Pioglitazone for Oral Premalignant Lesions

Oral Leukoplakia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00951379
• Other study ID #: NCI-2012-03152
• Secondary ID: NCI-2012-03152UW
• Status: Completed
• Phase: Phase 2
• First received: July 31, 2009
• Last updated: September 19, 2014
• Start date: February 2010
• Est. completion date: March 2014

Study information

• Verified date: June 2014
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Description:

PRIMARY OBJECTIVES:

I. To determine the clinical and histologic response of oral premalignant lesions to 24 weeks of therapy with pioglitazone, 45 mg 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 100
• Est. completion date: March 2014
• Est. primary completion date: March 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 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 x ULN

• BUN and serum creatinine =< 1.5 x ULN

• Glucose, serum < 200 mg/dL

• The participant's 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 > 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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukoplakia
• Leukoplakia, Oral
• Oral Leukoplakia
• Precancerous Conditions

Intervention

Drug:
• pioglitazone hydrochloride
Given PO

Other:
• placebo
Given PO
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
Italy	European Institute of Oncology	Milano
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Medical University of South Carolina	Charleston	South Carolina
United States	M D Anderson Cancer Center	Houston	Texas
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	Masonic Cancer Center, University of Minnesota	Minneapolis	Minnesota
United States	University of Minnesota Medical Center-Fairview	Minneapolis	Minnesota
United States	Columbia University Medical Center	New York	New York
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Weill Medical College of Cornell University	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Response will be summarized as proportion with a 90% confidence interval, by treatment arm. The primary comparison between the two groups will be based on Cochran-Mantel-Haenszel test with the stage of oral premalignant lesion and the group as stratification factors for testing the difference in the response.	Up to 26 weeks	No
Secondary	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 and loss of heterozygosity	Will be summarized with mean and standard deviation, median and range if continuous or with frequency if discrete, dichotomous or ordinal, by treatment stratified by stage and group. Generalized linear models will be used for tissue levels of biomarkers in an exploratory analysis with link functions suitable for the nature/type of measurements for these biomarkers.	Baseline	No
Secondary	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 and loss of heterozygosity	Will be summarized with mean and standard deviation, median and range if continuous or with frequency if discrete, dichotomous or ordinal, by treatment stratified by stage and group. Generalized linear models will be used for tissue levels of biomarkers in an exploratory analysis with link functions suitable for the nature/type of measurements for these biomarkers.	24 weeks	No
Secondary	Level of C-reactive protein in plasma	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	No
Secondary	Level of C-reactive protein in plasma	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.	24 weeks	No
Secondary	Tobacco and alcohol use	Tobacco and 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 will be assessed using statistical regression models in an exploratory fashion.	Up to 26 weeks	No
Secondary	Adverse events and clinical laboratory toxicity assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (v4.0)	Adverse events and clinical laboratory toxicity will be summarized based on the NCI CTCAE v4.0 by treatment.	Up to 26 weeks	Yes