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

BMC Gastroenterology

Study Protocol

Alfred Cohen¹  Elena Stoffel²  Evelien Dekker³  Carol A. Burke⁴  N. Jewel Samadder⁵ 

[1] Cancer Prevention Pharmaceuticals, Inc., 1760 E. River Rd, 85718, Tucson, AZ, USA;Comprehensive Cancer Center, University of Michigan Health System, 1500 E. Medical Center Dr, 48109, Ann Arbor, MI, USA;Department Gastroenterology & Hepatology, Academic Medical Center, C2-115, PO Box 22700, 1100, Amsterdam, DE, The Netherlands;Department Gastroenterology & Hepatology, Cleveland Clinic, Mail Code A30, 9500 Euclid Ave, 44195, Cleveland, OH, USA;Division of Gastroenterology, University of Utah, Huntsman Cancer Institute, 2000 Circle of Hope, 84112, Salt Lake City, UT, USA;

关键词: Chemoprevention;    Colon polyps;    Colorectal polyposis;    Duodenal polyposis;    Eflornithine;    Familial adenomatous polyposis;    Placebo controlled;    Polyamines;    Sulindac;   

DOI  :  10.1186/s12876-016-0494-4

 received in 2016-03-18, accepted in 2016-07-21,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundMolecular 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.MethodsEligible 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.DiscussionThe 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 registrationThis trial is registered at ClinicalTrials.gov (NCT01483144; November 21, 2011) and the EU Clinical Trials Register(EudraCT 2012-000427-41; May 15, 2014).

【 授权许可】

CC BY   
© The Author(s). 2016