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
Conditions
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.
Interventions
OTHERLaboratory Biomarker Analysis
Correlative studies
Given PO
OTHERQuality-of-Life Assessment
Ancillary studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Recruitment details
Ten subjects were pre-registered at one Cancer Prevention Network (CPN) member organization from 2011 to 2013.
Pre-assignment details
Four participants were deemed screen failures (3 without histologically-confirmed non-small cell lung cancer (NSCLC) and 1 with metastatic NSCLC and were excluded from all analyses.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Pioglitazone Hydrochloride) Patients receive pioglitazone hydrochloride PO QD for 14-42 days. Patients then undergo surgery. | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | Treatment (Pioglitazone Hydrochloride) |
|---|---|
| Age, Continuous | 64 years |
| Baseline Eastern Cooperative Oncology Group (ECOG) performance status 0=Asymptomatic and fully active | 5 participants |
| Baseline Eastern Cooperative Oncology Group (ECOG) performance status 1=Symptomatic and fully ambulatory | 1 participants |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 5 Participants |
| Smoking Status Current | 2 participants |
| Smoking Status Former | 4 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 2 / 5 |
| serious Total, serious adverse events | 0 / 5 |
Outcome results
Primary
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.
Time frame: Baseline and at the time of surgery, after 42 days of treatment
Population: Includes all registered participants with pre- and post-intervention tumor tissue samples except one participant who was deemed ineligible post-registration
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Pioglitazone Hydrochloride) | Percent Change in Ki-67 by Immunohistochemistry (IHC) | -20.0 Percent change in Ki-67 measurements |
p-value: 0.06Wilcoxon Signed Rank
Secondary
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.
Time frame: Baseline and at the time of surgery, after 42 days of treatment
Population: Data were not collected. Study team decision not to analyze this endpoint.
Secondary
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.
Time frame: Baseline and at the time of surgery, after 42 days of treatment
Population: Data were not collected due to a study team decision not to analyze this endpoint.
Secondary
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.
Time frame: Baseline and at the time of surgery, after 42 days of treatment
Population: Data not collected due to a study team decision not to analyze this endpoint.
Secondary
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.
Time frame: Up to the time of surgery, after 42 days of treatment
Population: Data not collected due to a study team decision not to analyze this endpoint.
Secondary
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.
Time frame: Up to the time of surgery, after 42 days of treatment
Population: Includes all registered eligible participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Pioglitazone Hydrochloride) | Incidence of Adverse Events Graded According to Common Terminology Criteria for Adverse Events Version 4.0 | No Adverse Events | 3 participants |
| Treatment (Pioglitazone Hydrochloride) | Incidence of Adverse Events Graded According to Common Terminology Criteria for Adverse Events Version 4.0 | Grade 1 Adverse Events | 2 participants |
Secondary
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.
Time frame: Up to the time of surgery, after 42 days of treatment
Population: Data not collected due to a study team decision not to analyze this endpoint.
Secondary
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.
Time frame: Up to the time of surgery, after 42 days of treatment
Population: Includes all registered participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Pioglitazone Hydrochloride) | Number of Participants With Complete Pathologic Response | Complete Response | 1 participants |
| Treatment (Pioglitazone Hydrochloride) | Number of Participants With Complete Pathologic Response | No Response | 5 participants |
Secondary
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.
Time frame: Baseline to the time of surgery, after 42 days of treatment
Population: Includes all registered participants with pre- and post-intervention tumor tissue samples except one participant who was deemed ineligible post-registration
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Pioglitazone Hydrochloride) | Percent Change in Cyclin D1 | -69 Percent change in Cyclin D1 measurements |
Secondary
Percent Change in MUC1
Changes in the expression levels from baseline (prior to intervention) to post intervention (resected tumor sample) will be plotted graphically.
Time frame: Baseline to the time of surgery, after 42 days of treatment
Population: Includes all registered participants with pre- and post-intervention tumor tissue samples except one participant who was deemed ineligible post-registration
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Pioglitazone Hydrochloride) | Percent Change in MUC1 | 0 Percent change in MUC1 measurements |
Secondary
Percent Change in p21
Changes in the expression levels from baseline (prior to intervention) to post intervention (resected tumor sample) will be plotted graphically.
Time frame: Baseline to the time of surgery, after 42 days of treatment
Population: Includes all registered participants with pre- and post-intervention tumor tissue samples except one participant who was deemed ineligible post-registration
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Pioglitazone Hydrochloride) | Percent Change in p21 | -5 Percent change in p21 measurements |
Secondary
Percent Change in PPARy
Changes in the expression levels from baseline (prior to intervention) to post intervention (resected tumor sample) will be plotted graphically.
Time frame: Baseline to the time of surgery, after 42 days of treatment
Population: Includes all registered participants with pre- and post-intervention tumor tissue samples except one participant who was deemed ineligible post-registration
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Pioglitazone Hydrochloride) | Percent Change in PPARy | 183.4 Percent change in PPARy measurements |
Secondary
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.
Time frame: Baseline to the time of surgery, after 42 days of treatment
Population: Includes registered eligible participants with pre- and post-intervention PET/CT images obtained
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Pioglitazone Hydrochloride) | Percent Change in SUVmax From the PET Scan | 0 Percent change in tumor SUV max values |
Secondary
Post-intervention SUV of PET Scan
The pre- and post-intervention SUV will be summarized using descriptive statistics and simple graphical plots.
Time frame: Time of surgery, after 42 days of treatment
Population: Includes registered eligible participants with pre- and post-intervention PET/CT images obtained
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Pioglitazone Hydrochloride) | Post-intervention SUV of PET Scan | 12.2 SUV |
Secondary
Pre-intervention SUV of PET Scan
The pre- and post-intervention SUV will be summarized using descriptive statistics and simple graphical plots.
Time frame: Baseline
Population: Includes registered eligible participants with pre- and post-intervention PET/CT images obtained
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Pioglitazone Hydrochloride) | Pre-intervention SUV of PET Scan | 13.0 SUV |