Clinical trial NCT00685568: Celecoxib in Preventing Colorectal Cancer in Young Patients With a Genetic Predisposition for Familial Adenomatous Polyposis
Official title: Phase I Pilot Toxicity/Methods Validation Study of Celecoxib in Genotype-Positive Children With Familial Adenomatous Polyposis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Colorectal Cancer
Precancerous Condition
Keywords: colon cancer
rectal cancer
familial adenomatous polyposis
Lead sponsor: M.D. Anderson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2008-05-28
Enrollment: 22
Sex: ALL
Minimum age (years): 10
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Toxicity
timeFrame: 3 months
Secondary outcomes:
measure: Aberrant crypt foci (ACF) and adenoma burden in the entire colorectum
timeFrame: 3 months
measure: Elimination of the learning curve in a phase II/III trial
timeFrame: 3 months
measure: Comparison of sedation strategies based on local standards
timeFrame: 3 months
measure: Validation of technique for scoring ACFs
timeFrame: 3 months
measure: Short-term (3 month) impact of celecoxib on ACF count
timeFrame: 3 months
measure: Adherence
timeFrame: 3 months
measure: Influence of polymorphisms on age of onset of phenotype or on the number of colorectal polyps
timeFrame: 3 months
measure: Feasibility of psychosocial questionnaires
timeFrame: 3 months
measure: Pharmacokinetics (plasma drug trough concentrations)
timeFrame: 3 months
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center
state: Ohio
city: Houston
country: United States
facility: M. D. Anderson Cancer Center at University of Texas
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Houston
country: United States
facility: University of Texas Medical School at Houston
state: Texas
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Patrick M. Lynch, MD, JD
role: STUDY_CHAIR
References:
citation: Lynch PM, Ayers GD, Hawk E, Richmond E, Eagle C, Woloj M, Church J, Hasson H, Patterson S, Half E, Burke CA. The safety and efficacy of celecoxib in children with familial adenomatous polyposis. Am J Gastroenterol. 2010 Jun;105(6):1437-43. doi: 10.1038/ajg.2009.758. Epub 2010 Mar 16.