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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Carcinoma, Non-Small-Cell Lung, Lung Cancer, Non-Small Cell Lung Cancer, Carcinoma, Esophageal, Malignant Pleural Mesotheliomas

Intervention / Treatment
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* Drug: Decitabine (DAC)
* Drug: Tetrahydrouridine (THU)
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Histologically or cytologically confirmed, inoperable or unresectable, locally advanced, or metastatic non-small cell lung cancers (NSCLC) or esophageal cancers including Seiwert-Stein Type I and Type II gastro-esophageal junction (GEJ) carcinomas, or malignant pleural mesothelioma (MPM). NSCLC patients with no prior systemic treatment or those with prior first line treatment including an immune checkpoint inhibitor, are eligible for study. Patients with esophageal and gastro-esophageal junction (GEJ) cancers are potentially eligible for study if they have received or refused first line standard of care cytotoxic therapy, and subsequent targeted therapy if appropriate. Patients with MPM are eligible for study if they have received, refused or are ineligible for first line chemotherapy. Patients who received deoxyribonucleic acid (DNA) demethylating agents or Programmed cell death protein 1 (PD-1)/Programmed Cell Death Ligand 1 (PD-L1)/PD-L1 inhibitors for another malignancy may be eligible for study if there were no dose-limiting immune related events, and there has been either no clinical evidence of disease or minimal residual disease that has been stable for at least three years. Patients must have analysis of PD-L1 expression in cancer cells quantitated by immunohistochemistry analysis. Patients in Cohort 1 (Dose Escalation) may have any level of expression. Patients in Cohort 2 (Dose Expansion: NSCLC with high PD-L1) must have greater than or equal to 50% expression in cancer cells. Patients in Cohort 3 (Dose Expansion: NSCLC with low PD-L1) must have 0-49% expression. Note: Patients in this cohort must have been offered and refused standard of care platinum-based chemotherapy Patients in Cohort 4 (Dose Expansion: Esophageal carcinomas (ESCs)) may have any level of expression. Patients in Cohort 5 (Dose Expansion: MPM) may have any level of expression. Measurable disease, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Willingness to undergo tumor biopsies if safely accessible per principal investigator (PI) discretion before and after treatment. Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of Decitabine (DAC) and Tetrahydrouridine (THU) in combination with Pembrolizumab in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials. Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2 Patients must be without evidence of unstable or decompensated myocardial disease; and must have adequate pulmonary reserve evidenced by Forced expiratory volume in the first second (FEV1) and diffusing capacity of lung for carbon monoxide (DLCO) greater than or equal to 35% predicted; oxygen saturation equal to or greater than 90% on room air by pulse oximetry or arterial blood gas (ABG) (to be drawn if pulse oximetry < 90% on room air) No immunosuppressive medications except non-systemic corticosteroids Patients must have normal organ and marrow function as defined below: leukocytes greater than or equal to 3,000/mcL absolute neutrophil count greater than or equal to 1,500/mcL (without transfusion or cytokine support) absolute lymphocyte count greater than or equal to 800/mcL platelets greater than or equal to 100,000/mcL Prothrombin time (PT) no more than 2 seconds above the upper limit of normal (ULN) total bilirubin < 1.5 X institutional upper limit of normal OR direct bilirubin less than or equal to ULN for patients with total bilirubin > 1.5 ULN serum albumin greater than or equal to 2.0 mg/dL Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase, (SGOT)/Alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) less than or equal to 2.5 X institutional ULN creatinine less than or equal to 1.6 mg/ml OR creatinine clearance (eGFR) greater than or equal to 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal at the time DAC-THU and pembrolizumab treatment commences. Patients with history of brain metastases except those with meningeal carcinomatosis or leptomeningeal disease may be eligible for treatment a minimum of 1 week following completion of gamma knife or whole brain radiotherapy, or 4 weeks following surgical resection of brain metastasis provided post-treatment magnetic resonance (MR) scan reveals no evidence of active disease, and no ongoing need for systemic steroids. Patients with laboratory evidence of autoimmune disease (e.g., positive anti-nuclear antibodies (ANA) or lupus anticoagulant) without associated symptoms; vitiligo, or mild autoimmunity not impacting the function of organs, such as Hashimoto or psoriasis may be eligible for study. The effects of DAC-THU and pembrolizumab on the developing human fetus are unknown. For this reason and because antineoplastic agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men who engage in sexual activity must agree to use 2 forms of contraception at least 1 of which must be highly effective (intrauterine device [IUD], hormonal, tubal ligation; not highly effective includes barrier method) prior to study entry, for the duration of study participation and for 60 days after completion of the study treatment. Should a woman become pregnant, or suspect she is pregnant, while she or her partner is participating in this study the study participant should inform the study physician immediately. Ability of subject to understand and the willingness to sign a written informed consent document. EXCLUSION CRITERIA: Patients with cancers harboring any targetable mutation for which there is approved first, or second line therapy, unless standard care of therapy refused. Clinically significant cardiovascular / cerebrovascular disease as follows: cerebral vascular accident / stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class greater than or equal to II), serious cardiac arrhythmia, clinically significant bleeding or clinically significant pulmonary embolism Active Hepatitis A, Hepatitis B (e.g., HB surface antigen (sAg) reactive) or Hepatitis C virus (e.g., HCV ribonucleic acid (RNA [qualitative] is detected). Human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness due to unknown effects of DAC-THU on systemic immunity. Other active infection requiring systemic therapy. Pregnant women are excluded from this study because DAC-THU may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with DACTHU, breastfeeding should be discontinued if the mother is treated with DAC-THU. These potential risks may also apply to other agents used in this study. Other severe acute or chronic medical or psychiatric conditions or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study. Patients who are receiving systemic corticosteroids. Patients with history of or active autoimmune disease including thyroiditis, colitis, nephritis, neuropathy or pneumonitis. Patients receiving another investigational agent. An additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in-situ cervical or anal cancer, or ductal carcinoma in-situ. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Thrombocytosis defined as platelet count >1,200,000/mcL.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/Dose Escalation<br>Decitabine (DAC)-Tetrahydrouridine (THU) + pembrolizumab at escalating doses | Drug: Decitabine (DAC)<br>* Administered orally on two consecutive days (preferably Tuesday and Wednesday) for two weeks out of three weeks x 9 weeks<br>* Other names: Dacogen;Drug: Tetrahydrouridine (THU)<br>* Administered orally on two consecutive days (preferably Tuesday and Wednesday) for two weeks out of three weeks x 9 weeks<br>Drug: Pembrolizumab<br>* 200 mg intravenous (IV) once a day every Wednesday, Thursday or Friday every 3 weeks.<br>* Other names: Keytruda;|
| Experimental: 2/Dose Expansion<br>Decitabine (DAC)-Tetrahydrouridine (THU) + pembrolizumab at the dose established in Arm 1 | Drug: Decitabine (DAC)<br>* Administered orally on two consecutive days (preferably Tuesday and Wednesday) for two weeks out of three weeks x 9 weeks<br>* Other names: Dacogen;Drug: Tetrahydrouridine (THU)<br>* Administered orally on two consecutive days (preferably Tuesday and Wednesday) for two weeks out of three weeks x 9 weeks<br>Drug: Pembrolizumab<br>* 200 mg intravenous (IV) once a day every Wednesday, Thursday or Friday every 3 weeks.<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | 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. | Every 10 weeks (± 1 week) until disease progression or unacceptable toxicity or off study criteria is met. Longest participant on study 11 months. | 
| Maximum Tolerated Dose (MTD) of Decitabine | 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. | Within the first 6 weeks (two cycles) | 
| Maximum Tolerated Dose (MTD) of Tetrahydrouridine | 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. | Within the first 6 weeks (two cycles) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Circulating Tumor Cells (CTCs) | 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). | Baseline and post-treatment after one course of therapy (Week 10 +/- one week) | 
| Changes in Immune Cell Subsets in Peripheral Blood Mononuclear Cells (PBMC) | 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). | Baseline and post-treatment after one course of therapy (Week 10 +/- one week) | 
| Percent Viable Tumor Cells | 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. | Baseline and post-treatment after one course of therapy (Week 10 +/- one week) | 
| Changes in Gene, Endogenous Retroviral (ERV), Micro Ribonucleic Acid (RNA) Expressions, Deoxyribonucleic Acid (DNA) Methylation Signatures and Tumor Microenvironment | 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. | Baseline and post-treatment after one course of therapy (Week 10 +/- one week) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PD-L1, Demethylating Agents and Histone Deacetylase (HDAC) Inhibitors, DNA Hypomethylating Agent, Cytidine Deaminase, Checkpoint Inhibitor