Comparing High-Dose Cisplatin Every Three Weeks to Low-Dose Cisplatin Weekly When Combined With Radiation for Patients With Advanced Head and Neck Cancer

Advanced Head and Neck Squamous Cell Carcinoma Clinical Trial

Official title:

Randomized Phase II/III Trial of Radiation With High-Dose Cisplatin (100 mg/m2) Every Three Weeks Versus Radiation With Low-Dose Weekly Cisplatin (40 mg/m2) for Patients With Locoregionally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05050162
• Other study ID #: NRG-HN009
• Secondary ID: NCI-2021-08925NR
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: October 27, 2021
• Est. completion date: February 9, 2036

Study information

• Verified date: February 2024
• Source: NRG Oncology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II/III trial compares the effect of the combination of high-dose cisplatin every three weeks and radiation therapy versus low-dose cisplatin weekly and radiation therapy for the treatment of patients with locoregionally advanced head and neck cancer. Chemotherapy drugs, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. This study is being done to find out if low-dose cisplatin given weekly together with radiation therapy is the same or better than high-dose cisplatin given every 3 weeks together with radiation therapy in treating patients with head and neck cancer.

Description:

PRIMARY OBJECTIVES:

I. To determine whether radiation with low-dose cisplatin weekly is superior in terms of acute toxicity, as measured by the T-scores (TAME method), to radiation with high-dose cisplatin every 3 weeks for patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). (Phase II) II. To determine whether radiation with low-dose cisplatin weekly is non-inferior to radiation with high-dose cisplatin every 3 weeks in terms of overall survival (OS) for patients with locoregionally advanced SCCHN. (Phase III) III. To determine whether radiation with low-dose cisplatin weekly is superior in terms of acute toxicity, as measured by the T-scores (TAME method), to radiation with high-dose cisplatin every 3 weeks for patients with locoregionally advanced SCCHN. (Phase III)

SECONDARY OBJECTIVES:

I. To assess and compare progression-free survival (PFS) between arms. II. To assess and compare locoregional failure and distant metastasis between arms .

III. To assess acute and late toxicity (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0).

IV. To assess patient-reported outcomes quality of life (PRO/QOL), as measured by the Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N) (primary PRO), between arms.

V. To assess hearing loss, as measured by audiograms and the modified TUNE grading scale between arms.

VI. To assess hearing loss, as measured by speech audiometry Consonant-Nucleus-Consonant word scores and tympanometry (subject to the modified TUNE grading scale testing results; otherwise, it will be an exploratory objective).

VII. To assess hearing-related QOL as measured by the Hearing Handicap Inventory-Screening (HHIA-S) (secondary PRO), between arms.

EXPLORATORY OBJECTIVE:

I. To collect blood and tissue specimens for future translational science studies. For instance, to examine how germline and somatic genetic variants, such as TP53, CDKN2A, PIK3CA, PTEN, NFE2L2, and KEAP1, may influence cisplatin-related efficacy and toxicity, and to assess the effect of regular nonsteroidal anti-inflammatory drugs (NSAIDs) use and genomic activation of PIK3CA (mutation or amplification) or loss of PTEN, the negative regulator of PI3K, on disease-free survival or overall survival.

OUTLINE: Patients are assigned to 1 of 2 groups.

GROUP I (NON-OROPHARYNGEAL CANCER [OPC]/p16-NEGATIVE OPC): Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive high-dose cisplatin intravenously (IV) once every 3 weeks (Q3W) (on days 1, 22, and 43) during radiation therapy in the absence of disease progression or unacceptable toxicity.

ARM II: Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive low-dose cisplatin IV once a week (QW) during radiation therapy in the absence of disease progression or unacceptable toxicity.

GROUP II (p16-POSITIVE OPC/CANCER OF UNKNOWN PRIMARY [CUP]): Patients are randomized to 1 of 2 arms.

ARM III: Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive high-dose cisplatin IV Q3W (on days 1, 22, and 43) during radiation therapy in the absence of disease progression or unacceptable toxicity.

ARM IV: Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive low-dose cisplatin IV QW during radiation therapy in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 1 month, every 3 months during year 1-2, every 6 months during year 3-5, then annually thereafter.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 464
• Est. completion date: February 9, 2036
• Est. primary completion date: February 9, 2031
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of SCCHN of the oropharynx, larynx, hypopharynx, or p16-positive unknown primary prior to registration; specimen from cervical lymph nodes with a well-defined primary site documented clinically or radiologically is acceptable; in patients with carcinoma of unknown primary this will be sufficient for pathologic confirmation without a clinically or radiographically defined primary site

• For patients with oropharyngeal cancer (OPC)/cancer of unknown primary (CUP):

P16 status based on local site immunohistochemical tissue staining is required. A cell block obtained from a fine needle aspiration (FNA) biopsy specimen may be used as the sole diagnostic tissue. Centers are encouraged to contact the pathology chair for clarification

• Note: Institutions must screen patients for p16 status by immunohistochemistry (IHC) in order to be eligible for the trial using a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. A rigorous laboratory accreditation process similar to the United States (U.S.) CLIA certification, such as the provincial accreditation status offered by the Ontario Laboratory Accreditation (OLA) Program in Canada, the College of American Pathologists (CAP), or an equivalent accreditation in other countries, is acceptable.

• The p16 results must be reported on the pathology report being submitted. The p16 positivity is defined as > 70% of tumor cells showing strong nuclear and/or cytoplasmic immunostaining with p16 antibody.

• For patients with laryngeal and hypopharyngeal primaries: Analysis of p16 status is NOT required

• Patients must have clinically or radiographically evident measurable disease at the primary site or at nodal stations. Simple tonsillectomy or local excision of the primary without removal of nodal disease is permitted, as is excision removing gross nodal disease but with intact primary site. Limited neck dissections retrieving =< 4 nodes are permitted and considered as non-therapeutic nodal excisions

• Clinical stage (American Joint Committee on Cancer [AJCC], 8th ed.), including no distant metastases based on the following diagnostic workup:

• History/physical examination within 60 days prior to registration

• One of the following imaging studies is required within 60 days prior to registration:

• Computed tomography (CT) scan of neck (diagnostic quality with contrast, unless contraindicated) OR

• Magnetic resonance imaging (MRI) of the neck (diagnostic quality with contrast, unless contraindicated) OR

• Fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/CT of the neck; the CT component must be of diagnostic quality with contrast, unless contraindicated.

• Note: A diagnostic quality CT or MRI with contrast or FDG-PET/CT scan of neck performed for the purposes of radiation planning may serve as both staging and planning tools

• One of the following imaging studies is required within 60 days prior to registration:

• FDG-PET/CT of the chest; FDG-PET/CT scan is strongly preferred and highly recommended to be used for eligibility OR

• Chest CT

• Exam with laryngopharyngoscopy (mirror or in office direct procedure acceptable) within 70 days prior to registration;

• Eligibility by patient cohort;

• Non-OPC/p16-negative OPC Cohort; Tumor Site: Larynx/Hypopharynx; Clinical Staging (AJCC, 8th ed.): T3-4 N0 or T1-4 N1-3 T2 N0 (hypopharynx only)

• Tumor Site: p16-negative OPC; Clinical Staging (AJCC, 8th ed.): T2N1, T1-4 N2-3, or T3-4 N0-1

• p16-positive OPC/CUP Cohort;

• Tumor Site: OPC; Smoking Status: =< 10 pack-years; Clinical Staging (AJCC, 8th ed.): T1-3 N2-3 or T4 N0-3

• Tumor Site: OPC; Smoking Status: > 10 pack-years; Clinical Staging (AJCC, 8th ed.): T1N2-3, T2N1-3 or T3-4 N0-3

• Tumor Site: CUP; Smoking Status: Any; Clinical Staging (AJCC, 8th ed.): T0 N2-3

Note: Cigar and pipe tobacco consumption is not included in calculating the lifetime pack-years. Marijuana consumption is likewise not considered in this calculation. There is also no clear scientific evidence regarding the role of chewing tobacco-containing products in oropharyngeal cancer, although this is possibly more concerning given the proximity of the oral cavity and oropharynx. In any case, investigators should not count use of non-cigarette tobacco products in the pack-years calculation.

• Age >= 18

• Zubrod (Eastern Cooperative Oncology Group [ECOG]) performance status of 0-1 within 14 days prior to registration

• Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (within 30 days prior to registration)

• Platelets >= 75,000 cells/mm^3 (within 30 days prior to registration)

• Hemoglobin >= 8.0 g/dL (within 30 days prior to registration)

• Note: The use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dL is acceptable)

• Calculated creatinine clearance (CrCl) >= 50 mL/min by the Cockcroft-Gault formula (within 30 days prior to registration)

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 30 days prior to registration) (not applicable to patients with known Gilbert's syndrome)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x institutional ULN (within 30 days prior to registration)

• Known human immunodeficiency virus (HIV) infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months and CD4 T Cell count > 200 cells/mm^3 are eligible for this trial. Testing is not required for entry into protocol

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes

• Willing to use highly effective contraceptives for participants of childbearing potential (participants who may become pregnant or who may impregnate a partner) during therapy and for 14 months (females); for 11 months (males) following last dose of cisplatin; this inclusion is necessary because the treatment in this study may be significantly teratogenic

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

Exclusion Criteria:

• Patients with oral cavity cancer, nasopharynx cancer, or p16-negative cancer of unknown primary (CUP)

• Recurrence of the study cancer

• Definitive clinical or radiologic evidence of distant metastatic disease

• Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable, however, any prior exposure to cisplatin is excluded

• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields

• Severe, active co-morbidity defined as follows:

• Unstable angina requiring hospitalization in the last 6 months

• Myocardial infarction within the last 6 months

• New York Heart Association Functional Classification III/IV (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.)

• Persistent grade 3-4 (CTCAE version 5.0) electrolyte abnormalities that cannot be reversed despite replacement as indicated by repeat testing

• Patient must not have an active infection requiring IV antibiotics prior to registration;

• Other chronic renal disease like nephrotic syndrome, that could be worsened by cisplatin therapy

• History of allogenic organ transplantation

• Any symptomatic peripheral sensory neuropathy grade >= 2 (CTCAE version 5.0);

• Pregnancy and individuals unwilling to discontinue nursing

• History of hypersensitivity to cisplatin or platinum-containing compounds

Related Conditions & MeSH terms

• Advanced Head and Neck Squamous Cell Carcinoma
• Advanced Hypopharyngeal Squamous Cell Carcinoma
• Advanced Laryngeal Squamous Cell Carcinoma
• Advanced Oropharyngeal Squamous Cell Carcinoma
• Carcinoma
• Carcinoma, Squamous Cell
• Squamous Cell Carcinoma of Head and Neck
• Squamous Cell Carcinoma of Unknown Primary

Intervention

Drug:
• Cisplatin
Given high-dose cisplatin IV
• Cisplatin
Given low-dose cisplatin IV

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

Radiation:
• Radiation Therapy
Undergo radiation therapy

Locations

Country	Name	City	State
Canada	The Research Institute of the McGill University Health Centre (MUHC)	Montreal	Quebec
Canada	Allan Blair Cancer Centre	Regina	Saskatchewan
Canada	Saskatoon Cancer Centre	Saskatoon	Saskatchewan
United States	Summa Health System - Akron Campus	Akron	Ohio
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Inova Alexandria Hospital	Alexandria	Virginia
United States	Kaiser Permanente-Anaheim	Anaheim	California
United States	Mission Cancer and Blood - Ankeny	Ankeny	Iowa
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	Kaiser Permanente-Deer Valley Medical Center	Antioch	California
United States	Sutter Auburn Faith Hospital	Auburn	California
United States	Sutter Cancer Centers Radiation Oncology Services-Auburn	Auburn	California
United States	Augusta University Medical Center	Augusta	Georgia
United States	Rush - Copley Medical Center	Aurora	Illinois
United States	UM Sylvester Comprehensive Cancer Center at Aventura	Aventura	Florida
United States	UH Seidman Cancer Center at UH Avon Health Center	Avon	Ohio
United States	Maryland Proton Treatment Center	Baltimore	Maryland
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	Summa Health System - Barberton Campus	Barberton	Ohio
United States	MaineHealth Coastal Cancer Treatment Center	Bath	Maine
United States	Veterans Administration Hospital	Bay Pines	Florida
United States	UM Upper Chesapeake Medical Center	Bel Air	Maryland
United States	FHCC Overlake	Bellevue	Washington
United States	Sanford Joe Lueken Cancer Center	Bemidji	Minnesota
United States	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California
United States	Tower Cancer Research Foundation	Beverly Hills	California
United States	MaineHealth/SMHC Cancer Care and Blood Disorders-Biddeford	Biddeford	Maine
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Lafayette Family Cancer Center-EMMC	Brewer	Maine
United States	Saint Joseph Mercy Brighton	Brighton	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	University of Michigan - Brighton Center for Specialty Care	Brighton	Michigan
United States	Henry Ford Cancer Institute-Downriver	Brownstown	Michigan
United States	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Saint James Community Hospital and Cancer Treatment Center	Butte	Montana
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Saint Joseph Mercy Canton	Canton	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Mercy Cancer Center ?? Carmichael	Carmichael	California
United States	Mercy San Juan Medical Center	Carmichael	California
United States	Illinois CancerCare-Carthage	Carthage	Illinois
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	Medical University of South Carolina	Charleston	South Carolina
United States	West Virginia University Charleston Division	Charleston	West Virginia
United States	Saint Joseph Mercy Chelsea	Chelsea	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	John H Stroger Jr Hospital of Cook County	Chicago	Illinois
United States	Michigan Healthcare Professionals Clarkston	Clarkston	Michigan
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	Henry Ford Macomb Hospital-Clinton Township	Clinton Township	Michigan
United States	Medical Oncology and Hematology Associates-West Des Moines	Clive	Iowa
United States	Mercy Cancer Center-West Lakes	Clive	Iowa
United States	Baptist Memorial Hospital and Cancer Center-Collierville	Collierville	Tennessee
United States	Central Maryland Radiation Oncology in Howard County	Columbia	Maryland
United States	Baptist Memorial Hospital and Cancer Center-Golden Triangle	Columbus	Mississippi
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	UM Sylvester Comprehensive Cancer Center at Coral Gables	Coral Gables	Florida
United States	Greater Regional Medical Center	Creston	Iowa
United States	Carle at The Riverfront	Danville	Illinois
United States	Dayton Blood and Cancer Center	Dayton	Ohio
United States	Dayton Physician LLC-Miami Valley Hospital North	Dayton	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	Miami Valley Hospital North	Dayton	Ohio
United States	Henry Ford Medical Center-Fairlane	Dearborn	Michigan
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	UM Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida
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	Broadlawns Medical Center	Des Moines	Iowa
United States	Iowa Lutheran Hospital	Des Moines	Iowa
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	Kaiser Permanente Dublin	Dublin	California
United States	Marshfield Medical Center-EC Cancer Center	Eau Claire	Wisconsin
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Mercy Cancer Center - Elk Grove	Elk Grove	California
United States	Elmhurst Memorial Hospital	Elmhurst	Illinois
United States	UC San Diego Health System - Encinitas	Encinitas	California
United States	Saint Vincent Hospital	Erie	Pennsylvania
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	Inova Fair Oaks Hospital	Fairfax	Virginia
United States	Inova Schar Cancer Institute	Fairfax	Virginia
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	Parkland Health Center - Farmington	Farmington	Missouri
United States	Michigan Healthcare Professionals Farmington	Farmington Hills	Michigan
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio
United States	Dayton Physicians LLC-Atrium	Franklin	Ohio
United States	Kaiser Permanente-Fremont	Fremont	California
United States	Fresno Cancer Center	Fresno	California
United States	Kaiser Permanente-Fresno	Fresno	California
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	UM Baltimore Washington Medical Center/Tate Cancer Center	Glen Burnie	Maryland
United States	Glens Falls Hospital	Glens Falls	New York
United States	SCL Health Cancer Centers of Colorado - Lutheran Medical Center	Golden	Colorado
United States	Miami Valley Cancer Care and Infusion	Greenville	Ohio
United States	Self Regional Healthcare	Greenwood	South Carolina
United States	Baptist Cancer Center-Grenada	Grenada	Mississippi
United States	Gulfport Memorial Hospital	Gulfport	Mississippi
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	Edward Hines Jr VA Hospital	Hines	Illinois
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	Michael E DeBakey VA Medical Center	Houston	Texas
United States	Capital Region Southwest Campus	Jefferson City	Missouri
United States	Jefferson Hospital	Jefferson Hills	Pennsylvania
United States	UW Cancer Center Johnson Creek	Johnson Creek	Wisconsin
United States	NEA Baptist Memorial Hospital and Fowler Family Cancer Center - Jonesboro	Jonesboro	Arkansas
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	University of Kansas Cancer Center - North	Kansas City	Missouri
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	Seattle Cancer Care Alliance at EvergreenHealth	Kirkland	Washington
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	Kaiser Permanente-Rock Creek	Lafayette	Colorado
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	University of Kansas Cancer Center - Lee's Summit	Lee's Summit	Missouri
United States	Saint Joseph Hospital	Lexington	Kentucky
United States	Saint Joseph Hospital East	Lexington	Kentucky
United States	Saint Joseph Radiation Oncology Resource Center	Lexington	Kentucky
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Littleton Adventist Hospital	Littleton	Colorado
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Kaiser Permanente-Lone Tree	Lone Tree	Colorado
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California
United States	Jewish Hospital	Louisville	Kentucky
United States	The James Graham Brown Cancer Center at University of Louisville	Louisville	Kentucky
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	Michigan Healthcare Professionals Macomb	Macomb	Michigan
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	William S Middleton VA Medical Center	Madison	Wisconsin
United States	Michigan Healthcare Professionals Madison Heights	Madison Heights	Michigan
United States	Cleveland Clinic Cancer Center Mansfield	Mansfield	Ohio
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	Riddle Memorial Hospital	Media	Pennsylvania
United States	Summa Health Medina Medical Center	Medina	Ohio
United States	Baptist Memorial Hospital and Cancer Center-Memphis	Memphis	Tennessee
United States	Froedtert Menomonee Falls Hospital	Menomonee Falls	Wisconsin
United States	UH Seidman Cancer Center at Lake Health Mentor Campus	Mentor	Ohio
United States	UM Sylvester Comprehensive Cancer Center at Kendall	Miami	Florida
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Zablocki Veterans Administration Medical Center	Milwaukee	Wisconsin
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	Mobile Infirmary Medical Center	Mobile	Alabama
United States	Kaiser Permanente-Modesto	Modesto	California
United States	Memorial Medical Center	Modesto	California
United States	Forbes Hospital	Monroeville	Pennsylvania
United States	Palo Alto Medical Foundation-Camino Division	Mountain View	California
United States	ProHealth D N Greenwald Center	Mukwonago	Wisconsin
United States	Edward Hospital/Cancer Center	Naperville	Illinois
United States	Baptist Memorial Hospital and Cancer Center-Union County	New Albany	Mississippi
United States	Louisiana State University Health Science Center	New Orleans	Louisiana
United States	University Medical Center New Orleans	New Orleans	Louisiana
United States	University of Kansas Cancer Center at North Kansas City Hospital	North Kansas City	Missouri
United States	Ascension Providence Hospitals - Novi	Novi	Michigan
United States	Henry Ford Medical Center-Columbus	Novi	Michigan
United States	Cancer Care Center of O'Fallon	O'Fallon	Illinois
United States	Drexel Town Square Health Center	Oak Creek	Wisconsin
United States	Kaiser Permanente Oakland-Broadway	Oakland	California
United States	Kaiser Permanente-Oakland	Oakland	California
United States	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Olathe Health Cancer Center	Olathe	Kansas
United States	Kaiser Permanente-Ontario	Ontario	California
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
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	Palo Alto Medical Foundation Health Care	Palo Alto	California
United States	Stanford Cancer Institute Palo Alto	Palo Alto	California
United States	Paoli Memorial Hospital	Paoli	Pennsylvania
United States	Parker Adventist Hospital	Parker	Colorado
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	FirstHealth of the Carolinas-Moore Regional Hospital	Pinehurst	North Carolina
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	UM Sylvester Comprehensive Cancer Center at Plantation	Plantation	Florida
United States	21st Century Oncology-Pontiac	Pontiac	Michigan
United States	Saint Joseph Mercy Oakland	Pontiac	Michigan
United States	Maine Medical Center-Bramhall Campus	Portland	Maine
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Kaiser Permanente-Rancho Cordova Cancer Center	Rancho Cordova	California
United States	University Hospitals Portage Medical Center	Ravenna	Ohio
United States	Kaiser Permanente- Marshall Medical Offices	Redwood City	California
United States	Ascension Saint Mary's Hospital	Rhinelander	Wisconsin
United States	Marshfield Medical Center-Rice Lake	Rice Lake	Wisconsin
United States	Kaiser Permanente-Richmond	Richmond	California
United States	Highland Hospital	Rochester	New York
United States	University of Rochester	Rochester	New York
United States	SwedishAmerican Regional Cancer Center/ACT	Rockford	Illinois
United States	Mercy Cancer Center - Rocklin	Rocklin	California
United States	Rohnert Park Cancer Center	Rohnert Park	California
United States	Delbert Day Cancer Institute at PCRMC	Rolla	Missouri
United States	Mercy Clinic-Rolla-Cancer and Hematology	Rolla	Missouri
United States	Kaiser Permanente-Roseville	Roseville	California
United States	Sutter Cancer Centers Radiation Oncology Services-Roseville	Roseville	California
United States	Sutter Roseville Medical Center	Roseville	California
United States	The Permanente Medical Group-Roseville Radiation Oncology	Roseville	California
United States	Kaiser Permanente Downtown Commons	Sacramento	California
United States	Kaiser Permanente-South Sacramento	Sacramento	California
United States	Mercy Cancer Center - Sacramento	Sacramento	California
United States	South Sacramento Cancer Center	Sacramento	California
United States	Sutter Medical Center Sacramento	Sacramento	California
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Norris Cotton Cancer Center-North	Saint Johnsbury	Vermont
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
United States	Sainte Genevieve County Memorial Hospital	Sainte Genevieve	Missouri
United States	Salina Regional Health Center	Salina	Kansas
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	UC San Diego Medical Center - Hillcrest	San Diego	California
United States	Kaiser Permanente-San Francisco	San Francisco	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	UCSF Medical Center-Mount Zion	San Francisco	California
United States	Kaiser Permanente-Santa Teresa-San Jose	San Jose	California
United States	Stanford Cancer Center South Bay	San Jose	California
United States	Kaiser Permanente San Leandro	San Leandro	California
United States	Kaiser San Rafael-Gallinas	San Rafael	California
United States	North Coast Cancer Care	Sandusky	Ohio
United States	MaineHealth Cancer Care Center of York County	Sanford	Maine
United States	MaineHealth/SMHC Cancer Care and Blood Disorders-Sanford	Sanford	Maine
United States	Kaiser Permanente Medical Center - Santa Clara	Santa Clara	California
United States	Kaiser Permanente-Santa Rosa	Santa Rosa	California
United States	Maine Medical Center- Scarborough Campus	Scarborough	Maine
United States	FHCC at Northwest Hospital	Seattle	Washington
United States	FHCC South Lake Union	Seattle	Washington
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	University of Washington Medical Center - Montlake	Seattle	Washington
United States	Avera Cancer Institute	Sioux Falls	South Dakota
United States	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Maine Medical Partners - South Portland	South Portland	Maine
United States	Kaiser Permanente Cancer Treatment Center	South San Francisco	California
United States	Kaiser Permanente-South San Francisco	South San Francisco	California
United States	Ascension Providence Hospitals - Southfield	Southfield	Michigan
United States	Baptist Memorial Hospital and Cancer Center-Desoto	Southhaven	Mississippi
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	Ascension Saint Michael's Hospital	Stevens Point	Wisconsin
United States	Marshfield Medical Center-River Region at Stevens Point	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	Missouri Baptist Sullivan Hospital	Sullivan	Missouri
United States	Palo Alto Medical Foundation-Sunnyvale	Sunnyvale	California
United States	BJC Outpatient Center at Sunset Hills	Sunset Hills	Missouri
United States	Novant Cancer Institute Radiation Oncology - Supply	Supply	North Carolina
United States	ProMedica Flower Hospital	Sylvania	Ohio
United States	Moffitt Cancer Center	Tampa	Florida
United States	Moffitt Cancer Center - McKinley Campus	Tampa	Florida
United States	Moffitt Cancer Center-International Plaza	Tampa	Florida
United States	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio
United States	University of Kansas Health System Saint Francis Campus	Topeka	Kansas
United States	GenesisCare USA - Troy	Troy	Michigan
United States	Upper Valley Medical Center	Troy	Ohio
United States	Gene Upshaw Memorial Tahoe Forest Cancer Center	Truckee	California
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	Kaiser Permanente-Vallejo	Vallejo	California
United States	Kaiser Permanente-Walnut Creek	Walnut Creek	California
United States	Saint John Macomb-Oakland Hospital	Warren	Michigan
United States	George Washington University Medical Center	Washington	District of Columbia
United States	Illinois CancerCare - Washington	Washington	Illinois
United States	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin
United States	Aspirus Regional Cancer Center	Wausau	Wisconsin
United States	Froedtert West Bend Hospital/Kraemer Cancer Center	West Bend	Wisconsin
United States	Henry Ford West Bloomfield Hospital	West Bloomfield	Michigan
United States	Mercy Medical Center-West Lakes	West Des Moines	Iowa
United States	Methodist West Hospital	West Des Moines	Iowa
United States	Marshfield Medical Center - Weston	Weston	Wisconsin
United States	University of Kansas Hospital-Westwood Cancer Center	Westwood	Kansas
United States	Wexford Health and Wellness Pavilion	Wexford	Pennsylvania
United States	Wake Forest Baptist Health - Wilkes Medical Center	Wilkesboro	North Carolina
United States	Novant Health Cancer Institute Radiation Oncology - Wilmington	Wilmington	North Carolina
United States	Novant Health New Hanover Regional Medical Center	Wilmington	North Carolina
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	Aspirus Cancer Care - Wisconsin Rapids	Wisconsin Rapids	Wisconsin
United States	Woodland Memorial Hospital	Woodland	California
United States	Cleveland Clinic Wooster Family Health and Surgery Center	Wooster	Ohio
United States	Lankenau Medical Center	Wynnewood	Pennsylvania
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
NRG Oncology	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of acute toxicity (Phase II)	Measured by the T-scores.	Up to 180 days post-treatment
Primary	Overall Survival (OS) (Phase III)	OS rates will be estimated using the Kaplan-Meier method.	From randomization to death of any cause, assessed up to 9 years
Primary	Incidence of acute toxicity (Phase III)	Measured by the T-scores.	Up to 180 days post-treatment
Secondary	Locoregional Failure Rates		Up to 9 years
Secondary	Progression-free survival (PFS)	PFS rates will be estimated using the Kaplan-Meier method and between-arm differences compared using the log-rank test with a two-sided alpha of 0.05 (Kaplan 1958).	From randomization to locoregional failure, distant metastasis or death due to any cause, whichever occurs first, assessed up to 9 years
Secondary	Incidence of acute toxicity	Measured by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.	Up to 180 days post-treatment
Secondary	Incidence of late toxicity	Measured by CTCAE v5.0.	Up to 9 years
Secondary	Hearing loss	Measured by Hearing Handicap Inventory for Adults-Screening.	At 6 months post-radiation therapy