Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Celecoxib in Preventing Colorectal Cancer in Young Patients With a Genetic Predisposition for Familial Adenomatous Polyposis

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Prevention	Completed	10 to 17	NCI	MDA-2006-0040 PFIZER-A3191193, N01-CN-05126-2, NCT00393016

Objectives

Primary

1. Compare the time from randomization to treatment failure in pediatric patients diagnosed with familial adenomatous polyposis by genetic predisposition testing treated with celecoxib vs placebo, where treatment failure is defined as the earliest occurrence of the appearance of ≥ 20 polyps at any colonoscopy during the study or diagnosis of colorectal cancer.

Secondary

1. Compare the time from randomization to treatment failure in patients treated with these regimens, where treatment failure is defined as the earliest occurrence of ≥ 20 polyps at any colonoscopy during the study, diagnosis of colorectal cancer, or treatment-related dropout.
2. Compare the total number of colorectal polyps in patients treated with these regimens.
3. Compare polyp burden over 5 years in these patients.
4. Compare the time to appearance of ≥ 5 colorectal adenomas in patients treated with these regimens.

Tertiary

1. Evaluate histopathological and molecular changes of colorectal adenomas in patients treated with these regimens.
2. Evaluate histopathological and molecular changes of aberrant crypt foci (ACF) in patients treated with these regimens. (ACF sites)
3. Characterize the pharmacokinetics (PK) of celecoxib in these patients using population compartmental model-based methodologies to identify covariates that are important determinants of celecoxib exposure; compare celecoxib exposure and oral clearance in pediatric patients vs historical data in adult patients; and evaluate potential PK/pharmacodynamic relationships (safety and efficacy). (PK sites)
4. Conduct an assessment of psychological and behavioral outcomes associated with participation in this clinical trial. (Outcomes Research [OR] sites)

Entry Criteria

Disease Characteristics:

• Confirmed diagnosis of familial adenomatous polyposis (FAP) by genotype based on genetic predisposition testing
• Meets 1 of the following criteria:
  • Phenotypic-negative FAP, defined as no visible (> 2 mm) colorectal polyps without dye enhancement
  • Phenotypic-positive FAP, defined as < 20 colorectal polyps visible (> 2 mm, visible without dye enhancement)
    • The polyps must be removed to render the colon polyp-free and thus amenable to serial endoscopic surveillance at baseline
• Must have an intact colon
  • Not requiring colectomy
• Baseline colonoscopy shows assessable colon endoscopically evaluated after an adequate preparative procedure
• No attenuated FAP
• No new diagnosis of carcinoma

Prior/Concurrent Therapy:

• See Disease Characteristics
• More than 3 months since prior nonsteroidal anti-inflammatory drugs (NSAIDs) or oral adrenocorticosteroids (at a frequency of ≥ 3 times/week)
• More than 1 month since prior NSAIDS or oral adrenocorticosteroids (at a frequency of < 3 times/week)
• More than 6 months since prior chemotherapy
• More than 3 months since prior investigational agents
• No prior pelvic radiotherapy
• No prior colectomy
• No planned colectomy within the next 6 months
• No concurrent chronic use of NSAIDs, aspirin, other selective cyclooxygenase (COX)-2 inhibitors, oral adrenocorticosteroids, or other nonsteroidal over-the-counter products
  • Chronic use is defined as a frequency of 1 week (i.e., 7 consecutive days) for > 3 weeks/year
  • Concurrent mometasone allowed if chronic inhaled steroid use is required*

     [Note: *In countries were mometasone is not available, only fluticasone is allowed]

• No concurrent fluconazole or lithium carbonate

Patient Characteristics:

• WBC > 3,000/mm³
• Platelet count > 100,000/mm³
• Hemoglobin > 10.0 g/dL
• Bilirubin < 1.5 times upper limit of normal (ULN) (≤ 2 times ULN if Gilbert's disease is present)
• ALT and AST < 1.5 times ULN
• Alkaline phosphatase < 1.5 times ULN
• Creatinine < 1.5 times ULN
• Cholesterol < 1.5 times ULN
• No other clinically significant laboratory abnormality that would preclude safe participation in the study
• No medical or psychiatric problems that, in the opinion of the investigator, would preclude study compliance
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Normal ECG
• No history of hypersensitivity to COX-2 inhibitors, sulfonamides, NSAIDs, or salicylates
• No active peptic ulcer disease by endoscopy
  • History of H. pylori-related peptic ulcer disease that has been successfully treated with antibiotics allowed
• No significant renal, hepatic, or hematologic dysfunction
• No invasive carcinoma within the past 5 years
• No familial hypercholesterolemia
• No familial hypertriglyceridemia
• No diabetes
• No coagulopathy

Expected Enrollment

A total of 200 patients will be accrued for this study.

Outcomes

Time to treatment failure (defined as in the primary objective)

Time to treatment failure (defined as in secondary objective I)
Total number of colorectal polyps (> 2 mm, visible without dye enhancement) over 1-5 years
Colorectal polyp burden, defined as the sum of the largest diameters of all polyps over 1-5 years
Time to appearance of ≥ 5 colorectal adenomas (> 2 mm, visible without dye enhancement)
Histopathology of colorectal adenomas (dysplasia, hyperplasia, or mixed) as assessed by morphology and size
Biomarkers as assessed by apoptotic rate, epithelial proliferation rate, cyclooxygenase (COX)-1 and COX-2 expression, and prostaglandin E2 (PGE2) concentration
Histopathology and biomarkers of aberrant crypt foci (ACF) as assessed by apoptotic rate, epithelial proliferation rate, COX-1 and COX-2 expression, and PGE2 concentration (ACF sites)
Population pharmacokinetic (PK) parameters as assessed by apparent celecoxib plasma clearance and exposure (PK sites)
Psychosocial outcomes as assessed by quality of life, psychological and social adjustment and well-being, and psychological distress (outcomes research sites)
Surgical and noncolorectal malignancy data

Outline

This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to participating center, age (≥ 12 years vs < 12 years), and familial adenomatous polyposis phenotype (negative vs positive). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral celecoxib twice daily.
• Arm II: Patients receive oral placebo twice daily.

In both arms, treatment continues for 5 years in the absence of disease progression or unacceptable toxicity.

All patients undergo colonoscopy at baseline and annually during study treatment. Cyclooxygenase (COX)-1/COX-2 expression and prostaglandin E₂ concentration are measured in biopsy specimens. Whole-crypt biomarker studies and pharmacokinetic studies are conducted in selected patient populations respectively.

Trial Contact Information

Trial Lead Organizations

M. D. Anderson Cancer Center at University of Texas

Patrick Lynch, MD, JD, Principal investigator		Ph: 713-794-5073; 800-392-1611 Email: plynch@mdanderson.org

Registry Information
Official Title		A Phase III Placebo-Controlled Trial of Celecoxib in Genotype Positive Subjects with Familial Adenomatous Polyposis
Trial Start Date		2006-08-30
Trial Completion Date		2007-06-30
Registered in ClinicalTrials.gov		NCT00393016
Date Submitted to PDQ		2006-09-07
Information Last Verified		2008-03-30
NCI Grant/Contract Number		CN05126, CA16672

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