Pembrolizumab in Combination With Cisplatin and Intensity Modulated Radiotherapy (IMRT) in Head and Neck Cancer

Inclusion Criteria: * Written informed consent * If a woman of childbearing potential, documentation of negative pregnancy * Histologically-confirmed head and neck squamous cell carcinoma with no evidence of distant metastasis. The primary site may be the oral cavity, oropharynx, larynx, or hypopharynx. Patients with squamous cell carcinoma of unknown primary, metastatic to cervical lymph nodes, are permitted to enroll. * High risk or intermediate risk disease, defined below. Staging evaluation should be determined by imaging studies and complete head and neck exam in accordance with the American Joint committee on Cancer Staging Manual, 7th edition. o High risk patient must meet one of the following criteria: * Surgically unresectable oral cavity. Patients who are technically resectable but refuse surgery due to morbidity (eg. total glossectomy) are also eligible. Medically inoperable patients are not eligible. * Larynx: T4 any N; T2-3 and ≥ N2a * Hypopharynx: T1-2N1-3 or T3-4N0-3 * Oropharynx: p16(-) AND T3-4 or ≥ N2a * Unknown primary: p16(-) AND ≥ N2a o Intermediate risk patients must meet one of the following criteria: * Oropharynx: p16(+) AND one of the following * T3 or ≥ N2a AND ≥ 10 pack-years tobacco exposure (see Tobacco Assessment Form, Appendix A) * T4 or N3 disease irrespective of tobacco exposure * Unknown primary: p16(+) AND one of the following * ≥ N2a AND ≥ 10 pack-years tobacco exposure * N3 disease irrespective of tobacco exposure * Patients must be untreated with curative-intent surgery for current diagnosis of Stage III, IVa, or IVb disease. Diagnostic biopsy of primary tumor and/or nodal sites is permitted. * Diagnostic simple tonsillectomy is permitted, provided patient has RECIST-measurable nodal disease. * Patients with a second HNSCC primary tumor are eligible for this study, provided more than 2 years have elapsed since the first diagnosis of HNSCC, the original tumor was managed with surgery only (no adjuvant chemotherapy or radiotherapy), and has not recurred. * Patients with simultaneous primaries or bilateral tumors are excluded, with the exception of patients with bilateral tonsil cancers or patients with T1-2, N0, M0 differentiated thyroid carcinoma (resected or management deferred), who are eligible. * No prior systemic (chemotherapy or biologic/molecular targeted therapy) or radiation treatment for head and neck cancer. * Patients may have received chemotherapy or radiation for a previous, curatively treated non-HNSCC malignancy, provided at least 2 years have elapsed. * Patients must be untreated with radiation above the clavicles. * Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 * Age ≥ 18 * Patients must have measurable disease according to RECIST 1.1 * Patients must demonstrate adequate organ function as defined. * Sexually active patients must agree to use adequate contraceptive measures, while on study and for 30 days after the last dose of study drug. Exclusion Criteria: * Nasopharyngeal primary site * Current participation in or previous participation in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of study treatment. * History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational agent. * Distant metastatic disease including CNS or leptomeningeal metastases is not allowed. * History of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. * Received prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. * History of second malignancy within 2 years prior to Study Day 1 (except for excised and cured non-melanoma skin cancer, carcinoma in situ of breast or cervix, superficial bladder cancer, or T1a or T1b prostate cancer comprising \< 5% of resected tissue with normal prostate specific antigen (PSA) since resection). * Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. * Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). * Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected). * Received a live vaccine within 30 days prior to the first dose of trial treatment. * Received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). * Significant pulmonary disease, including pulmonary hypertension, interstitial lung disease, or active, non-infectious pneumonitis. * History or current evidence of any other medical or psychiatric condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. * Peripheral neuropathy ≥ Grade 2 * Significant cardiovascular disease, including: * Cardiac failure New York Heart Association (NYHA) class III or IV. * Myocardial infarction, severe or unstable angina within 6 months prior to Study Day 1. * History of serious arrhythmia (i.e., ventricular tachycardia, or ventricular fibrillation). * Ventricular cardiac arrhythmias requiring anti-arrhythmic medications. * Known left ventricular ejection fraction (LVEF) ≤ 50%. * Significant thrombotic or embolic events within 3 months prior to Study Day 1. * Major surgery within 6 weeks prior to Study Day 1 (subjects must have completely recovered from any previous surgery prior to Study Day 1). Biopsy, diagnostic tonsillectomy, airway tumor debulking or excisional lymph node biopsy do not constitute major surgery. * Active infection requiring antibiotics or antifungals within 7 days prior to first dose of study drug. * Significant electrolyte imbalance prior to enrollment (note that patients may be supplemented to achieve acceptable electrolyte values): * Hypomagnesemia \<1.2 mg/dL or 0.5 mmol/L. * Hypokalemia \< 3.0 mmol/L. * Women must not be pregnant or breastfeeding.