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

Carol A Burke, Evelien Dekker, N Jewel Samadder, Elena Stoffel, Alfred Cohen, Carol A Burke, Evelien Dekker, N Jewel Samadder, Elena Stoffel, Alfred Cohen

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).

Keywords: Chemoprevention; Colon polyps; Colorectal polyposis; Duodenal polyposis; Eflornithine; Familial adenomatous polyposis; Placebo controlled; Polyamines; Sulindac.

Figures

Fig. 1
Fig. 1
CPP-1/sulindac downregulates PAs via dual MoA: CPP-1X decreases PA synthesis by blocking ODC1, and sulindac increases PA catabolism and export by upregulating transport genes (PPARγ and SAT). MoA, mechanism of action; ODC1, ornithine decarboxylase; PA, polyamine; PPAR, peroxisome proliferator activated receptor; SAT, sialic acid transport
Fig. 2
Fig. 2
Endoscopic images of patient strata of polyposis: a pre-colectomy, b rectal/pouch, and c duodenal (Spigelman stage 3/4)
Fig. 3
Fig. 3
Flowchart of the study (as of February 1, 2016). *Treatment arm is assigned in double-blinded fashion; exact numbers of randomized patients per treatment arm are not known. APC, adenomatous polyposis coli; CPP-1X, eflornithine; EOT, end of treatment; PBO, placebo

References

    1. Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB, et al. Identification of FAP locus genes from chromosome 5q21. Science. 1991;253:661–5. doi: 10.1126/science.1651562.
    1. Vasen HF, Moslein G, Alonso A, Aretz S, Bernstein I, Bertario L, et al. Guidelines for the clinical management of familial adenomatous polyposis (FAP) Gut. 2008;57:704–13. doi: 10.1136/gut.2007.136127.
    1. Campos FG. Surgical treatment of familial adenomatous polyposis: dilemmas and current recommendations. World J Gastroenterol. 2014;20:16620–9. doi: 10.3748/wjg.v20.i44.16620.
    1. Jung I, Gurzu S, Turdean GS. Current status of familial gastrointestinal polyposis syndromes. World J Gastrointest Oncol. 2015;7:347–55. doi: 10.4251/wjgo.v7.i11.347.
    1. Leoz ML, Carballal S, Moreira L, Ocana T, Balaguer F. The genetic basis of familial adenomatous polyposis and its implications for clinical practice and risk management. Appl Clin Genet. 2015;8:95–107.
    1. Bertario L, Russo A, Radice P, Varesco L, Eboli M, Spinelli P, et al. Genotype and phenotype factors as determinants for rectal stump cancer in patients with familial adenomatous polyposis. Hereditary Colorectal Tumors Registry Ann Surg. 2000;231:538–43.
    1. Jenner DC, Levitt S. Rectal cancer following colectomy and ileorectal anastomosis for familial adenomatous polyposis. Aust N Z J Surg. 1998;68:136–8. doi: 10.1111/j.1445-2197.1998.tb04724.x.
    1. Parc YR, Olschwang S, Desaint B, Schmitt G, Parc RG, Tiret E. Familial adenomatous polyposis: prevalence of adenomas in the ileal pouch after restorative proctocolectomy. Ann Surg. 2001;233:360–4. doi: 10.1097/00000658-200103000-00009.
    1. Thompson-Fawcett MW, Marcus VA, Redston M, Cohen Z, McLeod RS. Adenomatous polyps develop commonly in the ileal pouch of patients with familial adenomatous polyposis. Dis Colon Rectum. 2001;44:347–53. doi: 10.1007/BF02234731.
    1. Wu JS, McGannon EA, Church JM. Incidence of neoplastic polyps in the ileal pouch of patients with familial adenomatous polyposis after restorative proctocolectomy. Dis Colon Rectum. 1998;41:552–6. doi: 10.1007/BF02235258.
    1. Bulow S, Bjork J, Christensen IJ, Fausa O, Jarvinen H, Moesgaard F, et al. Duodenal adenomatosis in familial adenomatous polyposis. Gut. 2004;53:381–6. doi: 10.1136/gut.2003.027771.
    1. Giardiello FM, Hamilton SR, Hylind LM, Yang VW, Tamez P, Casero RA., Jr Ornithine decarboxylase and polyamines in familial adenomatous polyposis. Cancer Res. 1997;57:199–201.
    1. Babbar N, Gerner EW. Targeting polyamines and inflammation for cancer prevention. Recent Results Cancer Res. 2011;188:49–64. doi: 10.1007/978-3-642-10858-7_4.
    1. Ignatenko NA, Besselsen DG, Stringer DE, Blohm-Mangone KA, Cui H, Gerner EW. Combination chemoprevention of intestinal carcinogenesis in a murine model of familial adenomatous polyposis. Nutr Cancer. 2008;60(Suppl 1):30–5. doi: 10.1080/01635580802401317.
    1. : A Double-Blind, Randomized, Phase III Trial of the Safety and Efficacy of CPP-1X/Sulindac Compared With CPP-1X, Sulindac as Single Agents in Patients with Familial Adenomatous Polyposis (FAP), 2015.
    1. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365–76. doi: 10.1093/jnci/85.5.365.
    1. Whistance RN, Conroy T, Chie W, Costantini A, Sezer O, Koller M, et al. Clinical and psychometric validation of the EORTC QLQ-CR29 questionnaire module to assess health-related quality of life in patients with colorectal cancer. Eur J Cancer. 2009;45:3017–26. doi: 10.1016/j.ejca.2009.08.014.
    1. Brooks R. EuroQol: the current state of play. Health Policy. 1996;37:53–72. doi: 10.1016/0168-8510(96)00822-6.
    1. Drummond MF, Sculpher MJ, Torrance GW, O’Brien BJ, Stoddart GL. Methods for the Economic Evaluation of Health Care Programmes. New York: Oxford University Press; 1997.
    1. Lerman C, Trock B, Rimer BK, Jepson C, Brody D, Boyce A. Psychological side effects of breast cancer screening. Health Psychol. 1991;10:259–67. doi: 10.1037/0278-6133.10.4.259.
    1. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). Bethesda, MD: National Institutes of Health; 2010.
    1. Nugent KP, Farmer KC, Spigelman AD, Williams CB, Phillips RK. Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis. Br J Surg. 1993;80:1618–9. doi: 10.1002/bjs.1800801244.
    1. Richard CS, Berk T, Bapat BV, Haber G, Cohen Z, Gallinger S. Sulindac for periampullary polyps in FAP patients. Int J Colorectal Dis. 1997;12:14–8. doi: 10.1007/s003840050071.
    1. Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, et al. The effect of celecoxib, a cyclooxgenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med. 2000;342:1946-52.
    1. Lynch PM, Burke CA, Phillips R, Morris JS, Slack R, Wang X, et al. An international randomised trial of celecoxib versus celecoxib plus difluoromethylornithine in patients with familial adenomatous polyposis. Gut. 2016;65:286–95. doi: 10.1136/gutjnl-2014-307235.
    1. Saurin JC, Gutknecht C, Napoleon B, Chavaillon A, Ecochard R, Scoazec JY, et al. Surveillance of duodenal adenomas in familial adenomatous polyposis reveals high cumulative risk of advanced disease. J Clin Oncol. 2004;22:493–8. doi: 10.1200/JCO.2004.06.028.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj