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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

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ClinicalTrials.gov Identifier: NCT03233724
Recruitment Status : Completed
First Posted : July 31, 2017
Last Update Posted : February 17, 2023
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:


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.


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.


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


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.

Condition or disease Intervention/treatment Phase
Carcinoma, Non-Small-Cell Lung Lung Cancer Non-Small Cell Lung Cancer Carcinoma, Esophageal Malignant Pleural Mesotheliomas Drug: Decitabine (DAC) Drug: Tetrahydrouridine (THU) Drug: Pembrolizumab Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : April 11, 2018
Actual Primary Completion Date : October 6, 2021
Actual Study Completion Date : October 26, 2021

Arm Intervention/treatment
Experimental: 1/Dose Escalation
DAC-THU + pembrolizumab at escalating doses
Drug: Decitabine (DAC)
Administered orally on two consecutive days (preferably Tuesday and Wednesday) for two weeks out of three weeks x 9 weeks

Drug: Tetrahydrouridine (THU)
Administered orally on two consecutive days (preferably Tuesday and Wednesday) for two weeks out of three weeks x 9 weeks

Drug: Pembrolizumab
200 mg IV once a day every Wednesday, Thursday or Friday every 3 weeks.

Experimental: 2/Dose Expansion
DAC-THU + pembrolizumab at the dose established in Arm 1
Drug: Decitabine (DAC)
Administered orally on two consecutive days (preferably Tuesday and Wednesday) for two weeks out of three weeks x 9 weeks

Drug: Tetrahydrouridine (THU)
Administered orally on two consecutive days (preferably Tuesday and Wednesday) for two weeks out of three weeks x 9 weeks

Drug: Pembrolizumab
200 mg IV once a day every Wednesday, Thursday or Friday every 3 weeks.

Primary Outcome Measures :
  1. Overall response rate [ Time Frame: Every 9 weeks until at disease progression ]
    determine if this combination is associated with a response rate which exceeds that of Pembrolizumab alone in patients who have PD-L1 expression of at least 50% and those who do not

  2. Maximum tolerated dose [ Time Frame: After 3 weeks at cycle 1 at each dose level dose level ]

Secondary Outcome Measures :
  1. Examine if oral DAC-THU modulates plasma tumor DNA methylation, circulating tumor cells and peripheral immune subsets [ Time Frame: baseline and post-treatment after one course of therapy (Week 10 +/- one week) ]
    baseline and post-treatment specimen collection after one course of therapy (Week 10 +/- one week)

  2. Examine if oral DAC-THU modulates DNA methylation, as well as gene, micro-RNA, and endogenous retroviral expression profiles of NSCLC, EsC and MPM cells and alters the tumor micro-environment [ Time Frame: baseline and post-treatment after one course of therapy (Week 10 +/- one week) ]
    baseline and post-treatment specimen collection after one course of therapy (Week 10 +/- one week)

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
  • Histologically or cytologically confirmed, inoperable or unresectable, locally advanced, or metastatic NSCLC or esophageal cancers including Seiwert-Stein Type I and Type II gastro-esophageal junction (GEJ) carcinomas, or MPM.
  • NSCLC patients with no prior systemic treatment or those with prior first line treatment including an immune checkpoint inhibitor, are eligible for study.
  • Patients with esophageal and gastro-esophageal junction (GEJ) cancers are potentially eligible for study if they have received or refused first line standard of care cytotoxic therapy, and subsequent targeted therapy if appropriate.
  • Patients with MPM are eligible for study if they have received, refused or are ineligible for first line chemotherapy.
  • Patients who received 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.
  • Patients must have analysis of PD-L1 expression in cancer cells quantitated by immunohistochemistry analysis.

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

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


  • Patients with cancers harboring any targetable mutation for which there is approved first or second line therapy, unless standard care of therapy refused.
  • Clinically significant cardiovascular / cerebrovascular disease as follows: cerebral vascular accident / stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class greater than or equal to II), serious cardiac arrhythmia, clinically significant bleeding or clinically significant pulmonary embolism
  • Active Hepatitis A, Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  • Human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness due to unknown effects of DAC-THU on systemic immunity.
  • Other active infection requiring systemic therapy.
  • Pregnant women are excluded from this study because DAC-THU may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with DACTHU, breastfeeding should be discontinued if the mother is treated with DAC-THU. These potential risks may also apply to other agents used in this study
  • Other severe acute or chronic medical or psychiatric conditions or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.
  • Patients who are receiving systemic corticosteroids.
  • Patients with history of or active autoimmune disease including thyroiditis, colitis, nephritis, neuropathy or pneumonitis.
  • Patients receiving another investigational agent.
  • An additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in-situ cervical or anal cancer, or ductal carcinoma in-situ
  • History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  • Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • Thrombocytosis defined as platelet count >1,200,000/mcL.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03233724

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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
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Principal Investigator: David S Schrump, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03233724    
Other Study ID Numbers: 170140
First Posted: July 31, 2017    Key Record Dates
Last Update Posted: February 17, 2023
Last Verified: February 15, 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: .All 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 dbGaP.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Clinical data available during the study and indefinitely.@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.@@@@@@Genomic data are made available via dbGaP through requests to the data custodians.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Demethylating Agents and Histone Deacetylase (HDAC) Inhibitors
DNA Hypomethylating Agent
Cytidine Deaminase
Checkpoint Inhibitor
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Mesothelioma, Malignant
Esophageal Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Neoplasms, Mesothelial
Pleural Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Antineoplastic Agents, Immunological
Antineoplastic Agents