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

Colorectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00331786
• Other study ID #: CDR0000473094
• Secondary ID: SUNY-UH-20055574
• Status: Completed
• Phase: Phase 1
• First received: May 30, 2006
• Last updated: February 6, 2009
• Start date: July 2006

Study information

• Verified date: May 2007
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 240
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 50 Years and older

Eligibility

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 Design

Allocation: Randomized, Masking: Double-Blind, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms

Intervention

Drug:
• nitric oxide-releasing acetylsalicylic acid derivative

Other:
• laboratory biomarker analysis

Procedure:
• biopsy

Locations

Country	Name	City	State
United States	Stony Brook University Cancer Center	Stony Brook	New York

Sponsors (2)

Lead Sponsor	Collaborator
Stony Brook University	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Effects of nitric oxide-releasing acetylsalicyclic acid (NCX 4016) on aberrant cryptic foci (ACF) multiplicity after the second dose at 6 months			No
Secondary	Pharmacokinetic profile by blood, urine, and colon tissue sampling			No
Secondary	Incidence of ACF as measured by magnification chromoendoscopy			No
Secondary	Assessment of biomarkers expressed in colon tissue, including PGE2 (measured by immunoassay), COX-1, COX-2, NF-kB, and ß-catenin (measured by immunohistochemistry) at baseline and at the final visit			No
Secondary	Data on C-Reactive protein as a marker for inflammation			No
Secondary	Safety and tolerability of long-term oral administration of NCX 4016 as measured by NCI CTCAE v3.0			Yes