Oral Decitabine and Tetrahydrouridine as Epigenetic Priming for Pembrolizumab-Mediated Immune Checkpoint Blockade in Patients With Inoperable, or Unresectable Locally Advanced or Metastatic Non-Small Cell Lung Cancers and Esophageal Carcinomas

* INCLUSION CRITERIA:
* Histologically or cytologically confirmed, inoperable or unresectable, locally advanced, or metastatic non-small cell lung cancers (NSCLC) or esophageal cancers including Seiwert-Stein Type I and Type II gastro-esophageal junction (GEJ) carcinomas, or malignant pleural mesothelioma (MPM).
* NSCLC patients with no prior systemic treatment or those with prior first line treatment including an immune checkpoint inhibitor, are eligible for study.
* Patients with esophageal and gastro-esophageal junction (GEJ) cancers are potentially eligible for study if they have received or refused first line standard of care cytotoxic therapy, and subsequent targeted therapy if appropriate.
* Patients with MPM are eligible for study if they have received, refused or are ineligible for first line chemotherapy.
* Patients who received deoxyribonucleic acid (DNA) demethylating agents or Programmed cell death protein 1 (PD-1)/Programmed Cell Death Ligand 1 (PD-L1)/PD-L1 inhibitors for another malignancy may be eligible for study if there were no dose-limiting immune related events, and there has been either no clinical evidence of disease or minimal residual disease that has been stable for at least three years.
* Patients must have analysis of PD-L1 expression in cancer cells quantitated by immunohistochemistry analysis.

  * Patients in Cohort 1 (Dose Escalation) may have any level of expression.
  * Patients in Cohort 2 (Dose Expansion: NSCLC with high PD-L1) must have greater than or equal to 50% expression in cancer cells.
  * Patients in Cohort 3 (Dose Expansion: NSCLC with low PD-L1) must have 0-49% expression. Note: Patients in this cohort must have been offered and refused standard of care platinum-based chemotherapy
  * Patients in Cohort 4 (Dose Expansion: Esophageal carcinomas (ESCs)) may have any level of expression.
  * Patients in Cohort 5 (Dose Expansion: MPM) may have any level of expression.
* Measurable disease, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
* Willingness to undergo tumor biopsies if safely accessible per principal investigator (PI) discretion before and after treatment.
* Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of Decitabine (DAC) and Tetrahydrouridine (THU) in combination with Pembrolizumab in patients \<18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
* Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2
* Patients must be without evidence of unstable or decompensated myocardial disease; and must have adequate pulmonary reserve evidenced by Forced expiratory volume in the first second (FEV1) and diffusing capacity of lung for carbon monoxide (DLCO) greater than or equal to 35% predicted; oxygen saturation equal to or greater than 90% on room air by pulse oximetry or arterial blood gas (ABG) (to be drawn if pulse oximetry \< 90% on room air)
* No immunosuppressive medications except non-systemic corticosteroids
* Patients must have normal organ and marrow function as defined below:

  * leukocytes greater than or equal to 3,000/mcL
  * absolute neutrophil count greater than or equal to 1,500/mcL (without transfusion or cytokine support)
  * absolute lymphocyte count greater than or equal to 800/mcL
  * platelets greater than or equal to 100,000/mcL
  * Prothrombin time (PT) no more than 2 seconds above the upper limit of normal (ULN)
  * total bilirubin \< 1.5 X institutional upper limit of normal OR direct bilirubin less than or equal to ULN for patients with total bilirubin \> 1.5 ULN
  * serum albumin greater than or equal to 2.0 mg/dL
  * Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase, (SGOT)/Alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) less than or equal to 2.5 X institutional ULN
  * creatinine less than or equal to 1.6 mg/ml OR creatinine clearance (eGFR) greater than or equal to 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal at the time DAC-THU and pembrolizumab treatment commences.
* Patients with history of brain metastases except those with meningeal carcinomatosis or leptomeningeal disease may be eligible for treatment a minimum of 1 week following completion of gamma knife or whole brain radiotherapy, or 4 weeks following surgical resection of brain metastasis provided post-treatment magnetic resonance (MR) scan reveals no evidence of active disease, and no ongoing need for systemic steroids.
* Patients with laboratory evidence of autoimmune disease (e.g., positive anti-nuclear antibodies (ANA) or lupus anticoagulant) without associated symptoms; vitiligo, or mild autoimmunity not impacting the function of organs, such as Hashimoto or psoriasis may be eligible for study.
* The effects of DAC-THU and pembrolizumab on the developing human fetus are unknown. For this reason and because antineoplastic agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men who engage in sexual activity must agree to use 2 forms of contraception at least 1 of which must be highly effective (intrauterine device \[IUD\], hormonal, tubal ligation; not highly effective includes barrier method) prior to study entry, for the duration of study participation and for 60 days after completion of the study treatment. Should a woman become pregnant, or suspect she is pregnant, while she or her partner is participating in this study the study participant should inform the study physician immediately.
* Ability of subject to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

* Patients with cancers harboring any targetable mutation for which there is approved first, or second line therapy, unless standard care of therapy refused.
* Clinically significant cardiovascular / cerebrovascular disease as follows: cerebral vascular accident / stroke (\< 6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class greater than or equal to II), serious cardiac arrhythmia, clinically significant bleeding or clinically significant pulmonary embolism
* Active Hepatitis A, Hepatitis B (e.g., HB surface antigen (sAg) reactive) or Hepatitis C virus (e.g., HCV ribonucleic acid (RNA \[qualitative\] is detected).
* Human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness due to unknown effects of DAC-THU on systemic immunity.
* Other active infection requiring systemic therapy.
* Pregnant women are excluded from this study because DAC-THU may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with DACTHU, breastfeeding should be discontinued if the mother is treated with DAC-THU. These potential risks may also apply to other agents used in this study.
* Other severe acute or chronic medical or psychiatric conditions or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.
* Patients who are receiving systemic corticosteroids.
* Patients with history of or active autoimmune disease including thyroiditis, colitis, nephritis, neuropathy or pneumonitis.
* Patients receiving another investigational agent.
* An additional malignancy that is 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 or anal cancer, or ductal carcinoma in-situ.
* 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.
* Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Thrombocytosis defined as platelet count \>1,200,000/mcL.