Iloprost in Preventing Lung Cancer in Former Smokers

PRIMARY OBJECTIVES:

I. To evaluate the toxicity of inhalational iloprost administered to cohorts of patients
daily for 2 months, given four times a day (QID) in Cohort A followed by twice daily (BID) in
Cohort B.

SECONDARY OBJECTIVES:

I. To evaluate the compliance with BID or QID dosing regimens. II. To evaluate the effect on
endobronchial histology. III. To evaluate the effect on expectorated sputum cytology by both
standard cytologic analysis and an automated three-dimensional morphologic analysis.

IV. To evaluate the effect on endobronchial brushing and biopsy gene expression of peroxisome
proliferator-activated receptor gamma (PPARgamma), glutathione S-transferase mu (GSTmu),
carboxylesterase 1 (Ces1), Fos-related antigen 1 (FosL1), cytochrome p4502e1, stearoyl coA
desaturase 1, tumor necrosis factor (TNF) superfamily member 9, transforming growth factor
beta (TGFbeta), Jun and a 46 gene panel associated with dysplasia persistence, using
Affymetrix arrays.

V. To evaluate the improvement in chronic obstructive pulmonary disease (COPD) as measured by
arterial blood gas (ABG) (improved ventilation perfusion matching), pulmonary function
testing, 6-minute walk distance, quality of life (St. George's respiratory questionnaire,
COPD assessment test [CAT]).

VI. To evaluate whether the in vitro response of cultured airway epithelial progenitor cells
to iloprost is a predictor of in vivo response in study subjects.

OUTLINE: Patients are enrolled to Cohort A to completion prior to initiation of Cohort B.

COHORT A: Patients are assigned to 1 of 2 arms.

ARM I: Patients receive iloprost via inhalation using a nebulizer QID for 60 days.

ARM II: Patients receive placebo via inhalation using a nebulizer QID for 60 days.

COHORT B: Patients are assigned to 1 of 2 arms.

ARM III: Patients receive iloprost via inhalation using a nebulizer BID for 60 days.

ARM IV: Patients receive placebo via inhalation using a nebulizer BID for 60 days.

After completion of study treatment, patients are followed up at 90 days and then annually
for up to 5 years.

Inclusion Criteria:

- Participants must have either sputum cytologic atypia of mild dysplasia or greater or
a history of bronchial biopsy with mild or greater dysplasia within the past 12 months

- Participants must have a smoking history of 20 pack-years or greater

- Participants must have the ability to safely undergo bronchoscopy in the judgment of
the investigators

- Participants must have Eastern Cooperative Oncology Group (ECOG) performance status =<
1

- Leukocytes >= 3,000/microliter

- Platelets >= 100,000/microliter

- Total bilirubin =< 2.0 mg/dl

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

- Creatinine =< 2.0 mg/dl

- Women of child-bearing potential and men having intercourse with a woman of
childbearing potential 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 study physician immediately; Note:
women are considered to be of child-bearing potential if they are not surgically
sterile or are under the age of 65 and have menstruated within the last two years

- Participants must be able to understand and willing to sign a written informed consent
document

Exclusion Criteria:

- Participants must not have used any tobacco product in the past year

- Participants must not be currently receiving or have previously received
thiazolidinedione treatment unless sputum atypia or endobronchial dysplasia are
documented again after thiazolidinedione treatment and within 12 months of entry

- Participants must not have been treated with iloprost at any time; Note: participants
on the placebo arm of previous iloprost trials are eligible, but participants on the
placebo arm of cohort A of this study may not be enrolled in cohort B

- Participants must not have used any other investigation agent within the last six
months

- Participants must not have a history of allergic reactions attributed to compounds of
similar chemical or biologic composition of iloprost

- Participants must not have 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 in the opinion of investigators would jeopardize patient safety of data
integrity; Note: individuals who are human immunodeficiency virus (HIV) positive will
not necessarily be excluded, will be considered on a case-by-case basis, but will be
required to meet criteria related to patient safety and data integrity, as assessed by
investigators

- Participants must not have a current or prior invasive malignancy within the past 6
months; participants may enroll prior to biopsy result report, unless there are
findings at bronchoscopy suggesting an invasive malignancy; history of the following
curatively treated cancers during any time prior to screening is allowed: non-melanoma
skin cancer, cervical carcinoma in situ, and bladder carcinoma in situ

- Participants must not have received either chemotherapy or radiotherapy within the
previous 6 months; Note: participants receiving long-term adjuvant hormonal therapy
(such as tamoxifen or aromatase inhibitors for breast cancer) are allowed

- Women must not be pregnant or breastfeeding; breastfeeding should be discontinued if
the mother is treated with iloprost

- As iloprost inhibits platelet function, patients must not be taking anticoagulants,
with the exception of aspirin or other non-steroidal anti-inflammatory medications

- Participants must not have blood pressure < 95 mm Hg systolic