Pioglitazone Hydrochloride in Preventing Head and Neck Cancer in Patients With Oral Leukoplakia

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00099021
• Collaborator: (none)
• Enrollment: 21
• Location: 1
• Arm: 1
• Duration (Months): 60.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This phase II trial studies how well pioglitazone hydrochloride works in preventing head and neck cancer in patients who have oral leukoplakia. Chemoprevention therapy is the use of certain drugs to try to prevent the development or recurrence of cancer. The use of pioglitazone hydrochloride may be effective in preventing head and neck cancer.

Condition or Disease	Intervention/Treatment	Phase
Head and Neck Cancer; Oral Leukoplakia	Drug: pioglitazone hydrochloride	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Determine whether pioglitazone (pioglitazone hydrochloride) reverses leukoplakia in patients with hyperplastic or dysplastic oral cavity or oropharyngeal leukoplakia.

SECONDARY OBJECTIVES:

1. Determine the safety and tolerability of this drug in these patients.

OUTLINE: This is an open-label study.

Patients receive pioglitazone hydrochloride orally (PO) once daily (QD) for 12 weeks in the absence of disease progression, unacceptable toxicity, or the development of carcinoma.

Patients are followed up at 4, 8, 12, and 16 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Phase IIa Cancer Prevention Trial of the PPAR Gamma Agonist Pioglitazone in Oral Leukoplakia
• Study Start Date: Jun 1, 2003
• Actual Primary Completion Date: Jun 27, 2008
• Actual Study Completion Date: Jun 27, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Prevention (pioglitazone hydrochloride) Patients receive pioglitazone hydrochloride PO QD for 12 weeks in the absence of disease progression, unacceptable toxicity, or the development of carcinoma.	Drug: pioglitazone hydrochloride; Given PO; Other Names: Actos pioglitazone

Outcome Measures

Primary Outcome Measures

1. Patients' Overall Response [Week 16 (4 weeks post dose)]

   Overall Response= reviewing both the clinical and histological responses and assigning the worst category. Complete Response (CR) = Clinical CR and Histologic CR, or Histologic CR Partial Response (PR) = Clinical CR or PR and Histologic PR or Stable Disease (SD) Stable Disease (SD) = Clinical SD and Histologic PR or SD Progressive Disease (PD) = Clinical PD and/or Histologic PD

Secondary Outcome Measures

1. Patients' Clinical Response [Week 16 (4 weeks post dose)]

   Determined by measurement of lesions- Complete Response (CR)= disappearance of all lesions, Partial Response (PR)= >or= 50% decrease in sum of lesions, Stable Disease (SD) = does not meet CR,PR or Progressive Disease (PD), and PD= >or= 25% increase in sum of lesions

2. Patients' Histological (Tissue) Response [Week 16 (4 weeks post dose)]

   Determined by biopsy results before and 4 weeks after treatment: Complete Response (CR) =complete reversal of dysplasia or hyperplasia, Partial Response (PR) = >or=50% decrease in sum of lesions, no increase in 1 or more lesions and no new lesion occurs, Stable Disease (SD0 = not CR, PR or Progressive Disease (PD), PD = >or= 25% increase in sum of lesions or new lesion or progression to invasive carcinoma.

Other Outcome Measures

1. Interleukin 6, 8 and Vascular Endothelial Growth Factors Elaboration in the Oral Cavity and Serum [Pre (Day 0) and Post (Week 12) Treatment]

   Quantitative studies of serum and saliva components for a pre and post treatment possible biomarker.

2. Quantitative Oil Red O, AP2 (FABP4) and FABP5 Staining [Pre (Day 0) and Post (Week 12) Treatment]

   Immune histochemistry / tissue staining for a possible biomarker.

3. Involucrin and Transglutaminase Staining [Pre (Day 0) and Post (Week 12) Treatment]

   Immune histochemistry / tissue staining for a possible biomarker.

4. Cyclin D1 and p21 Immune Histochemistry [Pre (Day 0) and Post (Week 12) Treatment]

   Immune histochemistry / tissue staining for a possible biomarker.

5. Cyclooxygenase-2 Staining [Pre (Day 0) and Post (Week 12) Treatment]

   Immune histochemistry / tissue staining for a possible biomarker.

6. Piogliotazone Gamma Immune Histochemistry [Pre (Day 0) and Post (Week 12) Treatment]

   Immune histochemistry / tissue staining for a possible biomarker.

7. Ki 67 Labeling Index [Pre (Day 0) and Post (Week 12) Treatment]

   Immune histochemistry / tissue staining for a possible biomarker.

8. Apotosis (Cell Death) [Pre (Day 0) and Post (Week 12) Treatment]

   Immune histochemistry / tissue staining for a possible biomarker.

9. Nf Kappa B p65 [Pre (Day 0) and Post (Week 12) Treatment]

   Immune histochemistry / tissue staining for a possible biomarker.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria:

• ECOG 0-2

• Diagnosis of oral cavity or oropharyngeal leukoplakia meeting 1 of the following criteria:

• Biopsy-proven hyperplasia in high-risk anatomic areas (e.g., floor of the mouth, mobile tongue, oropharynx, or in any erythroplakia lesion)

• Mild, moderate, or severe dysplasia at any site of the oral cavity or oropharynx within the lesion

• Measurable lesion that is clinically characterized by leukoplakia, erythroplakia, or erythroleukoplakia

• Able to be assessed by bi-directional measurements

• Life expectancy: More than 3 months

• Hemoglobin >= lower limit of normal for males and post-menopausal females OR

• Hemoglobin >= 11 g/dL for premenopausal females

• WBC > 3,000/mm^3

• Hepatic: Bilirubin < 1.5 times upper limit of normal (ULN); AST and ALT < 1.5 times ULN

• Renal: BUN < 1.5 times ULN; Creatinine < 1.5 times ULN

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective barrier contraception

• No contraindication to thiazolidinediones

• No allergy to pioglitazone or other thiazolidinediones

• No serious oral infection

• No invasive carcinoma within the past 60 months except nonmelanoma skin cancer or carcinoma in situ of the cervix

• No concurrent malignancy

• More than 3 months since prior biologic or immunologic therapy

• No concurrent insulin for diabetes

• No prior radiotherapy to the oral cavity

• More than 3 months since prior chemopreventative agents

• More than 3 months since prior experimental therapy

• More than 3 months since prior megadose vitamins or alternative therapy

• No prior thiazolidinediones

• No prior participation in this study

• No concurrent pharmacologic treatment for diabetes

• Concurrent chronic use of non-steroidal anti-inflammatory drugs allowed

• Platelet count > 125,000/mm^3

• Index lesion must be located in an anatomic site accessible by punch biopsy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Minnesota Medical Center-Fairview	Minneapolis	Minnesota	United States	55455

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Frank Ondrey, University of Minnesota Medical Center-Fairview

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00099021
• Other Study ID Numbers: NCI-2009-00862; NCI-2009-00862; CDR0000393562; 2001LS068; 0109 M 07254; N01-CN-15000; N01CN15000
• First Posted: Dec 9, 2004
• Last Update Posted: Feb 11, 2022
• Last Verified: Jan 1, 2022

• Additional relevant MeSH terms: Head and Neck Neoplasms; Leukoplakia; Leukoplakia, Oral; Pioglitazone

Study Results

Participant Flow

Arm/Group Title	Pioglitazone Patients
Arm/Group Description	Patients with measurable leukoplakia who received all study medication (oral pioglitazone once daily for 12 weeks) and completed the trial.
Period Title: Overall Study
STARTED	21
COMPLETED	21
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Pioglitazone Patients
Arm/Group Description	Patients with measurable leukoplakia who received all study medication (oral pioglitazone once daily for 12 weeks) and completed the trial.
Overall Participants	21
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	19 90.5%
>=65 years	2 9.5%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	56.1
Sex: Female, Male (Count of Participants)
Female	12 57.1%
Male	9 42.9%
Region of Enrollment (participants) [Number]
United States	21 100%

Outcome Measures

1. Primary Outcome

Title	Patients' Overall Response
Description	Overall Response= reviewing both the clinical and histological responses and assigning the worst category. Complete Response (CR) = Clinical CR and Histologic CR, or Histologic CR Partial Response (PR) = Clinical CR or PR and Histologic PR or Stable Disease (SD) Stable Disease (SD) = Clinical SD and Histologic PR or SD Progressive Disease (PD) = Clinical PD and/or Histologic PD
Time Frame	Week 16 (4 weeks post dose)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pioglitazone Patients
Arm/Group Description	Patients with measurable leukoplakia who received all study medication (oral pioglitazone once daily for 12 weeks) and completed the trial.
Measure Participants	21
Complete Response	0 0%
Partial Response	15 71.4%
Stable Disease	2 9.5%
Progressive Disease	4 19%
Partial + Complete Response	15 71.4%

2. Secondary Outcome

Title	Patients' Clinical Response
Description	Determined by measurement of lesions- Complete Response (CR)= disappearance of all lesions, Partial Response (PR)= >or= 50% decrease in sum of lesions, Stable Disease (SD) = does not meet CR,PR or Progressive Disease (PD), and PD= >or= 25% increase in sum of lesions
Time Frame	Week 16 (4 weeks post dose)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pioglitazone Patients
Arm/Group Description	Patients with measurable leukoplakia who received all study medication (oral pioglitazone once daily for 12 weeks) and completed the trial.
Measure Participants	21
Complete Response	3 14.3%
Partial Response	14 66.7%
Stable Disease	4 19%
Progressive Disease	0 0%
Partial + Complete	17 81%

3. Secondary Outcome

Title	Patients' Histological (Tissue) Response
Description	Determined by biopsy results before and 4 weeks after treatment: Complete Response (CR) =complete reversal of dysplasia or hyperplasia, Partial Response (PR) = >or=50% decrease in sum of lesions, no increase in 1 or more lesions and no new lesion occurs, Stable Disease (SD0 = not CR, PR or Progressive Disease (PD), PD = >or= 25% increase in sum of lesions or new lesion or progression to invasive carcinoma.
Time Frame	Week 16 (4 weeks post dose)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pioglitazone Patients
Arm/Group Description	Patients with measurable leukoplakia who received all study medication (oral pioglitazone once daily for 12 weeks) and completed the trial.
Measure Participants	21
Complete Response	1 4.8%
Partial Response	2 9.5%
Stable Disease	14 66.7%
Progressive Disease	4 19%
Partial + Complete Response	3 14.3%

4. Other Pre-specified Outcome

Title	Interleukin 6, 8 and Vascular Endothelial Growth Factors Elaboration in the Oral Cavity and Serum
Description	Quantitative studies of serum and saliva components for a pre and post treatment possible biomarker.
Time Frame	Pre (Day 0) and Post (Week 12) Treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Other Pre-specified Outcome

Title	Quantitative Oil Red O, AP2 (FABP4) and FABP5 Staining
Description	Immune histochemistry / tissue staining for a possible biomarker.
Time Frame	Pre (Day 0) and Post (Week 12) Treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Other Pre-specified Outcome

Title	Involucrin and Transglutaminase Staining
Description	Immune histochemistry / tissue staining for a possible biomarker.
Time Frame	Pre (Day 0) and Post (Week 12) Treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Cyclin D1 and p21 Immune Histochemistry
Description	Immune histochemistry / tissue staining for a possible biomarker.
Time Frame	Pre (Day 0) and Post (Week 12) Treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Cyclooxygenase-2 Staining
Description	Immune histochemistry / tissue staining for a possible biomarker.
Time Frame	Pre (Day 0) and Post (Week 12) Treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Piogliotazone Gamma Immune Histochemistry
Description	Immune histochemistry / tissue staining for a possible biomarker.
Time Frame	Pre (Day 0) and Post (Week 12) Treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Ki 67 Labeling Index
Description	Immune histochemistry / tissue staining for a possible biomarker.
Time Frame	Pre (Day 0) and Post (Week 12) Treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Other Pre-specified Outcome

Title	Apotosis (Cell Death)
Description	Immune histochemistry / tissue staining for a possible biomarker.
Time Frame	Pre (Day 0) and Post (Week 12) Treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Other Pre-specified Outcome

Title	Nf Kappa B p65
Description	Immune histochemistry / tissue staining for a possible biomarker.
Time Frame	Pre (Day 0) and Post (Week 12) Treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	From first dose of Pioglitazone through Week 16 (end of study).
Arm/Group Title	Pioglitazone Patients
Arm/Group Description	Patients with measurable leukoplakia who received all study medication (oral pioglitazone once daily for 12 weeks) and completed the trial.
All Cause Mortality
	Pioglitazone Patients
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Pioglitazone Patients
	Affected / at Risk (%)	# Events
Total	0/21 (0%)
Other (Not Including Serious) Adverse Events
	Pioglitazone Patients
	Affected / at Risk (%)	# Events
Total	18/21 (85.7%)
Blood and lymphatic system disorders
Anemia	1/21 (4.8%)	1
Bleeding gums, occasional	1/21 (4.8%)	1
Peripheral edema	6/21 (28.6%)	7
Puffy eyes	1/21 (4.8%)	1
Cardiac disorders
Facial edema	1/21 (4.8%)	1
Pounding pulse	1/21 (4.8%)	1
Transient elevated blood pressure	1/21 (4.8%)	1
Ear and labyrinth disorders
Ear pain, right side	1/21 (4.8%)	1
Ringing in ears	1/21 (4.8%)	1
Eye disorders
Stye-inside corner, right eye	1/21 (4.8%)	1
Gastrointestinal disorders
Abdominal bloating	1/21 (4.8%)	1
Black stools	1/21 (4.8%)	1
Diarrhea	3/21 (14.3%)	3
Dry mouth	1/21 (4.8%)	1
Increased heartburn	1/21 (4.8%)	1
Nausea	4/21 (19%)	5
Oral canker sores	1/21 (4.8%)	2
Oral cavity/gum pain	2/21 (9.5%)	2
Sore throat	1/21 (4.8%)	1
General disorders
Chest pain	1/21 (4.8%)	1
Fatigue	3/21 (14.3%)	5
Headache	5/21 (23.8%)	5
Insomnia	2/21 (9.5%)	2
Weight loss	1/21 (4.8%)	1
Infections and infestations
Bronchitis	1/21 (4.8%)	1
Left eye crusty, burning, reddened	1/21 (4.8%)	1
Rhinitis	1/21 (4.8%)	1
Strep throat	1/21 (4.8%)	1
Upper respiratory infection	4/21 (19%)	4
Urinary tract infection	2/21 (9.5%)	2
Metabolism and nutrition disorders
AST elevated	1/21 (4.8%)	1
Decreased uric acid	1/21 (4.8%)	1
Hematuria	1/21 (4.8%)	1
Hypercholesterolemia	1/21 (4.8%)	1
Hypernatremia	1/21 (4.8%)	1
Hyponatremia	1/21 (4.8%)	1
Musculoskeletal and connective tissue disorders
Back pain	2/21 (9.5%)	2
Joint pain	4/21 (19%)	5
Muscle stiffness, aches, myalgia	3/21 (14.3%)	5
Weakness	1/21 (4.8%)	1
Nervous system disorders
Lightheadness, dizzy	3/21 (14.3%)	3
Pain, mild stinging sensation	1/21 (4.8%)	3
Shakey, tremor	1/21 (4.8%)	1
Psychiatric disorders
Anxiety	1/21 (4.8%)	1
Depression	1/21 (4.8%)	1
Renal and urinary disorders
WBCs in urine, asymptomatic	1/21 (4.8%)	1
Reproductive system and breast disorders
Post menopausal spotting	1/21 (4.8%)	1
Respiratory, thoracic and mediastinal disorders
Asthma symptoms	1/21 (4.8%)	2
Cough	2/21 (9.5%)	2
Skin and subcutaneous tissue disorders
Diaphoresis	1/21 (4.8%)	1
Eczema	1/21 (4.8%)	3
Groin pain right hernia site (wound)	1/21 (4.8%)	1
Nail splitting	1/21 (4.8%)	1
Ulcer at old gallbladder incision site	1/21 (4.8%)	1

Limitations/Caveats

Study was closed prior to full accrual because results were very good and funding was discontinued (R-01 application was filed.) Immunohistochemistry (Outcomes #4 through #12) were not done due to laboratory limitations of time.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.