A Phase II/III Randomized Study of Maintenance Nivolumab Versus Observation in Patients With Locally Advanced, Intermediate Risk HPV Positive OPCA

Primary Outcome Measures  :

1. Progression-free survival (PFS) (Phase II) [ Time Frame: From randomization to date of progression, second primary tumor from the head and neck region, or death, assessed up to 10 years ]Progression will be defined using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Log rank test will be used to compare PFS and OS. Both phase II and phase III analyses will be intent-to-treat analysis, and analysis will be stratified on stratification factors collected at the time of randomization. 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.
   
2. Overall survival (OS) (Phase III) [ Time Frame: From randomization to death, assessed up to 10 years ]Log rank test will be used to compare PFS and OS. Both phase II and phase III analyses will be intent-to-treat analysis, and analysis will be stratified on stratification factors collected at the time of randomization. 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.
   
3. 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 [ Time Frame: At 12 weeks post therapy ]Logrank tests and input hazard rates will be used.
   
4. Negative (standardized qualitative) 12 week post therapy (cisplatin + RT) FDG PET/CT associated with PFS for patients who have a PET/CT [ Time Frame: At 12 weeks post therapy ]Logrank tests and input hazard rates will be used.
   

Secondary Outcome Measures  :

1. Prognostic effect of baseline PD-L1 expression (positive versus [vs.] negative) on OS and PFS [ Time Frame: Baseline up to 10 years ]Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.
   
2. Prognostic effect of baseline saliva and/or plasma human papillomavirus (HPV) status (positive vs. negative) on OS and PFS [ Time Frame: Baseline up to 10 years ]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.
   
3. Prognostic value of maximum standardized uptake value (SUVmax) of primary tumor or neck nodal metastasis of baseline FDG PET/CT for OS [ Time Frame: Baseline up to 10 years ]Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.
   
4. Prognostic value of SUVmax of primary tumor or neck nodal metastasis of baseline FDG PET/CT for PFS [ Time Frame: Baseline up to 10 years ]Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.
   
5. SUVmax of primary tumor or nodal metastasis of baseline FDG PET/CT with PD-L1 expression (positive vs. negative) [ Time Frame: Baseline up to 10 years ]Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.
   
6. Post therapy (cisplatin + RT) FDG PET/CT with saliva or plasma levels of HPV deoxyribonucleic acid (DNA) [ Time Frame: Up to 9 months post-therapy ]Chi-square testing or Pearson correlation testing will be used for the secondary correlation analyses.
   
7. PET based therapy response assessment compared to RECIST 1.1 assessment for patients who have a PET/CT scan at 12 weeks [ Time Frame: At 12 weeks post chemoradiation therapy ]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.
   

Inclusion Criteria:

• STEP 1: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• STEP 1: Patients must have oropharynx cancer that is p16-positive by immunohistochemistry with smoking status: >= 10 pack-years, stage T1-2N2-N3 or T3-4N0-3 OR < 10 pack-years, stage T4N0-N3 or T1-3N2-3.
• STEP 1: Patients must not have known hypersensitivity to nivolumab or compounds of similar chemical or biologic composition.
• STEP 1: Patients with a history of allergic reactions attributed to platinum-based chemotherapy agents are excluded.
• STEP 1: Patients must not have had prior systemic therapy or radiation treatment for p16 positive oropharyngeal squamous cell carcinoma (OPSCC).
• STEP 1: Patients must not have received previous irradiation for head and neck tumor, skull base, or brain tumors.
• STEP 1: Patients must not receive investigational agents within 4 weeks of enrollment or at any time while on study.
• STEP 1: Patients with evidence of distant metastases or leptomeningeal disease (LMD) are excluded.
• STEP 1: Patients with uncontrolled inter-current illnesses which in the opinion of the investigator will interfere with the ability to undergo therapy including chemotherapy are excluded.
• STEP 1: Patients with a history of a different malignancy are excluded, unless the disease has not progressed for >= 2 years.
• STEP 1: Absolute neutrophil count (ANC) >= 1500/mm^3 (must be obtained =< 2 weeks prior to randomization).
• STEP 1: Hemoglobin (Hgb) >= 8.0 g/dL (must be obtained =< 2 weeks prior to randomization).
• STEP 1: Platelet count >= 100,000/mm^3 (must be obtained =< 2 weeks prior to randomization).
• STEP 1: Creatinine clearance of >= 60 ml/min (must be obtained =< 2 weeks prior to randomization). Creatinine clearance may be measured or calculated. If calculating, creatinine clearance, use the Cockcroft-Gault formula.
• STEP 1: Total bilirubin within 1.5 times the normal limits (must be obtained =< 2 weeks prior to randomization).
• STEP 1: Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) within 2.0 times the normal limits (must be obtained =< 2 weeks prior to randomization).
• STEP 1: Alkaline phosphatase within 1.5 times the normal limits (must be obtained =< 2 weeks prior to randomization).
• STEP 1: Women must not be pregnant or breast-feeding as chemotherapy, radiation, and immunotherapy may have possible teratogenicity effects; in addition, complications from pregnancy may interfere with the ability of patients to have an uninterrupted therapy.

All women of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy.

A woman of childbearing potential is any female, 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).

• STEP 1: Women of childbearing potential (WOCBP) and males who are sexually active with WOCBP must use an accepted and effective method of contraception or abstain from sexual intercourse for at least one week prior to the start of treatment, and continue for 5 months after the last dose of protocol treatment for women of childbearing potential and 7 months after the last dose of protocol treatment for males who are sexually active with WOCBP.
• STEP 1: Patients must have measurable disease as defined.
• STEP 1: Patients must have tumor measurements with CT of neck and CT of chest (or CT of neck and FDG PET/CT if standard of care) within 4 weeks prior to Step 1 randomization.
• STEP 2: Patients must have progression per RECIST criteria AND tissue-proven progression on Arm B treatment within 12 months after completion of radiation therapy.
• STEP 2: ECOG performance status of 0 or 1.
• STEP 2: Patients must not have known hypersensitivity to nivolumab or compounds of similar chemical or biologic composition.
• STEP 2: Patients must not have received non-protocol anti-cancer therapy after completion of radiation and chemotherapy.
• STEP 2: ANC >= 1500/mm^3 (must be obtained =< 2 weeks prior to registration).
• STEP 2: Hgb >= 8.0 g/dL (must be obtained =< 2 weeks prior to registration).
• STEP 2: Platelet count >= 100,000/mm^3 (must be obtained =< 2 weeks prior to registration).
• STEP 2: Creatinine clearance of >= 60 ml/min (must be obtained =< 2 weeks prior to registration). Creatinine clearance may be measured or calculated. If calculating, creatinine clearance, use the Cockcroft-Gault formula.
• STEP 2: Total bilirubin within 1.5 times the normal limits (must be obtained =< 2 weeks prior to registration).
• STEP 2: SGOT (AST) or SGPT (ALT) within 2.0 times the normal limits (must be obtained =< 2 weeks prior to registration).
• STEP 2: Alkaline phosphatase within 1.5 times the normal limits (must be obtained =< 2 weeks prior to registration).
• STEP 2: Women must not be pregnant or breast-feeding as chemotherapy, radiation, and immunotherapy may have possible teratogenicity effects; in addition, complications from pregnancy may interfere with the ability of patients to have an uninterrupted therapy.

All women of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy.

A women of childbearing potential is any female, 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).

• STEP 2: Women of childbearing potential (WOCBP) and males who are sexually active with WOCBP must use an accepted and effective method of contraception or abstain from sexual intercourse for at least one week prior to the start of treatment, and continue for 5 months after the last dose of protocol treatment for women of childbearing potential and 7 months after the last dose of protocol treatment for males who are sexually active with WOCBP.
• STEP 2: Patients must have measurable disease.
• STEP 2: Patients must have tumor measurements with CT of neck and CT of chest (or CT of neck and FDG PET/CT if standard of care) within 4 weeks prior to Step 2 registration.