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Adenomatous Polyps

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Familial Adenomatous Polyposis

MYH-associated Polyposis

Attenuated Familial Adenomatous Polyposis

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.

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.

Biopsy

Biospecimen Collection

Gastrointestinal Endoscopy

Obeticholic Acid

Placebo Administration

Questionnaire Administration

Niloy J. Samadder

Ramona M. Lim

Elena M. Stoffel

Carol A. Burke

Eduardo Vilar-Sanchez

Marcia R. Cruz-Correa

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.

PRIMARY OBJECTIVE:

I. To evaluate the effect of treatment with OCA versus treatment with placebo on duodenal polyp burden (sum of polyp diameters) in participants with FAP.

SECONDARY OBJECTIVES:

I. To assess the safety profile of treatment with OCA versus placebo in participants with FAP.

II. To evaluate the effect of treatment with OCA versus placebo on rectal and pouch polyp burden (sum of polyp diameters) in participants with FAP.

III. To assess the effect of treatment with OCA versus placebo on polyp burden (absolute number) in the duodenum of participants with FAP.

IV. To assess the effect of treatment with OCA versus placebo on polyp burden (absolute number) in the rectum and rectal pouch of participants with FAP.

V. To evaluate the effect of treatment with OCA versus placebo on serum levels of fibroblast growth factor-19 (FGF19) and 7 alpha-hydroxy-4-cholesten-3-one (7AC4, also known as C4) in participants with FAP.

VI. To determine the effects of treatment with OCA versus placebo on gene expression in duodenal, rectal pouch, and rectal adenomas and uninvolved mucosa in participants with FAP:

VIa. Identify differentially expressed genes between duodenal and colorectal adenomas and uninvolved tissue at baseline and post-intervention for participants who received OCA or placebo; VIb. Quantify the effect of OCA on the expression of downstream targets of FXR in adenomas and uninvolved tissue; VIc. Quantify the effect of OCA on the expression of cancer stem cell markers (e.g. LGR5, ASCL2, LRIG, BMI) and intestinal stem cell markers (e.g. Villin, KRT20, MUC, LYZ) in adenomas and uninvolved tissue.

VII. To evaluate the cell-type specific effects of treatment with OCA versus placebo on gene expression and abundance in duodenal, rectal pouch, and rectal adenomas and uninvolved mucosa in participants with FAP via single-cell transcriptomics.

VIII. To evaluate the effect of treatment with OCA versus placebo on microbiome diversity in duodenal, rectal pouch, and rectal adenomas and uninvolved tissue in participants with FAP.

VIIIa. Compare alpha- and beta-diversity analysis and identify differential abundance in adenomas and uninvolved tissue.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive OCA 25 mg orally (PO) once daily (QD) for 6 months in the absence of unacceptable toxicity. Patients also undergo gastrointestinal (GI) endoscopy with biopsy and collection of blood samples at screening and on study.

ARM II: Patients receive matching placebo PO QD for 6 months in the absence of unacceptable toxicity. Patients also undergo GI endoscopy biopsy and collection of blood samples at screening and on study.

After completion of the study treatment, patients are followed within 14-21 days.

Testing Obeticholic Acid for Familial Adenomatous Polyposis

A Phase IIa, Placebo-Controlled, Randomized Study of Daily Obeticholic Acid (OCA) to Reduce Intestinal Polyp Burden in Familial Adenomatous Polyposis (FAP)

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Change from baseline will be summarized by treatment arm. The difference in change from baseline between active treatment arms and the placebo arm will also be summarized.

Will summarize adverse events for each group by grade and study drug attribution using descriptive statistics.

Differences in the median serum levels of FGF19 and C4 between treatment arms will be compared.

Will use parametric models to evaluate the absolute and/or relative changes from baseline of these measures between obeticholic acid (OCA) and placebo groups.

Will use parametric models to evaluate the absolute and/or relative changes from baseline of these measures between OCA and placebo groups.

Will apply methods such as the beta-uniform mixture (BUM) model, the Wilcoxon rank-sum test with empirical Bayes, and the significance analysis of microarrays (SAM) to control the first degree relative (FDR).

Will apply methods such as the BUM model, the Wilcoxon rank-sum test with empirical Bayes, and the SAM to control the FDR.

National Cancer Institute (NCI)

Herbal and Botanical

All Drugs and Chemicals

Cola

Chart review study to evaluate the outcomes of subjects with Attenuated Familial Adenomatous Polyposis (AFAP) who have not undergone surgical resection of the colon.

Chart review study to evaluate the outcomes of subjects with Deleterious Familial Adenomatous Polyposis (FAP) who have not undergone surgical resection of the colon.

Database queried for the presence of cases meeting criteria (attenuated FAP, classical AFP \[i.e. identifiable APC mutation\], and/or a compatible family history or personal adenoma burden of \> 50 adenomas).

The data related to the patients with attenuated FAP and classical AFP who underwent endoscopic surveillance or surgery collected through chart review and all data is retrospective as of February 15, 2016.

Chart Review

Patrick Lynch, MD, JD

The primary objective of this chart review study is to evaluate the outcomes of subjects with Attenuated Familial Adenomatous Polyposis (AFAP) and Deleterious Familial Adenomatous Polyposis (FAP) who have not undergone surgical resection of the colon.

A secondary objective of this study is to compare 1) the colonoscopic and pathology histories including history of ampullary adenoma in the duodenum over family generations, 2) the use of chemopreventive medications, and 3) clinical features of subjects who pursued prophylactic surgical resection of the colon with those that have elected to continue routine colonoscopic surveillance in an effort to better characterize factors (e.g. polyp burden, ampullary adenoma and level of dysplasia, etc) which may influence management decisions.

The UTMDACC family history database will be queried for the presence of cases meeting the above criteria (attenuated Familial Adenomatous Polyposis (FAP), classical AFP \[i.e. identifiable APC mutation\], and/or a compatible family history or personal adenoma burden of \> 50 adenomas).

The data related to the patients with attenuated FAP and classical AFP who underwent endoscopic surveillance or surgery will be collected through chart review and all data is retrospective as of February 15, 2016.

The University of Texas MD Anderson Cancer Center (UTMDACC) medical record number for these cases will be used to identify the patient in ClinicStation: 1) records of endoscopy procedures, 2) operative reports, and 3) associated clinic notes will be reviewed for: a) whether the above evaluation criteria have been met, b) age, c) gender, d) age at initial colonoscopy, e) total number of colonoscopies, f) number of adenomas identified, g) cancer diagnoses, h) chemopreventive medications, i) type of surgery, j) number of hospitalizations, k) length of hospital stay, l) identification of an underlying APC mutation, and ll) family history information. The UT MDACC family history database will also be reviewed for updated family history information including ampullary adenomas and outcomes of genetic testing for identified cases.

Non-Surgical Management of Attenuated and Deleterious (Classical) Familial Adenomatous Polyposis: A Long-term Surveillance Program

For comparisons between groups, the Mann-Whitney test used.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Testing Obeticholic Acid for Familial Adenomatous Polyposis	NCT05223036	Attenuated Fami... Colorectal Carc... Duodenal Carcin... Familial Adenom...	Biopsy Biospecimen Col... Gastrointestina... Obeticholic Aci... Placebo Adminis... Questionnaire A...	18 Years -	National Cancer Institute (NCI)
Non-Surgical Management of Attenuated and Deleterious (Classical) Familial Adenomatous Polyposis: A Long-term Surveillance Program	NCT02747862	Attenuated Fami... Deleterious Fam...	Chart Review	-	M.D. Anderson Cancer Center
Testing Obeticholic Acid for Familial Adenomatous Polyposis	NCT05223036	Attenuated Fami... Colorectal Carc... Duodenal Carcin... Familial Adenom...	Biopsy Biospecimen Col... Gastrointestina... Obeticholic Aci... Placebo Adminis... Questionnaire A...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for attenuated familial adenomatous polyposis