ASTX727 and Nivolumab in Squamous Cell Carcinoma of the Head and Neck

Inclusion Criteria: * Participants must have histologically or cytologically confirmed recurrent or metastatic HNSCC considered incurable by local therapies and eligible to receive anti-PD-L1 as first-line treatment (PD-L1 positive with combined positive score (CPS) ≥1 as evaluated in pre-screening). * Participants must have primary tumor locations in following; oral cavity, hypopharynx, or larynx (nasopharynx is not allowed). * Participants must have not received prior therapies for this disease, no systemic therapy administered in the recurrent or metastatic setting (except for systemic therapy completed within 6 months or \> 6 months if given as part of multimodal treatment for locally advanced disease). * Participants must have not received prior treatment with immune checkpoint inhibitors. * Participants can provide archival tumor tissue not older than 12 months from a core or excisional biopsy for PD-L1 pre-screening using the PD-L1 IHC 22C3 pharmDx assay. * Participants must have lesions amenable to obtain pre-treatment tumor biopsies in screening period after eligibility confirmation and before start of treatment and on- treatment tumor biopsies on C1D8 \& C3D8 after start of treatment if lesions are still present at that time. If a recent archival biopsy is obtained within 3 months prior to start of treatment, this biopsy can be used as a pre-treatment biopsy. * Participants should be age \>18 years. * Participants should have ECOG Performance status ≤ 2. * Participants should have ability to swallow pills (participants will have to demonstrate the ability to swallow a placebo during screening). * Participants must have normal organ and marrow function as defined below: * Hemoglobin ≥ 9.0 g/dl * Leukocytes ≥ 3,000/mcL * Absolute neutrophil count ≥ 1,500/mcL * Platelet count ≥ 100,000/mcL * Total bilirubin within normal institutional limits (Gilbert's syndrome related elevated bilirubin is accepted as long as levels have been stable within last 3 months). * AST (SGOT) ≤ 2.5 X institutional upper limit of normal * ALT (SGPT) ≤ 2.5 X institutional upper limit of normal * Serum Creatinine within normal institutional limits * Women of child-bearing potential and sexually active men with female partners of child-bearing potential must agree to use a highly effective method of contraception beginning with the first dose of study therapy and for the duration of their participation in the study. This is expected for the entire duration of the study period through 6 months after the last dose. Highly effective methods of contraception include: female sterilization (tubal ligation, bilateral oophorectomy, and/or hysterectomy); male sterilization (at least 6 months prior to screening); intrauterine device; and oral, injected, or implanted hormonal contraception AND barrier methods of contraception. Women of child-bearing potential must have documented negative pregnancy test prior to start of investigational treatment regimen. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. * Participants must have the ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: * Participants with progressive disease within six months of completion of curatively Intended systemic treatment for locoregionally advanced HNSCC. * Participants with history of severe immune related adverse effects from prior immunotherapy, except hypothyroidism clinically stable on hormone replacement treatment and controlled type 1 diabetes. All other endocrinopathies are excluded even if controlled with medications. * Participants with Grade ≥ 3 infections within 4 weeks before the first study drug administration. Clinically active infections \> Grade 1 within 2 weeks before the first study drug administration. * Participants with previous or active myocarditis/myositis in history (independent of cause). * Participants with pneumonitis, idiopathic pulmonary fibrosis, organizing, interstitial lung disease active or history of autoimmune disease. . Autoimmune thyroid disease as well as other non-life threatening autoimmune diseases such as vitiligo or autoimmune alopecia that don't require systemic immunosuppression are not excluded. * Participants with known human immunodeficiency virus (HIV) infection, uncontrolled active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. * Participants with treatment with systemic immunosuppressant medications within 2 weeks before the first study drug administration. However, low-dose steroid use (prednisone equivalent \<=10mg daily) for other reasons is allowed. * Participants receiving any other investigational agents. * Participants with untreated brain metastases/CNS disease will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. * Participants with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Participants with confirmed COVID-19 within 7 days prior to start treatment will be excluded, however upon recovery with confirmation of negative COVID test, participant can be reconsidered for the study. * Participants with a history of hypersensitivity to active or inactive excipients of ASTX727 or nivolumab or drugs with a similar chemical structure or class to either agent. * Participants with any other condition which in the Investigator's opinion would not make the participant a good candidate for the clinical trial.