Obeticholic Acid for Familial Adenomatous Polyposis
Recruiting in Palo Alto (17 mi)
+6 other locations
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: National Cancer Institute (NCI)
Prior Safety Data
Approved in 2 jurisdictions
Trial Summary
What is the purpose of this trial?This phase IIa trial investigates if giving obeticholic acid (OCA) is safe and has a beneficial effect on the number of polyps in the small bowel and colon in patients with familial adenomatous polyposis (FAP). FAP is a rare gene defect that increases the risk of developing cancer of the intestines and colon. OCA is a drug similar to a bile acid the body makes. It is fluid made and released by the liver. OCA binds to a receptor in the intestine that is believed to have a positive effect on preventing cancer development. OCA has been effective in treating primary biliary cholangitis (PBC), a liver disease, and is approved by the Food and Drug Administration (FDA) for use at a lower dose (10 mg). There have been studies showing that OCA decreases inflammation and fibrosis. However, it is not yet known whether OCA works on reducing the number of polyps in patients with FAP.
Will I have to stop taking my current medications?
You may need to stop taking certain medications before joining the trial. Specifically, you cannot take investigational agents, certain bile acid medications, clozapine, theophylline derivatives, tizanidine, warfarin, and some drugs that affect the liver. If you're on these, you must stop them at least 5 days before starting the trial.
What data supports the effectiveness of the drug Obeticholic Acid for treating Familial Adenomatous Polyposis?
The research suggests that patients with familial adenomatous polyposis have different bile acid profiles, with higher levels of chenodeoxycholic acid, which is a component of Obeticholic Acid. This difference in bile acids may influence the growth of intestinal adenomas and cancer, indicating a potential role for Obeticholic Acid in treatment.
12345Is Obeticholic Acid generally safe for humans?
The research does not provide specific safety data for Obeticholic Acid in humans, but it mentions that chenodeoxycholic acid, a related bile acid, can increase tumor formation in animal models. This suggests caution may be needed when considering its safety.
16789How does the drug Obeticholic Acid differ from other treatments for familial adenomatous polyposis?
Obeticholic Acid is unique because it targets bile acid pathways, which are linked to the development of adenomas and cancers in familial adenomatous polyposis. Unlike other treatments, it specifically alters bile acid profiles, potentially influencing tumor growth in the gastrointestinal tract.
12457Eligibility Criteria
Adults with familial adenomatous polyposis (FAP), a condition causing many polyps in the intestine, can join this trial. They must have an APC gene mutation or clinical diagnosis of FAP, be in good general health (ECOG <=1), and not have had cancer treatment for at least 6 months. Participants need functioning major organs as indicated by specific blood tests and agree to use contraception.Inclusion Criteria
I haven't had signs of cancer coming back for at least 6 months.
My duodenal polyps are classified as stage II or III.
I have FAP affecting my duodenum and rectum, confirmed by genetic or clinical diagnosis.
I am fully active or can carry out light work.
My liver function tests are normal.
I am 18 years old or older.
Exclusion Criteria
My cholesterol levels are very high and not under control.
I do not have any uncontrolled illnesses.
I have had pancreatitis or issues with my pancreas.
I have an active hepatitis C or B infection that hasn't been treated.
I have a liver condition such as cirrhosis, NASH, or a biliary disorder.
I have previously used the drug being studied.
My biopsy shows high-grade dysplasia or cancer.
I have too many polyps in my duodenum or rectum to count.
Participant Groups
The trial is testing Obeticholic Acid (OCA) to see if it's safe and effective at reducing intestinal polyps in FAP patients. OCA mimics a bile acid made by the liver that may help prevent cancer growth. Patients will either receive OCA or a placebo while undergoing endoscopies, biopsies, and questionnaires to monitor effects.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Arm I (OCA)Experimental Treatment5 Interventions
Patients receive OCA PO QD for 6 months in the absence of unacceptable toxicity. Patients also undergo GI endoscopy with biopsy and collection of blood samples at screening and on study.
Group II: Arm II (placebo)Placebo Group5 Interventions
Patients receive placebo PO QD for 6 months in the absence of unacceptable toxicity. Patients also undergo GI endoscopy with biopsy and collection of blood samples at screening and on study.
Obeticholic Acid is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Ocaliva for:
- Primary biliary cholangitis (PBC) without liver problems or with compensated cirrhosis but without portal hypertension
🇪🇺 Approved in European Union as Ocaliva for:
- Primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
University of Kansas Cancer CenterKansas City, KS
Mayo Clinic in ArizonaScottsdale, AZ
M D Anderson Cancer CenterHouston, TX
Dana-Farber Cancer InstituteBoston, MA
More Trial Locations
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Who is running the clinical trial?
National Cancer Institute (NCI)Lead Sponsor
References
Biliary bile acid profiles in familial adenomatous polyposis. [2019]Patients with familial adenomatous polyposis have an excess risk for adenomas and cancers of the upper and lower gastrointestinal tract. In the upper intestine these lesions occur mainly around the ampulla of Vater and they parallel mucosal exposure to bile. In view of this finding and of evidence that bile acids play a role in colorectal carcinogenesis, biliary bile acid profiles were determined in 29 patients with familial adenomatous polyposis (12 before colectomy, 17 after colectomy) and in 28 patients without familial adenomatous polyposis (all with colons in situ). Patients with familial adenomatous polyposis had a higher total biliary bile acid concentration than the others. The bile of patients with polyposis had a greater proportion of chenodeoxycholic acid and a lower proportion of deoxycholic acid than did the bile of patients without polyposis. The ratio of chenodeoxycholic acid and its metabolite lithocholic acid to cholic acid and its metabolite deoxycholic acid, which is related to subsequent bile acid profiles in the colon, was higher in patients with polyposis. Because bile acids influence cellular proliferation, these findings may be of importance with respect to intestinal adenoma and cancer growth.
Unconjugated faecal bile acids in familial adenomatous polyposis analysed by gas-liquid chromatography and mass spectrometry. [2019]Previous studies have suggested reduced formation of secondary bile acids in patients with familial adenomatous polyposis (FAP). Developments in the collection, extraction and analysis of faecal bile acids as well as in the accurate diagnosis of FAP by DNA markers prompted reinvestigation of this hypothesis. The median (interquartile range (i.q.r.)) faecal bile acid concentration (3.69 (1.66-5.36) mumol per g dry weight) and daily excretion rate (60.5 (29-149) mumol per g per 24 h) in ten patients with FAP were similar to those of nine control subjects (3.31 (0.65-8.38) mumol per g dry weight and 30.1 (7.9-228) mumol per g per 24 h). Although the median (i.q.r.) concentration of only one bile acid (12-oxo-lithocholic acid) was significantly different between patients with FAP and controls (49 (34-70) versus 0 (0-20) nmol per g dry weight, P = 0.006), the derivatives of chenodeoxycholic acid (3.35 (1.76-5.32) versus 0.51 (0.13-2.37) mumol per g dry weight, P = 0.02) and cholic acid (1.63 (0.42-2.34) versus 0.80 (0.13-3.57) mumol per g dry weight, P = 0.006) were increased in those with polyposis. These results show increased bacterial biotransformation of faecal bile acids in patients with FAP.
Complete reversion and prevention of rectal adenomas in colectomized patients with familial adenomatous polyposis by rectal low-dose sulindac maintenance treatment. Advantages of a low-dose nonsteroidal anti-inflammatory drug regimen in reversing adenomas exceeding 33 months. [2019]This nonrandomized, controlled Phase II pilot study aims at the lowest effective dose of rectally applied sulindac to achieve and maintain adenoma reversion in colectomized patients with familial adenomatous polyposis (FAP).
Relationship between duodenal bile acids and colorectal neoplasia. [2019]To investigate a possible relationship between bile acids and colorectal neoplasia duodenal bile acids were analysed in 50 patients with colorectal adenomas and 14 with carcinoma. Using gas liquid and high performance liquid chromatography a small, but significant increase in the proportion of chenodeoxycholic acid was found in the bile of adenoma patients compared with controls (mean % +/- SD 31.0 +/- 10.8, 26.4 +/- 8.3, p = 0.01). The difference in the proportions of chenodeoxycholic acid correlated with increasing malignant potential of the adenomas as determined by increasing size, histological type, degree of dysplasia and number present. In carcinoma patients an increase in the proportion of chenodeoxycholic acid was also observed compared with controls (mean % +/- SD, 47.2 +/- 9.6, 28.0 +/- 4.5, p less than 0.01). The proportions of other bile acids in those with adenoma or carcinoma were normal.
[Chenodeoxycholic acid therapy and colorectal carcinoma--an experimental approach (author's transl)]. [2013]With respect to the potential significance of bile acids in the pathogenesis of colorectal cancer the effect of continuous oral administration of chenodeoxycholic acid--which is used for conservative therapy of radiolucent gallstones--on the rate of colonic tumors was examined. In rats treated with chenodeoxycholic acid a higher incidence of 1,2-dimethylhydrazine induced adenocarcinomas was detected. On the basis of these results it is postulated that all patients treated with chenodeoxycholic acid due to gallstones are registered systematically in order to gain definite information about its possible role as tumor promoter.
Ursodeoxycholic acid treatment in IBD-patients with colorectal dysplasia and/or DNA-aneuploidy: a prospective, double-blind, randomized controlled pilot study. [2013]There is an increased risk of colorectal carcinoma (CRC) in patients with longstanding, extensive colonic inflammatory bowel disease (IBD). Primary sclerosing cholangitis, family history of CRC, mucosal dysplasia and DNA-aneuploidy are other risk factors. Recently, results from animal studies have shown that the bile acid ursodeoxycholic acid (UDCA) has a favourable impact on experimentally-induced CRC/neoplasia in rats. The aim of this proof of the concept study was to explore the possible preventive/reverting effects of UDCA in patients with colorectal IBD with existing findings of low grade dysplasia and/or DNA-aneuploidy.
Effects of bile acids on colon carcinogenesis in rats treated with carcinogens. [2013]Primary bile acids were studied as possible colon tumor promoters or inhibitors in a rat model of chemically induced colon cancer. Cholic acid feeding increased the number of animals with tumors, the number of tumors per animal, and the number of tumors per tumor-bearing animal. Tumor enhancement was attributed to deoxycholic acid, the bacterial metabolite of cholic acid. When chenodeoxycholic acid was fed to the rats in our model, tumor incidence was increased, but the number of tumors per animal and the number of tumors per tumor-bearing animal were similar to controls. The different fecal bile acid pattern obtained with chenodeoxycholic acid may be responsible for the differences in tumor incidence. The methodology to characterize and identify all steroidal components of the feces requires extraction, thin-layer chromatography, gas-liquid chromatography, and gas-liquid chromatography-mass spectrometry. Newer techniques include LH-20 chromatography (for sulfated steroids) and high-pressure liquid chromatography.
Administration of an unconjugated bile acid increases duodenal tumors in a murine model of familial adenomatous polyposis. [2019]Intestinal carcinogenesis involves the successive accumulation of multiple genetic defects until cellular transformation to an invasive phenotype occurs. This process is modulated by many epigenetic factors. Unconjugated bile acids are tumor promoters whose presence in intestinal tissues is regulated by dietary factors. We studied the role of the unconjugated bile acid, chenodeoxycholate, in an animal model of familial adenomatous polyposis. Mice susceptible to intestinal tumors as a result of a germline mutation in Apc (Min/+ mice) were given a 10 week dietary treatment with 0.5% chenodeoxycholate. Following this, the mice were examined to determine tumor number, enterocyte proliferation, apoptosis and beta-catenin expression. Intestinal tissue prostaglandin E2 (PGE2) levels were also assessed. Administration of chenodeoxycholate in the diet increased duodenal tumor number in Min/+ mice. Promotion of duodenal tumor formation was accompanied by increased beta-catenin expression in duodenal cells, as well as increased PGE2 in duodenal tissue. These data suggest that unconjugated bile acids contribute to periampullary tumor formation in the setting of an Apc mutation.
Effect of ursodeoxycholic acid use on the risk of colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory bowel disease: a systematic review and meta-analysis. [2018]Ursodeoxycholic acid (UDCA) may modify the risk of inflammatory bowel disease (IBD)-associated colorectal cancer. We performed a systematic review and meta-analysis of studies evaluating the effect of UDCA on the risk of IBD-associated colorectal neoplasia (CRN) (defined as colorectal cancer and/or dysplasia) in patients with primary sclerosing cholangitis with concomitant IBD (PSC-IBD).