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

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

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.

Study Overview

• Status: Completed
• Conditions: Esophageal Cancer; Barrett Esophagus
• Intervention / Treatment: Other: placebo; Drug: acetylsalicylic acid; Drug: esomeprazole magnesium

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 122
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Falk GW, Buttar NS, Foster NR, Ziegler KL, Demars CJ, Romero Y, Marcon NE, Schnell T, Corley DA, Sharma P, Cruz-Correa MR, Hur C, Fleischer DE, Chak A, Devault KR, Weinberg DS, Della'Zanna G, Richmond E, Smyrk TC, Mandrekar SJ, Limburg PJ; Cancer Prevention Network. A combination of esomeprazole and aspirin reduces tissue concentrations of prostaglandin E(2) in patients with Barrett's esophagus. Gastroenterology. 2012 Oct;143(4):917-26.e1. doi: 10.1053/j.gastro.2012.06.044. Epub 2012 Jul 11.

Study record dates

Study Major Dates

• Study Start: April 1, 2007
• Primary Completion (Actual): March 1, 2011
• Study Completion (Actual): June 1, 2011

Study Registration Dates

• First Submitted: May 16, 2007
• First Submitted That Met QC Criteria: May 16, 2007
• First Posted (Estimate): May 17, 2007

Study Record Updates

• Last Update Posted (Estimate): July 2, 2014
• Last Update Submitted That Met QC Criteria: June 2, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Precancerous Conditions; Esophageal Neoplasms; Barrett Esophagus; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Aspirin; Esomeprazole
• Other Study ID Numbers: NCI-2009-00838 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); N01CN35000 (U.S. NIH Grant/Contract); MAY04-4-01 (Other Identifier: DCP); CDR0000544180; MAYO-MAY04-4-01 (Other Identifier: Mayo Clinic)