Testing the Use of Investigational Drugs Atezolizumab and/or Bevacizumab With or Without Standard Chemotherapy in the Second-Line Treatment of Advanced-Stage Head and Neck Cancers

Recurrent Head and Neck Squamous Cell Carcinoma Clinical Trial

Official title:

A Phase II/III Trial of Chemotherapy + Cetuximab vs Chemotherapy + Bevacizumab vs Atezolizumab + Bevacizumab Following Progression on Immune Checkpoint Inhibition in Recurrent/Metastatic Head and Neck Cancers

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05063552
• Other study ID #: NCI-2021-10021
• Secondary ID: NCI-2021-10021EA
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: March 13, 2023
• Est. completion date: December 15, 2027

Study information

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

Clinical Trial Summary

This phase II/III compares the standard therapy (chemotherapy plus cetuximab) versus adding bevacizumab to standard chemotherapy, versus combination of just bevacizumab and atezolizumab in treating patients with head and neck cancer that has spread to other places in the body (metastatic or advanced stage) or has come back after prior treatment (recurrent). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of cancer cells. This may help keep cancer cells from growing. Cisplatin and carboplatin are in a class of chemotherapy medications known as platinum-containing compounds. They work by killing, stopping, or slowing the growth of cancer cells. Docetaxel is in a class of chemotherapy medications called taxanes. It stops cancer cells from growing and dividing and may kill them. The addition of bevacizumab to standard chemotherapy or combination therapy with bevacizumab and atezolizumab may be better than standard chemotherapy plus cetuximab in treating patients with recurrent/metastatic head and neck cancers.

Description:

PRIMARY OBJECTIVES:

I. To evaluate progression-free survival (PFS) of patients treated with chemotherapy plus cetuximab, chemotherapy plus bevacizumab, and atezolizumab plus bevacizumab. (Phase II) II. To evaluate the overall survival (OS) of patients treated with chemotherapy plus cetuximab to the superior arm from the phase II portion of the protocol. (Phase III)

SECONDARY OBJECTIVES:

I. To evaluate the OS for the subset of patients with high PD-L1 expression, defined as combined positive score (CPS) >= 20% on all arms of treatment.

II. To evaluate the toxicity of each arm of treatment.

IMAGING OBJECTIVES:

I. To establish the correlation between fludeoxyglucose F-18 (18F-FDG) positron emission tomography (PET) and computed tomography (CT) neck imaging biomarkers (maximum standard uptake value [SUVmax], metabolic tumor volume [MTV], total lesion glycolysis [TLG], tumor volume) and expression of PD-L1 expression (Low versus high, defined as CPS < 20 versus CPS >= 20).

II. To determine if 18FDG-PET/CT and CT neck imaging biomarkers at baseline will predict treatment response at nine to twelve weeks post the initiation of treatment, PFS, and OS.

EXPLORATORY OBJECTIVE:

I. To establish the correlation between 18F-FDG PET and CT neck radiomics features and PD-L1 expressions (Low versus high - defined as CPS < 20 versus CPS >= 20).

OUTLINE: This is a randomized phase II trial followed by a randomized phase III trial.

PHASE II: Patients are randomized to 1 of 3 arms.

ARM A: Patients receive cetuximab intravenously (IV) over 60-120 minutes on days 1, 8, and 15 of each cycle, docetaxel IV over 1 hour on day 1 or days 1 and 8 of each cycle, and cisplatin IV or carboplatin IV on day 1 or days 1 and 8 of each cycle. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive cetuximab IV over 60-120 minutes on days 1, 8, and 15 or days 1 and 15 of each cycle of maintenance therapy. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan, a PET scan, and/or magnetic resonance imaging (MRI) throughout the trial. Patients may undergo echocardiography (ECHO) during screening.

ARM B: Patients receive bevacizumab IV over 30-90 minutes on day 1 of each cycle, docetaxel IV over 1 hour on day 1 or days 1 and 8 of each cycle, and cisplatin IV or carboplatin IV on day 1 or days 1 and 8 of each cycle. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive bevacizumab IV over 30-60 minutes on day 1 of each cycle of maintenance therapy. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan, a PET scan, and/or MRI throughout the trial. Patients may undergo ECHO during screening.

ARM C: Patients receive bevacizumab IV over 30-90 minutes on day 1 and atezolizumab over 30-60 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan, a PET scan, and/or MRI throughout the trial. Patients may undergo ECHO during screening.

PHASE III: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive cetuximab IV over 60-120 minutes on days 1, 8, and 15 of each cycle, docetaxel IV over 1 hour on day 1 or days 1 and 8 of each cycle, and cisplatin IV or carboplatin IV on day 1 or days 1 and 8 of each cycle. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive cetuximab IV over 60-120 minutes on days 1, 8, and 15 or days 1 and 15 of each cycle of maintenance therapy. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan, a PET scan, and/or MRI throughout the trial. Patients may undergo ECHO during screening.

ARM B: Patients receive treatment as in Arm B or C above based on results of the Phase II trial.

Patients undergo blood sample collection throughout the study.

After completion of study treatment, patients are followed up at 30 days and then every 3 months if patient is < 2 years from randomization and every 6 months if patient is 2-5 years from randomization.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 430
• Est. completion date: December 15, 2027
• Est. primary completion date: December 15, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patient must have histologically confirmed squamous cell carcinoma of the head and neck (HNSCC) (excluding SCC of salivary glands, Epstein-Barr virus [EBV]-associated nasopharynx and skin)

• Patient must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. Measurements must be obtained within 4 weeks prior to randomization

• Patient must be >= 18 years of age

• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1

• Patient must have disease progression after prior therapy with an immune checkpoint inhibitor (ICI) in the first-line setting for recurrent/metastatic disease. Patient must have received first-line immune checkpoint inhibition for at least 6 weeks. Patients who have recurred or progressed within 12 weeks of immune checkpoint inhibition administered in the definitive setting for locally advanced disease (for e.g., in the context of a clinical trial) will also be eligible if local therapies are not feasible

• Prior combination immunotherapies are permitted, but patient must not have had prior antiangiogenic treatment (e.g., bevacizumab, ziv-aflibercept, ramucirumab, sorafenib, sunitinib, pazopanib, regorafenib, lenvatinib, etc.). Patient must have completed any prior investigational therapy at least 28 days prior to randomization.

NOTE: Patients who received platinum/taxanes in the locally-advanced or recurrent/metastatic setting and did not progress for at least 4 months thereafter, will be eligible for this study. Patients who received cetuximab in the locally-advanced setting and did not progress for at least 4 months thereafter, will also be eligible for this study

• Patient must not have a history of >= grade 3 immune-related adverse event on prior ICI therapy (except those that could be managed with steroids [e.g., dermatologic toxicity, asymptomatic elevation of pancreatic enzymes, etc.]) and ICI could eventually be resumed. Patients who developed grade 3 endocrinopathies but are now stable on hormone supplementation and/or a daily prednisone dose of =< 10 mg (or equivalent doses of another glucocorticoid), will be permitted on this trial

• Patient must not have a history of PD-1 inhibitor-induced hyper-progression, defined as 100% increase in tumor burden within 8 weeks (or 50% within 4 weeks) of initiating ICI and associated with clinical deterioration

• Patient must not have any of the following criteria due to the possibility of increased risk for tumor bleeding with bevacizumab therapy:

• Prior carotid bleeding,

• Tumors that invade major vessels (e.g., the carotid) as shown unequivocally by imaging studies,

• Central (e.g., within 2 cm from the hilum) lung metastases that are cavitary as shown unequivocally by imaging studies,

• Any prior history of bleeding related to the current head and neck cancer,

• History of gross hemoptysis (bright red blood of 1/2 teaspoon or more per episode of coughing) within 3 months prior to randomization

• Patient must not have uncontrolled hypertension, a history of hypertensive crisis or hypertensive encephalopathy, or a history of grade 4 thromboembolism

• Patient must not have a history of coagulopathy or hemorrhagic disorders

• Patient must not have a history of thrombosis (e.g., pulmonary embolism or deep venous thrombosis) currently requiring therapeutic anticoagulation (prophylactic use of anticoagulation is allowed)

• Patient must not be receiving chronic daily treatment with aspirin (> 325 mg/day) or non-steroidal anti-inflammatory agents (NSAID's) known to inhibit platelet function. The use of anti-platelet agents [e.g., dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix)] is allowed only if patient is not receiving concurrent aspirin or NSAID's known to inhibit platelet function.

• Patient must have PD-L1 expression >= 1% by combined positive score (CPS) in the tumor and/or immune cells

• NOTE: Enrolling centers should test for PD-L1 CPS preferably using the SP263 assay. Where this is not feasible, using their preferred Clinical Laboratory Improvement Act (CLIA)-certified or similar assay will be accepted. It is preferred for standard of care (SOC) PD-L1 assessments to be done on post-first line ICI samples if available, but SOC PD-L1 assessments on pre-ICI samples will be accepted for eligibility

• Patient must not have a severe infection within 4 weeks prior to randomization, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia. Patients must not have active tuberculosis

• Patient must not have a history of non-infectious pneumonitis requiring steroids at doses greater than or equal to 10 mg per day of prednisone or the equivalent on first line immunotherapy

• Patient must not have a history of solid organ transplantation or stem-cell transplant

• Patient must not be on immunosuppressive medication within 7 days prior to randomization except for: intranasal, inhaled, or topical steroids, local steroid injection, systemic corticosteroids at doses less than or equal to 10 mg per day of prednisone or the equivalent, or steroids used as premedication for hypersensitivity reactions

• Patient must not have an active autoimmune disease that requires systemic treatment within 2 years prior to randomization. Patients who are receiving replacement therapy for adrenal or pituitary insufficiency will not be excluded

• Patient must not have had a severe hypersensitivity reaction to any of the drug components used on this protocol or to chimeric or humanized antibodies or fusion proteins

• Patient must not have received any live vaccine within 30 days prior to randomization and while participating in the study (and continue for 5 months after the last dose of atezolizumab on Arm C). Live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, bacillus Calmette-Guerin (BCG), and typhoid (oral) vaccine. Patients are permitted to receive inactivated vaccines and any non-live vaccines including those for the seasonal influenza and coronavirus disease 2019 (COVID-19) (Note: intranasal influenza vaccines, such as Flu-Mist (registered trademark) are live attenuated vaccines and are not allowed). If possible, it is recommended to separate study drug administration from vaccine administration by about a week (primarily, in order to minimize an overlap of adverse events

• Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used.

• All patients of childbearing potential must have a blood test or urine study within 14 days prior to randomization to rule out pregnancy.

• A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

• Patients must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and for 2 months after the last dose of treatment for patients assigned to Arm A and for 6 months after the last dose of protocol treatment for patients assigned to Arms B or C.

• NOTE: Patients must also not breastfeed while on treatment and for 2 months after the last dose of treatment for patients assigned to Arm A and for 6 months after the last dose of treatment for patients assigned to Arms B or C

• Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible

• Leukocytes >= 3,000/mcL (must be obtained =< 14 days prior to protocol randomization)

• Absolute neutrophil count (ANC) >= 1,500/mcL (must be obtained =< 14 days prior to protocol randomization)

• Platelets >= 100,000/mcL (must be obtained =< 14 days prior to protocol randomization)

• Hemoglobin (Hgb) > 9 g/dL (must be obtained =< 14 days prior to protocol randomization) (Note: Patient may be transfused to meet this criteria)

• Total bilirubin =< 2.0 x institutional upper limit of normal (ULN) (=< 5.0 x institutional ULN if hepatic metastases present or =< 3 x ULN for patients with known Gilbert's disease) (must be obtained =< 14 days prior to protocol randomization)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (< 5.0 x institutional ULN if hepatic metastases present) (must be obtained =< 14 days prior to protocol randomization)

• Alkaline phosphatase < 2.5 x institutional ULN (< 5.0 x institutional ULN if hepatic or bone metastases present) (must be obtained =< 14 days prior to protocol randomization)

• Creatinine =< 1.5 x institutional ULN (must be obtained =< 14 days prior to protocol randomization)

• Patients with uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN) must have their calcium levels corrected prior to randomization

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

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. Patients must not have untreated brain metastases or leptomeningeal disease

• 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

• Patients must not have uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Patients may have indwelling catheters (e.g., PleurX [registered trademark])

• Patient must not have significant cardiovascular disease (such as New York Heart Association class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to randomization, or unstable arrhythmia or unstable angina at the time of randomization

• Patient must not receive any other chemotherapy, immunotherapy, antitumor hormonal therapy (excluding contraceptives and replacement steroids), radiation therapy, or experimental medications while on protocol treatment. Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to randomization and patients must be recovered from the effects of radiation (there is no required minimum recovery period

• Patient must not have had a surgical procedure (including open biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to randomization, or anticipation of need for major surgical procedure while on protocol treatment

• Patient must not have any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of the agents used in this protocol, may affect the interpretation of the results, or may render the patient at high risk from treatment complications

• Patient must not have a history of abdominal fistula, gastrointestinal (GI) perforation, intra-abdominal abscess, or active GI bleeding within 6 months prior to randomization

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Squamous Cell
• Clinical Stage IV HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8
• Head and Neck Neoplasms
• Laryngeal Neoplasms
• Metastatic Head and Neck Squamous Cell Carcinoma
• Mouth Neoplasms
• Nasopharyngeal Carcinoma
• Recurrence
• Recurrent Head and Neck Squamous Cell Carcinoma
• Recurrent Hypopharyngeal Squamous Cell Carcinoma
• Recurrent Laryngeal Squamous Cell Carcinoma
• Recurrent Lip and Oral Cavity Squamous Cell Carcinoma
• Recurrent Pharyngeal Squamous Cell Carcinoma
• Recurrent Sinonasal Squamous Cell Carcinoma
• Squamous Cell Carcinoma of Head and Neck
• Stage IV Hypopharyngeal Carcinoma AJCC v8
• Stage IV Laryngeal Cancer AJCC v8
• Stage IV Lip and Oral Cavity Cancer AJCC v8
• Stage IV Nasopharyngeal Carcinoma AJCC v8
• Stage IV Oropharyngeal (p16-Negative) Carcinoma AJCC v8

Intervention

Biological:
• Atezolizumab
Given IV
• Bevacizumab
Given IV

Procedure:
• Biospecimen Collection
Undergo blood sample collection

Drug:
• Carboplatin
Given IV

Biological:
• Cetuximab
Given IV

Drug:
• Cisplatin
Given IV

Procedure:
• Computed Tomography
Undergo CT scan

Drug:
• Docetaxel
Given IV

Procedure:
• Echocardiography
Undergo ECHO
• Magnetic Resonance Imaging
Undergo MRI
• Positron Emission Tomography
Undergo PET scan

Locations

Country	Name	City	State
United States	Hawaii Cancer Care - Westridge	'Aiea	Hawaii
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	UPMC Altoona	Altoona	Pennsylvania
United States	Mary Greeley Medical Center	Ames	Iowa
United States	McFarland Clinic - Ames	Ames	Iowa
United States	Mission Cancer and Blood - Ankeny	Ankeny	Iowa
United States	Emory University Hospital Midtown	Atlanta	Georgia
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	Rush - Copley Medical Center	Aurora	Illinois
United States	Greater Baltimore Medical Center	Baltimore	Maryland
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	UPMC-Heritage Valley Health System Beaver	Beaver	Pennsylvania
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	McFarland Clinic - Boone	Boone	Iowa
United States	UPMC Hillman Cancer Center at Butler Health System	Butler	Pennsylvania
United States	UPMC Camp Hill	Camp Hill	Pennsylvania
United States	Carlisle Regional Cancer Center	Carlisle	Pennsylvania
United States	Miami Valley Hospital South	Centerville	Ohio
United States	West Virginia University Charleston Division	Charleston	West Virginia
United States	John H Stroger Jr Hospital of Cook County	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Providence Cancer Institute Clackamas Clinic	Clackamas	Oregon
United States	Southeastern Medical Oncology Center-Clinton	Clinton	North Carolina
United States	Mercy Cancer Center-West Lakes	Clive	Iowa
United States	Mission Cancer and Blood - West Des Moines	Clive	Iowa
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	UM Sylvester Comprehensive Cancer Center at Coral Gables	Coral Gables	Florida
United States	UPMC Hillman Cancer Center - Passavant - Cranberry	Cranberry Township	Pennsylvania
United States	Greater Regional Medical Center	Creston	Iowa
United States	UPMC Western Maryland	Cumberland	Maryland
United States	Carle at The Riverfront	Danville	Illinois
United States	Dayton Physician LLC - Englewood	Dayton	Ohio
United States	Miami Valley Hospital	Dayton	Ohio
United States	Miami Valley Hospital North	Dayton	Ohio
United States	Premier Blood and Cancer Center	Dayton	Ohio
United States	UM Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida
United States	Smilow Cancer Hospital-Derby Care Center	Derby	Connecticut
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Mission Cancer and Blood - Des Moines	Des Moines	Iowa
United States	Mission Cancer and Blood - Laurel	Des Moines	Iowa
United States	Epic Care-Dublin	Dublin	California
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Epic Care Partners in Cancer Care	Emeryville	California
United States	UPMC Hillman Cancer Center Erie	Erie	Pennsylvania
United States	Smilow Cancer Hospital Care Center-Fairfield	Fairfield	Connecticut
United States	UPMC Cancer Center at UPMC Horizon	Farrell	Pennsylvania
United States	McFarland Clinic - Trinity Cancer Center	Fort Dodge	Iowa
United States	Broward Health Medical Center	Fort Lauderdale	Florida
United States	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio
United States	Saint Luke's Cancer Institute - Fruitland	Fruitland	Idaho
United States	Smilow Cancer Hospital Care Center at Glastonbury	Glastonbury	Connecticut
United States	Southeastern Medical Oncology Center-Goldsboro	Goldsboro	North Carolina
United States	UPMC Cancer Centers - Arnold Palmer Pavilion	Greensburg	Pennsylvania
United States	Miami Valley Cancer Care and Infusion	Greenville	Ohio
United States	Oncology Hematology Associates	Greenville	Pennsylvania
United States	UPMC Hillman Cancer Center in Greenville/UPMC Horizon	Greenville	Pennsylvania
United States	Smilow Cancer Hospital Care Center at Greenwich	Greenwich	Connecticut
United States	Smilow Cancer Hospital Care Center - Guilford	Guilford	Connecticut
United States	UPMC Pinnacle Cancer Center/Community Osteopathic Campus	Harrisburg	Pennsylvania
United States	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut
United States	Ingalls Memorial Hospital	Harvey	Illinois
United States	Hawaii Cancer Care Inc - Waterfront Plaza	Honolulu	Hawaii
United States	Queen's Cancer Cenrer - POB I	Honolulu	Hawaii
United States	Queen's Cancer Center - Kuakini	Honolulu	Hawaii
United States	Queen's Medical Center	Honolulu	Hawaii
United States	IRMC Cancer Center	Indiana	Pennsylvania
United States	Southeastern Medical Oncology Center-Jacksonville	Jacksonville	North Carolina
United States	McFarland Clinic - Jefferson	Jefferson	Iowa
United States	UPMC-Johnstown/John P. Murtha Regional Cancer Center	Johnstown	Pennsylvania
United States	Kettering Medical Center	Kettering	Ohio
United States	Thompson Cancer Survival Center	Knoxville	Tennessee
United States	Thompson Cancer Survival Center - West	Knoxville	Tennessee
United States	Memorial Medical Center - Las Cruces	Las Cruces	New Mexico
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	Thompson Oncology Group-Lenoir City	Lenoir City	Tennessee
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	McFarland Clinic - Marshalltown	Marshalltown	Iowa
United States	Contra Costa Regional Medical Center	Martinez	California
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	UPMC Cancer Center at UPMC McKeesport	McKeesport	Pennsylvania
United States	UPMC Hillman Cancer Center at Rocco And Nancy Ortenzio Cancer Pavilion	Mechanicsburg	Pennsylvania
United States	Saint Luke's Cancer Institute - Meridian	Meridian	Idaho
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	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Forbes Hospital	Monroeville	Pennsylvania
United States	UPMC Hillman Cancer Center - Monroeville	Monroeville	Pennsylvania
United States	UPMC Hillman Cancer Center in Coraopolis	Moon	Pennsylvania
United States	UPMC Hillman Cancer Center - Part of Frick Hospital	Mount Pleasant	Pennsylvania
United States	ProHealth D N Greenwald Center	Mukwonago	Wisconsin
United States	Arnold Palmer Cancer Center Medical Oncology Norwin	N. Huntingdon	Pennsylvania
United States	Saint Luke's Cancer Institute - Nampa	Nampa	Idaho
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	UPMC Cancer Center-Natrona Heights	Natrona Heights	Pennsylvania
United States	UPMC Hillman Cancer Center - New Castle	New Castle	Pennsylvania
United States	Yale University	New Haven	Connecticut
United States	UC Comprehensive Cancer Center at Silver Cross	New Lenox	Illinois
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	Providence Newberg Medical Center	Newberg	Oregon
United States	Yale-New Haven Hospital North Haven Medical Center	North Haven	Connecticut
United States	Thompson Oncology Group-Oak Ridge	Oak Ridge	Tennessee
United States	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Smilow Cancer Hospital-Orange Care Center	Orange	Connecticut
United States	University of Chicago Medicine-Orland Park	Orland Park	Illinois
United States	Stanford Cancer Institute Palo Alto	Palo Alto	California
United States	VA Palo Alto Health Care System	Palo Alto	California
United States	ECOG-ACRIN Cancer Research Group	Philadelphia	Pennsylvania
United States	Jefferson Torresdale Hospital	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	UPMC-Mercy Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Passavant Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Saint Clair Hospital Cancer Center	Pittsburgh	Pennsylvania
United States	UPMC-Saint Margaret	Pittsburgh	Pennsylvania
United States	UM Sylvester Comprehensive Cancer Center at Plantation	Plantation	Florida
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	Dartmouth Cancer Center - North	Saint Johnsbury	Vermont
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	UPMC Cancer Center at UPMC Northwest	Seneca	Pennsylvania
United States	Smilow Cancer Hospital Care Center at Long Ridge	Stamford	Connecticut
United States	Trinity's Tony Teramana Cancer Center	Steubenville	Ohio
United States	Toledo Clinic Cancer Centers-Toledo	Toledo	Ohio
United States	Smilow Cancer Hospital-Torrington Care Center	Torrington	Connecticut
United States	Upper Valley Medical Center	Troy	Ohio
United States	Smilow Cancer Hospital Care Center-Trumbull	Trumbull	Connecticut
United States	Saint Luke's Cancer Institute - Twin Falls	Twin Falls	Idaho
United States	UPMC Cancer Center-Uniontown	Uniontown	Pennsylvania
United States	Carle Cancer Center	Urbana	Illinois
United States	MedStar Washington Hospital Center	Washington	District of Columbia
United States	UPMC Cancer Center-Washington	Washington	Pennsylvania
United States	Smilow Cancer Hospital-Waterbury Care Center	Waterbury	Connecticut
United States	Smilow Cancer Hospital Care Center - Waterford	Waterford	Connecticut
United States	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin
United States	Mercy Medical Center-West Lakes	West Des Moines	Iowa
United States	UPMC West Mifflin-Cancer Center Jefferson	West Mifflin	Pennsylvania
United States	Smilow Cancer Hospital Care Center - Westerly	Westerly	Rhode Island
United States	Divine Providence Hospital	Williamsport	Pennsylvania
United States	Asplundh Cancer Pavilion	Willow Grove	Pennsylvania
United States	UMass Memorial Medical Center - University Campus	Worcester	Massachusetts
United States	UPMC Memorial	York	Pennsylvania
United States	Rush-Copley Healthcare Center	Yorkville	Illinois

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Correlation between 18F-FDG PET and CT neck radiomics features and expression of PD-L1 expression	The imaging textural features from radiomics analysis will be associated with the dichotomized PD-L1 expressions. First, proper transformation will be applied to the textural features as needed to address the distribution skewness. Second, Pearson or Spearman rank correlations will be calculated between all pairs of textural features to identify highly correlated features. Third, to address overfitting and high collinearity, machine learning techniques (e.g., LASSO or XGBoost) will be employed for feature selection during the association analysis with PD-L1 expressions.	Up to 5 years from randomization
Primary	Progression free survival (PFS) (Phase II)		Time from treatment initiation until disease progression or death, assessed up to 5 years from randomization
Primary	Overall survival (OS) (Phase III)	Will be compared using a stratified log rank test.	Time from treatment initiation until death from any cause, assessed up to 5 years from randomization
Secondary	OS in the subset of patients with high PD-L1 expression (Phase III)	The interaction of PD-L1 by treatment will also be evaluated in a Cox proportional hazards model.	Up to 5 years from randomization
Secondary	Incidence of adverse events (Phase III)		Up to 30 days after completion of treatment
Secondary	Correlation between fludeoxyglucose F-18 (18F-FDG) positron emission tomography (PET) and computed tomography (CT) neck imaging biomarkers	The two-sample t-test will be used to compare the difference of baseline 18F -FDG PET /CT imaging biomarkers (maximum standardized uptake value [SUVmax], metabolic tumor volume [MTV], total lesion glycolysis [TLG], tumor volume) between low and high expression of PD-L1.	Up to 5 years from randomization
Secondary	Prediction of treatment response	Determined by 18FDG-PET/CT and CT neck imaging biomarkers. To determine if 18FDG-PET/CT and CT neck imaging biomarkers at baseline will predict treatment response at nine to twelve weeks post-treatment, PFS, and OS Logistic regression model will be fit to assess the association of the 18F -FDG PET /CT imaging biomarkers (e.g., SUVmax, MTV, TLG, tumor heterogeneity, tumor volume) with binary treatment response at 9-12 weeks post treatment. Cox proportional hazards models will be fit to assess the association of 18F -FDG PET /CT imaging biomarkers with time-to-event outcomes (PFS or OS).	Baseline up to 12 weeks