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

Phase 2

Terminated

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

Interventions: Other: Laboratory Biomarker Analysis
Drug: Pioglitazone Hydrochloride
Other: Quality-of-Life Assessment

Registration Number: NCT01342770

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 6

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (pioglitazone hydrochloride)	Laboratory Biomarker Analysis	Patients receive pioglitazone hydrochloride PO QD for 14-42 days. Patients then undergo surgery.
Treatment (pioglitazone hydrochloride)	Pioglitazone Hydrochloride	Patients receive pioglitazone hydrochloride PO QD for 14-42 days. Patients then undergo surgery.
Treatment (pioglitazone hydrochloride)	Quality-of-Life Assessment	Patients receive pioglitazone hydrochloride PO QD for 14-42 days. Patients then undergo surgery.

Primary Outcome Measures

Name	Time	Method
Percent Change in Ki-67 by Immunohistochemistry (IHC)	Baseline and at the time of surgery, after 42 days of treatment	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.

Secondary Outcome Measures

Name	Time	Method
Change in Apoptosis Assessment (e.g., Caspase-3)	Baseline and at the time of surgery, after 42 days of treatment	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.
Change in Levels of Serum CA-153	Baseline and at the time of surgery, after 42 days of treatment	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.
Change in Levels of Serum CRP	Baseline and at the time of surgery, after 42 days of treatment	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.
Gene Expression Analysis of RNA From Bronchial Brush Cells	Up to the time of surgery, after 42 days of treatment	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.
Incidence of Adverse Events Graded According to Common Terminology Criteria for Adverse Events Version 4.0	Up to the time of surgery, after 42 days of treatment	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.
Number of Participants With Clinical Response, Based on Response Evaluation Criteria in Solid Tumors ( RECIST) Version 1.1	Up to the time of surgery, after 42 days of treatment	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.
Number of Participants With Complete Pathologic Response	Up to the time of surgery, after 42 days of treatment	Complete pathologic response was defined as no viable residual tumor cells. Acellular residual mucin pools also considered a pathologic complete response.
Percent Change in Cyclin D1	Baseline to the time of surgery, after 42 days of treatment	Changes in the expression levels from baseline (prior to intervention) to post intervention (resected tumor sample) will be plotted graphically.
Percent Change in MUC1	Baseline to the time of surgery, after 42 days of treatment	Changes in the expression levels from baseline (prior to intervention) to post intervention (resected tumor sample) will be plotted graphically.
Percent Change in p21	Baseline to the time of surgery, after 42 days of treatment	Changes in the expression levels from baseline (prior to intervention) to post intervention (resected tumor sample) will be plotted graphically.
Percent Change in PPARy	Baseline to the time of surgery, after 42 days of treatment	Changes in the expression levels from baseline (prior to intervention) to post intervention (resected tumor sample) will be plotted graphically.
Percent Change in SUVmax From the PET Scan	Baseline to the time of surgery, after 42 days of treatment	The percent change from pre to post-intervention in SUV max values will be summarized using descriptive statistics and simple graphical plots.
Pre-intervention SUV of PET Scan	Baseline	The pre- and post-intervention SUV will be summarized using descriptive statistics and simple graphical plots.
Post-intervention SUV of PET Scan	Time of surgery, after 42 days of treatment	The pre- and post-intervention SUV will be summarized using descriptive statistics and simple graphical plots.