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.
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 IV 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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
430
Given IV
Given IV
Undergo blood sample collection
Given IV
Given IV
Given IV
Undergo CT scan
Given IV
Undergo ECHO
Undergo MRI
Undergo PET scan
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
Epic Care-Dublin
Dublin, California, United States
Epic Care Partners in Cancer Care
Emeryville, California, United States
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, United States
Contra Costa Regional Medical Center
Martinez, California, United States
Progression free survival (PFS) (Phase II)
Time frame: Time from treatment initiation until disease progression or death, assessed up to 5 years from randomization
Overall survival (OS) (Phase III)
Will be compared using a stratified log rank test.
Time frame: Time from treatment initiation until death from any cause, assessed up to 5 years from randomization
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.
Time frame: Up to 5 years from randomization
Incidence of adverse events (Phase III)
Time frame: Up to 30 days after completion of treatment
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.
Time frame: Up to 5 years from randomization
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).
Time frame: Baseline up to 12 weeks
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UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, United States
Stanford Cancer Institute Palo Alto
Palo Alto, California, United States
VA Palo Alto Health Care System
Palo Alto, California, United States
Smilow Cancer Hospital-Derby Care Center
Derby, Connecticut, United States
Smilow Cancer Hospital Care Center-Fairfield
Fairfield, Connecticut, United States
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