<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03233724</url>
  </required_header>
  <id_info>
    <org_study_id>170140</org_study_id>
    <secondary_id>17-C-0140</secondary_id>
    <nct_id>NCT03233724</nct_id>
  </id_info>
  <brief_title>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</brief_title>
  <official_title>Phase I/II Evaluation of Oral Decitabine/Tetrahydrouridine as Epigenetic Priming for Pembrolizumab Immune Checkpoint Blockade in Inoperable Locally Advanced or Metastatic Non-Small Cell Lung Cancers, Esophageal Carcinomas, or Pleural Mesotheliomas</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Lung cancer is the&#xD;
      leading cause of cancer-related death in the United States. Most people with lung cancer are&#xD;
      already in the advanced stages of the disease by the time they see a doctor. Researchers want&#xD;
      to see if combining an approved drug with two new drugs can help.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      To study if tetrahydrouridine-decitabine (THU-DAC) with pembrolizumab is safe and effective&#xD;
      in people with non-small cell lung cancer that cannot be removed by surgery.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      People 18 years and older who have NSCLC that cannot be removed by surgery&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Participants will be screened with&#xD;
&#xD;
        -  Medical history&#xD;
&#xD;
        -  Physical exam&#xD;
&#xD;
        -  Blood and urine tests&#xD;
&#xD;
        -  Tests of heart and lung function&#xD;
&#xD;
      They may have a small tumor sample taken (biopsy). They may have tumor scans.&#xD;
&#xD;
      Before starting treatment, participants will repeat the screening tests. They will also give&#xD;
      a stool sample.&#xD;
&#xD;
      The study will be done in 3-week cycles for up to 6 cycles.&#xD;
&#xD;
        -  Participants will take the 2 study drugs by mouth 3-5 days a week.&#xD;
&#xD;
        -  Participants will get pembrolizumab in a vein for 30 minutes 1 day each cycle.&#xD;
&#xD;
      Participants will keep a study medication diary.&#xD;
&#xD;
      During cycle 1, participants will have blood taken multiple times on days 1 and 2.&#xD;
&#xD;
      Every 3 cycles, participants will repeat screening tests.&#xD;
&#xD;
      Participants will have a mandatory tumor biopsy.&#xD;
&#xD;
      When they finish treatment, participants will have a physical exam and blood tests.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
        -  Non-small cell lung cancers (NSCLC) esophageal cancer (EsC) and malignant pleural&#xD;
           mesotheliomas (MPM) account for approximately 185,000 deaths annually in the United&#xD;
           States, with over two thirds of patients presenting with advanced, incurable disease.&#xD;
           1st-line platinum-based chemotherapy for advanced NSCLC, esophageal cancer (ESCs) or&#xD;
           malignant pleural mesothelioma (MPM) produces transient responses at best, with most&#xD;
           patients succumbing to disease within 12-16 months following diagnosis.&#xD;
&#xD;
        -  Recent randomized clinical trials have demonstrated response rates approximating 20% in&#xD;
           unselected patients with advanced NSCLC or EsC, and nearly 45% in patients with tumors&#xD;
           exhibiting high level expression of programmed death ligand 1 (PD-L1) following&#xD;
           administration of pembrolizumab, a humanized monoclonal anti-Programmed cell death&#xD;
           protein 1 (PD-1) antibody.&#xD;
&#xD;
        -  Approximately 17% of unselected MPM patients have exhibited objective responses&#xD;
           following administration of pembrolizumab or other PD-1 inhibitors.&#xD;
&#xD;
        -  Preclinical studies have demonstrated that epigenetic drugs such as deoxyribonucleic&#xD;
           acid (DNA) demethylating agents and histone deacetylase (HDAC) inhibitors can prime&#xD;
           cancer cells and tumor microenvironments thereby enhancing efficacy of immune checkpoint&#xD;
           inhibitors.&#xD;
&#xD;
        -  Although a potent DNA demethylating agent, Decitabine has poor bioavailability and&#xD;
           inconsistent distribution in solid tumors due to rapid inactivation by cytidine&#xD;
           deaminase (CDA) which is present in high levels in many organs.&#xD;
&#xD;
        -  Recent studies in rodents and nonhuman primates, as well as a Phase 1 clinical trial&#xD;
           (NCT#01685515) in patients with sickle cell disease have demonstrated that oral&#xD;
           tetrahydrouridine (THU), an inhibitor of CDA, significantly enhances&#xD;
           bioavailability/solid-tissue-distribution of low dose oral Decitabine (DAC), thereby&#xD;
           enhancing systemic DNA demethylation with acceptable toxicities.&#xD;
&#xD;
        -  Preliminary results of recent clinical trial suggest that oral DAC-THU can increase the&#xD;
           frequency and magnitude of responses to immune checkpoint inhibitors in lung cancer&#xD;
           patients with low or absent intra-tumoral PD-L1 expression.&#xD;
&#xD;
        -  These data support further evaluation of oral DAC-THU in combination with immune&#xD;
           checkpoint inhibitors for therapy of thoracic malignancies.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      Phase I&#xD;
&#xD;
      -To define pharmacokinetics, toxicities and maximum tolerated dose of oral DAC-THU in&#xD;
      combination with pembrolizumab in patients with inoperable, or unresectable locally advanced&#xD;
      or metastatic NSCLC, EsC, or MPM.&#xD;
&#xD;
      Phase II&#xD;
&#xD;
      -To determine clinical response by Response Evaluation Criteria in Solid Tumors (RECIST)&#xD;
      criteria to oral DAC-THU in combination with pembrolizumab in patients with inoperable, or&#xD;
      unresectable, locally advanced or metastatic NSCLC, EsC, or MPM.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      Inclusion Criteria&#xD;
&#xD;
        -  Male or female, 18 years or older with histologically or cytologically proven,&#xD;
           inoperable, or unresectable locally advanced, or metastatic NSCLC, EsC, or MPM.&#xD;
&#xD;
        -  Measurable disease.&#xD;
&#xD;
        -  Patients with high PD-L1 expression ((Bullet) 50%) and low PD-L1 expression (0-49%) in&#xD;
           cancer cells by immunohistochemistry are eligible.&#xD;
&#xD;
        -  NSCLC patients with no prior systemic treatment, or those with prior first line&#xD;
           treatment including an immune checkpoint inhibitor are eligible for study.&#xD;
&#xD;
        -  MPM patients who have received, refused, or are ineligible for first line chemotherapy&#xD;
           are eligible.&#xD;
&#xD;
        -  Patients with EsC including Seiwert-Stein Type I and Type II gastro-esophageal junction&#xD;
           (GEJ) carcinomas who have received or refused standard of care first line therapy and/or&#xD;
           targeted therapy are eligible.&#xD;
&#xD;
        -  Patients who received DNA demethylating agents or PD-1/PD-L1 inhibitors for another&#xD;
           malignancy may be eligible for study if there were no dose-limiting immune related&#xD;
           events, and there has been either no clinical evidence of disease or minimal residual&#xD;
           disease that has been stable for at least three years.&#xD;
&#xD;
        -  Willingness to undergo tumor biopsies if safely accessible per PI discretion before and&#xD;
           after treatment.&#xD;
&#xD;
        -  Eastern Cooperative Oncology Group (ECOG) performance status 0 2.&#xD;
&#xD;
        -  No evidence of unstable or decompensated myocardial disease; adequate pulmonary reserve.&#xD;
&#xD;
        -  Adequate renal, hepatic and hematopoietic function.&#xD;
&#xD;
      Exclusion Criteria&#xD;
&#xD;
        -  Patients with any targetable mutation for which there is approved first, or second line&#xD;
           therapy.&#xD;
&#xD;
        -  Serious cardiovascular conditions.&#xD;
&#xD;
        -  Active Hepatitis A, Hepatitis B or Hepatitis C.&#xD;
&#xD;
        -  Human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related&#xD;
           illness.&#xD;
&#xD;
        -  Other active infection requiring systemic therapy.&#xD;
&#xD;
        -  Pregnant or breastfeeding women.&#xD;
&#xD;
        -  Patients who are receiving systemic corticosteroids.&#xD;
&#xD;
        -  Patients receiving another investigational agent.&#xD;
&#xD;
        -  Another malignancy.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  The Phase I component will be a standard 3+3 design combining high and low PD-L1&#xD;
           expressers with incremental dose escalation of oral DAC-THU to define maximum tolerated&#xD;
           dose (MTD).&#xD;
&#xD;
        -  Simon 2-stage design for Phase II studies will be used to determine clinical response at&#xD;
           the MTD.&#xD;
&#xD;
        -  Patients will receive oral DAC-THU- on T-W for two weeks out of every 3 for 9 weeks&#xD;
&#xD;
        -  Pembrolizumab will be administered on Wednesday, Thursday or Friday at a fixed&#xD;
           intravenous dose of 200 mg every 3 weeks.&#xD;
&#xD;
        -  One cycle is three weeks; one course is 9 weeks. Treatment evaluation using RECIST 1.1&#xD;
           every 10 +/- 1 weeks.&#xD;
&#xD;
        -  Those patients exhibiting disease progression or unacceptable toxicities will be removed&#xD;
           from study. Patients exhibiting stable disease or disease regression will be offered an&#xD;
           additional course of therapy followed by treatment evaluation. Treatment will continue&#xD;
           in this manner until off-study criteria have been met.&#xD;
&#xD;
        -  Once the MTD for DAC/THU has been identified, the MTD dose level will be expanded by 4&#xD;
           patients to confirm its safety. Then, including these 10 patients at the MTD, a total of&#xD;
           10 NSCLC patients with high (50% or greater) intratumoral PD-L1 expression and 10 NSCLC&#xD;
           patients with low (0-49%) intratumoral PD-L1 expression will be accrued to the first&#xD;
           stage of each of two separate Phase II cohorts using individual Simon optimal designs.&#xD;
           If 5 or more patients of the 10 first stage NSCLC patients in the high PD-L1 cohort&#xD;
           respond to treatment, the cohort will be expanded to 23 patients. If 11 of 23 of these&#xD;
           patients respond to treatment, the trial will be deemed positive for NSCLC with high&#xD;
           PD-L1 expression. If 2 or more of the 10 first stage NSCLC patients in the low PD-L1&#xD;
           expression cohort respond to treatment, the cohort will be expanded to 29 patients. If 6&#xD;
           or more of these 29 patients experience a response, the trial will be deemed positive&#xD;
           for NSCLC with low PD-L1 expression. Up to 10 EsC patients, including those considered&#xD;
           to be part of the Phase I component after the MTD has been identified, will be enrolled&#xD;
           into a separate cohort to examine responses to DAC-THU/pembrolizumab at the MTD. If 2 or&#xD;
           more of these 10 EsC patients respond to treatment, these findings may warrant an&#xD;
           amendment or a separate Phase II trial to determine response rates to&#xD;
           DAC-THU/pembrolizumab in EsC patients. Similarly, if 2 or more of 10 MPM patients&#xD;
           respond to treatment, these findings may warrant an amendment or a separate Phase II&#xD;
           trial to determine response rates to DACTHU/pembrolizumab in MPM.&#xD;
&#xD;
        -  Biopsies of index lesions will be obtained at baseline and at treatment evaluation&#xD;
           following the first course of therapy for analysis of pharmacodynamic endpoints.&#xD;
&#xD;
        -  Patients will be followed for toxicity for at least 30 days after treatment has been&#xD;
           discontinued, start of new anti-cancer treatment or until death, whichever occurs first.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Study terminated due to drug supply issues.&#xD;
  </why_stopped>
  <start_date type="Actual">April 11, 2018</start_date>
  <completion_date type="Actual">October 26, 2021</completion_date>
  <primary_completion_date type="Actual">October 6, 2021</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall Response Rate</measure>
    <time_frame>Every 10 weeks (± 1 week) until disease progression or unacceptable toxicity or off study criteria is met. Longest participant on study 11 months.</time_frame>
    <description>Overall response rate was measured using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 to determine if the combination of decitabine and tetrahydrouridine is associated with a response rate which exceeds that of Pembrolizumab alone in participants who have programmed death-ligand 1 (PD-L1) expression of at least 50% and those who do not. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Tolerated Dose (MTD) of Decitabine</measure>
    <time_frame>Within the first 6 weeks (two cycles)</time_frame>
    <description>Maximum Tolerated Dose (MTD) is the maximum dose at which fewer than one-third of participants experience dose limiting toxicity (DLT) within the first 6 weeks (two cycles) of decitabine and tetrahydrouridine therapy. If one of three patients at any given dose level experiences DLT, up to three additional patients will be treated at this dose level. If only one of six patients exhibit DLT, subsequent patients will be enrolled into the next higher dose level. As soon as two patients at any given dose level develop DLT, no additional patients will be entered at that level. Subsequent patients will be accrued into the preceding dose level; if DLT is observed in less than two of six patients treated at this lower level, this dose will represent maximum tolerated dose (MTD). A DLT is any Grade 3 or greater toxicity that cannot be attributed to a cause other than study treatment during the first two cycles of Course 1 of therapy such as disease progression or intercurrent illness.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Tolerated Dose (MTD) of Tetrahydrouridine</measure>
    <time_frame>Within the first 6 weeks (two cycles)</time_frame>
    <description>Maximum Tolerated Dose (MTD) is the maximum dose at which fewer than one-third of participants experience dose limiting toxicity (DLT) within the first 6 weeks (two cycles) of decitabine and tetrahydrouridine therapy. If one of three patients at any given dose level experiences DLT, up to three additional patients will be treated at this dose level. If only one of six patients exhibit DLT, subsequent patients will be enrolled into the next higher dose level. As soon as two patients at any given dose level develop DLT, no additional patients will be entered at that level. Subsequent patients will be accrued into the preceding dose level; if DLT is observed in less than two of six patients treated at this lower level, this dose will represent maximum tolerated dose (MTD). A DLT is any Grade 3 or greater toxicity that cannot be attributed to a cause other than study treatment during the first two cycles of Course 1 of therapy such as disease progression or intercurrent illness.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in Circulating Tumor Cells (CTCs)</measure>
    <time_frame>Baseline and post-treatment after one course of therapy (Week 10 +/- one week)</time_frame>
    <description>Peripheral blood will be collected to correlate changes in circulating tumor cells with clinical response. CTCs will be assessed using ferrofluidic enrichment and multi-parameter flow cytometric detection. Baseline and post-treatment specimen collection after one course of therapy (Week 10 +/- one week).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Immune Cell Subsets in Peripheral Blood Mononuclear Cells (PBMC)</measure>
    <time_frame>Baseline and post-treatment after one course of therapy (Week 10 +/- one week)</time_frame>
    <description>Peripheral blood mononuclear cells (PBMC) will be assessed using multiparameter flow cytometry for immune subsets including but not necessarily limited to Tregs, myeloid-derived suppressor cells (MDSC), effector and exhausted cluster of differentiation 4 (CD4+), cytotoxic T lymphocytes (CD8+) T cells, and cluster of differentiation 14 (CD14 +) monocytes. Assessment will include functional markers, i.e., programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), T-cell immunoglobulin mucin-3 (TIM-3), cluster of differentiation 152 (CTLA-4), human leukocyte antigen (HLA) membrane heterodimeric glycoproteins (-DR) and/or cluster of differentiation 40 (CD40). Baseline and post-treatment specimen collection after one course of therapy (Week 10 +/- one week).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent Viable Tumor Cells</measure>
    <time_frame>Baseline and post-treatment after one course of therapy (Week 10 +/- one week)</time_frame>
    <description>Portions of biopsy materials will be sent for frozen section or permanent section confirmation of malignancy, i.e., non-small cell lung cancers (NSCLC), esophageal carcinomas (Esc), malignant pleural mesothelioma (MPM) cells, and percent viable tumor cells. All of the analyses are predicated on acquisition of sufficient materials.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Gene, Endogenous Retroviral (ERV), Micro Ribonucleic Acid (RNA) Expressions, Deoxyribonucleic Acid (DNA) Methylation Signatures and Tumor Microenvironment</measure>
    <time_frame>Baseline and post-treatment after one course of therapy (Week 10 +/- one week)</time_frame>
    <description>Tissue will be processed for focused gene, endogenous retroviral and microRNA expressions, and DNA methylation signatures using quantitative reverse-transcription polymerase chain reaction (RT-PCR), nanostring, pyrosequencing and digital droplet PCR techniques. Isolate serum for focused methylation analysis. If sufficient tissue is available, another portion will be imbedded in paraffin for subsequent immunostaining experiments, focusing on expression of genes focusing on those proteins encoded by genes that have been identified to be clearly activated by epigenetic therapy. If sufficient materials are present, additional more comprehensive analyses including multiplex immunohistochemistry analysis of tumor microenvironment may be performed with the focus of materials from participants treated at the maximum tolerated dose. All of the analyses are predicated on acquisition of sufficient materials.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)</measure>
    <time_frame>Date treatment consent signed to date off study, approximately 2 months/10 days, 10 months/29 days, 20 months/30 days for the first, second and third group respectively.</time_frame>
    <description>Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of Participants With a Dose Limiting Hematologic Toxicity (DLT)</measure>
    <time_frame>First two cycles of Course 1 of therapy</time_frame>
    <description>A DLT is any Grade 3 (severe) or greater toxicity that cannot be attributed to a cause other than study treatment during the first two cycles of Course 1 of therapy such as disease progression or intercurrent illness.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">9</enrollment>
  <condition>Carcinoma, Non-Small-Cell Lung</condition>
  <condition>Lung Cancer</condition>
  <condition>Non-Small Cell Lung Cancer</condition>
  <condition>Carcinoma, Esophageal</condition>
  <condition>Malignant Pleural Mesotheliomas</condition>
  <arm_group>
    <arm_group_label>1/Dose Escalation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Decitabine (DAC)-Tetrahydrouridine (THU) + pembrolizumab at escalating doses</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2/Dose Expansion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Decitabine (DAC)-Tetrahydrouridine (THU) + pembrolizumab at the dose established in Arm 1</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Decitabine (DAC)</intervention_name>
    <description>Administered orally on two consecutive days (preferably Tuesday and Wednesday) for two weeks out of three weeks x 9 weeks</description>
    <arm_group_label>1/Dose Escalation</arm_group_label>
    <arm_group_label>2/Dose Expansion</arm_group_label>
    <other_name>Dacogen</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tetrahydrouridine (THU)</intervention_name>
    <description>Administered orally on two consecutive days (preferably Tuesday and Wednesday) for two weeks out of three weeks x 9 weeks</description>
    <arm_group_label>1/Dose Escalation</arm_group_label>
    <arm_group_label>2/Dose Expansion</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>200 mg intravenous (IV) once a day every Wednesday, Thursday or Friday every 3 weeks.</description>
    <arm_group_label>1/Dose Escalation</arm_group_label>
    <arm_group_label>2/Dose Expansion</arm_group_label>
    <other_name>Keytruda</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
          -  Histologically or cytologically confirmed, inoperable or unresectable, locally&#xD;
             advanced, or metastatic non-small cell lung cancers (NSCLC) or esophageal cancers&#xD;
             including Seiwert-Stein Type I and Type II gastro-esophageal junction (GEJ)&#xD;
             carcinomas, or malignant pleural mesothelioma (MPM).&#xD;
&#xD;
          -  NSCLC patients with no prior systemic treatment or those with prior first line&#xD;
             treatment including an immune checkpoint inhibitor, are eligible for study.&#xD;
&#xD;
          -  Patients with esophageal and gastro-esophageal junction (GEJ) cancers are potentially&#xD;
             eligible for study if they have received or refused first line standard of care&#xD;
             cytotoxic therapy, and subsequent targeted therapy if appropriate.&#xD;
&#xD;
          -  Patients with MPM are eligible for study if they have received, refused or are&#xD;
             ineligible for first line chemotherapy.&#xD;
&#xD;
          -  Patients who received deoxyribonucleic acid (DNA) demethylating agents or Programmed&#xD;
             cell death protein 1 (PD-1)/Programmed Cell Death Ligand 1 (PD-L1)/PD-L1 inhibitors&#xD;
             for another malignancy may be eligible for study if there were no dose-limiting immune&#xD;
             related events, and there has been either no clinical evidence of disease or minimal&#xD;
             residual disease that has been stable for at least three years.&#xD;
&#xD;
          -  Patients must have analysis of PD-L1 expression in cancer cells quantitated by&#xD;
             immunohistochemistry analysis.&#xD;
&#xD;
               -  Patients in Cohort 1 (Dose Escalation) may have any level of expression.&#xD;
&#xD;
               -  Patients in Cohort 2 (Dose Expansion: NSCLC with high PD-L1) must have greater&#xD;
                  than or equal to 50% expression in cancer cells.&#xD;
&#xD;
               -  Patients in Cohort 3 (Dose Expansion: NSCLC with low PD-L1) must have 0-49%&#xD;
                  expression. Note: Patients in this cohort must have been offered and refused&#xD;
                  standard of care platinum-based chemotherapy&#xD;
&#xD;
               -  Patients in Cohort 4 (Dose Expansion: Esophageal carcinomas (ESCs)) may have any&#xD;
                  level of expression.&#xD;
&#xD;
               -  Patients in Cohort 5 (Dose Expansion: MPM) may have any level of expression.&#xD;
&#xD;
          -  Measurable disease, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.&#xD;
&#xD;
          -  Willingness to undergo tumor biopsies if safely accessible per principal investigator&#xD;
             (PI) discretion before and after treatment.&#xD;
&#xD;
          -  Age greater than or equal to 18 years. Because no dosing or adverse event data are&#xD;
             currently available on the use of Decitabine (DAC) and Tetrahydrouridine (THU) in&#xD;
             combination with Pembrolizumab in patients &lt;18 years of age, children are excluded&#xD;
             from this study, but will be eligible for future pediatric trials.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to&#xD;
             2&#xD;
&#xD;
          -  Patients must be without evidence of unstable or decompensated myocardial disease; and&#xD;
             must have adequate pulmonary reserve evidenced by Forced expiratory volume in the&#xD;
             first second (FEV1) and diffusing capacity of lung for carbon monoxide (DLCO) greater&#xD;
             than or equal to 35% predicted; oxygen saturation equal to or greater than 90% on room&#xD;
             air by pulse oximetry or arterial blood gas (ABG) (to be drawn if pulse oximetry &lt; 90%&#xD;
             on room air)&#xD;
&#xD;
          -  No immunosuppressive medications except non-systemic corticosteroids&#xD;
&#xD;
          -  Patients must have normal organ and marrow function as defined below:&#xD;
&#xD;
               -  leukocytes greater than or equal to 3,000/mcL&#xD;
&#xD;
               -  absolute neutrophil count greater than or equal to 1,500/mcL (without transfusion&#xD;
                  or cytokine support)&#xD;
&#xD;
               -  absolute lymphocyte count greater than or equal to 800/mcL&#xD;
&#xD;
               -  platelets greater than or equal to 100,000/mcL&#xD;
&#xD;
               -  Prothrombin time (PT) no more than 2 seconds above the upper limit of normal&#xD;
                  (ULN)&#xD;
&#xD;
               -  total bilirubin &lt; 1.5 X institutional upper limit of normal OR direct bilirubin&#xD;
                  less than or equal to ULN for patients with total bilirubin &gt; 1.5 ULN&#xD;
&#xD;
               -  serum albumin greater than or equal to 2.0 mg/dL&#xD;
&#xD;
               -  Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase,&#xD;
                  (SGOT)/Alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase&#xD;
                  (SGPT) less than or equal to 2.5 X institutional ULN&#xD;
&#xD;
               -  creatinine less than or equal to 1.6 mg/ml OR creatinine clearance (eGFR) greater&#xD;
                  than or equal to 60 mL/min/1.73 m^2 for patients with creatinine levels above&#xD;
                  institutional normal at the time DAC-THU and pembrolizumab treatment commences.&#xD;
&#xD;
          -  Patients with history of brain metastases except those with meningeal carcinomatosis&#xD;
             or leptomeningeal disease may be eligible for treatment a minimum of 1 week following&#xD;
             completion of gamma knife or whole brain radiotherapy, or 4 weeks following surgical&#xD;
             resection of brain metastasis provided post-treatment magnetic resonance (MR) scan&#xD;
             reveals no evidence of active disease, and no ongoing need for systemic steroids.&#xD;
&#xD;
          -  Patients with laboratory evidence of autoimmune disease (e.g., positive anti-nuclear&#xD;
             antibodies (ANA) or lupus anticoagulant) without associated symptoms; vitiligo, or&#xD;
             mild autoimmunity not impacting the function of organs, such as Hashimoto or psoriasis&#xD;
             may be eligible for study.&#xD;
&#xD;
          -  The effects of DAC-THU and pembrolizumab on the developing human fetus are unknown.&#xD;
             For this reason and because antineoplastic agents as well as other therapeutic agents&#xD;
             used in this trial are known to be teratogenic, women of child-bearing potential and&#xD;
             men who engage in sexual activity must agree to use 2 forms of contraception at least&#xD;
             1 of which must be highly effective (intrauterine device [IUD], hormonal, tubal&#xD;
             ligation; not highly effective includes barrier method) prior to study entry, for the&#xD;
             duration of study participation and for 60 days after completion of the study&#xD;
             treatment. Should a woman become pregnant, or suspect she is pregnant, while she or&#xD;
             her partner is participating in this study the study participant should inform the&#xD;
             study physician immediately.&#xD;
&#xD;
          -  Ability of subject to understand and the willingness to sign a written informed&#xD;
             consent document.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  Patients with cancers harboring any targetable mutation for which there is approved&#xD;
             first, or second line therapy, unless standard care of therapy refused.&#xD;
&#xD;
          -  Clinically significant cardiovascular / cerebrovascular disease as follows: cerebral&#xD;
             vascular accident / stroke (&lt; 6 months prior to enrollment), myocardial infarction (&lt;&#xD;
             6 months prior to enrollment), unstable angina, congestive heart failure (New York&#xD;
             Heart Association Classification Class greater than or equal to II), serious cardiac&#xD;
             arrhythmia, clinically significant bleeding or clinically significant pulmonary&#xD;
             embolism&#xD;
&#xD;
          -  Active Hepatitis A, Hepatitis B (e.g., HB surface antigen (sAg) reactive) or Hepatitis&#xD;
             C virus (e.g., HCV ribonucleic acid (RNA [qualitative] is detected).&#xD;
&#xD;
          -  Human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome&#xD;
             (AIDS)-related illness due to unknown effects of DAC-THU on systemic immunity.&#xD;
&#xD;
          -  Other active infection requiring systemic therapy.&#xD;
&#xD;
          -  Pregnant women are excluded from this study because DAC-THU may have the potential for&#xD;
             teratogenic or abortifacient effects. Because there is an unknown but potential risk&#xD;
             for adverse events in nursing infants secondary to treatment of the mother with&#xD;
             DACTHU, breastfeeding should be discontinued if the mother is treated with DAC-THU.&#xD;
             These potential risks may also apply to other agents used in this study.&#xD;
&#xD;
          -  Other severe acute or chronic medical or psychiatric conditions or laboratory&#xD;
             abnormality that may increase the risk associated with study participation or study&#xD;
             drug administration, or may interfere with the interpretation of study results, and in&#xD;
             the judgment of the investigator would make the patient inappropriate for entry into&#xD;
             this study.&#xD;
&#xD;
          -  Patients who are receiving systemic corticosteroids.&#xD;
&#xD;
          -  Patients with history of or active autoimmune disease including thyroiditis, colitis,&#xD;
             nephritis, neuropathy or pneumonitis.&#xD;
&#xD;
          -  Patients receiving another investigational agent.&#xD;
&#xD;
          -  An additional malignancy that is progressing or requires active treatment. Exceptions&#xD;
             include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that&#xD;
             has undergone potentially curative therapy, or in-situ cervical or anal cancer, or&#xD;
             ductal carcinoma in-situ.&#xD;
&#xD;
          -  History or current evidence of any condition, therapy, or laboratory abnormality that&#xD;
             might confound the results of the trial, interfere with the subject's participation&#xD;
             for the full duration of the trial, or is not in the best interest of the subject to&#xD;
             participate, in the opinion of the treating investigator.&#xD;
&#xD;
          -  Psychiatric or substance abuse disorders that would interfere with cooperation with&#xD;
             the requirements of the trial.&#xD;
&#xD;
          -  Thrombocytosis defined as platelet count &gt;1,200,000/mcL.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David S Schrump, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2017-C-0140.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>July 28, 2017</study_first_submitted>
  <study_first_submitted_qc>July 28, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2017</study_first_posted>
  <results_first_submitted>March 15, 2023</results_first_submitted>
  <results_first_submitted_qc>May 4, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">May 31, 2023</results_first_posted>
  <last_update_submitted>May 4, 2023</last_update_submitted>
  <last_update_submitted_qc>May 4, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 31, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>National Cancer Institute (NCI)</investigator_affiliation>
    <investigator_full_name>David Schrump, M.D.</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>PD-L1</keyword>
  <keyword>Demethylating Agents and Histone Deacetylase (HDAC) Inhibitors</keyword>
  <keyword>DNA Hypomethylating Agent</keyword>
  <keyword>Cytidine Deaminase</keyword>
  <keyword>Checkpoint Inhibitor</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Lung Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
    <mesh_term>Mesothelioma</mesh_term>
    <mesh_term>Mesothelioma, Malignant</mesh_term>
    <mesh_term>Esophageal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
    <mesh_term>Decitabine</mesh_term>
    <mesh_term>Tetrahydrouridine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the Database of Genotypes and Phenotypes (dbGaP).</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.</ipd_time_frame>
    <ipd_access_criteria>Clinical data will be made available via subscription to the Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.</ipd_access_criteria>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>August 1, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/24/NCT03233724/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>August 25, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/24/NCT03233724/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT)</title>
          <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level 1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT) q week with Pembrolizumab infusion q3weeks</description>
        </group>
        <group group_id="P2">
          <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT)</title>
          <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level -1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT) q week. Participants received Pembrolizumab infusion q3weeks.</description>
        </group>
        <group group_id="P3">
          <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Every (q) Tuesday,Wednesday (TW) x 2 Weeks q3Weeks</title>
          <description>Phase 1, Arm 1, Dose Escalation, Revised Dose Level 1. Participants received Decitabine 0.21 mg/kg + Tetrahydrouridine 10mg/kg TW weekly x 2 weeks q 3 weeks. Participants received pembrolizumab infusion q 3weeks.</description>
        </group>
        <group group_id="P4">
          <title>Decitabine 0.17mg/kg + Tetrahydrouridine 10mg/kg Every (q) Tuesday,Wednesday (TW) x 2 Weeks q3Weeks</title>
          <description>Phase 1, Arm 1, Dose Escalation, Revised Dose Level -1. Participants received Decitabine 0.17 mg/kg + Tetrahydrouridine 10mg/kg TW weekly x 2 weeks q 3 weeks. Participants received pembrolizumab infusion q 3weeks.</description>
        </group>
        <group group_id="P5">
          <title>Enrolled to Revised Dose Level 1 But Not Treated</title>
          <description>Participants who were enrolled but not treated.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Phase I Dose Escalation</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="0">No participants were enrolled in this Arm/Group.</participants>
                <participants group_id="P5" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="3"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Removed from protocol prior to treatment due to rapidly progressive esophageal obstruction.</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Best interest of participant</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Delay &gt;3 weeks on treatment</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Phase II Dose Expansion</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>No participants were enrolled on Decitabine 0.17mg/kg + Tetrahydrouridine 10mg/kg Every (q) Tuesday,Wednesday (TW) x 2 Weeks q3Weeks.</population>
      <group_list>
        <group group_id="B1">
          <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT)</title>
          <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level 1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT) q week with Pembrolizumab infusion q3weeks</description>
        </group>
        <group group_id="B2">
          <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT)</title>
          <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level -1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT) q week. Participants received Pembrolizumab infusion q3weeks.</description>
        </group>
        <group group_id="B3">
          <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Every (q) Tuesday,Wednesday (TW) x 2 Weeks q3Weeks</title>
          <description>Phase 1, Arm 1, Dose Escalation, Revised Dose Level 1. Participants received Decitabine 0.21 mg/kg + Tetrahydrouridine 10mg/kg TW weekly x 2 weeks q 3 weeks. Participants received pembrolizumab infusion q 3weeks.</description>
        </group>
        <group group_id="B4">
          <title>Decitabine 0.17mg/kg + Tetrahydrouridine 10mg/kg Every (q) Tuesday,Wednesday (TW) x 2 Weeks q3Weeks</title>
          <description>Phase 1, Arm 1, Dose Escalation, Revised Dose Level -1. Participants received Decitabine 0.17 mg/kg + Tetrahydrouridine 10mg/kg TW weekly x 2 weeks q 3 weeks. Participants received pembrolizumab infusion q 3weeks.</description>
        </group>
        <group group_id="B5">
          <title>Enrolled to Revised Dose Level 1 But Not Treated</title>
          <description>Participants who were enrolled but not treated.</description>
        </group>
        <group group_id="B6">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="2"/>
            <count group_id="B2" value="2"/>
            <count group_id="B3" value="4"/>
            <count group_id="B4" value="0"/>
            <count group_id="B5" value="1"/>
            <count group_id="B6" value="9"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B5" value="1"/>
                    <measurement group_id="B6" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="58.2" spread="11.74"/>
                    <measurement group_id="B2" value="80.85" spread="11.53"/>
                    <measurement group_id="B3" value="49.62" spread="10.02"/>
                    <measurement group_id="B5" value="62.4" spread="0"/>
                    <measurement group_id="B6" value="59.9" spread="15.34"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B5" value="1"/>
                    <measurement group_id="B6" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B5" value="1"/>
                    <measurement group_id="B6" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B5" value="1"/>
                    <measurement group_id="B6" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B5" value="1"/>
                    <measurement group_id="B6" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Overall Response Rate</title>
        <description>Overall response rate was measured using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 to determine if the combination of decitabine and tetrahydrouridine is associated with a response rate which exceeds that of Pembrolizumab alone in participants who have programmed death-ligand 1 (PD-L1) expression of at least 50% and those who do not. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.</description>
        <time_frame>Every 10 weeks (± 1 week) until disease progression or unacceptable toxicity or off study criteria is met. Longest participant on study 11 months.</time_frame>
        <population>1/9 participants did not receive any therapy.</population>
        <group_list>
          <group group_id="O1">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT)</title>
            <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level 1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT) q week with Pembrolizumab infusion q3weeks</description>
          </group>
          <group group_id="O2">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT)</title>
            <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level -1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT) q week. Participants received Pembrolizumab infusion q3weeks.</description>
          </group>
          <group group_id="O3">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Every (q) Tuesday,Wednesday (TW) x 2 Weeks q3Weeks</title>
            <description>Phase 1, Arm 1, Dose Escalation, Revised Dose Level 1. Participants received Decitabine 0.21 mg/kg + Tetrahydrouridine 10mg/kg TW weekly x 2 weeks q 3 weeks. Participants received pembrolizumab infusion q 3weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Response Rate</title>
          <description>Overall response rate was measured using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 to determine if the combination of decitabine and tetrahydrouridine is associated with a response rate which exceeds that of Pembrolizumab alone in participants who have programmed death-ligand 1 (PD-L1) expression of at least 50% and those who do not. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.</description>
          <population>1/9 participants did not receive any therapy.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="2"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Complete Response</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Partial Response</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Stable Disease</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Progressive Disease</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Unevaluable for response</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Maximum Tolerated Dose (MTD) of Decitabine</title>
        <description>Maximum Tolerated Dose (MTD) is the maximum dose at which fewer than one-third of participants experience dose limiting toxicity (DLT) within the first 6 weeks (two cycles) of decitabine and tetrahydrouridine therapy. If one of three patients at any given dose level experiences DLT, up to three additional patients will be treated at this dose level. If only one of six patients exhibit DLT, subsequent patients will be enrolled into the next higher dose level. As soon as two patients at any given dose level develop DLT, no additional patients will be entered at that level. Subsequent patients will be accrued into the preceding dose level; if DLT is observed in less than two of six patients treated at this lower level, this dose will represent maximum tolerated dose (MTD). A DLT is any Grade 3 or greater toxicity that cannot be attributed to a cause other than study treatment during the first two cycles of Course 1 of therapy such as disease progression or intercurrent illness.</description>
        <time_frame>Within the first 6 weeks (two cycles)</time_frame>
        <population>1/9 participants did not receive any therapy.</population>
        <group_list>
          <group group_id="O1">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT)</title>
            <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level 1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT) q week with Pembrolizumab infusion q3weeks</description>
          </group>
          <group group_id="O2">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT)</title>
            <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level -1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT) q week. Participants received Pembrolizumab infusion q3weeks.</description>
          </group>
          <group group_id="O3">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Every (q) Tuesday,Wednesday (TW) x 2 Weeks q3Weeks</title>
            <description>Phase 1, Arm 1, Dose Escalation, Revised Dose Level 1. Participants received Decitabine 0.21 mg/kg + Tetrahydrouridine 10mg/kg TW weekly x 2 weeks q 3 weeks. Participants received pembrolizumab infusion q 3weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Tolerated Dose (MTD) of Decitabine</title>
          <description>Maximum Tolerated Dose (MTD) is the maximum dose at which fewer than one-third of participants experience dose limiting toxicity (DLT) within the first 6 weeks (two cycles) of decitabine and tetrahydrouridine therapy. If one of three patients at any given dose level experiences DLT, up to three additional patients will be treated at this dose level. If only one of six patients exhibit DLT, subsequent patients will be enrolled into the next higher dose level. As soon as two patients at any given dose level develop DLT, no additional patients will be entered at that level. Subsequent patients will be accrued into the preceding dose level; if DLT is observed in less than two of six patients treated at this lower level, this dose will represent maximum tolerated dose (MTD). A DLT is any Grade 3 or greater toxicity that cannot be attributed to a cause other than study treatment during the first two cycles of Course 1 of therapy such as disease progression or intercurrent illness.</description>
          <population>1/9 participants did not receive any therapy.</population>
          <units>mg/kg</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="2"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">MTD was not found due to the termination of the study.</measurement>
                    <measurement group_id="O2" value="NA">MTD was not found due to the termination of the study.</measurement>
                    <measurement group_id="O3" value="NA">MTD was not found due to the termination of the study.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Maximum Tolerated Dose (MTD) of Tetrahydrouridine</title>
        <description>Maximum Tolerated Dose (MTD) is the maximum dose at which fewer than one-third of participants experience dose limiting toxicity (DLT) within the first 6 weeks (two cycles) of decitabine and tetrahydrouridine therapy. If one of three patients at any given dose level experiences DLT, up to three additional patients will be treated at this dose level. If only one of six patients exhibit DLT, subsequent patients will be enrolled into the next higher dose level. As soon as two patients at any given dose level develop DLT, no additional patients will be entered at that level. Subsequent patients will be accrued into the preceding dose level; if DLT is observed in less than two of six patients treated at this lower level, this dose will represent maximum tolerated dose (MTD). A DLT is any Grade 3 or greater toxicity that cannot be attributed to a cause other than study treatment during the first two cycles of Course 1 of therapy such as disease progression or intercurrent illness.</description>
        <time_frame>Within the first 6 weeks (two cycles)</time_frame>
        <population>Within the first 6 weeks (two cycles)</population>
        <group_list>
          <group group_id="O1">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT)</title>
            <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level 1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT) q week with Pembrolizumab infusion q3weeks</description>
          </group>
          <group group_id="O2">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT)</title>
            <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level -1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT) q week. Participants received Pembrolizumab infusion q3weeks.</description>
          </group>
          <group group_id="O3">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Every (q) Tuesday,Wednesday (TW) x 2 Weeks q3Weeks</title>
            <description>Phase 1, Arm 1, Dose Escalation, Revised Dose Level 1. Participants received Decitabine 0.21 mg/kg + Tetrahydrouridine 10mg/kg TW weekly x 2 weeks q 3 weeks. Participants received pembrolizumab infusion q 3weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Tolerated Dose (MTD) of Tetrahydrouridine</title>
          <description>Maximum Tolerated Dose (MTD) is the maximum dose at which fewer than one-third of participants experience dose limiting toxicity (DLT) within the first 6 weeks (two cycles) of decitabine and tetrahydrouridine therapy. If one of three patients at any given dose level experiences DLT, up to three additional patients will be treated at this dose level. If only one of six patients exhibit DLT, subsequent patients will be enrolled into the next higher dose level. As soon as two patients at any given dose level develop DLT, no additional patients will be entered at that level. Subsequent patients will be accrued into the preceding dose level; if DLT is observed in less than two of six patients treated at this lower level, this dose will represent maximum tolerated dose (MTD). A DLT is any Grade 3 or greater toxicity that cannot be attributed to a cause other than study treatment during the first two cycles of Course 1 of therapy such as disease progression or intercurrent illness.</description>
          <population>Within the first 6 weeks (two cycles)</population>
          <units>mg/kg</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="2"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">MTD was not found due to the termination of the study.</measurement>
                    <measurement group_id="O2" value="NA">MTD was not found due to the termination of the study.</measurement>
                    <measurement group_id="O3" value="NA">MTD was not found due to the termination of the study.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Circulating Tumor Cells (CTCs)</title>
        <description>Peripheral blood will be collected to correlate changes in circulating tumor cells with clinical response. CTCs will be assessed using ferrofluidic enrichment and multi-parameter flow cytometric detection. Baseline and post-treatment specimen collection after one course of therapy (Week 10 +/- one week).</description>
        <time_frame>Baseline and post-treatment after one course of therapy (Week 10 +/- one week)</time_frame>
        <population>This outcome measure was not evaluated and was to be performed in bulk. No assays were performed due to the pandemic. Participants could not travel to the National Institutes of Health (NIH) to have samples drawn.</population>
        <group_list>
          <group group_id="O1">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT)</title>
            <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level 1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT) q week with Pembrolizumab infusion q3weeks</description>
          </group>
          <group group_id="O2">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT)</title>
            <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level -1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT) q week. Participants received Pembrolizumab infusion q3weeks.</description>
          </group>
          <group group_id="O3">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Every (q) Tuesday,Wednesday (TW) x 2 Weeks q3Weeks</title>
            <description>Phase 1, Arm 1, Dose Escalation, Revised Dose Level 1. Participants received Decitabine 0.21 mg/kg + Tetrahydrouridine 10mg/kg TW weekly x 2 weeks q 3 weeks. Participants received pembrolizumab infusion q 3weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Circulating Tumor Cells (CTCs)</title>
          <description>Peripheral blood will be collected to correlate changes in circulating tumor cells with clinical response. CTCs will be assessed using ferrofluidic enrichment and multi-parameter flow cytometric detection. Baseline and post-treatment specimen collection after one course of therapy (Week 10 +/- one week).</description>
          <population>This outcome measure was not evaluated and was to be performed in bulk. No assays were performed due to the pandemic. Participants could not travel to the National Institutes of Health (NIH) to have samples drawn.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Immune Cell Subsets in Peripheral Blood Mononuclear Cells (PBMC)</title>
        <description>Peripheral blood mononuclear cells (PBMC) will be assessed using multiparameter flow cytometry for immune subsets including but not necessarily limited to Tregs, myeloid-derived suppressor cells (MDSC), effector and exhausted cluster of differentiation 4 (CD4+), cytotoxic T lymphocytes (CD8+) T cells, and cluster of differentiation 14 (CD14 +) monocytes. Assessment will include functional markers, i.e., programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), T-cell immunoglobulin mucin-3 (TIM-3), cluster of differentiation 152 (CTLA-4), human leukocyte antigen (HLA) membrane heterodimeric glycoproteins (-DR) and/or cluster of differentiation 40 (CD40). Baseline and post-treatment specimen collection after one course of therapy (Week 10 +/- one week).</description>
        <time_frame>Baseline and post-treatment after one course of therapy (Week 10 +/- one week)</time_frame>
        <population>This outcome measure was not evaluated and was to be performed in bulk. No assays were performed due to the pandemic. Participants could not travel to the National Institutes of Health (NIH) to have samples drawn.</population>
        <group_list>
          <group group_id="O1">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT)</title>
            <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level 1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT) q week with Pembrolizumab infusion q3weeks</description>
          </group>
          <group group_id="O2">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT)</title>
            <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level -1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT) q week. Participants received Pembrolizumab infusion q3weeks.</description>
          </group>
          <group group_id="O3">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Every (q) Tuesday,Wednesday (TW) x 2 Weeks q3Weeks</title>
            <description>Phase 1, Arm 1, Dose Escalation, Revised Dose Level 1. Participants received Decitabine 0.21 mg/kg + Tetrahydrouridine 10mg/kg TW weekly x 2 weeks q 3 weeks. Participants received pembrolizumab infusion q 3weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Immune Cell Subsets in Peripheral Blood Mononuclear Cells (PBMC)</title>
          <description>Peripheral blood mononuclear cells (PBMC) will be assessed using multiparameter flow cytometry for immune subsets including but not necessarily limited to Tregs, myeloid-derived suppressor cells (MDSC), effector and exhausted cluster of differentiation 4 (CD4+), cytotoxic T lymphocytes (CD8+) T cells, and cluster of differentiation 14 (CD14 +) monocytes. Assessment will include functional markers, i.e., programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), T-cell immunoglobulin mucin-3 (TIM-3), cluster of differentiation 152 (CTLA-4), human leukocyte antigen (HLA) membrane heterodimeric glycoproteins (-DR) and/or cluster of differentiation 40 (CD40). Baseline and post-treatment specimen collection after one course of therapy (Week 10 +/- one week).</description>
          <population>This outcome measure was not evaluated and was to be performed in bulk. No assays were performed due to the pandemic. Participants could not travel to the National Institutes of Health (NIH) to have samples drawn.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percent Viable Tumor Cells</title>
        <description>Portions of biopsy materials will be sent for frozen section or permanent section confirmation of malignancy, i.e., non-small cell lung cancers (NSCLC), esophageal carcinomas (Esc), malignant pleural mesothelioma (MPM) cells, and percent viable tumor cells. All of the analyses are predicated on acquisition of sufficient materials.</description>
        <time_frame>Baseline and post-treatment after one course of therapy (Week 10 +/- one week)</time_frame>
        <population>This outcome measure was not done because 1 participant declined biopsy due to the pandemic. And one participant did not have adequate tissue to evaluate. All other participants did not have biopsies.</population>
        <group_list>
          <group group_id="O1">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT)</title>
            <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level 1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT) q week with Pembrolizumab infusion q3weeks</description>
          </group>
          <group group_id="O2">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT)</title>
            <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level -1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT) q week. Participants received Pembrolizumab infusion q3weeks.</description>
          </group>
          <group group_id="O3">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Every (q) Tuesday,Wednesday (TW) x 2 Weeks q3Weeks</title>
            <description>Phase 1, Arm 1, Dose Escalation, Revised Dose Level 1. Participants received Decitabine 0.21 mg/kg + Tetrahydrouridine 10mg/kg TW weekly x 2 weeks q 3 weeks. Participants received pembrolizumab infusion q 3weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent Viable Tumor Cells</title>
          <description>Portions of biopsy materials will be sent for frozen section or permanent section confirmation of malignancy, i.e., non-small cell lung cancers (NSCLC), esophageal carcinomas (Esc), malignant pleural mesothelioma (MPM) cells, and percent viable tumor cells. All of the analyses are predicated on acquisition of sufficient materials.</description>
          <population>This outcome measure was not done because 1 participant declined biopsy due to the pandemic. And one participant did not have adequate tissue to evaluate. All other participants did not have biopsies.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Gene, Endogenous Retroviral (ERV), Micro Ribonucleic Acid (RNA) Expressions, Deoxyribonucleic Acid (DNA) Methylation Signatures and Tumor Microenvironment</title>
        <description>Tissue will be processed for focused gene, endogenous retroviral and microRNA expressions, and DNA methylation signatures using quantitative reverse-transcription polymerase chain reaction (RT-PCR), nanostring, pyrosequencing and digital droplet PCR techniques. Isolate serum for focused methylation analysis. If sufficient tissue is available, another portion will be imbedded in paraffin for subsequent immunostaining experiments, focusing on expression of genes focusing on those proteins encoded by genes that have been identified to be clearly activated by epigenetic therapy. If sufficient materials are present, additional more comprehensive analyses including multiplex immunohistochemistry analysis of tumor microenvironment may be performed with the focus of materials from participants treated at the maximum tolerated dose. All of the analyses are predicated on acquisition of sufficient materials.</description>
        <time_frame>Baseline and post-treatment after one course of therapy (Week 10 +/- one week)</time_frame>
        <population>This outcome measure was not done because 1 participant declined biopsy due to the pandemic. And one participant did not have adequate tissue to evaluate. All other participants did not have biopsies.</population>
        <group_list>
          <group group_id="O1">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT)</title>
            <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level 1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT) q week with Pembrolizumab infusion q3weeks</description>
          </group>
          <group group_id="O2">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT)</title>
            <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level -1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT) q week. Participants received Pembrolizumab infusion q3weeks.</description>
          </group>
          <group group_id="O3">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Every (q) Tuesday,Wednesday (TW) x 2 Weeks q3Weeks</title>
            <description>Phase 1, Arm 1, Dose Escalation, Revised Dose Level 1. Participants received Decitabine 0.21 mg/kg + Tetrahydrouridine 10mg/kg TW weekly x 2 weeks q 3 weeks. Participants received pembrolizumab infusion q 3weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Gene, Endogenous Retroviral (ERV), Micro Ribonucleic Acid (RNA) Expressions, Deoxyribonucleic Acid (DNA) Methylation Signatures and Tumor Microenvironment</title>
          <description>Tissue will be processed for focused gene, endogenous retroviral and microRNA expressions, and DNA methylation signatures using quantitative reverse-transcription polymerase chain reaction (RT-PCR), nanostring, pyrosequencing and digital droplet PCR techniques. Isolate serum for focused methylation analysis. If sufficient tissue is available, another portion will be imbedded in paraffin for subsequent immunostaining experiments, focusing on expression of genes focusing on those proteins encoded by genes that have been identified to be clearly activated by epigenetic therapy. If sufficient materials are present, additional more comprehensive analyses including multiplex immunohistochemistry analysis of tumor microenvironment may be performed with the focus of materials from participants treated at the maximum tolerated dose. All of the analyses are predicated on acquisition of sufficient materials.</description>
          <population>This outcome measure was not done because 1 participant declined biopsy due to the pandemic. And one participant did not have adequate tissue to evaluate. All other participants did not have biopsies.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)</title>
        <description>Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
        <time_frame>Date treatment consent signed to date off study, approximately 2 months/10 days, 10 months/29 days, 20 months/30 days for the first, second and third group respectively.</time_frame>
        <population>1/9 participants did not receive any therapy.</population>
        <group_list>
          <group group_id="O1">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT)</title>
            <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level 1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT) q week with Pembrolizumab infusion q3weeks</description>
          </group>
          <group group_id="O2">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT)</title>
            <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level -1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT) q week. Participants received Pembrolizumab infusion q3weeks.</description>
          </group>
          <group group_id="O3">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Every (q) Tuesday,Wednesday (TW) x 2 Weeks q3Weeks</title>
            <description>Phase 1, Arm 1, Dose Escalation, Revised Dose Level 1. Participants received Decitabine 0.21 mg/kg + Tetrahydrouridine 10mg/kg TW weekly x 2 weeks q 3 weeks. Participants received pembrolizumab infusion q 3weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)</title>
          <description>Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
          <population>1/9 participants did not receive any therapy.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="2"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Participants With a Dose Limiting Hematologic Toxicity (DLT)</title>
        <description>A DLT is any Grade 3 (severe) or greater toxicity that cannot be attributed to a cause other than study treatment during the first two cycles of Course 1 of therapy such as disease progression or intercurrent illness.</description>
        <time_frame>First two cycles of Course 1 of therapy</time_frame>
        <population>1/9 participants did not receive any therapy.</population>
        <group_list>
          <group group_id="O1">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT)</title>
            <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level 1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT) q week with Pembrolizumab infusion q3weeks</description>
          </group>
          <group group_id="O2">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT)</title>
            <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level -1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT) q week. Participants received Pembrolizumab infusion q3weeks.</description>
          </group>
          <group group_id="O3">
            <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Every (q) Tuesday,Wednesday (TW) x 2 Weeks q3Weeks</title>
            <description>Phase 1, Arm 1, Dose Escalation, Revised Dose Level 1. Participants received Decitabine 0.21 mg/kg + Tetrahydrouridine 10mg/kg TW weekly x 2 weeks q 3 weeks. Participants received pembrolizumab infusion q 3weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With a Dose Limiting Hematologic Toxicity (DLT)</title>
          <description>A DLT is any Grade 3 (severe) or greater toxicity that cannot be attributed to a cause other than study treatment during the first two cycles of Course 1 of therapy such as disease progression or intercurrent illness.</description>
          <population>1/9 participants did not receive any therapy.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="2"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Date treatment consent signed to date off study, approximately 2 months/10 days, 10 months/29 days, 20 months/30 days for the first, second and third group respectively.</time_frame>
      <desc>1/9 participants did not receive any therapy.</desc>
      <group_list>
        <group group_id="E1">
          <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT)</title>
          <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level 1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Sunday, Monday, Tuesday (SuMT) q week with Pembrolizumab infusion q3weeks</description>
        </group>
        <group group_id="E2">
          <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT)</title>
          <description>Phase 1, Arm 1, Dose Escalation, ORIGINAL Dose Level -1: Participants received Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Monday-Tuesday (MT) q week. Participants received Pembrolizumab infusion q3weeks.</description>
        </group>
        <group group_id="E3">
          <title>Decitabine 0.2mg/kg + Tetrahydrouridine 10mg/kg Every (q) Tuesday,Wednesday (TW) x 2 Weeks q3Weeks</title>
          <description>Phase 1, Arm 1, Dose Escalation, Revised Dose Level 1. Participants received Decitabine 0.21 mg/kg + Tetrahydrouridine 10mg/kg TW weekly x 2 weeks q 3 weeks. Participants received pembrolizumab infusion q 3weeks.</description>
        </group>
        <group group_id="E4">
          <title>Decitabine 0.17mg/kg + Tetrahydrouridine 10mg/kg Every (q) Tuesday,Wednesday (TW) x 2 Weeks q3Weeks</title>
          <description>Phase 1, Arm 1, Dose Escalation, Revised Dose Level -1. Participants received Decitabine 0.17 mg/kg + Tetrahydrouridine 10mg/kg TW weekly x 2 weeks q 3 weeks. Participants received pembrolizumab infusion q 3weeks.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (5.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E3" events="5" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (5.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="7" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurred vision</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Colitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Soft tissue infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Activated partial thromboplastin time prolonged</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="4" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="16" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" events="23" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="9" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" events="4" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E3" events="11" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Serum amylase increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="5" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="6" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" events="5" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E3" events="12" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Urinary incontinence</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bronchopulmonary hemorrhage</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Postnasal drip</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Skin ulceration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. David S. Schrump</name_or_title>
      <organization>National Cancer Institute</organization>
      <phone>240-760-6239</phone>
      <email>david_schrump@nih.gov</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03233724
org study id: 170140
secondary id: 17-C-0140
nct id: NCT03233724
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
Background:

      Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Lung cancer is the
      leading cause of cancer-related death in the United States. Most people with lung cancer are
      already in the advanced stages of the disease by the time they see a doctor. Researchers want
      to see if combining an approved drug with two new drugs can help.

      Objective:

      To study if tetrahydrouridine-decitabine (THU-DAC) with pembrolizumab is safe and effective
      in people with non-small cell lung cancer that cannot be removed by surgery.

      Eligibility:

      People 18 years and older who have NSCLC that cannot be removed by surgery

      Design:

      Participants will be screened with

        -  Medical history

        -  Physical exam

        -  Blood and urine tests

        -  Tests of heart and lung function

      They may have a small tumor sample taken (biopsy). They may have tumor scans.

      Before starting treatment, participants will repeat the screening tests. They will also give
      a stool sample.

      The study will be done in 3-week cycles for up to 6 cycles.

        -  Participants will take the 2 study drugs by mouth 3-5 days a week.

        -  Participants will get pembrolizumab in a vein for 30 minutes 1 day each cycle.

      Participants will keep a study medication diary.

      During cycle 1, participants will have blood taken multiple times on days 1 and 2.

      Every 3 cycles, participants will repeat screening tests.

      Participants will have a mandatory tumor biopsy.

      When they finish treatment, participants will have a physical exam and blood tests.
Background:

        -  Non-small cell lung cancers (NSCLC) esophageal cancer (EsC) and malignant pleural
           mesotheliomas (MPM) account for approximately 185,000 deaths annually in the United
           States, with over two thirds of patients presenting with advanced, incurable disease.
           1st-line platinum-based chemotherapy for advanced NSCLC, esophageal cancer (ESCs) or
           malignant pleural mesothelioma (MPM) produces transient responses at best, with most
           patients succumbing to disease within 12-16 months following diagnosis.

        -  Recent randomized clinical trials have demonstrated response rates approximating 20% in
           unselected patients with advanced NSCLC or EsC, and nearly 45% in patients with tumors
           exhibiting high level expression of programmed death ligand 1 (PD-L1) following
           administration of pembrolizumab, a humanized monoclonal anti-Programmed cell death
           protein 1 (PD-1) antibody.

        -  Approximately 17% of unselected MPM patients have exhibited objective responses
           following administration of pembrolizumab or other PD-1 inhibitors.

        -  Preclinical studies have demonstrated that epigenetic drugs such as deoxyribonucleic
           acid (DNA) demethylating agents and histone deacetylase (HDAC) inhibitors can prime
           cancer cells and tumor microenvironments thereby enhancing efficacy of immune checkpoint
           inhibitors.

        -  Although a potent DNA demethylating agent, Decitabine has poor bioavailability and
           inconsistent distribution in solid tumors due to rapid inactivation by cytidine
           deaminase (CDA) which is present in high levels in many organs.

        -  Recent studies in rodents and nonhuman primates, as well as a Phase 1 clinical trial
           (NCT#01685515) in patients with sickle cell disease have demonstrated that oral
           tetrahydrouridine (THU), an inhibitor of CDA, significantly enhances
           bioavailability/solid-tissue-distribution of low dose oral Decitabine (DAC), thereby
           enhancing systemic DNA demethylation with acceptable toxicities.

        -  Preliminary results of recent clinical trial suggest that oral DAC-THU can increase the
           frequency and magnitude of responses to immune checkpoint inhibitors in lung cancer
           patients with low or absent intra-tumoral PD-L1 expression.

        -  These data support further evaluation of oral DAC-THU in combination with immune
           checkpoint inhibitors for therapy of thoracic malignancies.

      Objectives:

      Phase I

      -To define pharmacokinetics, toxicities and maximum tolerated dose of oral DAC-THU in
      combination with pembrolizumab in patients with inoperable, or unresectable locally advanced
      or metastatic NSCLC, EsC, or MPM.

      Phase II

      -To determine clinical response by Response Evaluation Criteria in Solid Tumors (RECIST)
      criteria to oral DAC-THU in combination with pembrolizumab in patients with inoperable, or
      unresectable, locally advanced or metastatic NSCLC, EsC, or MPM.

      Eligibility:

      Inclusion Criteria

        -  Male or female, 18 years or older with histologically or cytologically proven,
           inoperable, or unresectable locally advanced, or metastatic NSCLC, EsC, or MPM.

        -  Measurable disease.

        -  Patients with high PD-L1 expression ((Bullet) 50%) and low PD-L1 expression (0-49%) in
           cancer cells by immunohistochemistry are eligible.

        -  NSCLC patients with no prior systemic treatment, or those with prior first line
           treatment including an immune checkpoint inhibitor are eligible for study.

        -  MPM patients who have received, refused, or are ineligible for first line chemotherapy
           are eligible.

        -  Patients with EsC including Seiwert-Stein Type I and Type II gastro-esophageal junction
           (GEJ) carcinomas who have received or refused standard of care first line therapy and/or
           targeted therapy are eligible.

        -  Patients who received DNA demethylating agents or PD-1/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.

        -  Willingness to undergo tumor biopsies if safely accessible per PI discretion before and
           after treatment.

        -  Eastern Cooperative Oncology Group (ECOG) performance status 0 2.

        -  No evidence of unstable or decompensated myocardial disease; adequate pulmonary reserve.

        -  Adequate renal, hepatic and hematopoietic function.

      Exclusion Criteria

        -  Patients with any targetable mutation for which there is approved first, or second line
           therapy.

        -  Serious cardiovascular conditions.

        -  Active Hepatitis A, Hepatitis B or Hepatitis C.

        -  Human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related
           illness.

        -  Other active infection requiring systemic therapy.

        -  Pregnant or breastfeeding women.

        -  Patients who are receiving systemic corticosteroids.

        -  Patients receiving another investigational agent.

        -  Another malignancy.

      Design:

        -  The Phase I component will be a standard 3+3 design combining high and low PD-L1
           expressers with incremental dose escalation of oral DAC-THU to define maximum tolerated
           dose (MTD).

        -  Simon 2-stage design for Phase II studies will be used to determine clinical response at
           the MTD.

        -  Patients will receive oral DAC-THU- on T-W for two weeks out of every 3 for 9 weeks

        -  Pembrolizumab will be administered on Wednesday, Thursday or Friday at a fixed
           intravenous dose of 200 mg every 3 weeks.

        -  One cycle is three weeks; one course is 9 weeks. Treatment evaluation using RECIST 1.1
           every 10 +/- 1 weeks.

        -  Those patients exhibiting disease progression or unacceptable toxicities will be removed
           from study. Patients exhibiting stable disease or disease regression will be offered an
           additional course of therapy followed by treatment evaluation. Treatment will continue
           in this manner until off-study criteria have been met.

        -  Once the MTD for DAC/THU has been identified, the MTD dose level will be expanded by 4
           patients to confirm its safety. Then, including these 10 patients at the MTD, a total of
           10 NSCLC patients with high (50% or greater) intratumoral PD-L1 expression and 10 NSCLC
           patients with low (0-49%) intratumoral PD-L1 expression will be accrued to the first
           stage of each of two separate Phase II cohorts using individual Simon optimal designs.
           If 5 or more patients of the 10 first stage NSCLC patients in the high PD-L1 cohort
           respond to treatment, the cohort will be expanded to 23 patients. If 11 of 23 of these
           patients respond to treatment, the trial will be deemed positive for NSCLC with high
           PD-L1 expression. If 2 or more of the 10 first stage NSCLC patients in the low PD-L1
           expression cohort respond to treatment, the cohort will be expanded to 29 patients. If 6
           or more of these 29 patients experience a response, the trial will be deemed positive
           for NSCLC with low PD-L1 expression. Up to 10 EsC patients, including those considered
           to be part of the Phase I component after the MTD has been identified, will be enrolled
           into a separate cohort to examine responses to DAC-THU/pembrolizumab at the MTD. If 2 or
           more of these 10 EsC patients respond to treatment, these findings may warrant an
           amendment or a separate Phase II trial to determine response rates to
           DAC-THU/pembrolizumab in EsC patients. Similarly, if 2 or more of 10 MPM patients
           respond to treatment, these findings may warrant an amendment or a separate Phase II
           trial to determine response rates to DACTHU/pembrolizumab in MPM.

        -  Biopsies of index lesions will be obtained at baseline and at treatment evaluation
           following the first course of therapy for analysis of pharmacodynamic endpoints.

        -  Patients will be followed for toxicity for at least 30 days after treatment has been
           discontinued, start of new anti-cancer treatment or until death, whichever occurs first.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall Response Rate
time frame: Every 10 weeks (± 1 week) until disease progression or unacceptable toxicity or off study criteria is met. Longest participant on study 11 months.
description: Overall response rate was measured using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 to determine if the combination of decitabine and tetrahydrouridine is associated with a response rate which exceeds that of Pembrolizumab alone in participants who have programmed death-ligand 1 (PD-L1) expression of at least 50% and those who do not. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.
measure: Maximum Tolerated Dose (MTD) of Decitabine
time frame: Within the first 6 weeks (two cycles)
description: Maximum Tolerated Dose (MTD) is the maximum dose at which fewer than one-third of participants experience dose limiting toxicity (DLT) within the first 6 weeks (two cycles) of decitabine and tetrahydrouridine therapy. If one of three patients at any given dose level experiences DLT, up to three additional patients will be treated at this dose level. If only one of six patients exhibit DLT, subsequent patients will be enrolled into the next higher dose level. As soon as two patients at any given dose level develop DLT, no additional patients will be entered at that level. Subsequent patients will be accrued into the preceding dose level; if DLT is observed in less than two of six patients treated at this lower level, this dose will represent maximum tolerated dose (MTD). A DLT is any Grade 3 or greater toxicity that cannot be attributed to a cause other than study treatment during the first two cycles of Course 1 of therapy such as disease progression or intercurrent illness.
measure: Maximum Tolerated Dose (MTD) of Tetrahydrouridine
time frame: Within the first 6 weeks (two cycles)
description: Maximum Tolerated Dose (MTD) is the maximum dose at which fewer than one-third of participants experience dose limiting toxicity (DLT) within the first 6 weeks (two cycles) of decitabine and tetrahydrouridine therapy. If one of three patients at any given dose level experiences DLT, up to three additional patients will be treated at this dose level. If only one of six patients exhibit DLT, subsequent patients will be enrolled into the next higher dose level. As soon as two patients at any given dose level develop DLT, no additional patients will be entered at that level. Subsequent patients will be accrued into the preceding dose level; if DLT is observed in less than two of six patients treated at this lower level, this dose will represent maximum tolerated dose (MTD). A DLT is any Grade 3 or greater toxicity that cannot be attributed to a cause other than study treatment during the first two cycles of Course 1 of therapy such as disease progression or intercurrent illness.
measure: Changes in Circulating Tumor Cells (CTCs)
time frame: Baseline and post-treatment after one course of therapy (Week 10 +/- one week)
description: Peripheral blood will be collected to correlate changes in circulating tumor cells with clinical response. CTCs will be assessed using ferrofluidic enrichment and multi-parameter flow cytometric detection. Baseline and post-treatment specimen collection after one course of therapy (Week 10 +/- one week).
measure: Changes in Immune Cell Subsets in Peripheral Blood Mononuclear Cells (PBMC)
time frame: Baseline and post-treatment after one course of therapy (Week 10 +/- one week)
description: Peripheral blood mononuclear cells (PBMC) will be assessed using multiparameter flow cytometry for immune subsets including but not necessarily limited to Tregs, myeloid-derived suppressor cells (MDSC), effector and exhausted cluster of differentiation 4 (CD4+), cytotoxic T lymphocytes (CD8+) T cells, and cluster of differentiation 14 (CD14 +) monocytes. Assessment will include functional markers, i.e., programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), T-cell immunoglobulin mucin-3 (TIM-3), cluster of differentiation 152 (CTLA-4), human leukocyte antigen (HLA) membrane heterodimeric glycoproteins (-DR) and/or cluster of differentiation 40 (CD40). Baseline and post-treatment specimen collection after one course of therapy (Week 10 +/- one week).
measure: Percent Viable Tumor Cells
time frame: Baseline and post-treatment after one course of therapy (Week 10 +/- one week)
description: Portions of biopsy materials will be sent for frozen section or permanent section confirmation of malignancy, i.e., non-small cell lung cancers (NSCLC), esophageal carcinomas (Esc), malignant pleural mesothelioma (MPM) cells, and percent viable tumor cells. All of the analyses are predicated on acquisition of sufficient materials.
measure: Changes in Gene, Endogenous Retroviral (ERV), Micro Ribonucleic Acid (RNA) Expressions, Deoxyribonucleic Acid (DNA) Methylation Signatures and Tumor Microenvironment
time frame: Baseline and post-treatment after one course of therapy (Week 10 +/- one week)
description: Tissue will be processed for focused gene, endogenous retroviral and microRNA expressions, and DNA methylation signatures using quantitative reverse-transcription polymerase chain reaction (RT-PCR), nanostring, pyrosequencing and digital droplet PCR techniques. Isolate serum for focused methylation analysis. If sufficient tissue is available, another portion will be imbedded in paraffin for subsequent immunostaining experiments, focusing on expression of genes focusing on those proteins encoded by genes that have been identified to be clearly activated by epigenetic therapy. If sufficient materials are present, additional more comprehensive analyses including multiplex immunohistochemistry analysis of tumor microenvironment may be performed with the focus of materials from participants treated at the maximum tolerated dose. All of the analyses are predicated on acquisition of sufficient materials.
measure: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)
time frame: Date treatment consent signed to date off study, approximately 2 months/10 days, 10 months/29 days, 20 months/30 days for the first, second and third group respectively.
description: Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
measure: Number of Participants With a Dose Limiting Hematologic Toxicity (DLT)
time frame: First two cycles of Course 1 of therapy
description: A DLT is any Grade 3 (severe) or greater toxicity that cannot be attributed to a cause other than study treatment during the first two cycles of Course 1 of therapy such as disease progression or intercurrent illness.
arm group label: 1/Dose Escalation
arm group type: Experimental
description: Decitabine (DAC)-Tetrahydrouridine (THU) + pembrolizumab at escalating doses
arm group label: 2/Dose Expansion
arm group type: Experimental
description: Decitabine (DAC)-Tetrahydrouridine (THU) + pembrolizumab at the dose established in Arm 1
intervention type: Drug
intervention name: Decitabine (DAC)
description: Administered orally on two consecutive days (preferably Tuesday and Wednesday) for two weeks out of three weeks x 9 weeks
arm group label: 1/Dose Escalation
arm group label: 2/Dose Expansion
other name: Dacogen
intervention type: Drug
intervention name: Tetrahydrouridine (THU)
description: Administered orally on two consecutive days (preferably Tuesday and Wednesday) for two weeks out of three weeks x 9 weeks
arm group label: 1/Dose Escalation
arm group label: 2/Dose Expansion
intervention type: Drug
intervention name: Pembrolizumab
description: 200 mg intravenous (IV) once a day every Wednesday, Thursday or Friday every 3 weeks.
arm group label: 1/Dose Escalation
arm group label: 2/Dose Expansion
other name: Keytruda
criteria: 
gender: All
minimum age: 18 Years
maximum age: 99 Years
healthy volunteers: No
last name: David S Schrump, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
facility: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2017-C-0140.html
description: NIH Clinical Center Detailed Web Page
responsible party type: Principal Investigator
investigator affiliation: National Cancer Institute (NCI)
investigator full name: David Schrump, M.D.
investigator title: Principal Investigator
mesh term: Carcinoma
mesh term: Lung Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Mesothelioma
mesh term: Mesothelioma, Malignant
mesh term: Esophageal Neoplasms
mesh term: Pembrolizumab
mesh term: Decitabine
mesh term: Tetrahydrouridine
sharing ipd: Yes
ipd description: All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the Database of Genotypes and Phenotypes (dbGaP).
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
ipd access criteria: Clinical data will be made available via subscription to the Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 