Azacitidine and Entinostat in Treating Patients With Recurrent Advanced Non-Small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To assess safety, characterize toxicities, and determine the maximum tolerated dose of
5-AZA (azacitidine) with a fixed-dose of entinostat in patients with recurrent advanced
non-small cell lung cancer (NSCLC). (Phase I) II. To determine the objective response rate
of 5-AZA and entinostat in patients with recurrent NSCLC. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the pharmacokinetic profile of 5-AZA and entinostat in patients with
recurrent NSCLC.

II. To assess the pharmacodynamic effects of 5-AZA and entinostat on deoxyribonucleic acid
(DNA) methylation, histone acetylation, and gene re-expression in patients with recurrent
NSCLC through analysis of blood, sputum and tissue biopsies.

III. To explore the effect of 5-AZA and entinostat on progression-free and overall survival
in patients with recurrent advanced non-small cell lung cancer.

IV. To explore the differing response rates and progression-free survivals of two schedules
of 5-AZA and entinostat in patients with recurrent advanced non-small cell lung cancer.

OUTLINE: This is a multicenter, phase I, dose-escalation study of azacitidine followed by an
open-label, phase II study.

Patients receive azacitidine subcutaneously (SC) on days 1-6 and 8-10 and entinostat orally
(PO) on days 3 and 10. Treatment repeats every 28 days in the absence of disease progression
or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed metastatic or
unresectable NSCLC

- Patient must have failed at least one previous chemotherapy regimen

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as >=
20 mm with conventional techniques or as >= 10 mm with spiral computed tomography
(CT) scan

- Life expectancy of greater than 12 weeks

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 2 (Karnofsky >=
60%)

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelet count >= 100,000/mcL

- Total bilirubin within normal institutional limits

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

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73m^2 for patients with creatinine levels above institutional normal

- 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

- Patients who have a major objective response to treatment on this protocol, and who
experience progression of disease at least 1 year after completion of protocol
consent and therapy, may be re-treated at the previously effective dose and schedule

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier

- Patients may not be receiving any other investigational agents

- Patients with uncontrolled brain metastases; patients with brain metastases must have
stable neurologic status following local therapy (surgery or radiation) for at least
4 weeks, and must be without neurologic dysfunction that would confound the
evaluation of neurologic and other adverse events

- Patients with liver metastases that replace greater than 30% of the liver parenchyma

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to entinostat, 5-AZA, mannitol 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; breastfeeding should be discontinued if
the mother is treated on this protocol

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible