• Stage I-IVA cytologically or histologically-proven head and neck squamous cell carcinoma (HNSCC), p16 positive and negative allowed

• Oropharyngeal tumors must have p16 testing done

• Cancer confirmed to be surgically resectable, with surgery evaluation with planned resection

• Archival tissue prior to treatment available from at most 6 months prior to study enrollment. Otherwise new pre-treatment biopsy mandatory

• No prior treatment for HNSCC

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

• Absolute neutrophil count ≥ 1,500 cells/µL

• Platelets ≥ 100,000/µL

• Hemoglobin ≥ 9.0g/dL (may receive packed red blood cell \[prbc\] transfusion)

• Total bilirubin ≤ 1.5 x the upper limit of normal (ULN)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN

• Albumin ≥ 3.0 g/dL

• Serum creatinine ≤ 1.5 x ULN

• Calculated creatinine clearance of ≤ 50 mL/min

• International normalized ratio (INR) ≤ 1.5. Anticoagulation is allowed only with low molecular weight heparin (LMWH). Patient receiving LMW heparin on stable therapeutic dose for more than 2 weeks or with factor Xa level \< 1.1 units/mL (U/mL) are allowed on the trial

• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures

• Ability to understand and willingness to sign a written informed consent document

• Female subjects of childbearing potential must agree to use adequate contraception (e.g., hormonal or barrier method of birth control; abstinence) for the duration of study treatment and 3 months after completion

• Male subjects must agree to use adequate contraception (e.g., condoms; abstinence) for the duration of study treatment and 3 months after completion

• Female subjects of childbearing age must have a negative serum pregnancy test at study entry