Genetic Events Leading to APC-Dependent Colon Cancer in High-Risk Families; a Clinical Trial of COX and EGFR Inhibition in Familial Polyposis Patients
This will be a single-center, phase-II, six-month-long, placebo-controlled, double blinded,
randomized trial of the epidermal growth factor receptor (EGFR) inhibitor, erlotinib
(Tarceva) and the cyclooxygenase (COX-2) inhibitor, sulindac in patients with familial
adenomatous polyposis (FAP) or attenuated FAP. FAP is an autosomal dominant inherited colon
cancer predisposition with a 100% risk of colon cancer in the absence of preventive care
(endoscopy and surgery). Efficacious chemoprevention for duodenal adenomas is an unmet
clinical need in FAP patients that would reduce the morbidity from duodenectomy and risk of
duodenal adenocarcinoma. Currently the only Food and Drug Administration (FDA)-approved
chemopreventive agent is celecoxib which results in a modest reduction of duodenal and
colorectal polyps and is associated with cardiac toxicity at effective doses. If it can be
shown that combinatorial inhibition of COX-2 and EGFR activity leads to successful
regression in duodenal adenomatous polyps in FAP, it could be used as an effective
chemopreventive regimen in FAP patients with duodenal adenomas or who have undergone
surgical resection of duodenal adenomas or have many rectal adenomas. FAP and AFAP patients
will be screened by endoscopy for presence of 5 or more duodenal polyps, then randomized to
either A) erlotinib at 75 mg/day and sulindac at 150 mg/day or B) placebo for 6 months. The
endpoint will be endoscopy at 6 months.
Primary Aim : To determine if the combination of sulindac and erlotinib causes a significant
regression of duodenal adenomas in FAP and attenuated FAP patients.
1. Measure if combination of sulindac and erlotinib cause a reduction in duodenal
polyposis based on Spigelman classification.
2. Determine if the combination of sulindac and erlotinib causes a significant regression
of colorectal adenomas.
3. Measure changes in COX-2 expression, EGFR phosphorylation, MEK1 phosphorylation, AKT
phosphorylation, Ki-67 expression and/or cyclin D1 expression in intestinal polyps and
normal intestinal mucosa with treatment.
4. Determine ß-catenin localization in adenomatous intestinal polyps with or without
oncogenic KRAS mutations.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Prevention
Compare the change in total duodenal and colorectal polyp burden at 6 months
A comparison of the total polyp burden in the duodenum, measured as the change in the sum if the diameters of the polyps from the duodenal segment and a comparison of the change in the total colorectal polyp burden, measured as the change in the sum of the diameters of the colorectal polyps in subjects with an intact colon. At the end of the 6-month treatment period, all visible polyps will be counted, measured, and recorded as performed in the pretreatment endoscopies. The primary analysis will be via Wilcoxon (Mann-Whitney) tests comparing the sulindac + erlotinib and placebo arms.
Every 6 months
Randall Burt, MD
University of Utah at Huntsman Cancer Institute
United States: Food and Drug Administration
|Huntsman Cancer Institute||Salt Lake City, Utah 84112|