Pioglitazone Hydrochloride in Treating Patients With Stage IA-IIIA Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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This pilot phase II trial studies how well pioglitazone works in treating patients with stage IA-IIIA non-small cell lung cancer. Pioglitazone hydrochloride may slow the growth of tumor cells and may be an effective treatment for non-small cell lung cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the mechanism(s) of action of pioglitazone as a candidate chemopreventive agent for lung cancer by investigating the effects on Ki-67 defined in non-small cell lung cancer (NSCLC) tumor tissue. SECONDARY OBJECTIVES: I. To determine the effects of pioglitazone on multiple markers listed below: Tumor tissue: caspase-3, cyclin D1, p21/Waf1, peroxisome proliferative activated receptor, gamma (PPARγ), mucin 1 (MUC1). Premalignant tissue: Ki-67, caspase-3, PPARγ. Histologically normal tissue: Ki-67, PPARγ. II. To evaluate the toxicity and safety of pioglitazone in this patient population. III. To analyze the expression of serum markers that are affected by pioglitazone. IV. To describe the effects of limited treatment with pioglitazone on tumor metabolic activity as determined by FDG-PET (assessed before and after a minimum of 2 weeks of treatment). OUTLINE: Patients receive pioglitazone hydrochloride orally (PO) once daily (QD) for 14-42 days. Patients then undergo surgery.

Official Title
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Pioglitazone as a Candidate Chemoprevention Agent for Lung Cancer: A Pilot Trial Using a Pre-surgical Model in Early Stage NSCLC

Conditions
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Stage IA Non-Small Cell Lung Carcinoma, Stage IB Non-Small Cell Lung Carcinoma, Stage IIA Non-Small Cell Lung Carcinoma, Stage IIB Non-Small Cell Lung Carcinoma, Stage IIIA Non-Small Cell Lung Cancer

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Pioglitazone Hydrochloride
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Suspected or biopsy-proven NSCLC Willingness to provide biopsy tissue for correlative studies Candidate for pulmonary resection; must be able to schedule >= 14 days and =< 42 days between registration and surgery to allow for treatment with pioglitazone Ability to understand and the willingness to sign a written informed consent document Ability and willingness to swallow oral tablets Ability and willingness to undergo two bronchoscopies (before treatment and at the time of surgery) For those participants who are undergoing mediastinoscopy as part of their standard-of-care, the pre-treatment bronchoscopy may be performed during the mediastinoscopy; if the participant remains eligible for definitive surgical resection after the mediastinoscopy, the participant may proceed to registration and pioglitazone treatment Current or former smoker with a >= 10 pack-year smoking history Women of child-bearing potential and men who agree to use adequate contraception for the duration of study participation; women must not be pregnant or lactating; women of child-bearing potential (women considered not of childbearing potential if they are at least two years postmenopausal and/or surgically sterile) must have used adequate contraception (abstinence; barrier methods such as intrauterine device [IUD], diaphragm with spermicidal gel, condom, or others; and hormonal methods such as birth control pills or others) since her last menses prior to study entry; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately Exclusion Criteria: Receiving any other investigational agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to pioglitazone 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 would limit compliance with study requirements Pregnant or lactating woman Currently treated diabetes Participants with >= class II New York Heart Association (NYHA) congestive heart failure or history of congestive heart failure Participants with >= grade 2 (moderate) edema Participants currently receiving an inhibitor of cytochrome P450 family 2, subfamily C, polypeptide 8 (CYP2C8) (gemfibrozil, ketoconazole, quercetin, trimethoprim), or an inducer of CYP2C8 (cortisol, dexamethasone, phenobarbital, rifampin), or cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) substrate Prior neoadjuvant therapy for NSCLC History of bladder cancer or in situ bladder cancer

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (pioglitazone hydrochloride)<br>Patients receive pioglitazone hydrochloride PO QD for 14-42 days. Patients then undergo surgery. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Pioglitazone Hydrochloride<br>* Given PO<br>* Other names: Pioglitazone.HCl;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Ki-67 by Immunohistochemistry (IHC) | Changes in the expression levels of Ki-67 will be plotted graphically, and percent change in expression levels will be formally assessed using the paired t-test or the Wilcoxon signed rank test, if the assumptions of the t-test (i.e. normality) are not met. | Baseline and at the time of surgery, after 42 days of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Apoptosis Assessment (e.g., Caspase-3) | Changes in the expression levels (or grades) from baseline (prior to intervention) to post-intervention (resected tumor sample) will be plotted graphically as well as formally assessed using the McNemar's tests (for categorical variables) or Wilcoxon signed rank tests (for continuous variables) respectively. | Baseline and at the time of surgery, after 42 days of treatment | 
| Change in Levels of Serum CA-153 | Each participant's pre- and post serum levels of CA-153 will be graphically represented and the mean levels analyzed using a paired t-test or Wilcoxon signed rank test, if the assumptions of the t-test are not met. | Baseline and at the time of surgery, after 42 days of treatment | 
| Change in Levels of Serum CRP | Each participant's pre- and post serum levels of CRP will be graphically represented and the mean levels analyzed using a paired t-test or Wilcoxon signed rank test, if the assumptions of the t-test are not met. | Baseline and at the time of surgery, after 42 days of treatment | 
| Gene Expression Analysis of RNA From Bronchial Brush Cells | For the gene expression profiles obtained from the data from normal bronchial brush cells, each participant's pre- and post gene expression will be graphically represented and the mean expression levels analyzed using a paired t-test or Wilcoxon signed rank test, if the assumptions of the t-test are not met. | Up to the time of surgery, after 42 days of treatment | 
| Incidence of Adverse Events Graded According to Common Terminology Criteria for Adverse Events Version 4.0 | To evaluate the adverse events profile, the maximum grade for each type of adverse event will be recorded for each participant and frequency tables will be reviewed to determine the overall patterns. The number and severity of adverse events (both regardless of attribution as well as those that are at least possibly, probably, or definitely related) will be tabulated and summarized. | Up to the time of surgery, after 42 days of treatment | 
| Number of Participants With Clinical Response, Based on Response Evaluation Criteria in Solid Tumors ( RECIST) Version 1.1 | Clinical response rates will be summarized. Complete response (CR) is the disappearance of all non-nodal target lesions (TL) and each target lymph node (LN) must have reduction in short axis to <1.0cm. Partial Response (PR) is at least a 30% decrease in the sum of the longest diameters (LD) of the non-nodal TR and the short axis of the target LN with the baseline sum diameters (BSD) as reference. Progression (PD) is at least 1 new malignant lesion or LN whose short axis increased to >1.5 cm or at least a 20% increase in the sum of TL diameters with the minimum sum of diameters as reference. | Up to the time of surgery, after 42 days of treatment | 
| Number of Participants With Complete Pathologic Response | Complete pathologic response was defined as no viable residual tumor cells. Acellular residual mucin pools also considered a pathologic complete response. | Up to the time of surgery, after 42 days of treatment | 
| Percent Change in Cyclin D1 | Changes in the expression levels from baseline (prior to intervention) to post intervention (resected tumor sample) will be plotted graphically. | Baseline to the time of surgery, after 42 days of treatment | 
| Percent Change in MUC1 | Changes in the expression levels from baseline (prior to intervention) to post intervention (resected tumor sample) will be plotted graphically. | Baseline to the time of surgery, after 42 days of treatment | 
| Percent Change in p21 | Changes in the expression levels from baseline (prior to intervention) to post intervention (resected tumor sample) will be plotted graphically. | Baseline to the time of surgery, after 42 days of treatment | 
| Percent Change in PPARy | Changes in the expression levels from baseline (prior to intervention) to post intervention (resected tumor sample) will be plotted graphically. | Baseline to the time of surgery, after 42 days of treatment | 
| Percent Change in SUVmax From the PET Scan | The percent change from pre to post-intervention in SUV max values will be summarized using descriptive statistics and simple graphical plots. | Baseline to the time of surgery, after 42 days of treatment | 
| Pre-intervention SUV of PET Scan | The pre- and post-intervention SUV will be summarized using descriptive statistics and simple graphical plots. | Baseline | 
| Post-intervention SUV of PET Scan | The pre- and post-intervention SUV will be summarized using descriptive statistics and simple graphical plots. | Time of surgery, after 42 days of treatment |