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

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

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.

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.

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