Ursodiol in Treating Patients With Barrett Esophagus and Low-Grade Dysplasia

Study Overview
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Brief Summary
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This pilot phase II trial studies how well ursodiol works in treating patients with Barrett esophagus or cells that look abnormal under a microscope but are not cancer (low-grade dysplasia). Chemoprevention is the use of certain drugs to keep cancer from forming. The use of ursodiol may keep cancer for forming in patients with Barrett esophagus or low-grade dysplasia.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the ability of UDCA (ursodiol) treatment to reverse oxidative deoxyribonucleic acid (DNA) damage in the esophageal epithelium of subjects with Barrett's esophagus. SECONDARY OBJECTIVES: I. To determine the effects of UDCA treatment on gastric bile acid composition and on cell proliferation in Barrett's epithelium. OUTLINE: Patients receive ursodiol orally (PO) twice daily (BID) for 6 months in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed up for 2 weeks.

Official Title
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Clinical Study of Ursodeoxycholic Acid in Barrett's Patients

Conditions
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Barrett Esophagus, Esophageal Carcinoma

Intervention / Treatment
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* Drug: Ursodiol
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Barrett's esophagus with histologically-confirmed intestinal metaplasia anywhere in the tubular esophagus either with >= 2 cm of involvement or with a minimum circumferential Barrett's esophagus (BE) length of 1 cm Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Leukocytes >= 3,000/uL Absolute neutrophil count >= 1,500/uL Platelets >= 100,000/uL Total bilirubin =< 2.0 mg/dL Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2 X institutional upper limit of normal (ULN) Creatinine =< 1X ULN Women of child-bearing potential (i.e., not surgically sterile or less than one year since last menstrual period) agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; women of childbearing potential must have a negative urine pregnancy test within 14 days prior to study agent administration; male subjects must agree to use adequate contraception (barrier method, abstinence, subject has had vasectomy or partner is using effective birth control or is postmenopausal) Ability to understand and the willingness to sign a written informed consent document Agree to refrain from any non-steroidal anti-inflammatory drug (NSAID) with the exception of low-dose aspirin (81 mg once daily [QD]) during the entire study period Agree not to take aluminum-containing antacids and anion exchange resins such as cholestyramine, colestimide or colestipol within 2 hours of taking UDCA Exclusion Criteria: Barrett's esophagus with high grade dysplasia or carcinoma at enrollment Medical conditions which would make completing endoscopies or completing the trial difficult including but not limited to previous transient ischemic attacks or cerebral vascular disease, severe respiratory disease, severe ischemic heart disease or myocardial infarction in the previous 6 months, inflammatory bowel disease Participants may not be receiving any other investigational agents within 1 month of study enrollment Have used NSAID for more than 5 days per month within 1 month of enrollment except low dose aspirin (81 mg QD) History of allergic reactions attributed to compounds of similar chemical or biologic composition to UDCA Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant and breastfeeding women are excluded from this study; breastfeeding should be discontinued during treatment; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately Have had major upper gastrointestinal (GI) surgeries within 6 months of enrollment including, but not limited to, fundoplication, bariatric surgery, cholecystectomy Erosive esophagitis detected at the baseline endoscopy Participants who need concurrent chemotherapy, radiotherapy, or cancer-related hormonal or immunotherapy during the time of study Participants who have had chemotherapy, radiotherapy, or cancer-related hormonal or immunotherapy within 18 months of the baseline visit Current or planned use of anticoagulant drugs including, but not limited to, warfarin, heparin, low molecular weight heparin, Plavix, or Aggrenox Use of cyclosporine during the time of study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (ursodiol)<br>Patients receive ursodiol PO BID for 6 months in the absence of disease progression or unacceptable toxicity. | Drug: Ursodiol<br>* Given PO<br>* Other names: URSO;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reversal of Oxidative DNA Damage as Assessed by Changes in 8-hydroxy-2' -Deoxyguanosine (8OHdG) Immunostaining | 8OHdG will be assessed by percentage of positively stained nuclear area. A paired t-test at a one-sided 0.05 significance level will be used to assess change during intervention. The observed results will be reported along with the corresponding confidence intervals. | Baseline to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Gastric Bile Acid Composition (Change in Percent of Total Bile Acid Present as Ursodeoxycholic Acid and Its Glycine/Taurine Conjugates) Measured by Liquid Chromatography-tandem Mass Spectrometry, From Baseline to Post-intervention |  | Baseline and 6 months | 
| Changes in Gastric Bile Acid Composition (Change in Percent of Total Bile Acid Present as Deoxycholic Acid and Its Glycine/Taurine Conjugates) Measured by Liquid Chromatography-tandem Mass Spectrometry, From Baseline to Post-intervention |  | Baseline and 6 months | 
| Changes in Cell Proliferation in BE Epithelium From Baseline to Post-intervention as Assessed by Proliferation-related Ki-67 Antigen (Ki67) Immunostaining, Percentage of Positively Stained Nuclei, in BE Tissue Sections | Results will be analyzed using paired t-tests. Results (mean values and changes during intervention) will be reported along with the corresponding confidence intervals. | Baseline and 6 months |