Official Title: “Phase IIa Trial of Rosiglitazone (Avandia) for Oral Leukoplakia”

RATIONALE: Chemoprevention is the use of certain drugs to keep cancer from forming, growing, or coming back. The use of rosiglitazone may keep cancer from forming in patients with oral leukoplakia.

PURPOSE: This phase II trial is studying how well rosiglitazone works in preventing oral cancer in patients with oral leukoplakia.

Study Type: Interventional

Study Design: Prevention, Non-Randomized, Open Label

Study Primary Completion Date: September 2007

OBJECTIVES:

Primary - Determine the rate of clinical response in patients with oral leukoplakia treated with rosiglitazone.

Secondary - Determine the rate and degree of change in putative biomarkers of rosiglitazone efficacy, as measured by cyclooxygenase-2, cyclin D1, Ki-67, p21/waf1, PPAR γ, K1 cytokeratin, involucrin, transglutaminase expressions, and TUNEL assay. - Correlate DNA-ploidy measurements or oral leukoplakia with clinical response and/or response of biomarkers to rosiglitazone. - Estimate the efficacy of rosiglitazone to normalize aberrant DNA-ploidy in these patients. - Assess smoking patterns among these patients and examine the relationship of smoking to treatment response. - Assess the safety of short-term use of rosiglitazone in these patients.

OUTLINE: This is a multicenter, open-label, nonrandomized study.

Patients receive oral rosiglitazone once daily. Treatment continues for 12 weeks in the absence of unacceptable toxicity.

Tissue samples are collected at baseline and then periodically throughout the study for correlative studies. Immunohistochemistry is used to analyze biologic markers, including cyclin D1, Ki-67, p21/waf1, PPAR γ, K1 cytokeratin, transglutaminase, involucrin, and TUNEL assay. Cyclooxygenase-2 expression is measured by reverse transcriptase-polymerase chain reaction. DNA-ploidy is also measured.

After completion of study treatment, patients are followed at 1 week.

PROJECTED ACCRUAL: A total of 25 patients will be accrued for this study.

Intervention(s) in this Clinical Trial

• Drug: rosiglitazone maleate
• Genetic: DNA ploidy analysis
• Genetic: reverse transcriptase-polymerase chain reaction
• Other: immunohistochemistry staining method
• Other: laboratory biomarker analysis
• Procedure: biopsy
• Procedure: evaluation of cancer risk factors

Primary Measures

• Clinical and/or histological response rate at week 12
  • Safety Issue?: No

Secondary Measures

• Tissue expressions of cyclooxygenase-2, cyclin D1, Ki-67, p21/waf1, PPAR γ, K1 cytokeratin, involucrin, and transglutaminase and tissue levels of apoptosis as assessed by TUNEL assay at baseline and week 12
  • Safety Issue?: No
• Tissue DNA-ploidy measurements at baseline and week 12
  • Safety Issue?: No
• Smoking and alcohol use at baseline and weeks 6 and 12
  • Safety Issue?: No
• Adverse event data and clinical laboratory data at baseline and weeks 6 and 12
  • Safety Issue?: Yes

DISEASE CHARACTERISTICS:

• Histologically confirmed oral premalignant lesion (excluding carcinoma in situ), meeting all of the following criteria:
• At least 12 mm in size
• Has not been biopsied in the past 6 weeks
• Must meet 1 of the following disease descriptions:
• Dysplastic measurable leukoplakia or erythroplakia in the oral cavity or accessible oropharynx
• Hyperplastic leukoplakia of high-risk sites, lateral and ventral tongue and floor of mouth
• No active cancer
• No carcinoma in situ of the head and neck

PATIENT CHARACTERISTICS:

• Karnofsky performance status 70-100%
• Life expectancy > 12 weeks
• Hemoglobin normal
• Hematocrit normal
• WBC ≥ 3,00/mm³
• Platelet count ≥ 125,00/mm³
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 1.5 times ULN
• BUN ≤ 1.5 times ULN
• Creatinine ≤ 1.5 times ULN
• Lactic dehydrogenase ≤ 1.5 times ULN
• Bacteria < 100,000
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No contraindication to biopsy
• No New York Heart Association class I-IV cardiac disease
• No history of congestive heart failure
• No history of myocardial infarction or angina
• No coronary artery disease within the past 6 months
• No active cardiac disease
• No clinical evidence of active liver disease or history of chronic liver disease or edema
• Diabetes allowed provided the following criteria are met:
• No concurrent treatment
• Not hyperglycemic (i.e., random blood glucose level > 200 mg/dL)
• No diabetic macular edema
• No history of jaundice with troglitazone
• No known hypersensitivity to rosiglitazone or any of its components
• No history of colorectal cancer, familial adenomatous polyposis (FAP), or hereditary non-polyposis colorectal cancer (HNPCC)
• No invasive cancer within the past 18 months except noninvasive bladder cancer, nonmelanoma skin cancer, or in situ cervical cancer
• No uncontrolled illness including, but not limited to, any of the following:
• Ongoing or active infection
• HIV
• Symptomatic congestive heart failure
• Unstable angina pectoris
• Cardiac arrhythmia
• Psychiatric illness or social situations that would limit study compliance

PRIOR CONCURRENT THERAPY:

• No prior rosiglitazone
• At least 12 weeks since other prior oral cancer chemopreventive therapy and recovered
• Daily acetylsalicylic acid (aspirin) is permitted
• At least 30 days since prior investigational therapy
• At least 18 months since prior and no concurrent chemotherapy, immunotherapy, hormonal therapy, or radiation therapy
• Prior and/or concurrent hormone replacement therapy for menopause allowed
• No concurrent insulin, sulfonylurea, metformin, or other thiazolidinediones
• No concurrent medical therapy for dysregulated blood sugar
• No other concurrent investigational drugs

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Memorial Sloan-Kettering Cancer Center

Overall Clinical Trial Officials and Contacts

Jay O. Boyle, MD Study Chair Memorial Sloan-Kettering Cancer Center  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00369174

Study ID Number: CDR0000491154

ClinicalTrials.gov Identifier: NCT00369174

Health Authority: United States: Federal Government

Clinical trial summary from the National Cancer Institute's PDQ® database