Barrett Esophagus, Esophageal Carcinoma
Conditions
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.
Interventions
DRUGUrsodiol
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Ursodiol) Patients receive ursodiol PO (13 to 15 mg/kg/day) BID for 6 months in the absence of disease progression or unacceptable toxicity.
Ursodiol: Given PO
Laboratory Biomarker Analysis: Correlative studies | 36 |
| Total | 36 |
Baseline characteristics
| Characteristic | Treatment (Ursodiol) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 16 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Age, Continuous | 62.8 years STANDARD_DEVIATION 10.4 |
| Region of Enrollment United States | 36 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 31 / 36 |
| serious Total, serious adverse events | 5 / 36 |
Outcome results
Primary
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.
Time frame: Baseline to 6 months
Population: participants with fewer than 500 total nuclei in longitudinally sectioned crypts opening to the lumen were excluded from analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Ursodiol) | Reversal of Oxidative DNA Damage as Assessed by Changes in 8-hydroxy-2' -Deoxyguanosine (8OHdG) Immunostaining | 1.62 % of strongly/moderately stained nuclei | Standard Deviation 13.13 |
p-value: 0.54t-test, 2 sided
Secondary
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.
Time frame: Baseline and 6 months
Population: tissue slides with fewer than 500 total nuclei in longitudinally sectioned crypts opening to the lumen were excluded from analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Ursodiol) | 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 | 1.36 % change | Standard Deviation 13.13 |
p-value: 0.48t-test, 2 sided
Secondary
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
Time frame: Baseline and 6 months
Population: analysis was limited to participants with baseline and 6-month gastric fluid
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Ursodiol) | 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 | -13.31 % of total bile acid |
p-value: <0.01signed rank test
Secondary
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
Time frame: Baseline and 6 months
Population: analysis was limited to participants with baseline and 6-month gastric fluid
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Ursodiol) | 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 | 66.28 % of total bile acid |
p-value: <0.0001signed rank test