NIH Clinical Research Studies

Protocol Number: 02-C-0194

Active Accrual, Protocols Recruiting New Patients

Title:
Rectal Aberrant Crypt Foci And Other Intermediate Biomarkers For Sporadic Colorectal Neoplasia: Cross-Sectional Prevalence And Modulation By Celecoxib
Number:
02-C-0194
Summary:
Colorectal cancer is a leading cause of malignant death in the United States. Cancer chemoprevention, defined as the administration of pharmaceutical agents to modulate tumorigenesis, appears to be a promising strategy for delaying, diminishing, or eliminating colorectal neoplasia. Nonsteroidal anti-inflammatory drugs have demonstrated exciting chemopreventive activity against intestinal tumors, presumably due to their cyclooxygenase-blocking properties. A new, more selective cyclooxygenase-2 inhibitor, celecoxib, has been recently approved for clinical use. This compound has an excellent safety profile and appears to also have enhanced chemopreventive efficacy relative to traditional nonsteroidal anti-inflammatory drugs.

The primary objective of this study is to investigate the effects of celecoxib on rectal aberrant crypt foci among individuals with above average-risk for developing colorectal tumors. All subjects will be prospectively recruited from among adult colonoscopy patients seen at the National Naval Medical Center. Eligible participants will include patients found to have one adenoma greater than 1 cm in diameter or three adenomas greater than or equal to 5 mm in diameter (if 18-49 years of age) or one adenoma greater than or equal to 5 mm in diameter (if greater than or equal to 50 years of age) and at least 5 rectal aberrant crypt foci. Enrolled subjects (n=40) will be randomly assigned to receive either celecoxib 400 mg by mouth twice per day or placebo. After an intervention period of six months, a follow-up endoscopic (flexible sigmoidoscopy) examination of the distal colorectum will be performed. At the baseline colonoscopy procedure, rectal aberrant crypt foci will be quantitated and ascending and descending colon normal-appearing mucosa will be biopsied to measure proliferation, apoptosis, and gene expression biomarkers. The same will occur on the samples collected during the follow-up flexible sigmoidoscopy with biopsies of normal-appearing mucosa of the descending colon. Efficacy of the chemopreventive agent will be assessed by comparing pre-versus post-intervention changes across treatment arms.

Informed consent for the baseline biomarker assessments will be documented prior to the initial colonoscopy. In most cases, the presence or absence of colorectal neoplasia will not be know prior to this procedure. Thus, we plan to obtain ascending and descending,normal,colonic mucosa samples from approximately 40 subjects with no colorectal adenomas and 40 subjects with at least one adenoma. Exact sample sizes will be determined by the subject subgroup distribution at the time of full accrual into the intervention trial. Colorectal neoplasms identified during the baseline colonoscopy will additionally be sampled to allow for biomarker comparisons to be made between normal and dysplastic tissues.

As designed, this study will (1) provide novel data regarding the baseline prevalence and effects of celecoxib on rectal aberrant crypt foci among patients with sporadic colorectal adenomas and (2) help to clarify the utility of rectal mucosal biomarkers for ongoing and future chemoprevention research.

Sponsoring Institute:
National Cancer Institute (NCI)
Recruitment Detail
Type: Active Accrual Of New Subjects
Gender: Male & Female
Referral Letter Required: No
Population Exclusion(s): None

Eligibility Criteria:
INCLUSION CRITERIA:

Baseline gene expression assessment:

Age greater than or equal to 18 years when a medically indicated colonoscopic procedure is pending.

DOD beneficiary.

Signed informed consent #1.

INCLUSION CRITERIA: Intervention trial:

Age greater than or equal to 18 years with at least one adenoma greater than or equal to 1 cm or greater than or equal to 3 of any size and at least 5 rectal ACF's OR age greater than or equal to 50 years with at least one adenoma greater than or equal to 5 mm and at least 5 rectal ACF's.

Participants greater than 50 years with a history of polyps (at lease one adenoma) within the past 5 years.

All female subjects of child bearing potential must be willing to use an acceptable method of birth control (e.g.: intrauterine device, hormonal contraceptive, diaphragm and spermicide).

The subject's anticipated use of oral/intravenous corticosteriods must be less than 2 weeks over a six-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 should agree 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 baseline.

The subject must meet laboratory eligibility criteria within 8 weeks of the baseline colonoscopy:

a) Hemoglobin greater than 11.5 gm/dl

b) WBC greater than 3000/ul

c) Platelet count greater than 125,000/ul

d) Creatinine less than or equal to 1.5 times upper limit of normal

e) AST less than or equal to 1.5 times upper limit of normal

f) ALT less than or equal to 1.5 times upper limit of normal

g) Total bilirubin less than or equal to 1.5 times upper limit of normal

h) Alk Phos. less than or equal to 1.5 times upper limit of normal

i) Pregnancy test negative

Signed informed consent #2

EXCLUSION CRITERIA:

Baseline biomarker assessment:

History of germline cancer syndrome.

Current colorectal cancer.

Inflammatory bowel disease (Crohn's disease or ulcerative colitis)

Active gastrointestinal ulcers

Regular NSAID or aspirin use at baseline (average of 3 or more doses per week for at least three months), with the exception of low-dose aspirin (81mg QD or QOD) used for cardiovascular disease prophylaxis.

History of uncontrolled hypertension

History of unstable angina

History of congestive heart failure

Known allergic reaction to indigo carmine

History of bleeding disorder

History of pelvic radiation therapy

Prior history of colorectal cancer Duke's C or greater or diagnosed less than 6 months ago

EXCLUSION CRITERIA: Intervention trial

History of hypersensitivity reaction to NSAIDs, aspirin, or sulfa drugs (as determined by subject self-report).

Pregnant or lactating women.

Medical contraindications to NSAID use (serum creatinine greater than or equal to 1.5 times the upper limit of normal at baseline, history of peptic ulcer disease, asthma, or severe chronic obstructive pulmonary disease).

History of chronic or acute renal or hepatic disorder or a significant bleeding disorder

The subject has received any investigational medication within the past 30 days or baseline colonoscopy or is scheduled to receive an investigational drug other than celecoxib during the course of the study

Current use of fluconazole or lithium

The subject participated in the study previously and was withdrawn.

Subjects who, in the opinion of the investigator, are unable to comply with the study requirements and will be unable to complete all study procedures as required by the protocol.

Subjects with a clinically significant medical condition or clinically significant abnormal laboratory value which could, in the opinion of the investigator, compromise patient safety or preclude treatment with celecoxib.

Subjects who have a known allergic reaction to indigo carmine.

Special Instructions: Currently Not Provided
Keywords:
Colorectal Cancer
NSAIDs
Intermediate Biomarkers
Chemoprevention
COX-2 Inhibitors
Recruitment Keywords:
Colorectal Cancer
Conditions:
Adenoma
Colorectal Neoplasms
Investigational Drug(s):
Celecoxib
Investigational Device(s):
None

Contacts:
CSSC
Clinical Studies Support Center/NCI
164 Rollins Avenue
2nd FLoor
Rockville, MD 20852
Phone: (888) 624-1937
Fax: (301) 881-8239
Electronic Address: ncicssc@mail.nih.gov

Citations:
Landis SH, Murray T, Bolden S, Wingo PA Cancer statistics, 1999 CA Cancer J Clin 1999 Jan-Feb;49(1):8-31, 1 PMID: 10200775

Muller AD, Sonnenberg A Prevention of colorectal cancer by flexible endoscopy and polypectomy Acase-control study of 32,702 veteransAnn Intern Med 1995 Dec 15;123(12):904-10PMID: 7486484

Van Dam J Prevention of colorectal cancer by endoscopic polypectomy Ann Intern Med 1995 Dec 15;123(12):949-50 No abstract available PMID: 7486491

Active Accrual, Protocols Recruiting New Patients

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