Inhaled Azacitidine in Patients With Advanced Non-small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To determine the tolerability and toxicity of inhaled Vidaza® (azacitidine) with special
emphasis on pulmonary toxicity.

II. To determine the minimum effective dose of inhaled Vidaza® required to induce the
re-expression of relevant 5 candidate tumor suppressor genes (cyclin-dependent kinase
inhibitor 2A [p16], h-cadherin [H-Cad], opioid binding protein/cell adhesion molecule-like
[OPCML], secreted frizzled-related protein 1 [SFRP-1], and ras association domain family 1
[RASSF1A]) that are silenced in 20-50% of bronchial tissue of heavy smokers with lung
cancer.

SECONDARY OBJECTIVES:

I. To evaluate the pharmacokinetics of inhaled Vidaza®. II. To determine the changes in
global methylation patterns in the bronchial epithelium (bronchial tissue samples) pre and
post treatment.

III. To determine the changes in methylation patterns in the exhaled breath. IV. To evaluate
the efficacy of inhaled Vidaza® on intra-thoracic tumors (response rate by Response
Evaluation Criteria in Solid Tumors [RECIST] criteria for intrapulmonary lesions).

V. To estimate the progression free, intra-thoracic tumor progression free and overall
survival.

OUTLINE: This is a dose-escalation study.

Patients receive azacitidine via nebulizer over 20 minutes once daily (QD) on days 1-5 and
15-19. Treatment repeats every 28 days for up to 24 weeks in the absence of disease
progression or unacceptable toxicity. Patients may continue treatment on a case-by-case
basis at the discretion of principal investigator and Institutional Review Board.

After completion of study treatment, patients are followed up at 4-6 weeks and then every 3
months thereafter.

Inclusion Criteria:

- Pathologically proven (either histologic or cytologic) diagnosis of stage IV or
recurrent non-small cell lung cancer (according to American Joint Committee on Cancer
[AJCC] Staging, 7th edition)

- Patient has received at least one prior standard chemotherapy or targeted therapy for
treatment of lung cancer

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Absolute neutrophil count (ANC) >= 1,500 cells/ul

- Platelets >= 100,000 cells/ul

- Hemoglobin >= 9.0 g/dl (note: the use of transfusion or other intervention to achieve
hemoglobin [Hgb] >= g/dl is acceptable)

- Serum creatinine =< 1.5 x upper limit of normal (ULN)

- Total bilirubin < 2.0 times the institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x the ULN

- Adequate pulmonary reserve defined as adequate airflow defined by a measured forced
expiratory volume (FEV1) not less than 50% of the predicted value and adequate
pulmonary reserve as evidenced by a FEV1/forced vital capacity (FVC) ratio of 65% or
greater

- Patient must sign study specific informed consent prior to study entry

- Women of childbearing potential must have:

- A negative serum or urine pregnancy test (sensitivity =< 25 IU human chorionic
gonadotropin [HCG]/L) within 72 hours prior to the start of study drug
administration

- Persons of reproductive potential must agree to use and utilize an adequate
method of contraception throughout treatment and for at least 4 weeks after
study drug is stopped prior to study enrollment, women of childbearing potential
must be advised of the importance of avoiding pregnancy during trial
participation and the potential risk factors for an unintentional pregnancy

Exclusion Criteria:

- Patients with prior chest or mediastinal radiotherapy

- Concomitant disease or condition that could interfere with the conduct of the study,
or that would, in the opinion of the investigator, pose an unacceptable risk to the
patient in this study

- Contraindication to or unwillingness to undergo study related procedures including a
repeat bronchoscopy

- Participation in an investigational drug or device study or treatment with any
antineoplastic agent within 14 days of the first day of dosing on this study

- History of significant bleeding disorder unrelated to cancer, including:

- Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)

- Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor
VIII antibodies)

- History of hypersensitivity to mannitol

- Unwillingness or inability to comply with the study protocol for any other reason

- Women who:

- Are unwilling or unable to use an acceptable method to avoid pregnancy for the
entire study period and for at least 4 weeks after cessation of study drug, or

- Have a positive pregnancy test at baseline, or

- Are pregnant or breastfeeding

- Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
treatment of either a psychiatric or physical (e.g., infectious) illness