Aspirin in Preventing Colorectal Cancer in Patients at Increased Risk of Colorectal Cancer

Study Overview
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Brief Summary
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This randomized phase II trial is studying how well aspirin works in preventing colorectal cancer in patients at increased risk of colorectal cancer. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of aspirin may prevent colorectal cancer.

Detailed Description
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PRIMARY OBJECTIVE: I. Determine whether acetylsalicylic acid (aspirin) will alter spectral markers (i.e., spectral slope and fractal dimension) in distal colonic mucosa of patients who are at increased risk for the development or recurrence of colorectal cancer. SECONDARY OBJECTIVES: I. Assess the effect of this drug on colonic epithelial apoptosis and cell proliferation in these patients. II. Assess the effect of this drug on rectal prostaglandin levels in these patients. III. Assess the effect of this drug on platelet cyclooxygenase activity in these patients. IV. Correlate changes in spectral markers with UGT1A6 genotype in patients treated with this drug. OUTLINE: This is a multicenter, randomized, double-blind, placebo-controlled study. Patients are stratified by clinical site and adenoma/carcinoma maximal size. Patients with abnormal spectral biomarkers are randomized to 1 of 2 treatment arms. ARM I: Patients receive oral acetylsalicylic acid (aspirin) once daily. ARM II: Patients receive oral placebo once daily. In both arms, treatment continues for 3 months in the absence of unacceptable toxicity. Patients undergo flexible sigmoidoscopy and biopsies as well as blood collection at baseline (during prestudy colonoscopy) and at completion of study treatment for comparison of spectral signatures with biomarkers of both aspirin activity (including plasma cyclooxygenase activity and rectal prostaglandin levels) as well as with biomarkers associated with antineoplastic alteration (including apoptosis and cell proliferation). UGT1A6 genotyping analysis is also performed. After completion of study treatment, patients are followed at 3 months.

Official Title
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Spectral Markers in Aspirin Chemoprevention of Colonic Neoplasia

Conditions
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Colon Cancer, Precancerous Condition, Rectal Cancer

Intervention / Treatment
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* Drug: acetylsalicylic acid
* Drug: placebo
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Criteria: No active or metastatic cancer within the past 6 months Scheduled to undergo colonoscopy for colonic neoplasia surveillance Hemoglobin >= 12.0 g/dL Platelet count >= 120,000/mm^3 AST or ALT =< 1.5 times upper limit of normal (ULN) Alkaline phosphatase =< 1.5 times ULN Bilirubin =< 1.5 times ULN BUN =< 40 mg/dL Glomerular filtration rate >= 45 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No coagulopathy No anemia No history of peptic ulcer disease or gastrointestinal hemorrhage No history of cerebrovascular accident No uncontrolled hypertension No history of intolerance or allergy to aspirin or to NSAIDs No liver disease as manifested by signs or symptoms of cirrhosis No endoscopic or radiographic evidence of portal hypertension No active colitis by endoscopy No history of inflammatory bowel disease No requirement for aspirin as medical therapy (i.e., post-myocardial infarction or transient ischemic attack) No untreated helicobacter pylori infection History of significant colonic neoplasia, defined as 1 of the following: Adenoma within the past 6 years Colorectal cancer within the past 6 years Known adenoma on present exam Histologically confirmed polyps seen on imaging INR =< 1.5 At least 6 months since prior cancer treatment No other concurrent acetylsalicylic acid (aspirin)-containing products or non-steroidal anti-inflammatory drugs (NSAIDs) No concurrent systemic corticosteroids No other concurrent anticoagulants or antiplatelet agents No concurrent investigational drugs

Ages Eligible for Study
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Maximum Age: 75 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<br>Patients receive oral acetylsalicylic acid (aspirin) once daily. | Drug: acetylsalicylic acid<br>* Given orally<br>* Other names: Extren;Other: laboratory biomarker analysis<br>* Correlative study<br>|
| Placebo Comparator: Arm II<br>Patients receive oral placebo once daily. | Drug: placebo<br>* Given orally<br>* Other names: PLCB;Other: laboratory biomarker analysis<br>* Correlative study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of a Spectral Biomarker for Colonic Carcinogenesis (Called Spectral Slope or SPEC) From Baseline to 3 Months. | Spectral marker assessment was performed via LEBS analysis (low-coherence enhanced backscattering spectroscopy) on the uninvolved mucosal biopsies of subjects taken at baseline and after 3 months of treatment with either aspirin or placebo. SPEC characterizes the size distribution of macromolecular complexes and other intracellular structures, with a decrease of the spectral slope implying a shift of the size distribution of intracellular structures toward smaller sizes. Spectral markers SPEC and FRAC provide a measure of the fundamental characteristics of the tissue nanoscale architecture. | 3 months from baseline colonoscopy to end of intervention. | 
| Change of a Spectral Biomarker for Colonic Carcinogenesis (Called Fractal Dimension or FRAC) From Baseline to 3 Months. | Spectral marker assessment was performed via LEBS analysis (low-coherence enhanced backscattering spectroscopy) on the uninvolved mucosal biopsies of subjects taken at baseline and after 3 months of treatment with either aspirin or placebo. FRAC characterizes the spatial autocorrelation function of mass density distribution in tissue. SPEC and FRAC provide a measure of the fundamental characteristics of the tissue nanoscale architecture | 3 months from baseline colonoscopy to end of intervention. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Colonic Epithelial Apoptosis as Measured by Immunohistochemical Detection of Cleaved Caspase 3 | Evaluate the effect of aspirin on colonic epithelial apoptosis and cell proliferation as assessed by immunohistochemical detection of cleaved caspase 3 .These were performed on samples that had been previously analyzed for 4D-ELF. | 3 months from baseline colonoscopy to end of intervention. | 
| Changes in Colonic Cell Proliferation as Measured by Immunohistochemical Detection of Ki67 | Evaluate the effect of aspirin on colonic epithelial apoptosis and cell proliferation as assessed by immunohistochemical detection of Ki-67. These were performed on samples that had been previously analyzed for 4D-ELF. | 3 months from baseline colonoscopy to end of intervention. | 
| Rectal Prostaglandin Levels as Measured by ELISA | Evaluate the effect of aspirin on rectal prostaglandin levels. | 3 months from baseline colonoscopy to end of intervention. |