Obeticholic Acid for Familial Adenomatous Polyposis

Recruiting at 6 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Bile acid resins, Clozapine, Theophylline, others

Disqualifiers: Chronic liver disease, Pancreatitis, Hyperlipidemia, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 6 months

80 Participants Needed

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. ^{1 2 3 4 5}

Is 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. ^{1 6 7 8 9}

How 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. ^{1 2 4 5 7}

Research Team

Eduardo Vilar-Sanchez

Principal Investigator

M.D. Anderson Cancer Center

Eligibility 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.

Absolute neutrophil count >= 1,500/microliter

Negative test results for HIV, hepatitis C virus (HCV), and hepatitis B virus (HBV)

Exclusion Criteria

My cholesterol levels are very high and not under control.

Known hypersensitivity or intolerance to study drug

I am not taking any medications that are not allowed in this trial.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive OCA or placebo orally once daily for 6 months. GI endoscopy with biopsy and blood sample collection are conducted.

6 months

Regular visits for endoscopy and sample collection

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

3 weeks

1 visit (in-person)

Treatment Details

Interventions

• Obeticholic Acid

Trial Overview 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.

Participant Groups

Group I: Arm I (OCA) Experimental Treatment 5 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 Group 5 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

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Patients with familial adenomatous polyposis (FAP) have higher total biliary bile acid concentrations compared to those without FAP, which may contribute to their increased risk of gastrointestinal cancers.

The bile of FAP patients contains a higher proportion of chenodeoxycholic acid and a lower proportion of deoxycholic acid, suggesting that these bile acid profiles could influence the growth of intestinal adenomas and cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biliary bile acid profiles in familial adenomatous polyposis. Spigelman, AD., Owen, RW., Hill, MJ., et al.[2019]

In a study of 10 patients with familial adenomatous polyposis (FAP), the overall concentration and daily excretion of faecal bile acids were similar to those of 9 control subjects, suggesting that bile acid formation may not be significantly reduced in FAP as previously thought.

However, specific bile acids, such as 12-oxo-lithocholic acid, were found at significantly higher levels in FAP patients, indicating increased bacterial transformation of bile acids in these individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unconjugated faecal bile acids in familial adenomatous polyposis analysed by gas-liquid chromatography and mass spectrometry. Barker, GM., Radley, S., Davis, A., et al.[2019]

In a Phase II pilot study involving 15 patients with familial adenomatous polyposis (FAP), low-dose rectal sulindac therapy led to complete adenoma reversion in 87% of patients after 48 weeks, demonstrating its efficacy in managing this condition.

The treatment was well-tolerated with minimal side effects, and significant reductions in proliferation indices of adenomatous tissue were observed, suggesting that rectal sulindac may be a promising alternative to surgical procedures for FAP management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Winde, G., Schmid, KW., Schlegel, W., et al.[2019]

In a study of 64 patients (50 with colorectal adenomas and 14 with carcinoma), a significant increase in chenodeoxycholic acid was found in the bile of adenoma patients compared to controls, suggesting a potential biomarker for colorectal neoplasia.

The increase in chenodeoxycholic acid correlated with the malignant potential of adenomas, indicating that higher levels may be associated with larger size, more severe dysplasia, and greater numbers of adenomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relationship between duodenal bile acids and colorectal neoplasia. Moorehead, RJ., Campbell, GR., Donaldson, JD., et al.[2019]

In a study involving rats, continuous oral administration of chenodeoxycholic acid, a treatment for gallstones, was linked to a higher incidence of adenocarcinomas induced by a carcinogen.

The findings suggest that patients treated with chenodeoxycholic acid should be monitored systematically to better understand its potential role as a tumor promoter in colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chenodeoxycholic acid therapy and colorectal carcinoma--an experimental approach (author's transl)]. Sauer, HD., de Heer, K., Mitschke, H.[2013]

In a two-year study involving 19 patients with long-standing inflammatory bowel disease (IBD), treatment with ursodeoxycholic acid (UDCA) showed potential in preventing the progression of low-grade dysplasia, as no patients in the UDCA group experienced worsening conditions compared to two patients in the placebo group who required colectomy.

Although the study did not find significant differences in overall dysplasia scores between the UDCA and placebo groups, the results suggest that UDCA may have chemopreventive properties, indicating that longer treatment durations or higher doses might be necessary for more pronounced effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ursodeoxycholic acid treatment in IBD-patients with colorectal dysplasia and/or DNA-aneuploidy: a prospective, double-blind, randomized controlled pilot study. Sjöqvist, U., Tribukait, B., Ost, A., et al.[2013]

Feeding cholic acid to rats increased the incidence and number of colon tumors, suggesting it may promote tumor growth, primarily due to its metabolite, deoxycholic acid.

Chenodeoxycholic acid also increased tumor incidence but did not raise the number of tumors per animal, indicating that different bile acids can have varying effects on colon cancer development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of bile acids on colon carcinogenesis in rats treated with carcinogens. Cohen, BI., Raicht, RF.[2013]

In a study involving Min/+ mice, which are genetically predisposed to intestinal tumors, a 10-week dietary treatment with 0.5% chenodeoxycholate significantly increased the number of duodenal tumors.

The increase in tumor formation was linked to elevated beta-catenin expression and higher levels of prostaglandin E2 (PGE2) in the intestinal tissue, suggesting that unconjugated bile acids like chenodeoxycholate may promote tumor development in individuals with specific genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Administration of an unconjugated bile acid increases duodenal tumors in a murine model of familial adenomatous polyposis. Mahmoud, NN., Dannenberg, AJ., Bilinski, RT., et al.[2019]

A systematic review of 8 studies involving 763 patients with primary sclerosing cholangitis and inflammatory bowel disease found no overall protective effect of ursodeoxycholic acid (UDCA) against colorectal neoplasia, but it did show a significant reduction in the risk of advanced colorectal neoplasia (cancer and high-grade dysplasia) with an odds ratio of 0.35.

Low-dose UDCA (8-15 mg/kg/d) was particularly effective, associated with a substantial risk reduction for colorectal neoplasia, with an odds ratio of 0.19, suggesting that dosage may play a critical role in its chemopreventive effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Singh, S., Khanna, S., Pardi, DS., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Biliary bile acid profiles in familial adenomatous polyposis. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Unconjugated faecal bile acids in familial adenomatous polyposis analysed by gas-liquid chromatography and mass spectrometry. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

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]

4. England pubmed.ncbi.nlm.nih.gov

Relationship between duodenal bile acids and colorectal neoplasia. [2019]

5. Germany pubmed.ncbi.nlm.nih.gov

[Chenodeoxycholic acid therapy and colorectal carcinoma--an experimental approach (author's transl)]. [2013]

6. Greece pubmed.ncbi.nlm.nih.gov

Ursodeoxycholic acid treatment in IBD-patients with colorectal dysplasia and/or DNA-aneuploidy: a prospective, double-blind, randomized controlled pilot study. [2013]

7. United States pubmed.ncbi.nlm.nih.gov

Effects of bile acids on colon carcinogenesis in rats treated with carcinogens. [2013]

8. England pubmed.ncbi.nlm.nih.gov

Administration of an unconjugated bile acid increases duodenal tumors in a murine model of familial adenomatous polyposis. [2019]

9. England pubmed.ncbi.nlm.nih.gov

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]