Pioglitazone for Oral Premalignant Lesions

NCT00951379 | Terminated Phase 2 Results DMC

• 7 other identifiers: NCI-2012-03152UWI H-2009-0106MDA-2009-0339INC07-10-01N01CN35159N01CN35153P30CA016672
• Study Type: interventional
• Target: 52
• Locations: 3 countries
• Sites: 13

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.

Conditions

Oral Leukoplakia

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (10)

• Number of Participants With >5.0 mg/L in Level of C-reactive Protein in Plasma

  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

  Baseline to end of study, 24 weeks

• Number of Participant With Clinical Response by Baseline Characteristics: Tobacco Use

  Up to 26 weeks

• Number of Participant With Clinical Response by Baseline Characteristics: Alcohol Use

  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)

  Up to 26 weeks

Study Arms (2)

Arm I (Pioglitazone Hydrochloride)

EXPERIMENTAL

Three (3) Pioglitazone 15 mg capsules by mouth once daily for 24 weeks

Drug: Pioglitazone hydrochloride; Other: laboratory biomarker analysis

Arm II (Placebo)

PLACEBO COMPARATOR

Three (3) placebo capsules by mouth once daily for 24 weeks

Other: placebo; Other: laboratory biomarker analysis

Interventions

Pioglitazone hydrochloride DRUG

Three (3) pioglitazone 15 mg capsules by mouth once daily for 24 weeks (+/- 1 week)

Also known as: Actos, pioglitazone

Arm I (Pioglitazone Hydrochloride)

placebo OTHER

Three (3) pioglitazone placebo capsules by mouth once daily for 24 weeks (+/- 1 week)

Also known as: PLCB

Arm II (Placebo)

laboratory biomarker analysis OTHER

Correlative studies

Arm I (Pioglitazone Hydrochloride); Arm II (Placebo)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (13)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Masonic Cancer Center, University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

Weill Medical College of Cornell University

New York, New York, 10065, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, 53792, United States

Location

BC Cancer Agency (Vancouver Cancer Centre)

Vancouver, British Columbia, V5Z 4E6, Canada

Location

European Institute of Oncology

Milan, 20141, Italy

Location

Related Publications (1)

• Gates JC, Abouyared M, Shnayder Y, Farwell DG, Day A, Alawi F, Moore M, Holcomb AJ, Birkeland A, Epstein J. Clinical Management Update of Oral Leukoplakia: A Review From the American Head and Neck Society Cancer Prevention Service. Head Neck. 2025 Feb;47(2):733-741. doi: 10.1002/hed.28013. Epub 2024 Nov 25.

  PMID: 39584361 DERIVED

Related Links

• University of Texas MD Anderson Cancer Center Official Website
• National Cancer Institute (NCI) Central Website for Cancer Research

MeSH Terms

Conditions

Leukoplakia, Oral

Interventions

Pioglitazone

Condition Hierarchy (Ancestors)

Mouth Neoplasms; Head and Neck Neoplasms; Neoplasms by Site; Neoplasms; Leukoplakia; Precancerous Conditions; Mouth Diseases; Stomatognathic Diseases; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thiazolidinediones; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: University of Texas MD Anderson Phase I/II Prevention Consortium
• Organization: University of Texas (UT) MD Anderson Cancer Center

CR_Study_Registration@mdanderson.org

Study Officials

• Powel H. Brown

  University of Texas MD Anderson Cancer Center, Consortium PI

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 31, 2009
• First Posted: August 4, 2009
• Study Start: February 1, 2010
• Primary Completion: March 1, 2014
• Study Completion: March 1, 2014
• Last Updated: April 6, 2016
• Results First Posted: April 6, 2016

Record last verified: 2014-06

Locations

CA (1); US (11); IT (1)