• Patients must have pathologically confirmed locally advanced, non-metastatic, human papillomavirus (HPV) negative head and neck squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, nasopharynx, larynx, or sinuses.

• Stage III or IV disease based on American Joint Committee on Cancer (AJCC) staging 8th edition.

• If a primary oropharyngeal squamous cell carcinoma is diagnosed, HPV must be ruled out by immunohistochemistry.

• Availability of ≥10 unstained 5 micron slides. Patients who cannot fulfill this requirement will need to undergo a new biopsy prior to enrollment on study.

• Patients must be at least 18 years of age.

• Measurable disease (either primary site and/or nodal disease) by RECIST 1.1 criteria.

• No previous radiation or chemotherapy for a head and neck cancer.

• No complete surgical resection for a head and neck cancer within 8 weeks of enrollment (although lymph node biopsy including excision of an individual node with presence of residual nodal disease, or surgical biopsy/excision of the tumor with residual measurable disease is acceptable.) No surgical procedures or core-needle or excisional biopsies will occur after baseline scans are performed and measurable lesions are identified. Fine-needle aspiration can be performed (i.e., to confirm extent of baseline lymph node involvement) following discussion with PI if not performed on a target lesion.

• Performance status 0-1

• Normal Organ Function

‣ Leukocytes ≥ 3000/mm3

⁃ Platelets ≥ 100,000/mm3

⁃ Absolute neutrophil count ≥ 1,500

⁃ Hemoglobin ≥ 9.0 gm/dL

⁃ Aspartate Aminotransferase (AST) ≤ 2.5x upper limit of normal

⁃ Alanine aminotransferase (ALT) ≤ 2.5x upper limit of normal

⁃ Alkaline phosphatase ≤ 2.5x upper limit of normal

⁃ Albumin \> 2.9 gm/dL

⁃ Total bilirubin ≤ 1.5 mg/dL

⁃ Creatinine clearance (CrCl) \> 45 mL/min, normal within 2 weeks prior to start of treatment (Of note, the standard Cockcroft and Gault formula must be used to calculate CrCl for enrollment or dosing)

• Patients must sign a study-specific informed consent form prior to study entry. Patients should have the ability to understand and the willingness to sign a written informed consent document.

• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.

• Women must not be breastfeeding

• Women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 months after completing chemoradiation or receiving the last dose of chemoradiation, whichever occurs latest.

• Men who are sexually active with women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 months after completing chemoradiation or receiving the last dose of chemoradiation, whichever occurs latest.