Nitric Oxide-Releasing Acetylsalicyclic Acid in Preventing Colorectal Cancer in Patients at High Risk of Colorectal Cancer

Study Overview
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Brief Summary
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RATIONALE: Chemoprevention is the use of certain drugs to keep cancer from forming, growing, or coming back. The use of nitric oxide-releasing acetylsalicyclic acid may prevent colorectal cancer. PURPOSE: This randomized phase I trial is studying the side effects and best dose of nitric oxide-releasing acetylsalicyclic acid in preventing colorectal cancer in patients at high risk of colorectal cancer.

Detailed Description
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OBJECTIVES: Primary Evaluate the effects of nitric oxide-releasing acetylsalicyclic acid on aberrant cryptic foci (ACF) in patients at high risk for colon cancer. Secondary Determine the pharmacokinetic profile of this drug in these patients. Determine the presence or absence of ACF in these patients. Determine the expression of PGE2, COX-1, COX-2, NF-kB, and β-catenin in colon tissue. Determine the safety and tolerability of long-term nitric oxide-releasing acetylsalicyclic acid in these patients. OUTLINE: This is a multicenter, double-blind, randomized, placebo-controlled, parallel group study. Patients are stratified according to gender and race (black vs non-Hispanic white vs Hispanic white vs Asian). Patients are randomized to 1 of 3 treatment arms. Arm I: Patients receive oral nitric oxide-releasing acetylsalicyclic acid twice daily for 6 months. Arm II: Patients receive nitric oxide-releasing acetylsalicyclic acid twice daily for 6 months at a higher dose than in arm I. Arm III: Patients receive oral placebo twice daily for 6 months. Patients undergo sigmoidoscopies at baseline and at the completion of study treatment. Biopsies of aberrant cryptic foci (ACF) and non-ACF sites are collected at both sigmoidoscopies. Tissue is examined for biomarkers (PGE_2, COX, NF-kB, β-catenin). After completion of study treatment, patients are followed periodically. PROJECTED ACCRUAL: A total of 240 patients will be accrued for this study.

Official Title
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Phase I Multiple-Dose Safety, Pharmacokinetic and Pharmacodynamic Clinical Study of Nitric Oxide Releasing Aspirin (NCX 4016)

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: nitric oxide-releasing acetylsalicylic acid derivative
* Other: laboratory biomarker analysis
* Procedure: biopsy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: At risk for colorectal cancer History of histologically proven sporadic colon adenomas or colon cancer At least 5 aberrant cryptic foci on sigmoidoscopy Less than 20 prior cumulative adenomas and no heredity nonpolyposis colorectal cancer No significant asymptomatic lesions on sigmoidoscopy, including any of the following: Inflammation Strictures Anorectal lesions Fistulae Vascular lesions No adenomas or colon carcinomas on flexible sigmoidoscopy No history of gastrointestinal (GI) cancer other than colorectal cancer No inherited colorectal cancer syndromes PATIENT CHARACTERISTICS: No other GI mucosal epithelial diseases (e.g., Barrett's esophagus, chronic or recurrent peptic ulcer disease, celiac sprue, or other disorders of nutrient absorption) No active peptic ulcer disease No history of inflammatory bowel disease (ulcerative colitis or Crohn's disease) No known or suspected alcohol ( > 5 glasses of wine or beer per day), drug, or medication abuse No quantitative or qualitative platelet or coagulation abnormalities No personal or family history of a bleeding disorder No uncontrolled diabetes No uncontrolled hypertension, or chronic congestive heart failure (New York Heart Association class II-IV heart disease) No myocardial infarction, transient ischemic attack, or stroke within the past 6 months No equilibrium disorders affecting gait or ability to stand that would preclude study participation No involuntary change in weight (up or down) of ≥ 15% of usual body weight within the past year Creatinine ≤ 2.0 mg/dL No chronic liver disease or pancreatitis No allergies to aspirin No prior severe adverse reactions to NSAIDs such as asthma, GI bleeding, or renal insufficiency No institutionalized, mentally disabled patients No prisoners Not pregnant or nursing Fertile patients must use effective contraception Negative pregnancy test PRIOR CONCURRENT THERAPY: No concurrent antibiotic prophylaxis More than 7 days since prior nonsteroidal anti-inflammatory drug (NSAID) treatment, including aspirin No concurrent frequent use (> 7 days in previous month) of NSAIDs, cyclooxygenase (COX)-2 inhibitors, nitrovasodilators, or oral corticosteroids No concurrent macronutrient consumption below the 1st or above the 99th percentile of U.S. consumption No concurrent anticoagulants, ticlopidine, and clopidogrel More than 3 months since prior general anesthesia More than 3 months since prior investigational agents No concurrent NSAIDs, including aspirin or COX-2 inhibitors Acetaminophen allowed No concurrent nitrovasodilating drugs More than 3 months since prior participation in other investigational trials

Ages Eligible for Study
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Minimum Age: 50 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
Masking: Double


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: nitric oxide-releasing acetylsalicylic acid derivative|nan|
|Other: laboratory biomarker analysis|nan|
|Procedure: biopsy|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effects of nitric oxide-releasing acetylsalicyclic acid (NCX 4016) on aberrant cryptic foci (ACF) multiplicity after the second dose at 6 months |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic profile by blood, urine, and colon tissue sampling |  |  | 
| Incidence of ACF as measured by magnification chromoendoscopy |  |  | 
| Assessment of biomarkers expressed in colon tissue, including PGE2 (measured by immunoassay), COX-1, COX-2, NF-kB, and β-catenin (measured by immunohistochemistry) at baseline and at the final visit |  |  | 
| Data on C-Reactive protein as a marker for inflammation |  |  | 
| Safety and tolerability of long-term oral administration of NCX 4016 as measured by NCI CTCAE v3.0 |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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colon cancer, rectal cancer