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

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

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.

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.

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