An Investigational Drug (TPST-1495) in Patients With Familial Adenomatous Polyposis

Phase 2 Study to Evaluate the Efficacy and Safety of TPST-1495 in Patients With Familial Adenomatous Polyposis (FAP)

This open-label phase II trial tests how well TPST-1495 works in reducing the number of polyps in the small bowel and colon in patients with familial adenomatous polyposis (FAP). FAP is an inherited condition in which numerous polyps (growths that protrude from mucous membranes) form on the inside walls of the colon and rectum. It increases the risk for colon cancer. TPST-1495 binds to specific prostaglandin receptors. TPST-1495 is a dual antagonist of the prostaglandin E2 (PGE2) receptor subtypes EP2 and EP4, while sparing the immune-stimulating EP1 and EP3 receptors. TPST-1495 may help reduce the number of polyps in the small bowel and colon in patients with FAP.

Study Overview

• Status: Recruiting
• Conditions: Familial Adenomatous Polyposis; Colorectal Carcinoma
• Intervention / Treatment: Other: Questionnaire Administration; Procedure: Biospecimen Collection; Procedure: Gastrointestinal Endoscopy; Procedure: Esophagogastroduodenoscopy; Drug: EP2/EP4 Antagonist TPST-1495; Procedure: Biopsy Procedure

Detailed Description

PRIMARY OBJECTIVES:

I. To assess the activity of TPST-1495 in reducing duodenal polyp burden in patients with FAP.

II. To assess the safety of TPST-1495 in patients with FAP; we will evaluate the incidence of grade 2 or 3 adverse events.

SECONDARY OBJECTIVE:

I. The activity of TPST-1495 in reducing rectum/IPAA (ileal pouch-anal anastomosis) polyp burden in patients with FAP.

EXPLORATORY OBJECTIVES:

I. Reduction in intestinal polyp burden as a function of immunohistochemical staining at baseline and end of intervention (6-months) of rectal and duodenal tissue samples for COX-2 expression level, beta-catenin, and Ki-67.

II. Proteomic profile of serum correlated to clinical response to therapy compared between baseline and end of intervention.

III. Biospecimen acquisition.

OUTLINE:

Patients receive TPST-1495 orally (PO) once daily (QD) for 6 months in the absence of unacceptable toxicity. Patients also undergo esophagogastroduodenoscopy (EGD) and gastrointestinal (GI) endoscopy with biopsy at baseline and end of treatment and undergo blood sample collection throughout the study.

After completion of study treatment, patients are followed up at 1 month.

• Study Type: Interventional
• Enrollment (Estimated): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Not yet recruiting
      • Mayo Clinic Hospital in Arizona
      • Contact: Niloy J. Samadder; Phone Number: 480-342-6263; Email: Samadder.jewel@mayo.edu
      • Principal Investigator: Niloy J. Samadder
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Not yet recruiting
      • Mayo Clinic in Rochester
      • Principal Investigator: Lisa A. Boardman
      • Contact: Lisa A. Boardman; Phone Number: 507-284-2175; Email: boardman.lisa@mayo.edu
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Not yet recruiting
      • Huntsman Cancer Institute/University of Utah
      • Contact: Jessica R. Stout; Phone Number: 801-585-6439; Email: jessica.stout@utah.edu
      • Principal Investigator: Jessica R. Stout
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Recruiting
      • University of Wisconsin Carbone Cancer Center - University Hospital
      • Principal Investigator: Lisa M. Barroilhet
      • Contact: Lisa M. Barroilhet; Phone Number: 608-265-2319; Email: barroilhet@wisc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of familial adenomatous polyposis (FAP), defined as at least one of the following:

  • Genetic diagnosis with confirmed APC mutation (clinical CLIA [clinical laboratory improvement amendments] certified lab or research testing)
  • Obligate carrier
  • Clinical diagnosis of classic FAP with ≥ 100 colorectal adenomas status post colectomy or a sub-total colectomy and a family history of FAP
  • Clinical diagnosis of FAP, based on personal and family history. Note: This criterion requires documented review and agreement from either the study chair or the MW consortium lead investigator
• Previously underwent prophylactic colectomy or sub-total colectomy with IRA (ileo-rectal or ileo-colonic anastomosis) or IPAA at least 12 months before pre-registration evaluation and without ongoing surgical complication
• Willing to discontinue taking non-steroidal anti-inflammatory drugs (NSAIDs) 5 days prior to initiation of study treatment and limit frequency of NSAID dosing during study treatment
• Age ≥ 18. Because no dosing or adverse event (AE) data are currently available on the use of TPST-1495 in participants < 18 years of age, children and adolescents are excluded from this study but will be eligible for future pediatric trials, if applicable
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
• Leukocytes (white blood count [WBC]) ≥ 3,000/uL (≥ 2,500/uL for African American participants)
• Platelet count ≥ 100 x 10^9/L
• Hemoglobin ≥ 11.5 g/dL
• Total bilirubin ≤ 1.5 x institutional upper limit normal (ULN) (unless patient has Gilbert's)
• Alkaline phosphatase ≤ 1.5 x institutional ULN
• Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) ≤ 2 x institutional ULN
• Alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) ≤ 2 x institutional ULN
• Creatinine ≤ institutional ULN
• Urinary testing results within institutional limits of normal or deemed clinically insignificant
• Individuals on chronic suppressive antiviral therapy for herpes simplex virus (HSV) are eligible
• Presence of Spigelman 2 or 3 duodenal polyposis stage assessed by endoscopy
• Not pregnant: The effects of TPST-1495 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 or for 90 days after stopping study agent. Additionally, men should not donate sperm for the purpose of reproduction during the study and for a minimum of 90 days after receiving the last dose of study agent. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately
• Not currently breastfeeding
• Ability to understand and the willingness to sign a written informed consent document
• Helicobacter (H.) pylori negative confirmed with gastric biopsy (at time of screening EGD). If positive for H. pylori the patient can be offered full course of approved therapy with confirmation of eradication and re-assessment for trial participation with likely need to repeat baseline endoscopies if > 45 days since date of baseline procedures

Exclusion Criteria:

• Use of any other investigational agents ≤ 12 weeks prior to pre-registration
• History of gastric or intestinal ulceration due to NSAID therapy
• Uncontrolled intercurrent illness or recent surgical procedure that in the opinion of the investigative team would limit compliance with study requirements
• History of invasive malignancy ≤ 3 years prior to pre-registration (exception: adequately treated carcinoma of the cervix, carcinoma in situ, or basal or squamous cell carcinomas of the skin)
• History of any upper GI surgery that does not permit access to or evaluation of a 10 cm segment of the duodenum that includes the duodenal bulb, i.e. Whipple procedure or similar
• Any histologically confirmed high grade dysplasia (HGD) or cancer, gastrointestinal bleeding and requirement for anticoagulation therapy after study start except for use of low dose aspirin
• Exclusion of patients utilizing strong a moderate inhibitors of CYP2D6 and CYP3A4
• Individuals with evidence of human immunodeficiency virus (HIV) infection will be excluded from the study even if the HIV viral load is undetectable on suppressive therapy. Many of the HIV suppression anti-viral medications are moderate/strong inhibitors of CYP2D6 and CYP3A4 and are exclusions based on above
• Individuals with evidence of chronic hepatitis B virus (HBV) or C virus (HCV) infection will be excluded from the study, even if the HBV/HCV viral load is undetectable on suppressive therapy. Many of the HBV/HCV suppression anti-viral medications are moderate/strong inhibitors of CYP2D6 and CYP3A4 and are exclusions based on above
• Individuals with active H. pylori infection that is untreated or refractory to standard antibiotic therapy
• Patients with prior history of peptic ulcers complicated by bleeding, New York Heart Association (NYHA) Classification II-IV, active autoimmune diseases, on anticoagulants at risk of bleeding or abnormal corrected QT interval (QTc) prolongation will also be excluded. Patients enrolled in this trial are status post colectomy or subtotal colectomy (with either IPAA or IRA or ileo-colonic anastomosis) and thus would not be expected to be at significant risk of diverticulitis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Prevention (TPST-1495); Patients receive TPST-1495 PO QD for 6 months in the absence of unacceptable toxicity. Patients also undergo EGD and GI endoscopy with biopsy at baseline and end of treatment and undergo blood sample collection throughout the study.

Other: Questionnaire Administration; Ancillary studies; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Procedure: Gastrointestinal Endoscopy; Undergo GI endoscopy; Other Names: Enteroscopy; Procedure: Esophagogastroduodenoscopy; Undergo EGD; Other Names: EGD; Upper Endoscopy; Drug: EP2/EP4 Antagonist TPST-1495; Given PO; Other Names: Dual EP2/4 Antagonist TPST-1495; PGE2 EP2/EP4 Receptor Antagonist TPST-1495; Prostaglandin E2 Receptor EP2/EP4 Antagonist TPST-1495; TPST 1495; TPST-1495; TPST1495; Procedure: Biopsy Procedure; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE; Biopsy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent change in duodenal polyp burden	Will be determined based on the sum of diameters from all polyps. Will be assessed by comparing upper gastrointestinal (GI) endoscopies respectively. Will be described using a two-sided 95% confidence interval and examined for difference from zero with a one-side paired t-test.	Baseline to 6 months
Incidence of adverse events	Will examine the proportion of patients with grade 2 or 3 adverse events according to the Common Terminology Criteria for Adverse Events version 6.0. Will be summarized as a proportion with a 1-sided 90% confidence interval.	Up to 7 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent change in rectal/pouch polyp burden	Will be assessed by comparing the lower GI endoscopies. Results will be presented using summary statistics and corresponding confidence intervals.	Baseline to 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent change in immunohistochemical staining levels	Will assess rectal and duodenal tissue samples for COX-2 expression level, beta-catenin, and Ki-67. Mean percent change in immunohistochemical staining levels will be associated with intestinal polyp burden using a scatterplot of the two variables and evaluated using a Spearman rank correlation statistic.	Baseline to 6 months
Proteomic profile	Will identify proteins that are statistically significantly differently expressed between patients after treatment. The proteomic profile of serum will be correlated to clinical response to therapy and compared between baseline and end of intervention. No formal statistical inference will be performed. Proteins will be described with summary statistics to assist in planning follow-up studies.	Baseline to 6 months

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Niloy J Samadder, University of Wisconsin Carbone Cancer Center - University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2026
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: August 15, 2024
• First Submitted That Met QC Criteria: August 15, 2024
• First Posted (Actual): August 16, 2024

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Genetic Diseases, Inborn; Intestinal Diseases; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplasms, Glandular and Epithelial; Colonic Diseases; Adenoma; Neoplastic Syndromes, Hereditary; Adenomatous Polyps; Intestinal Polyposis; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Colorectal Neoplasms; Adenomatous Polyposis Coli; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Minimally Invasive Surgical Procedures; Cytological Techniques; Cytodiagnosis; Diagnostic Techniques, Surgical; Diagnostic Techniques, Digestive System; Endoscopy; Digestive System Surgical Procedures; Biopsy; Specimen Handling; Endoscopy, Gastrointestinal; Endoscopy, Digestive System; Gastroscopy
• Other Study ID Numbers: NCI-2024-06758 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA014520 (U.S. NIH Grant/Contract); UG1CA242596 (U.S. NIH Grant/Contract); UG1CA242635 (U.S. NIH Grant/Contract); UWI23-16-01 (Other Identifier: DCP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No