A Randomized Phase II/III Trial of De-Intensified Radiation Therapy for Patients With Early-Stage, P16-Positive, Non-Smoking Associated Oropharyngeal Cancer
Overview
- Phase
- Phase 2
- Intervention
- Biospecimen Collection
- Conditions
- Basaloid Squamous Cell Carcinoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 384
- Locations
- 987
- Primary Endpoint
- Progression-free Survival (PFS) (Phase II) (Percentage of Participants Alive Without Progression)
- Status
- Active, not recruiting
- Last Updated
- 19 days ago
Overview
Brief Summary
This phase II/III trial studies how well a reduced dose of radiation therapy works with nivolumab compared to cisplatin in treating patients with human papillomavirus (HPV)-positive oropharyngeal cancer that is early in its growth and may not have spread to other parts of the body (early-stage), and is not associated with smoking. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. 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. 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. This trial is being done to see if a reduced dose of radiation therapy and nivolumab works as well as standard dose radiation therapy and cisplatin in treating patients with oropharyngeal cancer.
Detailed Description
PRIMARY OBJECTIVES: I. To demonstrate non-inferiority in terms of progression-free survival (PFS) of concurrent reduced-dose radiation therapy (RT) with cisplatin or concurrent reduced-dose radiation therapy with nivolumab to the current standard of care (standard-dose RT with cisplatin). (Phase II) (Arm 2 \[concurrent reduced-dose RT with cisplatin\] was dropped after interim futility analysis in phase II.) II. To demonstrate non-inferiority in terms of progression-free survival (PFS) of concurrent reduced-dose radiation therapy (RT) with nivolumab to the current standard of care (standard-dose RT with cisplatin). (Phase II) III. To demonstrate co-primary endpoints of non-inferiority of PFS and superiority of quality of life (QOL) as measured by the MD Anderson Dysphagia Inventory (MDADI) of concurrent reduced-dose radiation with cisplatin or concurrent reduced-dose radiation with nivolumab to the current standard of care (standard-dose RT with cisplatin). (Phase III) (Arm 2 \[concurrent reduced-dose RT with cisplatin\] was dropped after interim futility analysis in phase II.) IV. To demonstrate co-primary endpoints of non-inferiority of PFS and superiority of quality of life (QOL) as measured by the MD Anderson Dysphagia Inventory \[MDADI\] of concurrent reduced-dose radiation with nivolumab to the current standard of care (standard-dose RT with cisplatin). (Phase III) SECONDARY OBJECTIVES: I. To compare patterns of failure (local and regional relapse versus distant) and overall survival between the experimental arm and the control arm. II. To assess long term PFS, overall survival, and toxicity between the experimental arm and the control arm. III. To determine acute and late toxicity profiles as measured by the Common Terminology Criteria for Adverse Events (CTCAE). IV. To explore the symptomatic adverse events (AEs) for tolerability of each treatment arm as measured by the Patient-Reported Outcomes (PRO)-CTCAE. V. To compare changes in patient-reported outcomes (Hearing Handicap Inventory for Adults-Screening \[HHIA-S\], European Organization for Research and Treatment of Cancer \[EORTC\]-Quality of Life Questionnaire \[QLQ\]30) between the experimental arm and the control arm. VI. To assess the association of fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/computed tomography (CT) at baseline with locoregional control and PFS. VII. To estimate the negative predictive value of the 12-14 weeks post-radiation therapy (RT) FDG-PET/CT in terms of locoregional control rates and PFS rates at 1 and 2 years. EXPLORATORY OBJECTIVES: I. To collect blood and tissue specimens for future translation research. II. To optimize radiotherapy treatment plan quality assurance methodology for radiotherapy planning and imaging. III. To compare changes in patient-reported outcomes (European Quality of Life Five Dimension Five Level Scale \[EQ-5D-5L\]) between the experimental arm and the control arm. IV. To collect Modified Barium Swallow (MBS) data for future review and analysis. OUTLINE: PHASE II: Patients are randomized to 1 of 3 arms. ARM I: Patients undergo standard dose RT as 70 Gy intensity modulated radiation therapy (IMRT) or image-guided radiation therapy (IGRT) over 6 fractions per week and receive 100 mg/m\^2/day cisplatin intravenously (IV) over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive fludeoxyglucose F-18 (FDG) and undergo positron emission tomography (PET)/computed tomography (CT) or CT during screening and during follow up, and undergo magnetic resonance imaging (MRI) during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study. ARM II (CLOSED TO ACCRUAL 03-FEB-2023): Patients undergo reduced dose RT as 60 Gy IMRT or IGRT once daily (QD) over 5 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study. ARM III: Beginning 1 week prior to radiation, patients receive 240 mg fixed dose nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks (14 days) for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo reduced dose RT as 60 Gy IMRT or IGRT over 6 fractions per week for 5 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study. PHASE III: Patients are randomized to Arm I and/or Arm III. After completion of study treatment, patients are followed up at 12-14 weeks, every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Pathologically (histologically or cytologically) proven diagnosis of squamous cell carcinoma (including the histological variants papillary squamous cell carcinoma and basaloid squamous cell carcinoma but not neuroendocrine phenotype) of the oropharynx (tonsil, base of tongue, soft palate, or oropharyngeal walls); cytologic diagnosis from a cervical lymph node is sufficient in the presence of clinical evidence of a primary tumor in the oropharynx. Clinical evidence should be documented, may consist of palpation, imaging, or endoscopic evaluation, and should be sufficient to estimate the size of the primary (for T stage)
- •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
- •P16-positive based on local site immunohistochemical tissue staining (defined as greater than 70% strong diffuse nuclear or nuclear and cytoplasmic staining of tumor cells). Fine needle aspiration (FNA) biopsy specimens may be used as the sole diagnostic tissue. Centers are encouraged to contact the pathology chair for clarification
- •Note: Institutions must screen patients, whose tumors must be p16-positive 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-positive results must be reported on the pathology report being submitted
- •Note: If p16 result is equivocal, positive HPV deoxyribonucleic acid (DNA) test of tumor specimen is acceptable and fulfills the eligibility criteria
- •Clinical stage T1-2, N1, M0 (American Joint Committee on Cancer \[AJCC\], 8th edition \[ed.\]) or T3, N0-N1, M0 (AJCC, 8th ed.) including no distant metastases based on the following diagnostic workup:
- •General history and physical examination within 56 days prior to registration;
- •Exam with laryngopharyngoscopy (mirror or in office direct procedure acceptable) within 70 days prior to registration;
- •One of the following imaging studies is required within 56 days prior to registration:
- •FDG-PET/CT of the neck and chest (with or without contrast); FDG-PET/CT scan is strongly preferred and highly recommended to be used for eligibility OR
Exclusion Criteria
- •Clinical stages T0; T4; T1-2, N0; or any N2 (AJCC, 8th ed)
- •Recurrent disease
- •Definitive clinical or radiologic evidence of metastatic disease or adenopathy below the clavicles
- •Cancers considered to be from an oral cavity site (oral tongue, floor mouth, alveolar ridge, buccal or lip), or the nasopharynx, hypopharynx, or larynx, even if p16-positive, or histologies of adenosquamous, verrucous, or spindle cell carcinomas
- •Carcinoma of the neck of unknown primary site origin (T0 is ineligible, even if p16-positive)
- •Radiographically matted nodes, defined as 3 abutting nodes with loss of the intervening fat plane
- •Supraclavicular nodes, defined as nodes centered below the level of the cricoid cartilage
- •Gross total excision of both primary and nodal disease; this includes tonsillectomy, local excision of primary site, and nodal excision that removes all clinically and radiographically evident disease. In other words, to participate in this protocol, the patient must have clinically or radiographically evident gross disease for which disease response can be assessed
- •Patients with simultaneous primary cancers or separate bilateral primary tumor sites are excluded with the exception of patients with bilateral tonsil cancers
- •Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 1095 days (3 years) (of note, the exclusion applies only for invasive cancers such that carcinoma in situ of the breast, oral cavity, or cervix are all permissible)
Arms & Interventions
Arm II (Reduced RT + cisplatin)
Patients undergo reduced dose RT as 60 Gy IMRT or IGRT QD over 5 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Biospecimen Collection
Arm II (Reduced RT + cisplatin)
Patients undergo reduced dose RT as 60 Gy IMRT or IGRT QD over 5 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Magnetic Resonance Imaging
Arm III (Reduced RT + nivolumab)
Beginning 1 week prior to radiation, patients receive 240 mg fixed dose nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks (14 days) for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo reduced dose RT as 60 Gy IMRT or IGRT over 6 fractions per week for 5 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Biospecimen Collection
Arm I (Standard RT + cisplatin)
Patients undergo standard dose RT as 70 Gy IMRT or IGRT over 6 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Biospecimen Collection
Arm I (Standard RT + cisplatin)
Patients undergo standard dose RT as 70 Gy IMRT or IGRT over 6 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Questionnaire Administration
Arm I (Standard RT + cisplatin)
Patients undergo standard dose RT as 70 Gy IMRT or IGRT over 6 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Biopsy Procedure
Arm III (Reduced RT + nivolumab)
Beginning 1 week prior to radiation, patients receive 240 mg fixed dose nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks (14 days) for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo reduced dose RT as 60 Gy IMRT or IGRT over 6 fractions per week for 5 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Biopsy Procedure
Arm I (Standard RT + cisplatin)
Patients undergo standard dose RT as 70 Gy IMRT or IGRT over 6 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Computed Tomography
Arm I (Standard RT + cisplatin)
Patients undergo standard dose RT as 70 Gy IMRT or IGRT over 6 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Image Guided Radiation Therapy
Arm II (Reduced RT + cisplatin)
Patients undergo reduced dose RT as 60 Gy IMRT or IGRT QD over 5 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Computed Tomography
Arm II (Reduced RT + cisplatin)
Patients undergo reduced dose RT as 60 Gy IMRT or IGRT QD over 5 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Image Guided Radiation Therapy
Arm III (Reduced RT + nivolumab)
Beginning 1 week prior to radiation, patients receive 240 mg fixed dose nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks (14 days) for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo reduced dose RT as 60 Gy IMRT or IGRT over 6 fractions per week for 5 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Questionnaire Administration
Arm I (Standard RT + cisplatin)
Patients undergo standard dose RT as 70 Gy IMRT or IGRT over 6 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Intensity-Modulated Radiation Therapy
Arm I (Standard RT + cisplatin)
Patients undergo standard dose RT as 70 Gy IMRT or IGRT over 6 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Magnetic Resonance Imaging
Arm I (Standard RT + cisplatin)
Patients undergo standard dose RT as 70 Gy IMRT or IGRT over 6 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Positron Emission Tomography
Arm II (Reduced RT + cisplatin)
Patients undergo reduced dose RT as 60 Gy IMRT or IGRT QD over 5 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Biopsy Procedure
Arm I (Standard RT + cisplatin)
Patients undergo standard dose RT as 70 Gy IMRT or IGRT over 6 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Quality-of-Life Assessment
Arm III (Reduced RT + nivolumab)
Beginning 1 week prior to radiation, patients receive 240 mg fixed dose nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks (14 days) for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo reduced dose RT as 60 Gy IMRT or IGRT over 6 fractions per week for 5 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Computed Tomography
Arm III (Reduced RT + nivolumab)
Beginning 1 week prior to radiation, patients receive 240 mg fixed dose nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks (14 days) for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo reduced dose RT as 60 Gy IMRT or IGRT over 6 fractions per week for 5 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Image Guided Radiation Therapy
Arm I (Standard RT + cisplatin)
Patients undergo standard dose RT as 70 Gy IMRT or IGRT over 6 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Cisplatin
Arm III (Reduced RT + nivolumab)
Beginning 1 week prior to radiation, patients receive 240 mg fixed dose nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks (14 days) for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo reduced dose RT as 60 Gy IMRT or IGRT over 6 fractions per week for 5 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Nivolumab
Arm III (Reduced RT + nivolumab)
Beginning 1 week prior to radiation, patients receive 240 mg fixed dose nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks (14 days) for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo reduced dose RT as 60 Gy IMRT or IGRT over 6 fractions per week for 5 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Intensity-Modulated Radiation Therapy
Arm II (Reduced RT + cisplatin)
Patients undergo reduced dose RT as 60 Gy IMRT or IGRT QD over 5 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Positron Emission Tomography
Arm II (Reduced RT + cisplatin)
Patients undergo reduced dose RT as 60 Gy IMRT or IGRT QD over 5 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Quality-of-Life Assessment
Arm II (Reduced RT + cisplatin)
Patients undergo reduced dose RT as 60 Gy IMRT or IGRT QD over 5 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Questionnaire Administration
Arm II (Reduced RT + cisplatin)
Patients undergo reduced dose RT as 60 Gy IMRT or IGRT QD over 5 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Intensity-Modulated Radiation Therapy
Arm III (Reduced RT + nivolumab)
Beginning 1 week prior to radiation, patients receive 240 mg fixed dose nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks (14 days) for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo reduced dose RT as 60 Gy IMRT or IGRT over 6 fractions per week for 5 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Positron Emission Tomography
Arm III (Reduced RT + nivolumab)
Beginning 1 week prior to radiation, patients receive 240 mg fixed dose nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks (14 days) for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo reduced dose RT as 60 Gy IMRT or IGRT over 6 fractions per week for 5 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Quality-of-Life Assessment
Arm II (Reduced RT + cisplatin)
Patients undergo reduced dose RT as 60 Gy IMRT or IGRT QD over 5 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Cisplatin
Arm I (Standard RT + cisplatin)
Patients undergo standard dose RT as 70 Gy IMRT or IGRT over 6 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Fludeoxyglucose F-18
Arm II (Reduced RT + cisplatin)
Patients undergo reduced dose RT as 60 Gy IMRT or IGRT QD over 5 fractions per week and receive 100 mg/m\^2/day cisplatin IV over 30-60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Fludeoxyglucose F-18
Arm III (Reduced RT + nivolumab)
Beginning 1 week prior to radiation, patients receive 240 mg fixed dose nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks (14 days) for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo reduced dose RT as 60 Gy IMRT or IGRT over 6 fractions per week for 5 weeks in the absence of disease progression or unacceptable toxicity. Patients receive FDG and undergo PET/CT or CT during screening and during follow up, and undergo MRI during follow up. Patients may also undergo tissue biopsy and blood sample collection throughout the study.
Intervention: Fludeoxyglucose F-18
Outcomes
Primary Outcomes
Progression-free Survival (PFS) (Phase II) (Percentage of Participants Alive Without Progression)
Time Frame: From randomization to first progression or last follow-up. Maximum follow-up at the time of analysis was 4.6 years. The 1- and 2-year estimates are reported.
Progression is defined as local-regional progression or recurrence, distant metastasis, death due to any reason, salvage surgery of primary with tumor present/unknown, salvage neck dissection with tumor present/unknown, \> 20 weeks from end of radiation therapy. Progression-free survival rates are estimated using the Kaplan-Meier method, censoring participants alive at time of analysis. The primary phase IIR endpoint is tested using a confidence interval (CI) approach with each experimental arm compared to the standard arm (Arm 1).
Progression-free Survival (Phase III) (Percentage of Participants Alive Without Progression)
Time Frame: From randomization to first progression or last follow-up. Maximum follow-up was 4.6 years.
Progression is defined as local-regional progression or recurrence, distant metastasis, death due to any reason, salvage surgery of primary with tumor present/unknown, salvage neck dissection with tumor present/unknown, \> 20 weeks from end of radiation therapy. Progression-free survival rates are estimated using the Kaplan-Meier method, censoring participants alive at time of analysis.
MD Anderson Dysphagia Inventory (MDADI) Global Quality of Life (QOL) Score
Time Frame: Baseline to two years
The M. D. Anderson Dysphagia Inventory (MDADI) assesses how patients view their swallowing ability as a result of treatment and how this affects their QOL. It consists of a global quality of life question and a functional, emotional, and physical subscale. The global QOL question ranges from 1 to 5 and multiplied by 20 to obtain a score with a range of 0 to 100. Higher scores indicate better functioning.
Secondary Outcomes
- Hearing(Baseline up to 24 months from end of radiation therapy (RT))
- Locoregional Failure (Percentage of Participants With Locoregional Failure)(From randomization to first failure, competing event, or last known follow-up, whichever occurs first. Maximum follow-up at the time of analysis was 4.6 years. The 1- and 2-year estimates are reported.)
- Distant Failure (Percentage of Participants With Distant Failure)(From randomization to first failure, competing event, or last known follow-up, whichever occurs first. Maximum follow-up at the time of analysis was 4.6 years. The 1- and 2-year estimates are reported.)
- Overall Survival (Percentage of Participants Alive)(From randomization to death from any cause or last follow-up. Maximum follow-up at the time of analysis was 4.6 years. The 1- and 2-year estimates are reported.)
- Number of Participants by Highest Grade Adverse Event Reported(From randomization to last known follow-up. Maximum follow-up at the time of analysis was 4.6 years.)
- Quality of Life(Baseline up to 24 months from end of RT)
- Fludeoxyglucose F-18 (FDG)-Positron Emission Tomography (PET)/Computed Tomography (CT) Locoregional Control(Up to 6 years)
- Negative Predictive Value of Post-RT FDG-PET/CT for Locoregional Control(At 1 and 2 years)
- Negative Predictive Value of Post-RT FDG-PET/CT for PFS(At 1 and 2 years)
- Incidence of Adverse Events(Up to 6 years)