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

NCT03233724 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 17014017-C-0140
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

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

Keywords

PD-L1; Demethylating Agents and Histone Deacetylase (HDAC) Inhibitors; DNA Hypomethylating Agent; Cytidine Deaminase; Checkpoint Inhibitor

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (4)

• Changes in Circulating Tumor Cells (CTCs)

  Baseline and post-treatment after one course of therapy (Week 10 +/- one week)

• Changes in Immune Cell Subsets in Peripheral Blood Mononuclear Cells (PBMC)

  Baseline and post-treatment after one course of therapy (Week 10 +/- one week)

• Percent Viable Tumor Cells

  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

  Baseline and post-treatment after one course of therapy (Week 10 +/- one week)

Other Outcomes (2)

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

  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.

• Number of Participants With a Dose Limiting Hematologic Toxicity (DLT)

  First two cycles of Course 1 of therapy

Study Arms (2)

1/Dose Escalation

EXPERIMENTAL

Decitabine (DAC)-Tetrahydrouridine (THU) + pembrolizumab at escalating doses

Drug: Decitabine (DAC); Drug: Tetrahydrouridine (THU); Drug: Pembrolizumab

2/Dose Expansion

EXPERIMENTAL

Decitabine (DAC)-Tetrahydrouridine (THU) + pembrolizumab at the dose established in Arm 1

Drug: Decitabine (DAC); Drug: Tetrahydrouridine (THU); Drug: Pembrolizumab

Interventions

Decitabine (DAC) DRUG

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

Also known as: Dacogen

1/Dose Escalation; 2/Dose Expansion

Tetrahydrouridine (THU) DRUG

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

1/Dose Escalation; 2/Dose Expansion

Pembrolizumab DRUG

200 mg intravenous (IV) once a day every Wednesday, Thursday or Friday every 3 weeks.

Also known as: Keytruda

1/Dose Escalation; 2/Dose Expansion

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Esophageal Neoplasms; Mesothelioma, Malignant

Interventions

Decitabine; Tetrahydrouridine; pembrolizumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Head and Neck Neoplasms; Digestive System Diseases; Esophageal Diseases; Gastrointestinal Diseases; Mesothelioma; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms, Mesothelial; Pleural Neoplasms

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Uridine

Results Point of Contact

• Title: Dr. David S. Schrump
• Organization: National Cancer Institute

david_schrump@nih.gov

240-760-6239

Study Officials

• David S Schrump, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 28, 2017
• First Posted: July 31, 2017
• Study Start: April 11, 2018
• Primary Completion: October 6, 2021
• Study Completion: October 26, 2021
• Last Updated: May 31, 2023
• Results First Posted: May 31, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• 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.
• 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.

Locations

US (1)