Pilot Trial of Pioglitazone in Adults Undergoing Surgical Resection of Non-Small Cell Lung Cancer
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
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
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
- 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
- Tumor tissue biomarkers: apoptotic index (AI), cyclin D1, p21/Waf1, PPAR gamma,
mucin 1 (MUC1), gelsolin, proline oxidase, 15-hydroxyprostaglandin dehydrogenase
- 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).
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
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
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
Up to 25 patients are expected to be enrolled to identify 20 patients with adequate tissue
for biomarker analysis.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Number of Participants With a Change in Ki-67 Due to the Effect of Pioglitazone in Tumor Tissue
Antigen ki-67 (Ki-67) will be assessed by immunohistochemistry.
Giuseppe Giaccone, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|
|New York University||New York, New York 10016|