Oral Decitabine (ASTX727) and Durvalumab in Recurrent and/or Metastatic Head and Neck Cancer Patients

Inclusion Criteria: * Written informed consent and any locally-required authorization (e.g., HIPAA in the UEU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations * Age ≥ 18 years at time of study entry or adult male or female (according to age of majority as defined as ≥18 years) * Histologically confirmed recurrent or metastatic SCCHN (oral cavity, oropharynx, hypopharynx, or larynx) not amenable to therapy with curative intent (surgery or radiation therapy with or without chemotherapy). Patients who refuse radical resection are eligible. * Tumor progression or recurrence during or after treatment with anti-PD1, anti-PDL1, anti-PDL2, anti-CTLA4, or other immune checkpoint inhibitor where the most recent dose was given within 3 months prior to study registration. * Must give valid written consent to provide archival FFPE and/or newly acquired tumor tissue for the purpose of establishing baseline PD-L1 status as well as consent to provide on- and/or post-treatment tumor biopsy sample. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment * Life expectancy of \> 6 months * At least 1 lesion that can be accurately measured at baseline as \> 10 mm in the longest diameter (except lymph nodes which must have a short axis \>15 mm) with CT or MRI and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines. * Adequate normal organ and marrow function as defined below (within 28 days prior to study registration): * Hemoglobin ≥ 9.0 g/dL * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (\> 1500 per mm3) * Platelet count ≥ 100 x 109/L (\>100,000 per mm3) * Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician. * AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 5x ULN * Serum creatinine level \<1.5 x ULN and CL\>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance: Males: --Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL) Females: --Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL) * Female subjects must either be of non-reproductive potential (ie, post-menopausal by history: ≥60 years old and no menses for ≥1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry. * Male subjects with a female partner of childbearing potential must commit to true abstinence from heterosexual contact or commit to the use of male condom plus spermicide throughout the course of the study, and avoid fathering a child during the course of the study (including dose interruptions) and for 6 months following the last dose of azacitidine. * All men and women of childbearing potential must use acceptable methods of birth control throughout the study as described below: Females of childbearing potential: Recommendation is for at least one highly effective contraceptive methods during the study and must agree to continue using such precautions for 180 days after the last dose of investigational product. Non-sterilized males : Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use male condom plus spermicide from screening through 180 days after the last dose of investigational product. -Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follo Exclusion Criteria: * Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff and/or staff at the study site) * Histologically confirmed squamous cell carcinoma of any other primary anatomic location in the head and neck (eg. paranasal cavity) and non-squamous histologies (eg. nasopharynx or salivary gland) * History of another primary malignancy except for: * Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study drug and of low potential risk for recurrence * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease eg, cervical cancer in situ * Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) ≤ 21days prior to the first dose of study drug * Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia's Correction * Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab (MEDI4736) or tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid * Any unresolved toxicity NCI CTCAE grade 2 from previous anti-cancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. * Patients with Grade \> 2 neuropathy will be evaluated on a case-by-case basis and may be included after consultation with the Study Physician. --Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with their assigned IP (eg, hearing loss) may be included after consultation with the Study Physician. * Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE \>Grade 1 * Abnormal coagulation parameters (PT \>15 seconds, PTT\>40 seconds, and/or INR \>1.5) * Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded. * Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) * History of primary immunodeficiency * History of allogeneic organ transplant * History of hypersensitivity to durvalumab (MEDI4736), tremelimumab, or any excipient * Known or suspected hypersensitivity to azacitidine or mannitol * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, myocardial infarction in the past 6 months, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent * Known history of previous clinical diagnosis of tuberculosis * Uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment) * History of leptomeningeal carcinomatosis * Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab (MEDI4736) or tremelimumab * Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control * Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results * Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids. * Subjects with uncontrolled seizures. * Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of azacitidine, durvalumab (MEDI4736) and/or tremelimumab therapy. Lactating females must agree not to breast feed throughout this period