Radiation Therapy and Pembrolizumab or Cisplatin in Treating Patients with Stage III/IV p16 Positive Head and Neck Squamous Cell Carcinoma

Inclusion Criteria

• Informed consent for participation
• p16-positive squamous cell carcinoma of the pharynx, larynx or oral cavity
• High-intermediate risk disease, defined as: * T1-T3 N2 M0 or T3 N1 M0 or any stage III (T4 or N3) p16+ squamous cell carcinoma of the oropharynx (The American Joint Committee on Cancer [AJCC] 8th edition staging system) * T1-2 N1-3 M0 or T3-4 N0-3 M0 (stage III-IVB) p16+ squamous cell carcinoma of the hypopharynx or larynx * T1-2 N2-3 M0 or T3-4 N0-3 M0 (stage III-IVB) p16+ squamous cell carcinoma of the nasopharynx * Inoperable T4 N0-3 M0 (stage IVA-IVB) p16+ squamous cell carcinoma of the oral cavity
• Measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (obtained within 28 days prior to registration)
• Platelets >= 100,000 cells/mm^3 (obtained within 28 days prior to registration)
• Hemoglobin (Hgb) >= 8.0 g/dl; Note: The use of transfusion or other intervention to achieve Hgb >= 8.0 g/dl is acceptable (obtained within 28 days prior to registration)
• Serum creatinine < 1.5 mg/dl or creatinine clearance (CC) >= 50 ml/min determined by 24-hour collection or estimated by Cockcroft-Gault formula (obtained within 28 days prior to registration)
• Bilirubin < 2 mg/dl (obtained within 28 days prior to registration)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x the upper limit of normal (obtained within 28 days prior to registration)
• Female subject of childbearing potential should have a negative pregnancy test within 14 days prior to receiving the first dose of study medication
• Female subjects of childbearing potential must agree to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication (note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject)
• Male subjects must agree to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication (note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject)

Exclusion Criteria

• Prior malignancy within the past 3 years (except non-melanomatous skin cancer and early stage treated prostate cancer)
• Eastern Cooperative Oncology Group (ECOG) performance status >= 2
• Prior head and neck radiation, chemotherapy, or immunotherapy
• Prior oncologic (radical) surgery to the primary site
• Documented evidence of distant metastases
• Severe, active co-morbidity defined as follows * Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months * Transmural myocardial infarction within the last 6 months * Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration * Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days of registration * Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects * Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol
• Any medical or psychiatric illness, which, in the opinion of the principal investigator, would compromise the patient's ability to tolerate this treatment
• Psychiatric/social situations that would limit compliance with study requirements
• Hypersensitivity to pembrolizumab or any of its excipients
• Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Known history of, or any evidence of active, non-infectious pneumonitis
• Active infection requiring systemic therapy
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
• Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies); test only as clinically indicated
• Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected); test only as clinically indicated
• Has received a live vaccine within 30 days of planned start of study therapy * Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed