Pioglitazone to Treat Adults Undergoing Surgery for Non-small Cell Lung Cancer

Background:

Lung cancer is the leading cause of cancer deaths in the United States (US). Chemoprevention
is an active area of investigation for reducing the burden of this disease. However, the
choice of chemopreventive targets requires sufficient human data to justify extensive
clinical interventions.

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a ligand activated nuclear
transcription factor that is a key regulator of adipogenic differentiation. PPAR gamma
ligands, particularly the thiazolidinedione class of antidiabetic agents exemplified by
pioglitazone, are under investigation as chemopreventive agents.

PPAR gamma is expressed in normal lung and in NSCLC. PPAR gamma ligands induce apoptosis in
NSCLC cell lines and modulate their differentiation status. Animal carcinogenesis studies,
however, show equivocal efficacy in prevention of lung cancer.

Relevant human data are limited to an epidemiologic study showing that lung cancer risk is
decreased in diabetics taking thiazolidinediones and a small phase IIa trial of pioglitazone
in oral leukoplakia showing an 80% clinical response (partial response (PR)+ complete
response (CR)). Further data are needed prior to engaging in a phase II lung chemoprevention
trial.

Objectives:

The objectives of this pilot feasibility study are to evaluate the effect of pioglitazone on
the expression of multiple biomarkers in NSCLC tumor tissue and in histologically normal and
premalignant tissue.

- The primary endpoint will be the effect of pioglitazone on Ki-67, a marker of
proliferation, in tumor tissue.

- The secondary objectives are to determine the effects of pioglitazone on multiple
biomarkers in tumor, premalignant, and histologically normal bronchial epithelium and
in serum:

- Tumor tissue biomarkers: apoptotic index (AI), cyclin D1, p21/Waf1, PPAR gamma,
mucin 1 (MUC1), gelsolin, proline oxidase, 15-hydroxyprostaglandin dehydrogenase
(15-PGDH)

- Premalignant tissue biomarkers: Ki-67, apoptotic index, PPAR gamma

- Histologically normal tissue biomarkers: Ki-67, PPAR gamma

- Serum markers affected by pioglitazone; C-reactive protein, CA 15-3

- Serum tumor markers: carcinoembryonic antigen (CEA), cancer antigen 125 (CA-125)

- Additional secondary objectives are:

- To evaluate the toxicity and safety of pioglitazone in this patient population,

- To determine if limited treatment with pioglitazone affects tumor metabolic
activity as determined by fludeoxyglucose positron-emission tomography (FDG-PET).

Eligibility:

Adult patients with newly diagnosed histologically confirmed stage Ia-IIb resectable
non-small cell lung cancer who are eligible for and scheduled to undergo definitive surgery.

Eastern Cooperative Oncology Group (ECOG) 0-2

Normal organ function

Design:

Open label, multi-center, non-randomized pilot study to evaluate the effect of pioglitazone
on the expression of multiple biomarkers in NSCLC tumor tissue and in histologically normal
and premalignant tissue obtained from treatment-naive individuals who will receive oral
pioglitazone prior to definitive surgery. The primary endpoint is Ki-67 measured in tumor
tissue.

Patients will receive pioglitazone 45 mg po qd for a minimum of 2 weeks or a maximum of 6
weeks, with duration of treatment determined by standard of care and scheduling of surgery.

The study will consist of a screening visit, baseline bronchoscopy with tissue acquisition,
pioglitazone treatment for 2-6 weeks, a 2-week on-treatment clinic visit, definitive
surgical resection with bronchoscopy performed at the time of resection, and a post-surgery
visit. Tissue (visually normal and abnormal areas identified during bronchoscopy) and tumor
will be obtained at baseline and at the time of surgery. Patients who receive their
treatment at NCI will also undergo a follow up FDG-PET scan after a minimum of 2 weeks of
pioglitazone treatment.

Up to 25 patients are expected to be enrolled to identify 20 patients with adequate tissue
for biomarker analysis.

- INCLUSION CRITERIA:

1. Adult patients with newly diagnosed stage Ia-IIb resectable non-small cell lung
cancer who will be undergoing definitive surgery. If histologic confirmation of
lung cancer has not previously been made, the baseline study bronchoscopy, as
outlined in section 3.6.2, or computed tomography (CT)-guided biopsy with tissue
saved for protocol use may be used to document NSCLC, after obtaining informed
consent. Should the bronchoscopy or CT-guided biopsy be negative for non-small
cell lung cancer (NSCLC), the patient will be taken off study prior to drug
treatment. At National Cancer Institute (NCI), histologic confirmation of the
diagnosis will be performed by the NCI Laboratory of Pathology.

2. Age greater than or equal to 18 years of age.

3. Eastern Cooperative Oncology Group (ECOG) performance score of less than or
equal to 2.

4. Patients must have the capacity and willingness to sign a written informed
consent and demonstrate willingness to comply with an oral regimen.

5. The time between initial diagnosis and the scheduled surgery date allow for the
subject to receive a minimum of 2 weeks or a maximum of 6 weeks treatment with
pioglitazone. The maximum time between enrollment on this trial and surgery will
be 6-weeks and there will be no delay between the end of pioglitazone treatment
and surgery.

6. Patients must have normal organ and marrow function as defined below:

- absolute neutrophil count greater than or equal to 1,500/mL

- hemoglobin greater than 10 g/dL

- platelets greater than or equal to 100,000/mL

- Bilirubin less than 1.8 mg/dL

- aspartate aminotransferase (AST)/alanine aminotransferase (ALT) less than 1.5 times
upper limits of institutional normal

- creatinine less than 1.5 times upper limit of institutional normal

7. Patients must agree to swallow oral tablets.

8. Patients who will agree to undergo two bronchoscopies as detailed in section 3.6.2
(before treatment and at the time of surgery).

- For those patients who are undergoing mediastinoscopy as part of their
standard-of-care, the pre-treatment bronchoscopy may be performed during the
mediastinoscopy. If the patient remains eligible for definitive surgical resection
after the mediastinoscopy, the patient may begin pioglitazone treatment on this
protocol.

9. Females are eligible to participate in the study if

- She is of non-childbearing potential as defined by having had a hysterectomy, a
bilateral oophorectomy, a bilateral tubal ligation, or having been post-menopausal
for greater than or equal to 1 year.

- She is of childbearing potential and has a negative pregnancy test within 2 weeks of
the starting the study drug and agrees to the use of non-hormonal methods of birth
control, e.g., barrier methods, for the duration of the study due to possible drug
interactions.

EXCLUSION CRITERIA:

1. Pregnant or lactating women.

2. Patients who are undergoing chemotherapy, treatment with biologic agents, or
radiation therapy. Prior chemotherapy, biologic agent treatment, or radiation
therapy, greater than 1 year ago, is allowed.

3. Patients with greater than or equal to class II New York Heart Association (NYHA)
congestive heart failure or history of congestive heart failure.

4. Patients with greater than or equal to grade 2 (moderate) edema.

5. Patients with diabetes mellitus being treated with insulin or any pharmacologic
therapy.

6. Patients taking gemfibrozil or rifampin, due to drug interactions with pioglitazone.

7. Patients with uncontrolled intercurrent illness including, but not limited to,
ongoing or active infection, active liver disease, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.