This phase III trials studies whether maintenance immunotherapy (nivolumab) following definitive treatment with radiation and chemotherapy (cisplatin) result in significant improvement in overall survival (time being alive) and progression-free survival (time being alive without cancer) for patients with intermediate risk human papillomavirus (HPV) positive oropharynx cancer (throat cancer) that has spread to nearby tissue or lymph nodes. Drugs used in chemotherapy 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 rays to kill tumor cells and shrink tumors. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether chemotherapy and radiation therapy followed by maintenance nivolumab therapy works better than chemotherapy and radiation therapy alone in treating patients with HPV positive oropharyngeal cancer.
PRIMARY OBJECTIVE: I. To assess the efficacy of concurrent definitive therapy followed by nivolumab compared with concurrent definitive therapy followed by observation in terms of overall survival (OS). SECONDARY OBJECTIVES: I. To further assess the efficacy of nivolumab compared with observation in terms of: Ia. To evaluate treatment effect within the subset of patients tested as PD-L1+ . Ib. To evaluate the prognostic effect of baseline saliva and/or plasma HPV status . Ic. To evaluate the prognostic effect of mutation burden among patients on the nivolumab arm. Id. To evaluate the association of 12-week post therapy fludeoxyglucose F-18 (FDG) positron emission tomography(PET)/computed tomography (CT) OS and progression free survival (PFS). Ie. To establish the prognostic value of standardized uptake value (SUV) max of primary tumor or neck nodal metastasis of baseline FDG PET/CT for OS (and/or PFS). If. To correlate SUV max of primary tumor or nodal metastasis of baseline FDG PET/CT with PD-L1 expression (positive versus \[vs.\] negative). Ig. To compare the PET based therapy response assessment (Hopkins criteria) to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessment at 12 week post chemoradiation therapy, for patients who have a PET/CT scan at 12 weeks. II. To assess the efficacy of concurrent definitive therapy followed by nivolumab in terms of progression free survival (PFS). OUTLINE: Patients are randomized to Arm A or Arm B. Patients in Arm B may cross-over to Arm C with clearly documented disease progression. ARM A: Patients receive cisplatin intravenously (IV) over 60 minutes weekly and intensity modulated radiation therapy (IMRT) 5 days a week for 7 weeks for a total of 35 fractions. Within 4 weeks after completion of concurrent therapy, patients receive nivolumab IV once weekly over 30 minutes every 4 weeks for 12 months in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive cisplatin IV over 60 minutes weekly and IMRT 5 days a week for 7 weeks for a total of 35 fractions, and then go on observation. Patients will be offered the option to cross-over to Arm C if they have clearly documented progression within 12 months from the end of cisplatin/radiation therapy. ARM C: Patients receive nivolumab IV over 30 minutes every 4 weeks for 12 months in the absence of disease progression or unacceptable toxicity. All patients undergo computed tomography (CT) or Fludeoxyglucose F-18 (FDG) positron emission tomography (PET)/CT scans throughout the trial. Patients may undergo echocardiography (ECHO) as clinically indicated. Additionally, patients undergo blood sample collection during screening. After completion of study treatment, patients are followed up every 3-6 months for 3 years and then annually for a total of 10 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
636
Undergo blood sample collection
Given IV
Undergo CT or PET/CT
Undergo ECHO
Receive FDG
Undergo IMRT
Given IV
Undergo observation
Undergo PET/CT
Thomas Hospital
Fairhope, Alabama, United States
Mobile Infirmary Medical Center
Mobile, Alabama, United States
Anchorage Associates in Radiation Medicine
Anchorage, Alaska, United States
Anchorage Radiation Therapy Center
Anchorage, Alaska, United States
Alaska Breast Care and Surgery LLC
Anchorage, Alaska, United States
Overall survival (OS)
Log rank test will be used to compare OS. As patients on the observation arm are allowed to cross-over to the nivolumab arm upon progression, an overall survival analysis using inverse probability censoring weights (IPCW, Robins et. al, 2000) will also be considered. Kaplan-Meier method and Cox regression will be used for the survival outcome analyses.
Time frame: From randomization to death, assessed up to 10 years
Negative (standardized qualitative) 12 week post therapy (cisplatin + radiation therapy [RT]) FDG positron emission tomography/computed tomography (PET/CT) associated with OS for patients who have a PET/CT
Logrank tests and input hazard rates will be used.
Time frame: At 12 weeks post therapy
Negative (standardized qualitative) 12 week post therapy (cisplatin + RT) FDG PET/CT associated with PFS for patients who have a PET/CT
Logrank tests and input hazard rates will be used.
Time frame: At 12 weeks post therapy
Progression-free survival (PFS)
Progression will be defined using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. The comparison of PFS will use stratified log rank test and will be intent-to-treat analyses.
Time frame: From randomization to date of progression, second primary tumor from the head and neck region, or death, assessed up to 10 years
Prognostic effect of baseline PD-L1 expression (positive versus [vs.] negative) on OS and PFS
Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.
Time frame: Baseline up to 10 years
Prognostic effect of baseline saliva and/or plasma human papillomavirus (HPV) status (positive vs. negative) on OS and PFS
Saliva and plasma HPV status at 12 weeks and 9 months following completion of concurrent therapy will also be analyzed regarding effect on outcome. Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.
Time frame: Baseline up to 10 years
Prognostic value of maximum standardized uptake value (SUVmax) of primary tumor or neck nodal metastasis of baseline FDG PET/CT for OS
Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.
Time frame: Baseline up to 10 years
Prognostic value of SUVmax of primary tumor or neck nodal metastasis of baseline FDG PET/CT for PFS
Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.
Time frame: Baseline up to 10 years
SUVmax of primary tumor or nodal metastasis of baseline FDG PET/CT with PD-L1 expression (positive vs. negative)
Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.
Time frame: Baseline up to 10 years
Post therapy (cisplatin + RT) FDG PET/CT with saliva or plasma levels of HPV deoxyribonucleic acid (DNA)
Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.
Time frame: Up to 9 months post-therapy
PET based therapy response assessment compared to RECIST 1.1 assessment for patients who have a PET/CT scan at 12 weeks
Kappa statistics will be applied to evaluate the agreement between PET based therapy response assessment (Hopkins criteria) and RECIST 1.1 assessment at 12 weeks post chemoradiation therapy.
Time frame: At 12 weeks post chemoradiation therapy
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