Azacitidine and Entinostat in Treating Patients With Stage I Non-Small Cell Lung Cancer That Has Been Removed By Surgery

PRIMARY OBJECTIVES:

I. To assess the effect of 5-azacitidine and entinostat on the hazard of 3 year
progression-free survival in patients with resected stage I non-small cell lung cancer.

SECONDARY OBJECTIVES:

I. To assess the safety, tolerability and toxicity of entinostat and 5-azacitidine in
patients with resected stage I non-small cell lung cancer.

II. To explore the effect of entinostat and 5-azacitidine on median disease-free and overall
survival in patients with resected stage I non-small cell lung cancer.

III. To assess the pharmacodynamic effects of 5-azacitidine and entinostat on DNA methylation
and gene re-expression in patients with resected stage I NSCLC through analysis of sputum.

IV. To estimate the effect of entinostat and 5-azacitidine on progression free survival
comparing patients with N2 lymph nodes categorized as methylated pre-treatment with those who
are categorized as unmethylated.

V. To establish factors that predict clinical outcome in patients treated with combination
epigenetic therapy by performing genome-wide analyses on pre-treatment tumor DNA.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive azacitidine subcutaneously (SC) on days 1-5 and 8-10 and entinostat
orally (PO) once daily (QD) on days 3 and 10. Treatment repeats every 28 days for up to 6
courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive standard of care.

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

Inclusion Criteria:

- Patients must be status post complete (R0) surgical resection of pathologically-proven
NSCLC (stage IA-IB according to AJCC version 7)

- Patients must be at least 4 weeks out from completion of surgery

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Absolute neutrophil count >= 1,000/mcL

- Platelets >= 100,000/mcL

- Total bilirubin =< 1.5 X institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal

- Creatinine =< 1.5 X institutional upper limit of normal

- 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

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients must be within 8 weeks of completing surgery

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

- Patients with sub-lobar resections (ie: wedge resection or segmentectomy)

- Patients without mediastinal lymph node specimens from mediastinoscopy or surgery (at
least level R4 or 7 for right sided tumors OR at least level 5, 6 or 7 for left sided
tumors)

- Patients may not be receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to entinostat, 5-azacitidine or other agents used in the study

- 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-azacitidine, breastfeeding should be
discontinued if the mother is treated on this protocol; these potential risks may also
apply to other agents used in this study

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
entinostat or 5-azacitidine; in addition, these patients are at increased risk of
lethal infections when treated with marrow-suppressive therapy