Efficacy and safety of eflornithine (CPP-1X)/sulindac combination therapy versus each as monotherapy in patients with familial adenomatous polyposis (FAP): design and rationale of a randomized, double-blind, Phase III trial. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Burke, Carol; Dekker, Evelien; Samadder, N.; Stoffel, Elena; Cohen, Alfred
• Is Part Of: BMC gastroenterology. Volume 16:Issue 1(2016)
• Page Start: 1
• Page End: 9
• Publication Date: 2016-12
• Subjects: Chemoprevention -- Colon polyps -- Colorectal polyposis -- Duodenal polyposis -- Eflornithine -- Familial adenomatous polyposis -- Placebo controlled -- Polyamines -- Sulindac; Gastroenterology -- Periodicals; Gastrointestinal Diseases -- Periodicals; Biliary Tract Diseases -- Periodicals; Molecular Biology -- Periodicals; Liver Diseases -- Periodicals; 616.33005
• DOI: 10.1186/s12876-016-0494-4
• Languages: English
• ISSNs: 1471-230X

Abstract

Abstract Background Molecular studies suggest inhibition of colorectal mucosal polyamines (PAs) may be a promising approach to prevent colorectal cancer (CRC). Inhibition of ornithine decarboxylase (ODC) using low-dose eflornithine (DFMO, CPP-1X), combined with maximal PA export using low-dose sulindac, results in greatly reduced levels of normal mucosal PAs. In a clinical trial, this combination (compared with placebo) reduced the 3-year incidence of subsequent high-risk adenomas by >90 %. Familial Adenomatous Polyposis (FAP) is characterized by marked up-regulation of ODC in normal intestinal epithelial and adenoma tissue, and therefore PA reduction might be a potential strategy to control progression of FAP-related intestinal polyposis. CPP FAP-310, a randomized, double-blind, Phase III trial was designed to examine the safety and efficacy of sulindac and DFMO (alone or in combination) for preventing a clinically relevant FAP-related progression event in individuals with FAP. Methods Eligible adults with FAP will be randomized to: CPP-1X 750 mg and sulindac 150 mg, CPP-1X placebo and sulindac 150 mg, or CPP-1X 750 mg and sulindac placebo once daily for 24 months. Patients will be stratified based on time-to-event prognosis into one of the three treatment arms: best (ie, longest time to first FAP-related event [rectal/pouch polyposis]), intermediate (duodenal polyposis) and worst (pre-colectomy). Stage-specific, "delayed time to" FAP-related events are the primary endpoints. Change in polyp burden (upper and/or lower intestine) is a key secondary endpoint. Discussion The trial is ongoing. As of February 1, 2016, 214 individuals have been screened; 138 eligible subjects have been randomized to three treatment groups at 15 North American sites and 6 European sites. By disease strata, 26, 80 and 32 patients are included for assessment of polyp burden in the rectum/pouch, duodenal polyposis and pre-colectomy groups, respectively. Median age is 40 years; 59 % are men. The most common reasons for screening failure include minimal polyp burden (n = 22), withdrawal of consent (n = 9) and extensive polyposis requiring immediate surgical intervention (n = 9). Enrollment is ongoing. Trial registration This trial is registered at ClinicalTrials.gov (NCT01483144 ; November 21, 2011) and the EU Clinical Trials Register(EudraCT 2012-000427-41 ; May 15, 2014).