Testing Obeticholic Acid (OCA) for Familial Adenomatous Polyposis (FAP)

Familial Adenomatous Polyposis Clinical Trial

Official title:

MDA20-01-01: A Phase IIa, Placebo-Controlled, Randomized Study of Daily Obeticholic Acid (OCA) to Reduce Intestinal Polyp Burden in Familial Adenomatous Polyposis (FAP)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05112822
• Other study ID #: 2021-0286
• Status: Not yet recruiting
• Phase: Phase 1
• Start date: March 31, 2022
• Est. completion date: February 28, 2024

Study information

• Verified date: November 2021
• Source: M.D. Anderson Cancer Center
• Contact: Eduardo Sanchez, MD, PhD
• Phone: (713) 563-4743
• Email: evilar[@]mdanderson.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a trial that intends to evaluate the effect of treatment with the drug obeticholic acid in the treatment of the Familial Adenomatous Polyposis condition.

Description:

OBJECTIVES

Primary Objectives

-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

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

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

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

• 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.

• 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.

• 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.

Identify differentially expressed genes between duodenal and colorectal adenomas and uninvolved tissue at baseline and post-intervention for participants who received OCA or placebo.

Quantify the effect of OCA on the expression of downstream targets of FXR in adenomas and uninvolved tissue.

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.

• 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.

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

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 80
• Est. completion date: February 28, 2024
• Est. primary completion date: February 28, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Participants must have a diagnosis of phenotypic FAP with disease involvement of the duodenum and rectum as defined by:

1. Genetic diagnosis: APC germline mutation (with or without family history) or obligate carrier.

2. Clinical diagnosis: FAP phenotype with >100 adenomas in large intestine and participant has a family history of FAP.

3. Clinical diagnosis: FAP phenotype who are status post colectomy for polyposis, participant has a family history of FAP, and 2 FAP experts agree to the diagnosis.

4. Attenuated FAP diagnosis: APC germline mutation required.

• Participants must have no evidence of active or recurrent invasive cancer for 6 months prior to screening and must be at least 6 months from any prior cancer-directed treatment (such as surgical resection, chemotherapy, immunotherapy, hormonal therapy or radiation).

• Age = 18 years. Because no dosing or adverse event (AE) data are currently available on the use of OCA in participants <18 years of age, children are excluded from this study but will be eligible for future pediatric trials, if applicable.

• ECOG performance status =1 (Karnofsky =70%; see Appendix A)

• Participants must have normal organ and marrow function as defined below:

Hemoglobin >10 g/dL or Hematocrit > 30 % Leukocyte count =3,500/microliter Platelet count =100,000/microliter Absolute neutrophil count =1,500/microliter Creatinine clearance (calculated if measured is not available) =60 mL/min/1.73m2

AST (SGOT)/ALT (SGPT) =2 times the institutional upper limit of normal (ULN) Total bilirubin =1.5 the ULN; participants with Gilbert's disease may be enrolled with higher Total bilirubin if their Direct bilirubin is = 1.5 times the ULN.

Presence of Spigelman stage II or III duodenal polyposis at screening

• Presence of intact rectum or ileo-rectal anastomosis (IRA) or ileal pouch-anal anastomosis (IPAA)

• Willing and able to adhere to the prohibitions and restrictions specified in the final approved protocol

• The effects of OCA on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately.

• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Prior use of study drug

• Duodenal or rectal/pouch polyp burden that is not quantifiable

• Histologically-confirmed high-grade dysplasia or cancer on biopsy at screening

• Individuals with active, known or suspected chronic liver disease including cirrhosis, nonalcoholic steatohepatitis with liver fibrosis, NASH with cirrhosis, primary sclerosing cholangitis, biliary atresia

• Individuals with acute cholecystitis (defined by a syndrome of right upper quadrant pain, fever, and leukocytosis associated with gallbladder inflammation diagnosed within the prior 6 weeks) or biliary obstruction (defined by extrahepatic cholestasis)

• Individuals with hyperlipidemia not well controlled with the use of pharmacotherapy and/or dietary modifications

• History of severe, progressive, or uncontrolled renal, genitourinary, hepatic, hematologic, endocrine, cardiac, vascular, pulmonary, rheumatologic, neurologic, psychiatric, or metabolic disturbances, or signs and symptoms thereof.

• Pregnant, breast-feeding, or women of childbearing potential unwilling to use a reliable contraceptive method. Pregnant women are excluded from this study because OCA is an agent with unknown effects on the developing human fetus. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with OCA, breastfeeding should be discontinued if the mother is treated with OCA.

• Known hypersensitivity, allergies, or intolerance to the study drug or compounds of similar chemical or biologic composition.

• Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with participant's safety, obtaining informed consent, or compliance to the study procedures.

• Participants may not be receiving any other investigational agents.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

• Individuals taking the drugs listed below may not be randomized unless they are willing to stop the medications (and possibly change to alternative non-excluded medications to treat the same conditions) no less than 5 half-lives days prior to starting OCA or placebo on this study. Consultation with the participant's primary care provider may be obtained but is not required. The use of the following drugs or drug classes is prohibited during OCA/placebo treatment:

• Investigational agents;

• Bile acid sequestrants (bile acid binding resins): cholestyramine, colestipol, or colesevelam

• Bile salt efflux pump (BSEP) inhibitors

• Clozapine

• Theophylline derivatives

• Tizanidine

• Warfarin

Related Conditions & MeSH terms

• Adenomatous Polyposis Coli
• Colorectal Neoplasms
• Familial Adenomatous Polyposis
• Nasopharyngeal Neoplasms

Intervention

Drug:
• Obeticholic Acid
Given by PO
• Placebo
Given by PO

Locations

Country	Name	City	State
Puerto Rico	University of Puerto Rico, Medical Sciences Campus	San Juan
United States	University of Michigan	Ann Arbor	Michigan
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Cleveland Clinic	Cleveland	Ohio
United States	Mayo Clinic Arizona	Phoenix	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
M.D. Anderson Cancer Center

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To evaluate the effect of treatment with OCA versus treatment with placebo on duodenal polyp burden (sum of polyp diameters) in participants with FAP.		through study completion, an average of 1 year

External Links

•   MD Anderson Cancer Center Website