Pioglitazone for Oral Premalignant Lesions

Condition(s) targeted: Mouth Cancer; Oral Cancer

Intervention: Pioglitazone (Drug); Placebo (Drug)

Phase: Phase 2/Phase 3

Status: Not yet recruiting

Sponsored by: M.D. Anderson Cancer Center

Official(s) and/or principal investigator(s):
William N. William Jr., MD, Principal Investigator, Affiliation: UT MD Anderson Cancer Center

Overall contact:
William N. William Jr., MD, Phone: 713-792-6363

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.

Primary Objective:

To determine the clinical and histologic response of oral premalignant lesions to 24 weeks of therapy with pioglitazone, 45 mg daily, defined as 50% or greater reduction in the measured product of perpendicular dimensions of the target lesion, or improvement in the degree of dysplasia or hyperplasia.

Secondary Objective:

1. 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).

2. To determine the degree of change of C-reactive protein (CRP) in serum.

3. To assess tobacco and alcohol use among trial participants and to examine the relationship of tobacco and alcohol use to treatment response.

4. To assess the safety of this agent in this population.

Official title: Phase IIB Randomized, Placebo Controlled Trial of Pioglitazone for Oral Premalignant Lesions An Inter-Consortium Collaborative Study

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator), Single Group Assignment, Safety/Efficacy Study

Primary outcome: Complete or partial response in either clinical or histologic outcome

Detailed description: Study Drug:

Pioglitazone is commonly used to lower the blood sugar in patients with diabetes. It is designed to target a protein that may change how genes affect the body's metabolism. It also may decrease the growth of cancer cells.

Screening Tests:

Signing this consent form does not mean that you will be able to take part in this study. You will have "screening tests" to help the doctor decide if you are eligible to take part in this study. If you have had some of them done recently, they may not need to be repeated. This will be up to your study doctor.

The screening tests will be done in 2 stages. First, the following tests and procedures will be performed:

- Your medical history will be recorded.

- You will be asked about any drugs you are taking.

- You will have a routine exam of your mouth.

- The lesions will be measured, and photos of them will be taken for comparison to the

lesion photos taken later during the study.

- You will have a biopsy of the affected area of your mouth, if this procedure was not

performed in the last 6-8 weeks. The biopsy will be performed on at least 1 white and/or 1 red patch in the mouth. To collect a biopsy, the area is numbed with anesthetic, and a small amount of tissue is removed with a small, sharp tool. The tissue will be studied to see if there are microscopic (very small) changes. The biopsy samples will also be looked at by an M. D. Anderson doctor (pathologist) to confirm the diagnosis of an OPL. If you have had a biopsy in the last 6-8 weeks, then the pathologist will use the results of that biopsy and you will not need to have another biopsy.

- If you have not had a biopsy in the last 6-8 weeks, you will also have a small biopsy

performed on a normal area of your mouth. This tissue sample will be compared with the sample from the affected area.

If you are found to be still eligible based on the tests above, you will have a second set of screening tests. This "baseline" visit will occur about 4 weeks after your screening biopsies.

- You will have a physical exam, including an exam of your mouth.

- The lesions will be measured.

- You will be asked about any drugs you are taking. At every visit starting at this

visit, you will also be asked about any alcohol and tobacco you may be using.

- Blood (about 3 teaspoons) will be drawn for routine tests.

- You will have an electrocardiogram (ECG -- a test that measures the electrical activity

of the heart).

- Women who are able to become pregnant must have a negative blood (about (2 tablespoons)

pregnancy test.

The study doctor will discuss the screening test results with you. If the screening tests show that you are not eligible to take part in the study, you will not be enrolled. Other treatment options will be discussed with you.

Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the toss of a coin) to a study group. You will have an equal chance of being placed in either group.

- Group 1 will take pioglitazone.

- Group 2 will take a placebo (a substance that looks like the study drug but has no

active ingredients).

Neither you nor the study doctor will know if you are receiving the study drug or the placebo. However, if needed for your safety, the study doctor will be able to find out.

Study Drug Administration:

You will take 3 capsules of study drug/placebo by mouth, once a day, at about the same time each day.

If you forget to take a dose and you remember that same day, take the missed dose as soon as you remember it. However, if you do not remember until the next day, do not take 2 doses to make up for the missed dose. Instead, skip the missed dose and continue your regular dosing schedule.

You will be given a pill diary to help you keep track of your doses of the study drug/placebo. Every day, you should write down when you take the study drug/placebo.

You should bring your completed pill diary and your bottle of capsules to every study visit. The study staff will review the diary with you at every study visit and phone call.

Study Visits and Calls:

At Weeks 4, 12, and 24, you will have study visits. The following tests and procedures will be performed:

- You will have a physical exam, including an exam of your mouth.

- You will be asked about any drugs you are taking and any side effects you have

experienced.

- Blood (about 3 teaspoons) will be drawn for routine tests.

- At Weeks 12 and 24 only, the lesions will be measured.

- At Week 24 only, photos of the lesions will be taken.

- At Week 24 only, you will have a biopsy of the lesion area and a biopsy of a

normal-looking area of your mouth.

At Weeks 8 and 18, the research staff will call you to ask about any drugs you are taking and any side effects you have experienced.

Length of Study Participation:

You may take the study drug/placebo for up to 25 weeks. You will be taken off the study drug/placebo early if intolerable side effects occur or the doctor thinks it is in your best interest.

Tell the study doctor if you are thinking about stopping the study or decide to stop. The doctor will tell you how to stop safely.

Follow-Up Phone Call:

After you finish taking the study drug/placebo, the research staff will call you to ask about any drugs you are taking and any side effects you have experienced. You will also be told the results of the Week 24 lesion biopsy.

Other Information:

Be sure to tell the study doctor or staff about all drugs you may be taking, including prescription drugs, over-the-counter drugs, vitamins, and herbal supplements. Other drugs may not mix well with the study drug.

You should talk to your study doctor about any side effects you may have during the study.

This is an investigational study. Pioglitazone is commercially available and FDA approved to treat a type of diabetes. It is investigational to give pioglitazone to patients with OPLs.

Up to 100 patients will take part in this study. Up to 9 will be enrolled at M. D. Anderson.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

1. Males or females with a suspected or histologically confirmed index oral premalignant lesion (OPL) 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.

2. Participants with suspected OPL must not have had a biopsy within 6 weeks prior to the Screening biopsy (the 6 week limitation before re-biopsy is to minimize inflammation in study tissue). The Screening biopsy must be histologically confirmed before the second stage of registration can be completed.

3. Participants presenting with histologically confirmed OPL at the Screening visit must have had the diagnostic biopsy within 8 weeks of randomization (or no more than 6 weeks before stage one registration). Adequate archival tissue for biomarker analysis must be available. The pre-Screening biopsy must undergo centralized pathology review before the second stage of registration can be completed. To allow for centralized review, the pre-Screening biopsy must have been performed no more than 6 weeks before the Screening visit.

4. Age >/= 18 years

5. The participant's life expectancy is > 6 months.

6. The participant's ECOG performance status is 0 or 1.

7. The participant has discontinued any other oral cancer chemopreventive therapy, including use of more than one multi-vitamin per day and use of any particular vitamin supplement at >3 times the United States Dietary Reference Intake (DRI) [Recommended Dietary Allowance (RDA) or Adequate Intake (AI) as applicable) (see Appendix B) at least 12 weeks prior to the Baseline visit and all toxicities have been fully resolved. Daily aspirin is permitted.

8. The participant is willing and able to fully participate for the duration of the study.

9. The effects of pioglitazone on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, 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.

10. Continuation of Inclusion 9.) 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.

11. Ability to understand and the willingness to sign a written informed consent document.

12. Stage Two: The participant has a histologically confirmed index lesion that is either: An EARLY premalignant lesion defined to be at high risk as indicated by the presence of at least one of the following: atypical cells, mild dysplasia, or hyperplastic leukoplakia of high-risk sites, dorsal, lateral or ventral tongue and floor of mouth OR An ADVANCED premalignant lesion defined as the presence of at least one of the following: moderate dysplasia, severe dysplasia (excluding carcinoma in situ) or erythroplakia*.

13. continuation of Inclusion 12.) Stage Two: * Due to the high risk for progression associated with erythroplakia, erythroplakia of any histology will be defined as an ADVANCED oral premalignant lesion

14. The participant meets the following laboratory eligibility criteria during a time not to exceed 4 weeks prior to randomization: Hemoglobin levels equal to or above the lower limit of normal, White blood cells >/= 3,000/microL, Platelets >/= 125,000/microL, Total bilirubin 15. Refer to Inclusion 9.) & 10.) If the participant is female and of childbearing potential she has a documented negative serum pregnancy test within 14 days prior to randomization.

16. 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.

17. Both men and women and members of all races and ethnic groups are eligible for this trial. The investigators will strive to recruit subjects of a demographic that reflect those affected with oral premalignant lesions in the general population. Cancer statistics show that the prevalence of oral precancer and oral cancer is higher among males than females, at a ratio of 1. 3: 1. All consenting investigators and professionals will be informed of the importance of recruiting women to the current trial. This effort will ensure that we have adequate representation of women.

18. Continuation of Inclusion 17.) Similarly, our investigators are extremely aware of the importance of recruiting minority. In summary, a specific effort will be made to recruit and retain woman and minorities to the current trial. It is anticipated that 40% of the subjects enrolled to the current trial will be female, and that approximately 12% of the study population will be Hispanic or Latino.

Exclusion Criteria:

1. The participant has active cancer or carcinoma in situ of the head and neck.

2. The participant has a contraindication to biopsy.

3. 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.

4. The participant has any history of congestive heart failure or history of myocardial infarction within the past 6 months.

5. The participant exhibits clinical evidence of active liver disease or history of chronic liver disease.

6. The participant has > CTCAE Grade 1 edema.

7. The participant has known diabetes and is on insulin or oral agents. The participant is receiving medical therapy for dysregulated blood sugar. The participant has a random blood glucose level >200 mg/dl.

8. The participant currently receives an enzyme inhibitor of CYP2C8 (such as gemfibrozil), or enzyme inducer (such as rifampin).

9. The participant has experienced jaundice with Rezulin® (troglitazone).

10. The participant has a history of colorectal cancer, familial adenomatous polyposis (FAP) or hereditary non-polyposis colorectal cancer (HNPCC).

11. The participant has a history of bladder cancer or in situ bladder cancer.

12. The participant has a history of invasive cancer within the past 18 months (excluding nonmelanoma 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.

13. The participant has had chemotherapy, cancer-related immunotherapy, hormonal therapy (other than HRT for menopause), or radiation therapy within 18 months of the Baseline visit.

14. The participant will need concurrent chemotherapy, radiotherapy, hormonal (other than HRT for menopause), or cancer-related immunotherapy during the time of study.

15. The participant has received any investigational medication within 30 days of the Baseline visit or is scheduled to receive an investigational drug during the course of the study.

16. The participant has participated in the study previously and was withdrawn.

17. The participant is pregnant or nursing.

18. Participants who have received pioglitazone or rosiglitazone prior to this study.

19. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, HIV, or psychiatric illness/social situations that would limit compliance with study requirements. Medical and scientific reasons for the exclusion of pregnant or nursing participants or participants who are HIV-positive from this study are detailed below. Pregnant women are excluded from this study because pioglitazone is an agent with the potential for teratogenic or abortifacient effects.

20. Continuation of Exclusion 19.) Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pioglitazone, breastfeeding should be discontinued if the mother is treated with pioglitazone.

21. Continuation of Exclusion 20.) HIV-positive: Known HIV-positive participants will be excluded from this study due to the high prevalence of confounding oral lesions in this population. Specifically, HIV infection is a risk factor for developing Epstein-Barr virus related abnormalities including Greenspan's leukoplakia or oral hairy leukoplakia. In addition, HIV-positive patients are susceptible to candidiasis which can cause white patches of the mouth.

William N. William Jr., MD, Phone: 713-792-6363

European Institute of Oncology (EIO), Milan, Italy

University of Alabama-Birmingham (UAB), Birmingham, Alabama 35283, United States

University of Iowa, Iowa City, Iowa 52242, United States

University of Minnesota, (UM), Minneapolis, Minnesota 55455-0213, United States

Columbia University Medical Center (CUMC), New York, New York 10032, United States

Memorial Sloan-Kettering Cancer Center, New York, New York 10065, United States

Weill Medical College of Cornell University (CU), New York, New York 10021, United States

UT MD Anderson Cancer Center, Houston, Texas 77030, United States

University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin 53792-6164, United States

UT MD Anderson Cancer Center website

Starting date: August 2009
Last updated: August 3, 2009