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

Condition(s) targeted: Colorectal Cancer; Precancerous/Nonmalignant Condition

Intervention: celecoxib (Drug); anti-cytokine therapy (Procedure); antiangiogenesis therapy (Procedure); biological therapy (Procedure); cancer prevention intervention (Procedure); chemoprevention of cancer (Procedure); enzyme inhibitor therapy (Procedure); growth factor antagonist therapy (Procedure)

Phase: Phase 3

Status: Recruiting

Sponsored by: Pfizer

Official(s) and/or principal investigator(s):
Patrick M. Lynch, MD, JD, Principal Investigator, Affiliation: M.D. Anderson Cancer Center

RATIONALE: Chemoprevention is the use of certain drugs to keep cancer from forming, growing, or coming back. The use of celecoxib may keep polyps and colorectal cancer from forming in patients with familial adenomatous polyposis. It is not yet known whether celecoxib is more effective than a placebo in preventing colorectal cancer in patients with a genetic predisposition for familial adenomatous polyposis. PURPOSE: This randomized phase III trial is studying celecoxib to see how well it works compared with a placebo in preventing colorectal cancer in young patients with a genetic predisposition for familial adenomatous polyposis.

Official title: A Phase III Placebo-Controlled Trial of Celecoxib in Genotype Positive Subjects With Familial Adenomatous Polyposis

Study design: Prevention, Randomized, Double-Blind, Placebo Control

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

Secondary outcome:

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

Detailed description: OBJECTIVES: Primary 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 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. Compare the total number of colorectal polyps in patients treated with these regimens. Compare polyp burden over 5 years in these patients. Compare the time to appearance of ≥ 5 colorectal adenomas in patients treated with these regimens. Tertiary Evaluate histopathological and molecular changes of colorectal adenomas in patients treated with these regimens. Evaluate histopathological and molecular changes of aberrant crypt foci (ACF) in patients treated with these regimens. (ACF sites) 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) Conduct an assessment of psychological and behavioral outcomes associated with participation in this clinical trial. (Outcomes Research [OR] sites) 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 E_2 concentration are measured in biopsy specimens. Whole-crypt biomarker studies and pharmacokinetic studies are conducted in selected patient populations respectively. PROJECTED ACCRUAL: A total of 200 patients will be accrued for this study.

Minimum age: 10 Years. Maximum age: 17 Years. Gender(s): Both.

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 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 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

M. D. Anderson Cancer Center at University of Texas, Houston, Texas 77030-4009, United States; Recruiting
Clinical Trials Office - M. D. Anderson Cancer Center at the U, Phone: 713-792-3245

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: August 2006
Last updated: August 21, 2007