Atorvastatin Calcium, Oligofructose-Enriched Inulin, or Sulindac in Preventing Cancer in Patients at Increased Risk of Developing Colorectal Neoplasia

Study Overview
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Brief Summary
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This randomized phase II trial is studying atorvastatin calcium to see how well it works compared to oligofructose-enriched inulin, sulindac, or a placebo in preventing cancer in patients at increased risk of developing colorectal neoplasia. Chemoprevention is the use of certain drugs or substances to keep cancer from forming, growing, or coming back. The use of atorvastatin calcium, oligofructose-enriched inulin, or sulindac may stop cancer from forming in patients at increased risk of colorectal neoplasia. It is not yet known whether atorvastatin calcium, oligofructose-enriched inulin, or sulindac are more effective than a placebo in preventing cancer in patients at increased risk of developing colorectal neoplasia.

Detailed Description
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PRIMARY OBJECTIVE: I. Percent change in number of rectal aberrant cryptic foci (ACF) as measured by magnification chromoendoscopy SECONDARY OBJECTIVES: I. Screening for possible phase III testing II. Effects on proliferation (Ki67 expression) and apoptosis (caspase-3 expression) as measured by biopsy samples obtained from normal-appearing rectal mucosa at baseline and after completion of study treatment III. Correlation of endoscopic features with histologic characteristics of rectal ACF IV. Observation of the natural history of rectal ACF in patients receiving placebo V. Adverse events VI. Utilization of a biospecimen repository archive OUTLINE: This is a multicenter, prospective, randomized, partially blinded, placebo-controlled study. Patients are stratified according to history of prior surgical resection of the colon (yes vs no) and number of rectal aberrant cryptic foci (ACF) (5-9 vs >= 10). Patients are randomized to 1 of 4 treatment arms. ARM I: Patients receive oral atorvastatin calcium once daily. ARM II: Patients receive oral sulindac twice daily. ARM III (blinded arm): Patients receive oral oligofructose-enriched inulin (Raftilose Synergy 1) twice daily. ARM IV (blinded arm): Patients receive an oral placebo twice daily. In all arms, treatment continues for 6 months in the absence of unacceptable toxicity. Tissue samples are collected at baseline and at the completion of study treatment. Tissue is examined by immunohistochemistry for proliferation (Ki67) and apoptosis (cleaved caspase-3). After completion of study treatment, patients are followed at approximately 30 days.

Official Title
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Randomized, Phase II Trial of Atorvastatin, RAFTILOSE Synergy 1, and Sulindac Among Patients at Increased Risk for Sporadic Colorectal Neoplasia

Conditions
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Colon Cancer, Precancerous Condition, Rectal Cancer

Intervention / Treatment
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* Drug: oligofructose-enriched inulin
* Drug: sulindac
* Drug: placebo
* Drug: atorvastatin calcium
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Criteria: ECOG performance status 0-2 Platelet count >= 100,000/mm^3 Fertile patients must agree to use effective contraception No history of inflammatory bowel disease (i.e., Crohn's disease or ulcerative colitis) No invasive malignancy within the past 5 years except nonmelanoma skin cancer or colorectal cancer No history of endoscopically-confirmed peptic ulcer disease No history of allergic reactions attributed to compounds of similar chemical or biological composition to the study agents No history of chronic liver disease or unexplained persistent elevations of serum transaminases No history of allergic-type reactions, including asthma or urticaria, to aspirin or NSAIDs No uncontrolled intercurrent illness including, but not limited to, any of the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric illness or social situations that would preclude study compliance At least 6 weeks since prior oral corticosteroids Creatinine =< 1.5 times ULN Creatine phosphokinase =< 1.5 times ULN Not pregnant or nursing At least 6 weeks since prior statins At increased risk for developing sporadic colorectal neoplasia, as defined by 1 of the following: History of colon cancer (excluding stage IV or Dukes' D tumors) Must have completed prior adjuvant therapy for colon cancer >= 12 months ago History of colorectal adenomas, meeting any of the following criteria: >= 1 cm in diameter >= 3 in total number Any component of villous morphology High-grade dysplasia At least 5 rectal aberrant cryptic foci (ACF), by magnification chromoendoscopy, meeting both of the following criteria: At least 5 aggregated crypts in a single grouping (maximum spacing between crypts must be =< 2 times the average crypt diameter) Crypt diameter >= 1.5 times the diameter of surrounding normal crypts No history of rectal cancer, familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer Negative pregnancy test At least 6 months since prior and no concurrent regular use* of nonsteroidal anti-inflammatory drugs** (NSAIDs) or statins Concurrent aspirin at cardioprotective doses (=< 162.5 mg/day or 325 mg every other day) allowed No prior rectal surgery involving mucosal resection No prior pelvic radiation therapy No concurrent regular use* of cyclooxygenase-2 inhibitors No concurrent anticoagulant drugs (i.e., warfarin, heparin, clopidogrel bisulfate, or extended-release dipyridamole) No concurrent use of any of the following: Fibrates (e.g., gemfibrozil or fenofibrate) Cyclosporine Erythromycin or macrolide antibiotics Protease inhibitors Azole antifungals Diltiazem Verapamil Compounds containing niacin or nicotinic acid Defined as 7 consecutive days for > 3 weeks OR > 21 days total during study participation Patients may be eligible for study treatment after discontinuing NSAIDs for 12 weeks, at the discretion of their health care provider No other concurrent investigational agents No planned (or likely to require) clinically indicated colonoscopy or flexible sigmoidoscopy during study treatment Bilirubin =< 1.5 times ULN Hemoglobin >= lower limit of normal AST =< 1.5 times upper limit of normal (ULN) Alkaline phosphatase =< 1.5 times ULN

Ages Eligible for Study
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Minimum Age: 40 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 (atorvastatin calcium)<br>Patients receive oral atorvastatin once daily. | Drug: atorvastatin calcium<br>* Given orally<br>* Other names: Lipitor;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Arm II (sulindac)<br>Patients receive oral sulindac twice daily. | Drug: sulindac<br>* Given orally<br>* Other names: SULIN;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Arm III (oligofructose-enriched inulin)<br>Patients receive oral oligofructose-enriched inulin (Raftilose Synergy 1) twice daily. | Drug: oligofructose-enriched inulin<br>* Given orally<br>* Other names: Synergy 1;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Placebo Comparator: Arm IV (placebo)<br>Patients receive an oral placebo twice daily. | Drug: placebo<br>* Given orally<br>* Other names: PLCB;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Number of Rectal Aberrant Cryptic Foci (ACF) as Measured by Magnification Chromoendoscopy | At the Pre-Intervention Evaluation, rectal ACF will be classified with respect to ACF number, crypt number, crypt size, tissue plane, staining intensity, and (optional) lumen shape for each subject. At the Post- Intervention Evaluation, these same parameters will be recorded and incident vs prevalent rectal ACF status will also be recorded. Compare each non-placebo arms versus the placebo arm to screen the three active study agents for possible phase III testing. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effects on Proliferation (Ki67 Expression). | Tissue is examined by immunohistochemistry for Ki67. Measured by biopsy samples obtained from normal-appearing rectal mucosa at baseline and after completion of study treatment. Wilcoxon will be used to assess significant differences between the intervention arms. | Up to 6 months | 
| Effects on Apoptosis (Caspase-3 Expression). | Tissue is examined by immunohistochemistry for cleaved caspase-3. Measured by biopsy samples obtained from normal-appearing rectal mucosa at baseline and after completion of study treatment. Wilcoxon will be used to assess significant differences between the intervention arms. | Up to 6 months | 
| Adverse Events. | Defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with participation in a study, whether or not related to that participation. Graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 3.0. Number of adverse events per grade level. | Up to 30 days after completion of study treatment |