Intensity-Modulated Radiation Therapy and Nivolumab in Treating Participants with Recurrent or Second Primary Head and Neck Squamous Cell Cancer

Inclusion Criteria

• All patients included in this trial must be candidates for re-irradiation with IMRT
• Patients with recurrent squamous cell carcinoma or a second primary arising in a previously irradiated field
• Patients must be >= 18 years of age.
• Life expectancy of greater than 6 months
• Patients cannot have distant metastases and have to be candidates for curative re-irradiation
• Patients with salivary gland tumors are excluded (patients with nasopharynx carcinoma [CA] or sinonasal cancers can participate)
• Patients with unresectable disease are eligible
• Patients who undergo surgical resection will be allowed regardless of human papilloma virus (HPV) status provided they have one of the following criteria: * Positive margins on pathology * Evidence of extracapsular spread on nodal pathology * Gross residual disease on postoperative or simulation imaging * N2/3 disease * T3/4 disease * Multifocal perineural invasion and/or lymphovascular space invasion
• The majority of the anticipated target volume (> 50%) must have been previously treated to >= 40 Gy; prior radiation therapy (RT) must have been completed > 6 months prior to initiation of IMRT reirradiation; if previous RT records are unavailable, investigators can estimate the dose to previously treated tissues based on completion notes or other treatment history
• An Eastern Cooperative Oncology Group (ECOG) performance score 0-2
• Granulocytes > 1500/mm^3
• Platelets > 100,000/mm^3
• Bilirubin < 1.5 mg/dl
• Creatinine < 1.5 mg/dl
• No other concurrent invasive malignancies treated for the past year (localized prostate cancer or early stage skin cancer are not exclusion criteria)
• Patients with carotid artery involvement or encasement will be allowed provided they have no symptoms related to carotid involvement
• No prior exposure to immunotherapy agents
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Any known factors that would pose a contraindication to receiving nivolumab
• Recursive partitioning analysis (RPA) class III patients defined as those expected to begin reirradiation within 2 years of first course of radiation therapy AND are percutaneous endoscopic gastrostomy [PEG] dependent or have a tracheostomy (patients who have undergone total laryngectomy are not excluded)
• Patients with metastases
• Prior treatment with a PD-1/PD-L1 inhibitor
• Female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to enrollment
• Patients with primary salivary gland cancers are excluded
• Patients who have had chemotherapy or biological therapy within 4 weeks of registration
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, autoimmune disease requiring systemic steroids, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Patients who are pregnant or breast-feeding
• Patients with known active human immunodeficiency virus (HIV), hepatitis (hep) B, or hep C infection
• Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease