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.

Study Overview

• Status: Completed
• Conditions: Rectal Cancer; Colon Cancer; Precancerous Condition
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: sulindac; Drug: atorvastatin calcium; Drug: oligofructose-enriched inulin; Drug: placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 85
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (atorvastatin calcium); Patients receive oral atorvastatin once daily.	Other: laboratory biomarker analysis; Correlative studies; Drug: atorvastatin calcium; Given orally; Other Names: Lipitor; CI-981
Experimental: Arm II (sulindac); Patients receive oral sulindac twice daily.	Other: laboratory biomarker analysis; Correlative studies; Drug: sulindac; Given orally; Other Names: Aflodac; Algocetil; Clinoril; SULIN
Experimental: Arm III (oligofructose-enriched inulin); Patients receive oral oligofructose-enriched inulin (Raftilose Synergy 1) twice daily.	Other: laboratory biomarker analysis; Correlative studies; Drug: oligofructose-enriched inulin; Given orally; Other Names: Beneo Synergy 1; Synergy 1
Placebo Comparator: Arm IV (placebo); Patients receive an oral placebo twice daily.	Other: laboratory biomarker analysis; Correlative studies; Drug: placebo; Given orally; Other Names: PLCB

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start: March 1, 2006
• Primary Completion (Actual): April 1, 2009
• Study Completion (Actual): April 1, 2009

Study Registration Dates

• First Submitted: June 8, 2006
• First Submitted That Met QC Criteria: June 8, 2006
• First Posted (Estimate): June 12, 2006

Study Record Updates

• Last Update Posted (Actual): February 15, 2017
• Last Update Submitted That Met QC Criteria: December 28, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Precancerous Conditions; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antimetabolites; Antineoplastic Agents; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Calcium-Regulating Hormones and Agents; Atorvastatin; Calcium; Sulindac
• Other Study ID Numbers: NCI-2009-00837 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA015083 (U.S. NIH Grant/Contract); N01CN35000 (U.S. NIH Grant/Contract); CDR0000467755; MAY03-1-03 (Other Identifier: DCP)