Pioglitazone for Oral Premalignant Lesions

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00951379
First received: July 31, 2009
Last updated: July 8, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Oral Leukoplakia
Drug: pioglitazone hydrochloride
Other: placebo
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Phase IIB Randomized, Placebo Controlled Trial of Pioglitazone for Oral Premalignant Lesions an Inter-consortium Collaborative Study

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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 [ Time Frame: Up to 26 weeks ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • 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 [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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.

  • 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 [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    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.

  • Level of C-reactive protein in plasma [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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.

  • Level of C-reactive protein in plasma [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    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.

  • Tobacco and alcohol use [ Time Frame: Up to 26 weeks ] [ Designated as safety issue: No ]
    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.

  • Adverse events and clinical laboratory toxicity assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (v4.0) [ Time Frame: Up to 26 weeks ] [ Designated as safety issue: Yes ]
    Adverse events and clinical laboratory toxicity will be summarized based on the NCI CTCAE v4.0 by treatment.


Enrollment: 100
Study Start Date: February 2010
Study Completion Date: March 2014
Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (pioglitazone hydrochloride)
Patients receive pioglitazone hydrochloride PO QD for 24 weeks.
Drug: pioglitazone hydrochloride
Given PO
Other Names:
  • Actos
  • pioglitazone
Other: laboratory biomarker analysis
Correlative studies
Placebo Comparator: Arm II (placebo)
Patients receive placebo PO QD for 24 weeks.
Other: placebo
Given PO
Other Name: PLCB
Other: laboratory biomarker analysis
Correlative studies

Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00951379

Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294
United States, Iowa
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States, 52242
United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
United States, Minnesota
Masonic Cancer Center, University of Minnesota
Minneapolis, Minnesota, United States, 55455
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
Columbia University Medical Center
New York, New York, United States, 10032
Weill Medical College of Cornell University
New York, New York, United States, 10065
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
United States, Wisconsin
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States, 53792
Italy
European Institute of Oncology
Milano, Italy, 20141
Sponsors and Collaborators
Investigators
Principal Investigator: Jay Boyle M.D. Anderson Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00951379     History of Changes
Other Study ID Numbers: NCI-2012-03152, NCI-2012-03152, UWI H-2009-0106, MDA-2009-0339, INC07-10-01, INC07-10-01, P30CA016672, N01CN35159, N01CN35153
Study First Received: July 31, 2009
Last Updated: July 8, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukoplakia
Precancerous Conditions
Leukoplakia, Oral
Neoplasms
Pathological Conditions, Anatomical
Mouth Neoplasms
Head and Neck Neoplasms
Neoplasms by Site
Mouth Diseases
Stomatognathic Diseases
Pioglitazone
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 18, 2014