Aspirin in Preventing Colorectal Cancer in Patients With Colorectal Adenoma

Study Overview
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Brief Summary
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This phase IIa trial studies how well aspirin works in preventing colorectal cancer in patients with colorectal adenoma. Aspirin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVE: I. To test for the equivalency of the two aspirin schedules. SECONDARY OBJECTIVES: I. To evaluate the effects of aspirin treatments on: Ia. The ratio of cell proliferation (Ki-67)/apoptosis (TUNEL) in rectal biopsies; Ib. The ratio of cell proliferation (Ki-67)/necroptosis (pMLKL) in rectal biopsies; Ic. Fecal occult blood test (measures of adverse events) as measured by stool samples. EXPLORATORY OBJECTIVES: I. To evaluate the effects of aspirin treatments on: Ia. Cyclooxygenase-2 (COX-2) in rectal biopsies; Ib. Bcl-2-like protein 4 (BAX) in rectal biopsies; Ic. Transient receptor potential cation channel subfamily M member (7TRPM7) in rectal biopsies; Id. Joint index of COX-2 with TRPM7 expression in rectal biopsies; Ie. Joint index of TRPM7 with BAX in rectal biopsies; If. Methylation assays using the MethylationEPIC BeadChip to identify methylation biomarkers in genes (i.e. CDKN2A [cell cycle regulation], MGMT [deoxyribonucleic acid (DNA) repair], DAPK1 [apoptosis], CDH1 [cell invasion], WNT16 [Wnt pathway] and RASSF1 [RAS signaling]) involved in colorectal carcinogenesis, and other epigenome-wide methylation biomarkers as measured in rectal biopsies; Ig. Metagenomics analysis to measure abundance of Escherichia coli (E. coli) and Fusobacterium and other microbiota in rectal swabs. OUTLINE: Patients are randomized to 1 of 3 arms. ARM I: Patients receive aspirin orally (PO) daily for 12 weeks in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial. ARM II: Patients receive aspirin PO daily at weeks 1-3 and 7-9 and placebo PO daily at weeks 4-6 and 10-12 in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial. ARM III: Patients receive placebo PO daily for 12 weeks in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial. After completion of study, patients are followed up at 1 month.

Official Title
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Evaluating Intermittent Dosing of Aspirin for Colorectal Cancer Chemoprevention

Conditions
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Colorectal Adenoma

Intervention / Treatment
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* Drug: Aspirin
* Procedure: Biospecimen Collection
* Other: Placebo Administration
* Other: Questionnaire Administration
* Procedure: Rectal Biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of colorectal adenoma of any grade Age >= 18 years. Because no dosing or adverse event (AE) data are currently available on the use of aspirin in participants < 18 years of age, children are excluded from this study but will be eligible for future pediatric trials, if applicable Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) Leukocytes >= 3,000/microliter Absolute neutrophil count >= 1,500/microliter Platelets >= 150,000/microliter Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x institutional ULN Creatinine =< 1.5 x institutional ULN Blood hemoglobin >= 12.0 g/dL Alkaline phosphatase =< 1.5 x institutional ULN Blood urea nitrogen (BUN) =< 40 mg/dL Estimated glomerular filtration rate (eGFR) >= 45 mL/min Negative fecal occult blood test The effects of aspirin on the developing human fetus at the recommended therapeutic dose are unknown; for this reason, women of child-bearing 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 woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Current (within three weeks of randomization) or planned use during the study intervention of the following: Aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), or COX-2 inhibitors Anticoagulants, anti-platelet agents, or corticosteroids Gingko Ethanol consumption > 1 standard drinks/day for women, or > 2 standard drinks/day for men Methotrexate (MTX) Study participants will be instructed to use Tylenol or some other non-excluded agent to treat common ailments (i.e. headache/minor aches and pains) History of Any invasive malignancy within the past 2 years, with the exception of non-melanoma skin cancer Chronic renal diseases or liver cirrhosis Diseases such as anemia, peptic ulcer, gastrointestinal bleeding, active colitis and inflammatory bowel disease Hemorrhagic stroke or uncontrolled hypertension Participants may not be receiving any other investigational agents History of allergic reactions or intolerance attributed to aspirin or compounds of similar chemical or biologic composition Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness that would limit compliance with study requirements Women who are pregnant or breastfeeding; pregnant women are excluded from this study because aspirin has the potential for abortifacient effects; because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with aspirin, breastfeeding should be discontinued if the mother is treated with aspirin

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (aspirin)<br>Patients receive aspirin PO daily for 12 weeks in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial. | Drug: Aspirin<br>* Given PO<br>* Other names: Measurin;Procedure: Biospecimen Collection<br>* Undergo collection of blood, urine, stool, and rectal swab samples<br>* Other names: Specimen Collection;Other: Questionnaire Administration<br>* Ancillary studies<br>Procedure: Rectal Biopsy<br>* Undergo rectal biopsy<br>* Other names: Biopsy of Rectum;|
| Experimental: Arm II (aspirin, placebo)<br>Patients receive aspirin PO daily at weeks 1-3 and 7-9 and placebo PO daily at weeks 4-6 and 10-12 in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial. | Drug: Aspirin<br>* Given PO<br>* Other names: Measurin;Procedure: Biospecimen Collection<br>* Undergo collection of blood, urine, stool, and rectal swab samples<br>* Other names: Specimen Collection;Other: Placebo Administration<br>* Given PO<br>Other: Questionnaire Administration<br>* Ancillary studies<br>Procedure: Rectal Biopsy<br>* Undergo rectal biopsy<br>* Other names: Biopsy of Rectum;|
| Placebo Comparator: Arm III (placebo)<br>Patients receive placebo PO daily for 12 weeks in the absence of unacceptable toxicity. Patients also undergo collection of blood, urine, stool, rectal swab samples, and rectal biopsies throughout the trial. | Procedure: Biospecimen Collection<br>* Undergo collection of blood, urine, stool, and rectal swab samples<br>* Other names: Specimen Collection;Other: Placebo Administration<br>* Given PO<br>Other: Questionnaire Administration<br>* Ancillary studies<br>Procedure: Rectal Biopsy<br>* Undergo rectal biopsy<br>* Other names: Biopsy of Rectum;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio of cell proliferation to apoptosis biomarkers (Ki67 index and BAX index) |  | Up to 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio of cell proliferation (Ki-67)/apoptosis (TdT-mediated dUTP nick end labeling [TUNEL]) in rectal biopsies | All of these variables will be described using appropriate statistics such as means (for continuous) and proportions (for discrete outcomes). Typically, basic scientists like to present the data to each other as bar graphs with standard deviation/standard error bars. Such and other, more appropriate graphic presentations, as confidence intervals for the true mean or true proportion will be provided, as well as scatter plots presenting two variables relationship in the Cartesian axes context. Tests of difference for continuous data (t-test, Wilcoxon test) and of association for discrete data (Chi-square, Fisher) will be provided. | Up to 12 weeks | 
| Ratio of cell proliferation (Ki-67)/necroptosis (MLKL) in rectal biopsies | All of these variables will be described using appropriate statistics such as means (for continuous) and proportions (for discrete outcomes). Typically, basic scientists like to present the data to each other as bar graphs with standard deviation/standard error bars. Such and other, more appropriate graphic presentations, as confidence intervals for the true mean or true proportion will be provided, as well as scatter plots presenting two variables relationship in the Cartesian axes context. Tests of difference for continuous data (t-test, Wilcoxon test) and of association for discrete data (Chi-square, Fisher) will be provided. | Up to 12 weeks | 
| Fecal occult blood test (measures of adverse events) as measured by stool samples | All of these variables will be described using appropriate statistics such as means (for continuous) and proportions (for discrete outcomes). Typically, basic scientists like to present the data to each other as bar graphs with standard deviation/standard error bars. Such and other, more appropriate graphic presentations, as confidence intervals for the true mean or true proportion will be provided, as well as scatter plots presenting two variables relationship in the Cartesian axes context. Tests of difference for continuous data (t-test, Wilcoxon test) and of association for discrete data (Chi-square, Fisher) will be provided. | Up to 12 weeks |