Clinical trial NCT00923949
Conditions: Non-Small-Cell Lung Cancer
Keywords: NSCLC Stage Ia-IIb Resectable NSCLC Non-Small Cell Lung Cancer NSCLC
Sponsor: National Cancer Institute (NCI)
Start date: 2008-08-01; Completion date: 2010-03-01
Enrollment: 1 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Background:

* Pioglitazone is a drug that belongs to the class of antidiabetic agents called thiazolidinediones. It is approved for treatment of type 2 diabetes mellitus.
* Research suggests that the thiazolidinediones may have anticancer activity that can reduce cancer risk or cause tumors to shrink.

Objectives:

-To test how a pioglitazone works as a treatment of Stage IA to IIB Non-Small Cell Lung Cancer (NSCLC) and to look at the effect of the drug on cancer cells.

Eligibility:

-Patients 18 years of age or older who will undergo surgery for Stage IA to IIB non-small cell lung cancer (NSCLC).

Design:

-The study includes a screening visit to determine eligibility, treatment with pioglitazone, a follow-up visit after 2 to 3 weeks of treatment and a post-surgery visit. Procedures include:

1. Medical history, physical examination, blood tests, electrocardiogram
2. Bronchoscopy to obtain cancer cells. This is done before pioglitazone treatment begins and again during lung surgery. Some patients may also require mediastinoscopy or biopsy to collect cells.
3. Treatment with pioglitazone tablets once a day for at least 2 weeks and no more than 6 weeks, depending on when surgery has been scheduled.
4. Positron emission tomography (PET) scan before starting pioglitazone treatment. National Cancer Institute (NCI) patients also have a follow-up PET scan after treatment but before surgery.

Detailed description:
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.

Arms: arm 1: 45 mg tablet daily by mouth for six weeks
Interventions: intervention 1: Pioglitazone
Intervention descriptions: intervention 1: 45 mg tablet daily by mouth for six weeks

Protocol documents: