	Savannah	Georgia
United States	Memorial University Medical Center	Savannah	Georgia
United States	Summit Cancer Care-Candler	Savannah	Georgia
United States	Summit Cancer Care-Memorial	Savannah	Georgia
United States	Guthrie Medical Group PC-Robert Packer Hospital	Sayre	Pennsylvania
United States	Regional West Medical Center Cancer Center	Scottsbluff	Nebraska
United States	Nanticoke Memorial Hospital	Seaford	Delaware
United States	Greenville Health System Cancer Institute-Seneca	Seneca	South Carolina
United States	UPMC Cancer Center at UPMC Northwest	Seneca	Pennsylvania
United States	Saint Francis Regional Medical Center	Shakopee	Minnesota
United States	Vince Lombardi Cancer Clinic-Sheboygan	Sheboygan	Wisconsin
United States	Jewish Hospital Medical Center South	Shepherdsville	Kentucky
United States	Welch Cancer Center	Sheridan	Wyoming
United States	Dayton Physicians LLC-Wilson	Sidney	Ohio
United States	Siouxland Regional Cancer Center	Sioux City	Iowa
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	Baptist Memorial Hospital and Cancer Center-Desoto	Southhaven	Mississippi
United States	Greenville Health System Cancer Institute-Spartanburg	Spartanburg	South Carolina
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	Springfield Regional Cancer Center	Springfield	Ohio
United States	Springfield Regional Medical Center	Springfield	Ohio
United States	Bhadresh Nayak MD PC-Sterling Heights	Sterling Heights	Michigan
United States	Ascension Saint Michael's Hospital	Stevens Point	Wisconsin
United States	Marshfield Clinic Stevens Point Center	Stevens Point	Wisconsin
United States	Saint Michael's Hospital	Stevens Point	Wisconsin
United States	Lakeview Hospital	Stillwater	Minnesota
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	Missouri Baptist Outpatient Center-Sunset Hills	Sunset Hills	Missouri
United States	Cancer Care Specialists of Illinois-Swansea	Swansea	Illinois
United States	Memorial and Saint Elizabeth's Health Care Services LLP	Swansea	Illinois
United States	Flower Hospital	Sylvania	Ohio
United States	Franciscan Research Center-Northwest Medical Plaza	Tacoma	Washington
United States	Northwest Medical Specialties PLLC	Tacoma	Washington
United States	Saint Joseph Health System-Tawas City	Tawas City	Michigan
United States	Rocky Mountain Cancer Centers-Thornton	Thornton	Colorado
United States	The Toledo Hospital/Toledo Children's Hospital	Toledo	Ohio
United States	Saint Francis Hospital and Medical Center - Topeka	Topeka	Kansas
United States	Smilow Cancer Hospital-Torrington Care Center	Torrington	Connecticut
United States	Munson Medical Center	Traverse City	Michigan
United States	Dayton Physicians LLC-Upper Valley	Troy	Ohio
United States	Upper Valley Medical Center	Troy	Ohio
United States	Gene Upshaw Memorial Tahoe Forest Cancer Center	Truckee	California
United States	Smilow Cancer Hospital Care Center-Trumbull	Trumbull	Connecticut
United States	Vince Lombardi Cancer Clinic-Two Rivers	Two Rivers	Wisconsin
United States	UPMC Uniontown Hospital Radiation Oncology	Uniontown	Pennsylvania
United States	Carle Cancer Center	Urbana	Illinois
United States	The Carle Foundation Hospital	Urbana	Illinois
United States	Faxton-Saint Luke's Healthcare	Utica	New York
United States	Northbay Cancer Center	Vacaville	California
United States	Sutter Cancer Centers Radiation Oncology Services-Vacaville	Vacaville	California
United States	South Georgia Medical Center/Pearlman Cancer Center	Valdosta	Georgia
United States	Sutter Solano Medical Center/Cancer Center	Vallejo	California
United States	Inspira Medical Center Vineland	Vineland	New Jersey
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	Advanced Breast Care Center PLLC	Warren	Michigan
United States	Bhadresh Nayak MD PC-Warren	Warren	Michigan
United States	Great Lakes Cancer Management Specialists-Macomb Professional Building	Warren	Michigan
United States	Macomb Hematology Oncology PC	Warren	Michigan
United States	Michigan Breast Specialists-Warren	Warren	Michigan
United States	Saint John Macomb-Oakland Hospital	Warren	Michigan
United States	UPMC Washington Hospital Radiation Oncology	Washington	Pennsylvania
United States	Smilow Cancer Hospital-Waterbury Care Center	Waterbury	Connecticut
United States	Aurora Cancer Care-Waukesha	Waukesha	Wisconsin
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	Saint Mary's Oncology/Hematology Associates of West Branch	West Branch	Michigan
United States	Chester County Hospital	West Chester	Pennsylvania
United States	Mercy Medical Center-West Lakes	West Des Moines	Iowa
United States	Saint Ann's Hospital	Westerville	Ohio
United States	Diagnostic and Treatment Center	Weston	Wisconsin
United States	Marshfield Clinic - Weston Center	Weston	Wisconsin
United States	University of Kansas Hospital-Westwood Cancer Center	Westwood	Kansas
United States	Associates In Womens Health	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	Via Christi Regional Medical Center	Wichita	Kansas
United States	UPMC Susquehanna	Williamsport	Pennsylvania
United States	Rice Memorial Hospital	Willmar	Minnesota
United States	Christiana Care Health System-Wilmington Hospital	Wilmington	Delaware
United States	Southeastern Medical Oncology Center-Wilson	Wilson	North Carolina
United States	Winchester Hospital	Winchester	Massachusetts
United States	Cancer Center of Kansas - Winfield	Winfield	Kansas
United States	Aspirus UW Cancer Center	Wisconsin Rapids	Wisconsin
United States	Marshfield Clinic - Wisconsin Rapids Center	Wisconsin Rapids	Wisconsin
United States	Inspira Medical Center Woodbury	Woodbury	New Jersey
United States	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota
United States	Kaiser Permanente-Woodland Hills	Woodland Hills	California
United States	Fairview Lakes Medical Center	Wyoming	Minnesota
United States	Metro Health Hospital	Wyoming	Michigan
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	Huron Gastroenterology PC	Ypsilanti	Michigan
United States	IHA Hematology Oncology Consultants-Ann Arbor	Ypsilanti	Michigan
United States	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
SWOG Cancer Research Network	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in Copy Number Alterations in MET, EGFR, and HER2, Analyzed Using Fluorescence in Situ Hybridization	For each of these markers, a one-sample t-test (or Wilcoxon signed-rank test) will be used to test the null hypothesis that the absolute difference between the copy number after progression and the copy number in the pre-treatment specimen (or an appropriate transformation of the difference, determined after exploratory data analysis) is not equal to zero.	Baseline up to 3 years (after disease progression)
Other	Change in the Ratio of Sensitizing EGFR Mutation to EGFR T790 Mutation	To evaluate if EGFRs/EGFR T790M is lower at progression than in pre-treatment specimens among patients with results available for pre-treatment and progression, a one-sample t-test (or Wilcoxon signed-rank test) will be used to test the null hypothesis that the difference between the progression ratio and the pre-treatment ratio (or an appropriate transformation of the difference, determined after exploratory data analysis) is greater than zero in favor of the alternative that the difference is less than zero.	Baseline up to 3 years (at progression)
Other	EGFR Immunohistochemistry H-score	To evaluate the hypothesis that H-score positive status at baseline is associated with absolute difference in PFS (and OS) among patients randomized to receive afatinib dimaleate monotherapy a test of interaction will be performed at the 1-sided 20% level.	Baseline
Other	Levels of Circulating Tumor Markers	Tumor marker levels over time will be evaluated using a linear mixed model for continuous markers and using generalized estimating equations for binary markers. A landmark analysis will be used to evaluate the correlation between post-randomization biomarker values and PFS and OS (from the landmark timepoint) using a Cox proportional hazards model.	Up to 3 years
Other	Presence of de Novo EGFR T790M Mutation or Other Molecular Alterations	To evaluate if the presence of de novo T790M mutation is associated with primary resistance to afatinib dimaleate, PFS and OS will be compared between T790M mutation positive and negative patients randomized to the afatinib dimaleate monotherapy arm using a log-rank test..	Baseline
Other	Ratio of Sensitizing EGFR Mutation to EGFR T790 Mutation	To evaluate if the ratio of EGFR sensitizing mutation to EGFR T790M mutation (EGFRs/EGFR T790M) among patients with T790M is predictive for afatinib dimaleate monotherapy, analyses will be performed in a similar fashion to the evaluation of T790M among patients with measurable T790M (which defines T790M). Cox regression will be used to assess the predictive association of the ratio in the afatinib dimaleate monotherapy arm with both OS and PFS	Up to 3 years
Primary	2-year Overall Survival Rate	Percentage of participants still alive 2 years post registration.; KM estimate at 2 years is presented, Overall Survival assessed for a total of 3 years in order to calculate value.	Up to 3 years post registration
Primary	Progression-Free Survival	From date of registration to date of first documentation of progression or symptomatic deterioration or death due to any cause.; Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of appropriate diameters of target measurable lesions over smallest sum observed, as well as an absolute increase of at least 0.5 cm. Unequivocal progression of non-measurable disease in the opinion of treating physician. Appearance of any new lesion/site. Death due to disease without prior documentation of progression and without symptomatic deterioration.	up to 3 years post registration
Secondary	Response Rates	Percentage of participants with confirmed and unconfirmed, partial response and complete response to treatment Response Evaluation Criteria in Solid Tumors Criteria (RECIST 1.1).; Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of appropriate diameters of all target measurable lesions; Overall Response (OR) = CR + PR.	Up to 3 years
Secondary	Time to Treatment Discontinuation	From date of registration to date of discontinuation of treatment or death due to any cause	up to 3 years post-registration
Secondary	Time to Treatment Failure	From date of registration to date of first documentation of progression or symptomatic deterioration, early discontinuation of treatment, or death due to any cause.	assessed up to 3 years post registration
Secondary	Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs	Routine Adverse Events are reported by CTCAE4.0. For serious adverse event reporting, we updated from CTCAE4.0 to CTCAE5.0. . Only adverse events that are possibly, probably or definitely related to study drug are reported.	Duration of treatment and follow up until death or 3 years post registration