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Genome-Wide Methylation and Gene Re-Expression Analysis of Resectable Lung Tumor Tissue Pairs Obtained Pre- and Post-Treatment With 5-Azacytidine and Entinostat

18 Years
Not Enrolling
Stage IA Non-small Cell Lung Cancer, Stage IB Non-small Cell Lung Cancer, Stage IIA Non-small Cell Lung Cancer, Stage IIB Non-small Cell Lung Cancer, Stage IIIA Non-small Cell Lung Cancer

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Trial Information

Genome-Wide Methylation and Gene Re-Expression Analysis of Resectable Lung Tumor Tissue Pairs Obtained Pre- and Post-Treatment With 5-Azacytidine and Entinostat


I. To measure reversal of aberrant genome-wide promoter methylation and gene re-expression
in paired, pre- and post- treatment lung tumor tissue pairs from patients with newly
diagnosed, surgically resectable non-small cell lung cancer before and after exposure to a
single neoadjuvant cycle of 5-azacytidine (azacitidine) and entinostat.


I. To measure the 3-year disease-free survival of operable non-small cell lung cancer
(NSCLC) patients who receive 1 cycle of preoperative epigenetic treatment.

II. To determine any potential toxicities, and reversibility of toxicities, of a single
pre-operative cycle of 5-azacytidine and entinostat.


Patients receive azacitidine subcutaneously (SC) on days 1-6 and 8-10 and entinostat orally
(PO) on days 3 and 10. Patients undergo surgery between days 11-20 (this period can be
extended 10 more days if adverse events from therapy impose a surgical risk).

After completion of study treatment, patients are followed up at 4 weeks, every 3 months for
2 years and then every 6 months for 1 year.

Inclusion Criteria:

- Known or suspected diagnosis of operable NSCLC that has not been previously treated

- Undergoing a diagnostic biopsy, including computed tomography (CT)-guided or

- Able to understand and sign an informed consent discussing the risks and benefits of
obtaining a concurrent research biopsy; patients who have a fresh frozen biopsy
available secondary to institutional tissue collection protocols may substitute such
a biopsy for the study-required pre-treatment biopsy

- Appropriate candidate for surgical management, in the opinion of the treating
thoracic surgeon

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 at the time of
initiation of neoadjuvant epigenetic therapy

- Absolute neutrophil count > 1,000/mcL

- Platelets > 100,000/mcL

- Total bilirubin < 1.5 x institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT])
< 2.5 x institutional ULN

- Creatinine < 1.5 x institutional ULN

- Able to understand and sign an informed consent

- The effects of entinostat and 5-azacitidine on the developing human fetus at the
recommended therapeutic dose are unknown; for this reason, women of child-bearing
potential and men must agree to use adequate contraception (hormonal or barrier
method of birth control; abstinence) prior to study entry and for the duration of
study participation; should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately

- Inclusion of women and minorities:

- Both men and women and members of all races and ethnic groups are eligible for
this trial; the coordinating center will be responsible for ensuring each
participating site is accruing a representative sample consistent with the
estimate of population representation in the site's geographical location for
race and ethnic groups as determined by the Census Bureau to assure overall
target goals are met

- Clinical stage IA-IIIA

Exclusion Criteria:

- Patients who have received prior chemotherapy or radiation for their diagnosis of
lung cancer

- Patients may not be receiving any other investigational agent

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to entinostat or 5-azacytidine

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study because entinostat and 5-Azacitidine are
agents with 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 entinostat or 5-Azacytidine, breastfeeding should be
discontinued if the mother is treated on this protocol

- Any co-morbid condition that' in the view of the attending physician' renders the
patient at high risk from treatment complications

- Human immunodeficiency virus (HIV) positive patients on combination antiretroviral
therapy are ineligible due to the potential for pharmacokinetic interactions with
entinostat or 5-azacytidine

- Known or suspected hypersensitivity to azacitidine or mannitol

- Patients with advanced malignant hepatic tumors

- Use of anti-neoplastic or anti-tumor agents that are not part of the study therapy,
including chemotherapy, radiation therapy, immunotherapy, and hormonal anticancer
therapy, is not permitted while participating in this study; Note: study participants
with stage II or III NSCLC, or stage I NSCLC with tumor size greater than 4 cm,
should be offered standard adjuvant platinum-based chemotherapy in accordance with
local practice (post-operatively)

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Change in aberrant genome-wide promoter methylation

Outcome Description:

Genome-wide DNA methylation and gene expression profiles of each pre- and post-treatment tumor will be assessed using validated DNA methylation and gene expression arrays. Response will be measured based on the degree of epigenomic reprogramming (i.e., number of genes affected, degree of demethylation, and class of genes [e.g., PRC2]) and pathways affected.

Outcome Time Frame:

Baseline up to day 20

Safety Issue:


Principal Investigator

Montaser Shaheen

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of New Mexico


United States: Food and Drug Administration

Study ID:




Start Date:

June 2013

Completion Date:

Related Keywords:

  • Stage IA Non-small Cell Lung Cancer
  • Stage IB Non-small Cell Lung Cancer
  • Stage IIA Non-small Cell Lung Cancer
  • Stage IIB Non-small Cell Lung Cancer
  • Stage IIIA Non-Small Cell Lung Cancer
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms



University of Texas Southwestern Medical Center Dallas, Texas  
University of Kentucky Lexington, Kentucky  40536-0098
University of New Mexico Albuquerque, New Mexico  87131