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.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Other: laboratory biomarker analysis; Procedure: biopsy; Drug: nitric oxide-releasing acetylsalicylic acid derivative

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 240
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • Stony Brook, New York, United States, 11794-8174
      • Stony Brook University Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Masking: Double

What is the study measuring?

Primary Outcome Measures

Outcome Measure
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
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

Collaborators and Investigators

• Sponsor: Stony Brook University
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Basil Rigas, MD, Stony Brook University

Study record dates

Study Major Dates

• Study Start: July 1, 2006

Study Registration Dates

• First Submitted: May 30, 2006
• First Submitted That Met QC Criteria: May 30, 2006
• First Posted (Estimate): May 31, 2006

Study Record Updates

• Last Update Posted (Estimate): February 9, 2009
• Last Update Submitted That Met QC Criteria: February 6, 2009
• Last Verified: May 1, 2007

More Information

Terms related to this study

• Keywords: rectal cancer; colon cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Protease Inhibitors; Protective Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Antioxidants; Free Radical Scavengers; Endothelium-Dependent Relaxing Factors; Gasotransmitters; Cysteine Proteinase Inhibitors; Aspirin; Nitric Oxide; Nitroaspirin
• Other Study ID Numbers: CDR0000473094; SUNY-UH-20055574