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

OBJECTIVES:

Primary

• Determine the safety and toxicity of celecoxib in pediatric patients with genotype-positive familial adenomatous polyposis.

Secondary

• Determine the aberrant crypt foci (ACF) and adenoma burden in the entire colorectum of these patients.
• Eliminate the learning curve in a phase II/III trial (reproducibility of endoscopic techniques, tolerability of procedure).
• Compare sedation strategies based on local standards (monitored anesthesia care vs conscious sedation).
• Validate the ACF scoring technique.
• Establish the short-term (3 month) impact of celecoxib on ACF count in order to determine appropriateness of ACF as a pathologic endpoint in a phase II/III trial.

OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral celecoxib twice daily for 3 months in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive oral placebo twice daily for 3 months in the absence of disease progression or unacceptable toxicity.

Patients undergo colonoscopy at baseline and at 3 months. Patients also complete psychosocial questionnaires at baseline.

Blood samples are collected at baseline to assess the influence of polymorphisms (CYP2C9, uridine diphosphate (UDP)-glucuronosyl transferase, A6, glutathione S-transferase [GST] M1, and Glutathione S-transferase (GST) theta 1 (GSTT1)) on age of onset of phenotype or number of colorectal polyps. Plasma drug trough levels are assessed at baseline, 1 month, and 3 months.

After completion of study treatment, patients are followed periodically for up to 2 months.

DISEASE CHARACTERISTICS:

• Diagnosis of familial adenomatous polyposis (FAP) based on genetic predisposition testing
• Genotype-positive FAP (pathologic Adenomatous polyposis coli (APC) mutation)

• No attenuated FAP genotype, defined by any of the following:

• Mutation at the 5' end of APC and exon 4
• Exon 9-associated phenotypes
• 3' region mutations
• Has an intact colon

• No requirement for colectomy
• Parent(s) do not desire colectomy (regardless of adenoma burden)
• Colorectal adenoma burden as assessed by baseline colonoscopy

• No diagnosis of severe dysplasia or greater
• No more than 10 adenomas ≥ 1 cm
• No more than 100 adenomas of any size
• No evidence of anemia (hematocrit < 33%)
• No new diagnosis of carcinoma

PATIENT CHARACTERISTICS:

• White Blood Count (WBC) > 3,000/μL
• Platelet count > 100,000/μL
• Hemoglobin > 10.0 g/dL
• Aspartate aminotransferase/alanine aminotransferase (AST/ALT) < 1.5 times upper limit of normal (ULN)
• Alkaline phosphatase < 1.5 times ULN
• Total bilirubin < 1.5 times ULN
• Creatinine < 1.5 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No history of hypersensitivity to COX-2 inhibitors, sulfonamides, NSAIDs, or salicylates
• No history of peptic ulcer disease
• No significant medical or psychiatric problem that, in the opinion of the principal investigator, would make the patient a poor candidate for the study
• No other unacceptable clinical risk (e.g., previously unknown bleeding diatheses)
• No invasive carcinoma within the past 5 years

PRIOR CONCURRENT THERAPY:

• More than 3 months since prior investigational agent
• More than 6 months since prior chemotherapy
• No prior radiotherapy to the pelvis
• At least 3 months since prior NSAIDs (at any dose) at a frequency of ≥ 3 times/week
• At least 1 month since prior NSAIDs (at any dose) at a frequency of < 3 times/week
• At least 1 month since prior nasal steroids
• Concurrent Nonsteroidal Antiinflammatory Drugs (NSAIDs) allowed provided they are administered ≤ 5 times per month
• Concurrent orally inhaled steroids allowed provided they are administered for ≤ 4 weeks over a 6-month period
• Concurrent oral or intravenous (IV) corticosteroids allowed provided they are administered for ≤ 2 consecutive weeks over a 6-month period
• Concurrent proton pump inhibitors to treat gastric reflux allowed
• No concurrent nasal steroids except mometasone (Nasonex)
• No concurrent fluconazole, lithium, or adrenocorticosteroids