Aspirin in Preventing Disease Recurrence in Patients With Barrett Esophagus After Successful Elimination by Radiofrequency Ablation

PRIMARY OBJECTIVES:

I. To conduct a randomized, double blind, placebo-controlled phase II chemoprevention trial,
investigating whether supplementation with aspirin 325 mg/day for 12 months is safe and
reduces the expression of CDX2 messenger ribonucleic acid (mRNA) (a biomarker which has been
associated with the risk of developing Barrett's esophagus [BE]) in comparison to placebo
after successful radiofrequency ablation (RFA).

SECONDARY OBJECTIVES:

I. To assess safety at 12 months. II. To assess differences in the expression of CDX2 at 18
months, activation status of NF-kB by assessing levels of total and phosphorylated
(phospho)-p65 and cytoplasmic to nuclear translocation of phospho-p65 which is likely to be
affected by aspirin.

III. To assess the prostanoid marker, prostaglandin E2, and prostaglandin synthases, which
are known to respond to aspirin and to correlation with clinicopathological factors in the
esophageal cancer.

IV. To assess differences in the expression of proinflammatory cytokines known to induce
activation of NFkB, i.e., TNFalpha, IL-1beta, IL-6, IL-10, IL-17A, IL-23 will be measured.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive aspirin orally (PO) once daily (QD) for 12 months.

ARM B: Patients receive placebo PO QD for 12 months.

After completion of study treatment, patients are followed up at 1, 3, 6, 9, 12, and 18
months.

Inclusion Criteria:

- Known diagnosis of histologically-confirmed BE with or without dysplasia (as defined
by the presence of specialized columnar epithelium anywhere in the tubular esophagus
with >= 1 cm of circumferential involvement or non-circumferential involvement of
specialized columnar epithelium) requiring radiofrequency ablation

- Documentation of complete ablation of BE after radiofrequency ablation on two
endoscopic examinations at least 3 months apart (including no evidence of BE on
surveillance biopsies) as determined by the pathologist at each site; completion of
ablation should have occurred no greater than 36 months prior to randomization

- Persons of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation; should a participant become pregnant or suspect
she is pregnant while participating in this trial, she should inform the research
personnel and her clinical care provider immediately

- Willingness to provide tissue samples for research purposes

- No chronic use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) or
selective cyclooxygenase-2 (COX-2) inhibitors during one month prior to randomization;
chronic use is defined as any aspirin or NSAID use on >= 7 days during one month
preceding the beginning of randomization

- Hemoglobin >= 10 g/dL or hematocrit >= 30% obtained =< 45 days prior to randomization

- Leukocyte count >= 3,000/microliter obtained =< 45 days prior to randomization

- Platelet count >= 100,000/microliter obtained =< 45 days prior to randomization

- Absolute neutrophil count >= 1,500/microliter obtained =< 45 days prior to
randomization

- Creatinine =< 2.5 x institutional upper limit of normal (ULN) obtained =< 45 days
prior to randomization

- OR glomerular filtration rate (GFR) > 30 ml/min/1.73 m^2 obtained =< 45 days prior to
randomization

- Total bilirubin =< 2 x institutional ULN obtained =< 45 days prior to randomization

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =<
2.5 x institutional ULN obtained =< 45 days prior to randomization

- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
institutional ULN obtained =< 45 days prior to randomization

- A negative serum pregnancy test at baseline, but within 21 days of randomization, for
persons of childbearing potential only

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Ability to understand and the willingness to sign a written informed consent document;
a legally authorized representative (LAR) may sign informed consent for persons who do
not have the capacity to legally consent to take part in the study

Exclusion Criteria:

- Inability to abstain from, NSAID (including aspirin), and selective COX-2 inhibitor
therapy at the time of randomization through the completion of the study (the study
period is defined as baseline to exit endoscopy at 18 months after randomization which
defines the completion of the study); participants may take Tylenol and non-NSAID pain
relievers

- Current or planned use of anticoagulant drugs such as: warfarin, heparin, low
molecular weight heparin, Plavix, or Aggrenox throughout the course of the study

- Individuals taking the drugs listed below may not be randomized unless they are
willing to stop the medications (and possibly change to alternative non-excluded
medications to treat the same conditions) no less than 1 month prior to starting
aspirin or placebo on this study; consultation with the participant's primary care
provider will be obtained prior to stopping any agent; the use of the following drugs
or drug classes is prohibited during aspirin/placebo treatment:

- NSAIDs: such as aspirin, Naprosyn, ketorolac and others NSAIDs

- COX-2 inhibitors: such as celecoxib, rofecoxib

- Valproic acid

- Sulfinpyrazone

- Probenecid

- Corticosteroids (other than short-term use defined as less than 2 weeks or pro re
nata [prn (when necessary)] use of an inhaler less than twice per month)

- Platelet aggregation inhibitors, except in a monitored antithrombotic regimen

- Methotrexate (MTX)

- Vaccines containing live viruses

- Gingko

- Individuals with uncontrolled renal insufficiency or renal failure

- Participants with fundoplication within the past year, bariatric surgery or any other
major upper gastrointestinal (GI) surgery; fundoplication more than one year ago will
not be grounds for exclusion; cholecystectomy will not be grounds for exclusion

- History of invasive cancer diagnosis =< 12 months prior to randomization, excepting
nonmelanoma skin cancer; patients with T1a adenocarcinoma of the esophagus arising in
the setting of Barrett's esophagus are eligible for enrollment in the trial

- History of cancer treatment =< 12 months prior to randomization, excepting hormonal
therapy (except treatment for non-melanoma skin cancer or carcinoma-in-situ of the
cervix)

- Receipt of any other investigational agents =< 3 months prior to randomization, except
innocuous agents with no known interaction with the study agents (e.g., standard dose
multivitamins or topical agents for limited skin conditions), at the discretion of the
protocol lead investigator at each participating site

- History of allergic reactions attributed to aspirin or compounds of similar chemical
or biologic composition to the study agent

- History of endoscopically or radiographically diagnosed peptic ulcer disease with
upper GI bleeding during the past 5 years or history of endoscopically or
radiographically diagnosed peptic ulcer disease with upper GI bleeding any time while
taking aspirin

- Uncontrolled intercurrent illness including, but not limited to: 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 or more drinks per day) or psychiatric illness/social situations that
would limit compliance with study requirements

- Pregnant women

- Breast feeding women

- Surveillance biopsies demonstrating residual BE at qualifying exam

- Presence of an esophageal stricture defined as "any recognizable change in esophageal
luminal caliber that is accompanied by symptoms of dysphagia, or any asymptomatic
narrowing that either will not allow any adult endoscope to pass or allows passage
with resistance"

- Patients with human immunodeficiency virus (HIV) infection