Neoadjuvant Pembrolizumab + Epacadostat Prior to Curative Surgical Care for Squamous Cell Carcinoma of the Head and Neck

Inclusion Criteria: * Be willing and able to provide written informed consent/assent for the trial. * Be 18 years of age or older on day of signing informed consent. * Patients with non-bulky/non-bulky squamous cell carcinomas of the head and neck, with an indication for surgical therapy. 1. T1N1-N2B, T2-4N0-N2b stage are generally eligible 2. If determined per tumor board that a low-volume/non-bulky tumor of another stage is appropriate for resection (e.g. small volume T4 with a small amount of bone invasion) such tumors may also be considered for this study if recommendation in tumor board is such. * Be appropriate candidates for resection and curative intent therapy in general. * Have a performance status of 0 or 1 on the ECOG Performance Scale. * Consent to undergo biopsy from a newly obtained core or excisional biopsy of a tumor lesion before study drug administration, and during treatment. Biopsy in case of progressive disease is optional. * Ability to swallow tablets (at future point administration via G-tube may be allowed if approved by drug manufacturer) * Measurable disease per RECIST 1.1. * Known HPV status for oropharyngeal primary tumors. * Pre-operative scans including MRI/CT neck and, CT chest with contrast. If contrast is contraindicated, Staging PET or PET-CT is acceptable although high quality / diagnostic cross-sectional imaging of the head and neck area is recommended. * Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 10 days of treatment initiation. Table 1 Adequate Organ Function Laboratory Values System Laboratory Value Hematological Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets ≥100,000 / mcL Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment) Renal Serum creatinine OR within upper limit of normal (ULN) OR Measured or calculateda creatinine clearance ≥60 mL/min for subject with creatinine (GFR can also be used in place of creatinine or levels \> institutional ULN CrCl) Hepatic Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN Albumin \>2.5 mg/dL Coagulation International Normalized Ratio (INR) or ≤1.5 X ULN unless subject is receiving Prothrombin Time (PT) anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants aCreatinine clearance should be calculated per institutional standard. * Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. * Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year. * Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy. Abstinence is considered an adequate contraception method. Exclusion Criteria: * Has a diagnosis now or in the past of immunodeficiency requiring systemic steroid therapy in excess of physiologic dose (or any other form of immunosuppressive therapy within 10 days prior to the first dose of trial treatment). * Has bulky tumor (define as N3 lymph node or equivalent lymph conglomerate (≥ 6 cm in one dimension), or primary tumor \> 4 cm). Cystic HPV+ lymph nodes should be assessed in tumor board and may not be considered bulky. * Has a known history of active TB (Bacillus Tuberculosis). * Other life-threatening illness that is expected to impact life expectancy within 3 years. * Hypersensitivity to pembrolizumab, epacadostat or any of its excipients. * Has a known additional malignancy that was diagnosed within the last five years that is either progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer, or in a broader sense is not felt to impact life-expectancy. * Has active autoimmune disease that has required systemic (large physiologic dose) treatment in the past year (i.e. with use of disease modifying agents, corticosteroids or any other 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 immunosuppressive treatment. * History of non-infectious pneumonitis requiring steroids or current pneumonitis * Has an active viral infection requiring systemic therapy. * Has a history or current evidence of any 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. * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. * 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 a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). * Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected). * Has received a live vaccine within 30 days of planned start of study therapy. * Allogeneic organ or stem cell transplant * History of interstitial lung disease (ILD)/pneumonitis requiring treatment with steroids and patients with active ILD/pneumonitis 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.