Esomeprazole Magnesium With or Without Aspirin in Preventing Esophageal Cancer in Patients With Barrett Esophagus

Study Overview
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Brief Summary
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This randomized phase II trial is studying the effect of esomeprazole magnesium and aspirin on tissue PGE2 levels compared with esomeprazole and placebo. This type of chemoprevention treatment investigates the use of certain drugs to assess whether they assist in the prevention of cancer. The use of esomeprazole magnesium with or without aspirin may help prevent esophageal cancer in patients with Barrett esophagus.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the effects of a 28 day intervention with aspirin 81 mg placebo orally (PO) once daily (QD) + aspirin 325 mg placebo PO QD + esomeprazole 40 mg PO BID versus aspirin 81 mg PO QD + aspirin 325 mg placebo PO QD + esomeprazole 40 mg PO BID versus aspirin 325 mg PO QD + aspirin 81 mg placebo PO QD + esomeprazole 40 mg PO BID on the absolute change in tissue prostaglandin E2 (PGE2) concentration, as determined from Barrett's esophagus mucosal biopsy samples obtained pre- and post-intervention (i.e. two pair-wise comparisons of two different doses of active aspirin regimens versus aspirin placebo group), Specifically, the two active aspirin + esomeprazole arms will be independently analyzed to see if they significantly reduce the mean tissue PGE2 concentration from Pre- to Post-intervention as compared to the aspirin placebo + esomeprazole arm. SECONDARY OBJECTIVES: I. To determine if the change in the tissue PGE2 concentration decreases significantly in the aspirin placebo + esomeprazole arm. II. To compare the change in mean tissue PGE2 concentration between the two active intervention arms to determine which one appears the most promising for further testing. III. To assess the effects of the three agents (arms) with respect to proliferation (Ki-67), apoptosis (caspase-3 expression), COX-2 expression, and p16 methylation using Pre- and Post-Intervention biopsy samples obtained from Barrett's mucosal tissue. IV. To evaluate all adverse events associated with each of the three intervention arms. V. To provide exploratory summaries of PGE2 concentration values by patient subgroups of interest. VI. To provide descriptive summaries of the esophagogastroduodenoscopy (EGD) results, the rate of dysplasia, adverse events, and the Run-In Agent compliance on all participants that signed a consent form and started the Run-In phase of the trial. VII. To establish a biospecimen repository archive for future correlative studies. OUTLINE: This is a multicenter, randomized, double-blind, placebo-controlled study. Patients are stratified according to dysplasia status, gender, and length of Barrett segment of circumferential involvement (5 cm vs = 5 cm). Patients are randomized to 1 of 3 treatment arms. ARM I: Patients receive two oral placebos once daily and oral esomeprazole magnesium twice daily. ARM II: Patients receive oral acetylsalicylic acid (aspirin) and oral placebo once daily and oral esomeprazole magnesium twice daily. ARM III: Patients receive a higher-dose of oral aspirin (higher than in arm II) and a lower-dose of oral placebo (lower than in arm II) once daily and oral esomeprazole magnesium twice daily. In all arms, treatment continues for 28 days in the absence of unacceptable toxicity. Tissue samples are collected before and after treatment and examined for tissue-based biomarkers (i.e., PGE_2, Ki-67, caspase-3 apoptosis, and cyclooxygenase-2) by immunohistochemistry, enzyme immunoassay, Western blot, and polymerase chain reaction. After completion of study therapy, patients are followed 7 - 30 days.

Official Title
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Randomized, Double-Blinded Phase II Trial of Esomeprazole Versus Esomeprazole + Two Doses of Aspirin in Barrett's Esophagus Patients

Conditions
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Barrett Esophagus, Esophageal Cancer

Intervention / Treatment
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* Drug: acetylsalicylic acid
* Drug: esomeprazole magnesium
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed Barrett esophagus, meeting all of the following criteria: Presence of specialized columnar epithelium anywhere in the tubular esophagus with ≥ 2 cm of circumferential involvement No evidence of high-grade dysplasia or cancer by esophagogastroduodenoscopy (EGD) No prior histologically confirmed esophageal dysplasia, including cancer Adequate Barrett mucosa, defined as ≥ 4 of 8 research samples with≥ 50% intestinal metaplasia in research biopsies No ulcer, erosion, plaque, nodule, stricture, or other luminal irregularity within the Barrett's segment or erosive esophagitis (Los Angeles classification > grade A) detected at pre-intervention EGD exam Eastern Cooperative Group (ECOG) performance status 0-2 Hemoglobin normal Platelet count ≥ 100,000/mm³ Aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal (ULN) Alkaline phosphatase ≤ 2.5 times ULN Bilirubin ≤ 2.5 times ULN Creatinine ≤ 2.5 times ULN Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No nasal polyps associated with asthma or induced or exacerbated by aspirin No malignancy within the past 5 years except for nonmelanoma skin cancer No history of allergic reactions attributed to compounds of similar chemical or biologic composition to the study agents or rescue medication No history of endoscopically or radiographically diagnosed peptic ulcer disease (bleeding or nonbleeding) No other uncontrolled illness including, but not limited to, any of the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Bleeding disorder Vitamin K deficiency Alcohol abuse (defined as ingestion of ≥ 3 drinks per day) Psychiatric illness or social situations that would limit study compliance At least 3 months since prior chronic use (defined as ≥ 7 days during the 3 months preceding the beginning of the Run-in phase) of acetylsalicylic acid (aspirin), nonsteroidal antiinflammatory drug (NSAIDs), or selective cyclooxygenase (COX-2) inhibitors At least 3 months since prior investigational agents except innocuous agents with no known interaction with the study agents (e.g., standard dose multivitamins or topical agents for limited skin conditions) No prior fundoplication, bariatric surgery, or any other major upper gastrointestinal surgery Prior cholecystectomy allowed No other concurrent NSAIDs (including aspirin) or selective COX-2 inhibitor therapy No concurrent anticoagulant drugs including, but not limited to, any of the following: Warfarin Heparin Low-molecular weight heparin Clopidogrel bisulfate Extended-release dipyridamole

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (placebo, esomeprazole magnesium)<br>Patients receive two oral placebos once daily and oral esomeprazole magnesium (40 mg, twice daily). | Drug: esomeprazole magnesium<br>* Given orally<br>Other: placebo<br>* Given orally<br>|
| Experimental: Arm II (low-dose aspirin, esomeprazole magnesium)<br>Patients receive both an oral placebo and acetylsalicylic acid (81 mg dose), once daily and oral esomeprazole magnesium (40 mg, twice daily). | Drug: acetylsalicylic acid<br>* Given orally<br>Drug: esomeprazole magnesium<br>* Given orally<br>Other: placebo<br>* Given orally<br>|
| Experimental: Arm III (higher-dose aspirin, esomeprazole magnesium)<br>Patients receive both an oral placebo and acetylsalicylic acid (325 mg dose), once daily and oral esomeprazole magnesium (40 mg, twice daily). | Drug: acetylsalicylic acid<br>* Given orally<br>Drug: esomeprazole magnesium<br>* Given orally<br>Other: placebo<br>* Given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mean Tissue Prostaglandin E2 (PGE2) Concentration as Determined From Barrett's Research Mucosal Biopsy Samples | The mean tissue PGE2 is reported for each Arm. | Baseline to 30 days after completion of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity | Toxicity is defined as adverse events that are classified as either possibly, probably, or definitely related to the interventional agent, graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The number of patients reporting adverse events will be tabulated by grade. | Up to 30 days after completion of study treatment |