Celecoxib to Prevent Colorectal Cancer in Patients Who Have Undergone Surgery to Remove Polyps

PRIMARY OBJECTIVES:

I. Determine the safety and efficacy of celecoxib in reducing the occurrence of new sporadic adenomatous polyps (SAP) in the colon and rectum in patients who have undergone polypectomy for previous SAP.

OUTLINE: This is a randomized, double blind, placebo controlled study. Patients are entered on one of two treatment arms.

Arm I: Patients receive celecoxib twice a day for 3 years.

Arm II: Patients receive placebo twice a day for 3 years.

Patients are evaluated for adenomatous colorectal polyps at 1 and 3 years.

PROJECTED ACCRUAL: Over 1000 patients will be accrued for this study.

Inclusion criteria

• The subject has had a documented colonoscopy to the cecum, by a study physician, with adequate preparation resulting in diagnosis and clearance of an adenomatous polyp(s) within 24 weeks prior to study entry; the 24- week period begins from the time of colonoscopy, which had resulted in full visualization of colon/rectum or the time of removal of adenoma which ever had occurred first
• At the baseline colonoscopy, the subject must have one of the following documented:

• One adenomatous polyp > 6 mm;

• If the colonoscopy report says that a 6 mm polyp was removed, and the local pathology report confirms that this adenoma was AT LEAST 6mm in any dimension, the subject is eligible
• If the colonoscopy report says that the 6mm polyp was removed, and the local pathology report says that multiple fragments of adenoma were obtained, the subject is eligible
• If the colonoscopy report says that a 6mm polyp was removed, but the pathologist measured this as 5mm or less in greatest dimension, the subject is NOT eligible
• Two or more adenomatous polyps of any size documented by local pathology report plus colonoscopy report; or
• One adenomatous polyp of any size and a documented history of adenomatous polyp(s); if the colonoscopy report indicates that polyps of any size were left in the subject, the subject is NOT eligible; if the colonoscopy report says that all visible adenomas were removed, the subject is eligible.

If the colonoscopy report does not specifically state that all visible adenomas were removed, but does not describe any adenomas that were left in, the subject is eligible

• The subject is willing to abstain from chronic use of all NSAIDs or COX-2 inhibitors, excluding aspirin (cardioprotective doses of less than or equal to 325mg po QOD or 162.5mg po QD) for the duration of the study; chronic use of NSAIDs is defined as a frequency 1 week (7 consecutive days) for more than three weeks per year
• The subject is willing to limit aspirin use to less than or equal to 325mg po QOD or 162.5mg po QD for the duration of the study
• The subset of subjects undergoing SEB analysis will be required to abstain from any aspirin use for the duration of the study
• The subjects' anticipated use of oral/intravenous corticosteroid must be less than 2 weeks over a 6 month period
• The subject's anticipated use of orally inhaled steroid must be less than 4 weeks over a 6 month period; if nasally inhaled steroid use is anticipated, the subject agrees to use mometasone (Nasonex) only. Use of mometasone is not restricted (all other nasal steroids are prohibited); subjects may change to mometasone, but must have discontinued the previous nasal steroid for at least 30 days prior to randomization
• If a subject is female and of child-bearing potential (women are considered not of childbearing potential if they are at least 2 years post-menopausal and/or surgically sterile), she:

• Has been using adequate contraception (abstinence, IUD, birth control pills, or spermicidal gel with diaphragm or condom) since her last menses and will use adequate contraception during the study,
• Is not lactating, and
• Has a documented negative serum or negative urine pregnancy tests within 14 days prior to study entry
• The subject must sign and date the informed consent statement
• Hemoglobin level of greater than 11.5 (both men and women)
• WBC count greater than 3000/mm^3
• Platelet count greater than 125,000
• Creatinine =< 1.5 X ULN
• AST =< 1.5 X ULN
• ALT =< 1.5 X ULN
• Total bilirubin =< 1.5 X ULN, unless the subject has Gilbert's disease, for which total bilirubin must be =< 2.0 X ULN
• Inclusion Criteria for the 2-year post-treatment safety assessment:

• Subjects who were enrolled in the Year-3 study will be eligible for a 2-year post-treatment safety assessment
• Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 2-year post-treatment safety assessment:

• Have been enrolled on the 3-year randomized portion of the clinical trial
• Willingness to continue with follow-up annual contacts for safety data collection
• The subject has signed and dated an addendum (Subject Letter) to the informed consent document prior to performing any post-treatment safety assessment procedures
• Inclusion Criteria for Post-treatment Follow-up Colonoscopy:

• All Subjects who completed Year 3 colonoscopy will be eligible for a post-treatment follow up colonoscopy 2 years after Year 3 colonoscopy
• Subjects must meet all of the following inclusion criteria to be eligible for follow up colonoscopy:

• Completion of study treatment (3 years of study drug or on study drug on December 17, 2004) on the 3-year randomized portion of the clinical trial
• Willingness to continue with follow-up contacts every 6 months for collecting concomitant medications use data and end-of-study colonoscopy at Year 5
• The subject has signed and dated a separate informed consent document prior to performing any follow-up procedures; while delay in obtaining consent is not optimal, patients may be consented and entered into the post-treatment follow-up study at any time prior to their Year 5 colonoscopy but no later than 1Q2007

Exclusion criteria

• The subject has a history of Familial Adenomatous Polyposis or Hereditary Non-Polyposis Colorectal Cancer (as defined by the Amsterdam Criteria)
• The subject has a history of inflammatory bowel disease
• Subject has a chronic or acute renal or hepatic disorder or a significant bleeding disorder
• The subject has a history of hypersensitivity to COX-2 inhibitors, NSAIDs, salicylates, or sulfonamides
• The subject has a history of large bowel resection, except appendectomy
• The subject has used NSAIDs, excluding aspirin at any dose at a frequency equal to or greater than three times per week during the two months prior to randomization
• The subject used aspirin at a dose exceeding 325mg QOD or 162.5mg QD at a frequency equal to or greater than three times per week during the two months prior to study entry
• For SEB measurement participants only: the subject used any dose of aspirin at a frequency greater than once weekly during the two months prior to study entry
• The subject used oral/intravenous corticosteroids for more than 2 weeks in past 6 months
• The subject used orally inhaled corticosteroids for more than 4 weeks in past 6 months and/or the subject has used nasally inhaled corticosteroids (except mometasone) within the last month prior to randomization
• The subject has treatment for a gastrointestinal ulcer in the past month prior to study entry
• The subject has a history of invasive cancer within the past five years (excluding non-melanoma skin cancer)
• The subject has received any investigational medication within 30 days prior to randomization or is scheduled to receive an investigational drug other than celecoxib during the course of the study
• The subject is unable to return for follow-up tests
• The subject participated in the study previously and had been withdrawn
• Subjects whom, in the opinion of the Lead PI, Institutional PI, or Subinvestigator are not appropriate candidates for Study participation
• Subjects currently using triazole or azole antifungal agents (i.e., fluconazole) or lithium