Pioglitazone for Oral Premalignant Lesions

Study Overview
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Brief Summary
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The goal of this clinical research study is to learn how Actos (pioglitazone) may affect oral premalignant lesions (OPLs) and/or the risk of mouth cancer. The safety of this drug will also be studied.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the clinical and histologic response of oral premalignant lesions to 24 weeks of therapy with pioglitazone, 45 mg once daily (qd), defined as 50% or greater reduction in the sum of all measured products of perpendicular dimensions of target lesions, or improvement in the degree of dysplasia or hyperplasia. SECONDARY OBJECTIVES: I. To determine the degree of change of putative biomarkers of pioglitazone efficacy including (but not restricted to) and in order of priority, tissue levels of: PPAR gamma, cyclin D1 and p21 as indirect measures of pharmacological effect TUNEL for apoptosis and Ki-67 for proliferation transglutaminase and involucrin as markers of squamous differentiation 15-PGDH, loss of heterozygosity (LOH). II. To determine the degree of change of C-reactive protein (CRP) in plasma. III. To assess tobacco and alcohol use among trial participants and to examine the relationship of tobacco and alcohol use to treatment response. IV. To assess the safety of this agent in this population. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive pioglitazone hydrochloride orally (PO) once daily (QD) for 24 weeks. ARM II: Patients receive placebo PO QD for 24 weeks. After completion of study treatment, patients are followed up for 2 weeks.

Official Title
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Phase IIB Randomized, Placebo Controlled Trial of Pioglitazone for Oral Premalignant Lesions an Inter-consortium Collaborative Study

Conditions
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Oral Leukoplakia

Intervention / Treatment
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* Drug: Pioglitazone hydrochloride
* Other: placebo
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: STAGE I: Males or females with a suspected or histologically confirmed oral premalignant lesion(s) (up to three target lesions may be followed for the purpose of the study) that has a length (longest diameter) of 8 mm or greater and width (diameter perpendicular to greatest length) of 3 mm or greater in size If a participant has had a biopsy of the target oral premalignant lesions (OPL) lesion(s) within 6 weeks prior to the screening visit and archival tissue is available and the participant agrees to have archival tissue used for histologic confirmation and biomarker analysis, then NO additional biopsies (of the OPL) need to be performed at the screening visit; the pre-screening biopsy must undergo centralized pathology review before the second stage of registration can be performed; if archival tissue is not available, a waiting period of 6 weeks from the time of the last biopsy must be observed before re-biopsy for study purposes If a participant has not had a biopsy of the suspected OPL at the time of the screening visit, then a biopsy of the lesion must be performed during the screening visit; the screening biopsy must undergo centralized pathology review before the second stage of registration can be performed The participant's life expectancy is > 6 months The participant has discontinued any other oral cancer chemopreventive therapy at least 12 weeks prior to the baseline visit and all toxicities have been fully resolved; daily aspirin is permitted The participant is willing and able to fully participate for the duration of the study Women must not be pregnant or lactating; women of child-bearing potential (women are 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 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; women of child-bearing potential and men must agree to use adequate contraception for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately Ability to understand and the willingness to sign a written informed consent document STAGE II: The participant has one or more target lesions histologically confirmed by a biopsy obtained no more than 9 weeks prior to randomization, that is either: An EARLY premalignant lesion defined to be at high risk: Mild dysplasia of any site Hyperplastic leukoplakia of a high-risk site Dorsal, lateral or ventral tongue Floor of mouth An ADVANCED premalignant lesion defined as the presence of at least one of the following: Moderate dysplasia Severe dysplasia (excluding carcinoma in situ) Erythroplakia (due to the high risk for progression associated with erythroplakia, erythroplakia of any histology will be defined as an ADVANCED oral premalignant lesion) Hemoglobin levels equal to or above the lower limit of normal White blood cells >= 3,000/uL Platelets >= 125,000/uL Total bilirubin =< 1.5 * upper limit of normal (ULN) BUN and serum creatinine =< 1.5 * ULN Glucose, serum < 200 mg/dL The participant's Eastern Cooperative Oncology Group (ECOG) performance status is 0 or 1 If the participant is female and of childbearing potential and not lactating she has a documented negative serum pregnancy test within 14 days prior to randomization The participant has a baseline EKG that does not show signs of acute cardiac ischemia or cardiac dysrhythmia (except for 1st degree AV block or chronic atrial fibrillation); EKG can be an earlier report within 12 weeks prior to registration Participants using the drugs listed below may not be randomized unless they are willing to stop the medications (and possibly change to alternative non-excluded medications to treat the same conditions) no less than 3 days prior to starting pioglitazone or placebo on this study; the use of the following drugs or drug classes is prohibited during pioglitazone/placebo treatment: participants taking inhibitors of CYP2C8 (gemfibrozil, ketoconazole, quercetin, trimethoprim), enzyme inducers of CYP2C8 (cortisol, dexamethasone, phenobarbital, rifampin), and CYP3A4 substrate Exclusion Criteria: The participant has active cancer or carcinoma in situ of the head and neck The participant has a contraindication to biopsy The participant has presence of congestive heart failure (New York Heart Association (NYHA) class II-IV), uncontrolled hypertension (systolic > 150 or diastolic > 100), or unstable angina The participant has any history of congestive heart failure or history of myocardial infarction within the past 6 months The participant exhibits clinical evidence of active liver disease or history of chronic liver disease The participant has > Common Terminology Criteria for Adverse Events (CTCAE) grade 1 edema The participant has known diabetes and is on insulin or oral agents; the participant is receiving medical therapy for dysregulated blood sugar The participant who currently receives an enzyme inhibitor of CYP2C8 (gemfibrozil, ketoconazole, quercetin, trimethoprim), or enzyme inducer of CYP2C8 (cortisol, dexamethasone, phenobarbital, rifampin), or CYP3A4 substrate will not be eligible for randomization after assessing eligibility in stage two unless he/she will not be eligible for randomization after assessing eligibility in stage two unless he/she is willing to stop these drugs and possibly replace them with alternative therapies The participant currently receives pregabalin or thioridazine The participant has experienced jaundice with Rezulin (troglitazone) The participant has a history of colorectal cancer, familial adenomatous polyposis (FAP) or hereditary non-polyposis colorectal cancer (HNPCC) The participant has a history of bladder cancer or in situ bladder cancer The participant has a history of invasive cancer within the past 18 months (excluding non-melanoma skin cancer and in situ cervical cancer); participants (excluding those with a history of colorectal cancer, FAP, HNPCC, bladder cancer or in situ bladder cancer) who received curative treatment and have shown no evidence of recurrence for 18 months will be eligible

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (Pioglitazone Hydrochloride)<br>Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks | Drug: Pioglitazone hydrochloride<br>* Three (3) pioglitazone 15 mg capsules by mouth once daily for 24 weeks (+/- 1 week)<br>* Other names: pioglitazone;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Placebo Comparator: Arm II (Placebo)<br>Three (3) placebo capsules by mouth once daily for 24 weeks | Other: placebo<br>* Three (3) pioglitazone placebo capsules by mouth once daily for 24 weeks (+/- 1 week)<br>* Other names: PLCB;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response <Clinical and Histologic Response Defined as 50% or Greater Reduction in the Sum of the Measured Products of Perpendicular Dimensions of the Target Lesion(s) or Improvement in the Degree of Dysplasia or Hyperplasia> | Overall Dichotomized Clinical and Histologic Response defined as 50% or greater reduction in sum of the measured products of perpendicular dimensions of the target lesion(s) or improvement in the degree of dysplasia or hyperplasia where complete (CR) or partial response (PR) in either clinical or histologic outcome assessed according to criteria given recorded as Response or No Response and analyzed as a dichotomous variable. Clinical Response = CR: Disappearance all evidence target & non-target lesions; PR: >/=50% reduction in sum products of diameters all target lesion(s). Non-target lesions may not increase >/=25% in size & no new lesion. Histologic Response = CR: Complete reversal of dysplasia or hyperplasia to normal epithelium in all biopsied lesions. PR: Improvement of degree of dysplasia or hyperplasia in all biopsied lesion(s) from advanced to early, or from early to normal epithelium in some lesions while other biopsied lesions remain stable. | Response assessed at Week 24 ±1 Week | 
| Dichotomized Histologic Response (HR): Participant Complete or Partial Response Defined as =/>50% Reduction in the Sum of the Measured Products of Perpendicular Dimensions of the Target Lesion(s) or Improvement in the Degree of Dysplasia or Hyperplasia | HR according to criteria & recorded as Response or No Response, analyzed as dichotomous variable. CR: Complete reversal dysplasia/hyperplasia to normal epithelium in all biopsied lesions. PR: Improvement of degree dysplasia/hyperplasia in all biopsied lesion from advanced to early, or from early to normal epithelium in some lesions while other biopsied lesions remain stable. No Change (NC): No change in degree dysplasia/hyperplasia in all biopsied lesions, anything not CR, PR or PD. Progressive Disease (PD): Any increase in severity histology grade any biopsied lesion. Early premalignant lesion: lesion defined high risk, indicated by presence of one: hyperplasia at high-risk sites (dorsal, lateral or ventral tongue, or floor of mouth) ONLY, or mild dysplasia. Advanced premalignant lesion: lesion with presence of one: moderate dysplasia or severe dysplasia (excluding CIS), erythroplakia with hyperplasia or of any severity of dysplasia. | Response assessed at Week 24 ±1 Week | 
| Dichotomized Clinical Response: Participant Complete or Partial Response Defined as =/>50% Reduction in the Sum of the Measured Products of Perpendicular Dimensions of the Target Lesion(s) or Improvement in the Degree of Dysplasia or Hyperplasia | Clinical Response assessed according to criteria & recorded as Response or No Response, analyzed as dichotomous variable. Complete Response (CR): Disappearance of all evidence of target AND non-target lesions. Partial Response (PR): greater than or equal to 50% reduction in the sum of the products of diameters of all target lesion(s). Non-target lesions may not increase greater than or equal 25% in size and no new lesion may appear. No Change (NC): No change in the size of the lesion(s) and no new lesions appearing, i.e. anything that is not CR, PR or PD. Progressive Disease (PD): Any increase greater than or equal to 25% in the product of the diameters of any measurable lesions or in the estimated size of non-measurable lesions or the appearance of an unequivocal new lesion. | Response assessed at Week 24 ±1 Week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With >5.0 mg/L in Level of C-reactive Protein in Plasma | Degree of change of C-reactive protein (CRP) in plasma serum via blood tests. The longitudinal regression models for analysis of the change in CRP in plasma used, with suitable transformation if necessary to satisfy the model assumptions, with treatment, stage and biomarker value at screening visit as covariates. | Baseline to end of study, 24 weeks | 
| Number of Participants With Level of C-reactive Protein in Plasma Decrease From >5.0 mg/L to <= 5.0 mg/L From Baseline to End of Study | The longitudinal regression models for analysis of the change in CRP in plasma will be used, with suitable transformation if necessary to satisfy the model assumptions, with treatment, stage and biomarker value at screening visit as covariates. | Baseline to end of study, 24 weeks | 
| Number of Participant With Clinical Response by Baseline Characteristics: Tobacco Use | Tobacco use summarized by treatment stratified by stage and by group. In addition, the effects of tobacco and alcohol use on the primary endpoint of clinical response assessed. | Up to 26 weeks | 
| Number of Participant With Clinical Response by Baseline Characteristics: Alcohol Use | Alcohol use will be summarized by treatment stratified by stage and by group. In addition, the effects of tobacco and alcohol use on the primary endpoint of clinical and pathological response assessed using statistical regression models in an exploratory fashion. Heavy drinkers are participants who drank every day; Light drinkers are participants who drank on some days; Non-drinkers are former drinkers or those who never drank alcohol. | Up to 26 weeks | 
| Number of Participants Affected by Adverse Events Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4.0) | All adverse events (including serious) and clinical laboratory toxicity summarized affected organ system. Reporting based on the NCI CTCAE v4.0 by treatment, details included in later Adverse Event Module of results. | Up to 26 weeks | 
| Biomarker Measurements at Scheduled Visits: Tissue Levels of Cyclin D1 | Tissue levels of Cyclin D1 as indirect measures of pharmacological effect assessed by immunohistochemistry (IHC). Tissue levels of biomarkers assessed from the biopsy obtained at the Screening Clinic Visit and Week 24 ± 1 Week, and plasma levels of biomarkers assessed from blood collected at the Baseline Clinic Visit and Week 24 ± 1 Week. Data reported as percentage of cells staining positive, according to nuclear or cytoplasmic compartments. | Baseline to end of study, 24 weeks | 
| Biomarker Measurements at Scheduled Visits: Tissue Levels of Ki-67 | Tissue levels of Ki-67 for proliferation assessed by immunohistochemistry (IHC). Tissue levels of biomarkers assessed from the biopsy obtained at the Screening Clinic Visit and Week 24 ± 1 Week, and plasma levels of biomarkers assessed from blood collected at the Baseline Clinic Visit and Week 24 ± 1 Week. Data reported as percentage of cells staining positive, according to nuclear or cytoplasmic compartments. | Baseline to end of study, 24 weeks | 
| Biomarker Measurements at Scheduled Visits: Tissue Levels of p21 | Tissue levels of p21 as indirect measures of pharmacological effect assessed by immunohistochemistry (IHC). Tissue levels of biomarkers assessed from the biopsy obtained at the Screening Clinic Visit and Week 24 ± 1 Week, and plasma levels of biomarkers assessed from blood collected at the Baseline Clinic Visit and Week 24 ± 1 Week. Data reported as percentage of cells staining positive, according to nuclear or cytoplasmic compartments. | Baseline to end of study, 24 weeks | 
| Biomarker Measurements at Scheduled Visits: Tissue Levels of B-cell Lymphoma 2 (Bcl2) | Tissue levels of Bcl2 as indirect measures of pharmacological effect assessed by immunohistochemistry (IHC). Tissue levels of biomarkers assessed from the biopsy obtained at the Screening Clinic Visit and Week 24 ± 1 Week, and plasma levels of biomarkers assessed from blood collected at the Baseline Clinic Visit and Week 24 ± 1 Week. Data reported a percentage of cells staining positive, according to nuclear or cytoplasmic compartments. | Baseline to end of study, 24 weeks | 
| Biomarker Measurements at Scheduled Visits: Tissue Levels of PPARG Nucleus and PPARG Cytoplasm | Tissue levels of Peroxisome proliferator-activated receptor gamma (PPARG) Nucleus and PPARG Cytoplasm as indirect measures of pharmacological effect, PPAR gamma assessed by immunohistochemistry. Tissue levels of biomarkers assessed from the biopsy obtained at the Screening Clinic Visit and Week 24 ± 1 Week, and plasma levels of biomarkers assessed from blood collected at the Baseline Clinic Visit and Week 24 ± 1 Week. Data reported as percentage of cells staining positive, according to nuclear or cytoplasmic compartments. | Baseline to end of study, 24 weeks |