Clinical trial NCT02521285: Aspirin in Preventing Disease Recurrence in Patients With Barrett Esophagus After Successful Elimination by Radiofrequency Ablation
Official title: Effect of Aspirin on Biomarkers of Barrett's Esophagus After Successful Eradication of Barrett's Esophagus With Radiofrequency Ablation
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Barrett Esophagus
Esophageal Adenocarcinoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2015-08-13
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This randomized phase II trial studies the safety of and how well aspirin works in preventing Barrett's esophagus from returning after it has been successfully eliminated by radiofrequency ablation. Studying samples of tissue from patients with Barrett's esophagus for the levels of a specific protein that is linked to developing Barrett's esophagus may help doctors learn whether aspirin can prevent it from returning after it has been successfully treated.

Detailed description: 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.

Eligibility criteria: 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
* The effects of the candidate chemoprevention agents on the developing human fetus remain incompletely defined; for this reason, 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

Primary outcomes:
measure: Difference in the Change of CDX2 mRNA Levels in Esophageal Mucosa Between Participants Taking Aspirin and Placebo at 12 Months (Location A)
timeFrame: Baseline and 12 months
measure: Differences in the Change of CDX2 Messenger Ribonucleic Acid (mRNA) Levels in Esophageal Squamous Tissue Between Participants Taking Aspirin Supplementation Versus Those Taking Placebo (Location B)
timeFrame: Baseline and 12 months
measure: Differences in the Change of CDX2 Messenger Ribonucleic Acid (mRNA) Levels in Esophageal Squamous Tissue Between Participants Taking Aspirin Supplementation Versus Those Taking Placebo ( Location C)
timeFrame: Baseline and 12 months
measure: Differences in the Activation Status of NF-kB by Assessing Levels of Total and Phospho-p65 and Cytoplasmic to Nuclear Translocation of Phospho-p65 at 12 Months (Location A)
timeFrame: Baseline and 12 months
measure: Differences in the Activation Status of NF-kB by Assessing Levels of Total and Phospho-p65 and Cytoplasmic to Nuclear Translocation of Phospho-p65 at 12 Months (Location B)
timeFrame: Baseline and 12 months
measure: Differences in the Activation Status of NF-kB by Assessing Levels of Total and Phospho-p65 and Cytoplasmic to Nuclear Translocation of Phospho-p65 at 12 Months (Location C)
timeFrame: Baseline and 12 months
Secondary outcomes:
measure: Number of Participants With Adverse Events (AE)
timeFrame: Up to 18 months
measure: Differences in the Change of CDX2 mRNA Levels in Esophageal Squamous Tissue Between Participants Taking Aspirin Supplementation Versus Those Taking Placebo at 18 Months (Location A)
timeFrame: Baseline to 18 months
measure: Differences in the Change of CDX2 mRNA Levels in Esophageal Squamous Tissue Between Participants Taking Aspirin Supplementation Versus Those Taking Placebo at 18 Months (Location B)
timeFrame: Up to 18 months
measure: Differences in the Change of CDX2 mRNA Levels in Esophageal Squamous Tissue Between Participants Taking Aspirin Supplementation Versus Those Taking Placebo at 18 Months (Location C)
timeFrame: Baseline to 18 months
measure: Differences in the Activation Status of NF-kB by Assessing Levels of Total and Phospho-p65 and Cytoplasmic to Nuclear Translocation of Phospho-p65 at 18 Months (Location A)
timeFrame: Baseline up to 18 months
measure: Differences in the Activation Status of NF-kB by Assessing Levels of Total and Phospho-p65 and Cytoplasmic to Nuclear Translocation of Phospho-p65 at 18 Months (Location B)
timeFrame: Baseline up to 18 months
measure: Differences in the Activation Status of NF-kB by Assessing Levels of Total and Phospho-p65 and Cytoplasmic to Nuclear Translocation of Phospho-p65 at 18 Months (Location C)
timeFrame: Baseline up to 18 months
measure: Differences in the Change of txb2 at 12 Months (Location A)
timeFrame: Baseline and 12 months
measure: Differences in the Change of tbx2 at 12 Months (Location B)
timeFrame: Baseline and 12 months
measure: Differences in the Change of tbx2 at 12 Months (Location C)
timeFrame: Baseline and 12 months
measure: Differences in the Change of pge1 at 12 Months ( Location A)
timeFrame: Baseline and 12 months
measure: Differences in the Change of pge1 at 12 Months (Location B)
timeFrame: Baseline and 12 months
measure: Differences in the Change of pge1 at 12 Months (Location C)
timeFrame: Baseline and 12 months
measure: Differences in the Change of pge2 at 12 Months (Location A)
timeFrame: Baseline and 12 months
measure: Differences in the Change of pge2 at 12 Months (Location B)
timeFrame: Baseline and 12 months
measure: Differences in the Change in pge2 at 12 Months (Location C)
timeFrame: Baseline and 12 months
measure: Differences in the Change of a13pge1 at 12 Months (Location A)
timeFrame: Baseline and 12 months
measure: Differences in the Change of a13pge1 at 12 Months ( Location B)
timeFrame: Baseline and 12 months
measure: Differences in the Change in a13pge1 at 12 Months (Location C)
timeFrame: Baseline and 12 months
measure: Differences in the Change of a13pge2 at 12 Months (Location A)
timeFrame: Baseline and 12 months
measure: Differences in the Change of a13pge2 at 12month (Location B)
timeFrame: Baseline and 12 months
measure: Differences in the Change of a13pge2 at 12 Months (Location C)
timeFrame: Baseline and 12 months
Other outcomes:
measure: Differences in the Prostanoid Marker, Prostaglandin E2, and Prostaglandin Synthases
timeFrame: Baseline up to 18 months
measure: Differences in the Expression of Proinflammatory Cytokines Known to Induce Activation of NFkB
timeFrame: Baseline up to 18 months
measure: Incidence of Barrett's Esophagus (BE) Recurrence
timeFrame: Baseline up to 18 months
Locations:
city: Los Angeles
country: United States
facility: UCLA / Jonsson Comprehensive Cancer Center
state: California
city: Aurora
country: United States
facility: UCHealth University of Colorado Hospital
state: Colorado
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
city: Kansas City
country: United States
facility: Kansas City Veterans Affairs Medical Center
state: Missouri
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Philadelphia
country: United States
facility: University of Pennsylvania/Abramson Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
state: Texas
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Toronto
country: Canada
facility: Saint Michael's Hospital
state: Ontario
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Robert S Bresalier
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bresalier RS. Chemoprevention of Barrett's Esophagus and Esophageal Adenocarcinoma. Dig Dis Sci. 2018 Aug;63(8):2155-2162. doi: 10.1007/s10620-018-5149-6.