A phase III study of pharmacological prevention of progression in patients with familial adenomatous polyposis (FAP) did not show a lower incidence of disease progression with the combination of eflornithine (CPP-1X, also known as DFMO)* and sulindac** than with either drug alone, according to a study published in the September 10, 2020 edition of The New England Journal of Medicine.
Based on the results of the study, funded by Cancer Prevention Pharmaceuticals, the investigators believe that additional studies that focus on clinical endpoints in the lower gastrointestinal tract are warranted to better understand the potential of this combination for pharmacologic prevention in specific groups of patients with FAP, especially those who have not yet undergone prophylactic colectomy.
A rare syndrome
Familial adenomatous polyposis is a rare, autosomal dominant, hereditary colorectal cancer syndrome that is most commonly caused by pathogenic germline variants in the adenomatous polyposis coli (APC) gene, which is found on the long arm of chromosome 5 and follows an autosomal dominant inheritance pattern.
In its classical presentation, characterized by the progressive development of an unusually large number of adenomatous polyps in the lower gastrointestinal tract, primarily in the colon and rectum. Polyps are the precursor to the development of colorectal cancer, and, if left untreated, FAP is associated with up to a 100% lifetime risk of colorectal cancer.
In more than 80% of patients with familial adenomatous polyposis upper gastrointestinal tract polyposis develops in the duodenum. In addition, duodenal or periampullary cancer occurs in 5 to 12% of these patients.
Signs & Symptoms
The symptoms of familial adenomatous polyposis*** may mimic other gastrointestinal disturbances and, as a result, not all patients do experience specific symptoms until they have numerous growth of polyps or until colorectal cancer is present.
Standard of care
Proctocolectomy is the standard of care for the management of colorectal polyposis and among patients who had undergone an initial colectomy and ileorectal anastomosis, proctectomy with ileal pouch-anal anastomosis (IPAA), also known as an ileo-anal pouch resection, is performed in up to 30% because of progressive polyposis or cancer.
Colectomy and proctocolectomy are associated with complications, including diarrhea, fecal incontinence, and adverse effects on sexual function, fertility, and health-related quality of life.
In the majority of patients with FAP, management of duodenal adenomas is necessary for addition to management of the initial colorectal polyposis; mesenteric desmoid tumors may also develop in these patients.
Surgical and endoscopic treatment does not completely eliminate the potential for future polyps or extraintestinal neoplasms. Therefore, the most important and unmet clinical needs that could be addressed with pharmacological agents are to delay or avoid surgery or advanced endoscopic resection and to prevent the progression of polyposis.
In the randomized, double-blind, phase III FAP-310 trial, investigators evaluated the efficacy and safety of a combination treatment with eflornithine and sulindac (CPP-1X/sul), as compared with either drug alone and used a time-to-event analysis with a composite efficacy endpoint to determine the delay in disease progression or major endoscopic or surgical procedures in patients with FAP.
The patients were stratified on the basis of the anatomical site with the highest polyp burden and surgical status. The patients were randomly assigned in a 1:1:1 ratio to receive eflornithine (750 mg), sulindac (150 mg), or both once daily for up to 48 months. The primary endpoint, assessed in a time-to-event analysis, was disease progression, defined as a composite of major surgery, endoscopic excision of advanced adenomas, diagnosis of high-grade dysplasia in the rectum or pouch, or progression of duodenal disease.
In total 171 patients underwent randomization. Disease progression occurred in 18 of 56 patients (32%) in the group treated with the combination of eflornithine plus sulindac, 22 of 58 (38%) in the sulindac group, and 23 of 57 (40%) in the eflornithine group, with a hazard ratio (HR) of 0.71 (95% confidence interval [CI] 0.39 to 1.32) for eflornithine plus sulindac as compared with sulindac and 0.66 (95% CI 0.36 to 1.24) for eflornithine plus sulindac as compared with eflornithine. Furthermore:
- In the group of precolectomy patients (n=36), the corresponding values in the treatment groups were 2 of 12 patients (17%), 6 of 13 (46%) and 5 of 12 (42%) (HR 0.30 [95% CI 0.07 to 1.32] and HR 0.20 [95% CI 0.03 to 1.32]).
- Patients with rectal or ileal pouch polyposis (n=34), the values were 4 of 11 patients (36%), 2 of 11 (18%) and 5 of 12 (42%) (HR 2.03 [95% CI 0.43 to 9.62] and HR 0.84 [95% CI 0.24 to 2.90]).
- Among patients with duodenal polyposis (n=100), the values were 12 of 33 patients (36%), 14 of 34 (41%) and 13 of 33 (39%) (HR 0.73 [95% CI 0.34 to 1.52] and HR 0.76 [95% CI 0.35 to 1.64]).
In this study, side effects with the combination therapy with eflornithine and sulindac were similar to those with single-agent treatment and the majority of side effects observed were mild to moderate in severity.
Although larger than previous studies on pharmacologic prevention in patients with FAP, this study was still relatively small. The authors of the study noted that the trial did not demonstrate that the percentage of FAP patients with disease progression was significantly lower with combination therapy than with either single agent. However, the data showed that in a subgroup of patients with intact colons, representing the vast majority of young FAP patients, there was a 70% decreased risk of disease progression when treated with the combination therapy.
“The results ofthe Phase III trial demonstrate that the combination of eflornithine and sulindac may be a potential pharmaco-preventive option for FAP patients in delaying surgical procedures,” said Alfred Cohen, M.D., Chief Medical Officer of Cancer Prevention Pharmaceuticals and a co-author of the article published in the New England Journal of Medicine.
“These surgeries are life-altering and we are encouraged by this positive data for pre-colectomy FAP patients,” he added.
“No patient with an intact colon who received combination therapy underwent surgical intervention. Additionally, the combination therapy was well tolerated over long-term treatment of 2-4 years,” concluded Niloy Jewel Samadder, M.D., a gastroenterologist at the Mayo Clinic in Arizona and a co-author of the NEJM article, quoted,
Based on the results of the trial and observed benefits in a broad group of patients diagnosed with familial adenomatous polyposis, Cancer Prevention Pharmaceuticals will pursue regulatory approval from the U.S. Food and Drug Administration (FDA) and a Marketing Authorization Application (MAA) with the European Medicines Agency for approval of the combination of eflornithine and sulindac to delay or prevent surgeries in patients with an intact colon, retained rectum, or surgical pouch.
“For most FAP patients, the current medical practice involves a lifetime of periodic monitoring as well as highly invasive surgical procedures. If approved, the combination therapy could provide an alternative to surgery for many patients, significantly improving their quality of life,” concluded Jeff Jacob, Chief Executive Officer of Cancer Prevention Pharmaceuticals.
* Eflornithine is an experimental, irreversible inhibitor of ornithine decarboxylase (ODC) that has shown to reduce the growth of polyps in the colon.
** Sulindac (Clinoril®; Merck & Co), a nonsteroidal anti-inflammatory drug (NSAID) of the arylalkanoic acid class that has, in several studies, been shown to reduce the growth of colon polyps, but has not been approved by the U.S. Food and Drug Administration (FDA) for this indication.
*** In some cases familial adenomatous polyposis, while still technically inherited, are a spontaneous mutation. This means that there is no indication of polyps or colorectal cancer in the patient’s family history. Hence, these patients are not urged to procure the genetic testing that will discover FAP. These patients may not see symptoms until the middle- or late-stage colorectal cancer has developed.
Trial of Eflornithine Plus Sulindac in Patients With Familial Adenomatous Polyposis (FAP) – NCT01483144 (EudraCT number, 2012-000427-41)
Highlights of prescribing information
Sulindac (Clinoril®; Merck & Co) [Prescribing Information]]
 Burke CA, Dekker E, Lynch P, et al. Eflornithine plus Sulindac for Prevention of Progression in Familial Adenomatous Polyposis. N Engl J Med. 2020;383(11):1028-1039. doi:10.1056/NEJMoa1916063
 Burke CA, Dekker E, Samadder NJ, Stoffel E, Cohen A. 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 Gastroenterol. 2016;16(1):87. Published 2016 Aug 2. doi:10.1186/s12876-016-0494-4