Clinical Trial: Pioglitazone for Oral Premalignant Lesions

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

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

Brief 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.

Detailed Summary:

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.
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome:

  • 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> [ Time Frame: Response assessed at Week 24 ±1 Week ]
    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.
  • 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 [ Time Frame: Response assessed at Week 24 ±1 Week ]
    HR according to criteria & recorded as Response or No Response, analyzed as dichotomous variable. CR: Complete reversal dysplasia/hyperplasia to normal epithelium

    Original Primary Outcome: Complete or partial response in either clinical or histologic outcome [ Time Frame: Weeks 4, 12, and 24 (Lesion biopsy at Week 24) ]

    Current Secondary Outcome:

    • Number of Participants With >5.0 mg/L in Level of C-reactive Protein in Plasma [ Time Frame: Baseline to end of study, 24 weeks ]

      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.

    • 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 [ Time Frame: Baseline to end of study, 24 weeks ]
      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.
    • Number of Participant With Clinical Response by Baseline Characteristics: Tobacco Use [ Time Frame: Up to 26 weeks ]
      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.
    • Number of Participant With Clinical Response by Baseline Characteristics: Alcohol Use [ Time Frame: Up to 26 weeks ]
      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.
    • 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) [ Time Frame: Up to 26 weeks ]
      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.
    • Biomarker Measurements at Scheduled Visits: Tissue Levels of Cyclin D1 [ Time Frame: Baseline to end of study, 24 weeks ]
      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.
    • Biomarker Measurements at Scheduled Visits: Tissue Levels of Ki-67 [ Time Frame: Baseline to end of study, 24 weeks ]
      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.
    • Biomarker Measurements at Scheduled Visits: Tissue Levels of p21 [ Time Frame: Baseline to end of study, 24 weeks ]
      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.
    • Biomarker Measurements at Scheduled Visits: Tissue Levels of B-cell Lymphoma 2 (Bcl2) [ Time Frame: Baseline to end of study, 24 weeks ]
      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.
    • Biomarker Measurements at Scheduled Visits: Tissue Levels of PPARG Nucleus and PPARG Cytoplasm [ Time Frame: Baseline to end of study, 24 weeks ]
      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 o

      Original Secondary Outcome:

      Information By: National Cancer Institute (NCI)

      Dates:
      Date Received: July 31, 2009
      Date Started: February 2010
      Date Completion:
      Last Updated: March 29, 2016
      Last Verified: June 2014