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

Phase 2

Completed

Conditions: Barrett Esophagus
Esophageal Carcinoma

Interventions: Drug: Ursodiol
Other: Laboratory Biomarker Analysis

Registration Number: NCT01097304

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 36

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (ursodiol)	Ursodiol	Patients receive ursodiol PO BID for 6 months in the absence of disease progression or unacceptable toxicity.
Treatment (ursodiol)	Laboratory Biomarker Analysis	Patients receive ursodiol PO BID for 6 months in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Reversal of Oxidative DNA Damage as Assessed by Changes in 8-hydroxy-2' -Deoxyguanosine (8OHdG) Immunostaining	Baseline to 6 months	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.

Secondary Outcome Measures

Name	Time	Method
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	Baseline and 6 months	Results will be analyzed using paired t-tests. Results (mean values and changes during intervention) will be reported along with the corresponding confidence intervals.

Trial Locations

Locations (4): Arizona Cancer Center-North Campus
🇺🇸
Tucson, Arizona, United States
Southern Arizona Veterans Affairs Health Center
🇺🇸
Tucson, Arizona, United States
University of Arizona Health Sciences Center
🇺🇸
Tucson, Arizona, United States
University of North Carolina
🇺🇸
Chapel Hill, North Carolina, United States