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

Study Overview
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Brief Summary
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RATIONALE: Chemoprevention is the use of certain drugs to keep cancer from forming. The use of celecoxib may keep polyps and colorectal cancer from forming in patients with familial adenomatous polyposis. PURPOSE: This randomized phase I trial is studying the side effects and best dose of celecoxib in treating young patients with a genetic predisposition for familial adenomatous polyposis.

Detailed Description
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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.

Official Title
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Phase I Pilot Toxicity/Methods Validation Study of Celecoxib in Genotype-Positive Children With Familial Adenomatous Polyposis

Conditions
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Colorectal Cancer, Precancerous Condition

Intervention / Treatment
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* Drug: celecoxib
* Other: placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 14 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral celecoxib twice daily for 3 months in the absence of disease progression or unacceptable toxicity. | Drug: celecoxib<br>* Orally, twice daily for 3 months; 50 mg tablets. Celecoxib escalating doses starting at 4 mg/kg/day.<br>|
| Placebo Comparator: Arm II<br>Patients receive oral placebo twice daily for 3 months in the absence of disease progression or unacceptable toxicity. | Other: placebo<br>* Orally, twice daily for 3 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity |  | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Aberrant crypt foci (ACF) and adenoma burden in the entire colorectum |  | 3 months | 
| Elimination of the learning curve in a phase II/III trial |  | 3 months | 
| Comparison of sedation strategies based on local standards |  | 3 months | 
| Validation of technique for scoring ACFs |  | 3 months | 
| Short-term (3 month) impact of celecoxib on ACF count |  | 3 months | 
| Adherence |  | 3 months | 
| Influence of polymorphisms on age of onset of phenotype or on the number of colorectal polyps |  | 3 months | 
| Feasibility of psychosocial questionnaires |  | 3 months | 
| Pharmacokinetics (plasma drug trough concentrations) |  | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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colon cancer, rectal cancer, familial adenomatous polyposis