title: 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.
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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  This trial is registered at ClinicalTrials.gov ( NCT01483144 ; November 21, 2011) and the EU Clinical Trials Register( EudraCT 2012-000427-41 ; May 15, 2014).
authors.affiliation: Department Gastroenterology & Hepatology, Cleveland Clinic, Mail Code A30, 9500 Euclid Ave, Cleveland, OH, 44195, USA. burkec1@ccf.org.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Burke
authors.affiliation: Department Gastroenterology & Hepatology, Academic Medical Center, C2-115, PO Box 22700, Amsterdam, 1100, DE, The Netherlands.
authors.forename: Evelien
authors.initials: E
authors.lastname: Dekker
authors.affiliation: Division of Gastroenterology, University of Utah, Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.
authors.forename: N Jewel
authors.initials: NJ
authors.lastname: Samadder
authors.affiliation: Comprehensive Cancer Center, University of Michigan Health System, 1500 E. Medical Center Dr, Ann Arbor, MI, 48109, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Stoffel
authors.affiliation: Cancer Prevention Pharmaceuticals, Inc., 1760 E. River Rd, Tucson, AZ, 85718, USA.
authors.forename: Alfred
authors.initials: A
authors.lastname: Cohen
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000188:drug therapy* / Q000378:metabolism; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D018450:Disease Progression; D004311:Double-Blind Method; D004379:Duodenal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D000518:Eflornithine / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D011073:Polyamines / Q000037:antagonists & inhibitors / Q000378:metabolism; D013467:Sulindac / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D011073:Polyamines; D013467:Sulindac; D000518:Eflornithine
keywords: Chemoprevention; Colon polyps; Colorectal polyposis; Duodenal polyposis; Eflornithine; Familial adenomatous polyposis; Placebo controlled; Polyamines; Sulindac