Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase II Biomarker/Laboratory analysis, Prevention Temporarily closed 40 and over NCI MAYO-030103 MAYO-1395-05, MAY03-1-03, NCT00335504

Objectives

Primary

1. Compare the percent change in number of rectal aberrant cryptic foci (ACF), as measured by magnification chromoendoscopy performed pre- and post-study, in patients at increased risk of developing sporadic colorectal neoplasia treated with atorvastatin versus oligofructose-enriched inulin (Raftilose Synergy 1) versus sulindac versus placebo.

Secondary

1. Compare the primary endpoint across each of the treatment arms to screen for possible phase III testing.
2. Assess effects of the treatments versus placebo on proliferation (Ki67 expression) and apoptosis (caspase-3 expression) using biopsy samples obtained from normal-appearing rectal mucosa pre- and post-study treatment.
3. Correlate endoscopic features with histological characteristics of rectal ACF.
4. Observe the natural history of rectal ACF among patients randomly assigned to the placebo arm.
5. Evaluate adverse events associated with each of the 4 intervention arms.
6. Evaluate the distribution, endoscopic features, histologic and molecular characteristics of rectal ACF in patients with < 5 ACF.
7. Establish a biospecimen repository archive for future correlative studies.

Entry Criteria

Disease Characteristics:

• 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

Prior/Concurrent Therapy:

• See Disease Characteristics
• At least 6 weeks since prior oral corticosteroids
• At least 6 weeks since prior statins
• 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
• No other concurrent investigational agents
• No planned (or likely to require) clinically indicated colonoscopy or flexible sigmoidoscopy during study treatment

 [Note: *Defined as 7 consecutive days for > 3 weeks OR > 21 days total during study participation]

 [Note: **Patients may be eligible for study treatment after discontinuing NSAIDs for 12 weeks, at the discretion of their health care provider]

Patient Characteristics:

• ECOG performance status 0-2
• Hemoglobin ≥ lower limit of normal
• Platelet count ≥ 100,000/mm³
• AST ≤ 1.5 times upper limit of normal (ULN)
• Alkaline phosphatase ≤ 1.5 times ULN
• Bilirubin ≤ 1.5 times ULN
• Creatinine ≤ 1.5 times ULN
• Creatine phosphokinase ≤ 1.5 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• 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

Expected Enrollment

A total of 112 patients will be accrued for this study.

Outcomes

Percent change in number of rectal aberrant cryptic foci (ACF) as measured by magnification chromoendoscopy

Screening for possible phase III testing
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
Correlation of endoscopic features with histologic characteristics of rectal ACF
Observation of the natural history of rectal ACF in patients receiving placebo
Adverse events
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 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.

Trial Contact Information

Trial Lead Organizations

Mayo Clinic Cancer Center

Paul Limburg, MD, MPH, Protocol chair		Ph: 507-284-2511

Registry Information
Official Title		Randomized Phase II Trial of Atorvastatin, RAFTILOSE®Synergy1, and Sulindac Among Patients at Increased Risk for Sporadic Colorectal Neoplasia
Trial Start Date		2006-03-24
Trial Completion Date		2008-11-14 (estimated)
Registered in ClinicalTrials.gov		NCT00335504
Date Submitted to PDQ		2006-02-06
Information Last Verified		2008-03-30
NCI Grant/Contract Number		CA15083, CN35000