REC-4881 for Familial Adenomatous Polyposis

(TUPELO Trial)

Recruiting at 15 trial locations

Overseen By Recursion Pharmaceuticals

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Recursion Pharmaceuticals Inc.

Must not be taking: NSAIDs, Omega-3, Corticosteroids, others

Disqualifiers: Cancer, Desmoid tumors, Eye abnormality, others

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called REC-4881 in people with Familial Adenomatous Polyposis (FAP). The goal is to see if the drug can reduce or slow the growth of polyps in their intestines, making the condition easier to manage and potentially avoiding more surgeries.

Will I have to stop taking my current medications?

You will need to stop using non-steroidal anti-inflammatory drugs (NSAIDs), omega-3 fatty acids, oral corticosteroids, strong CYP3A inhibitors or inducers, and strong BCRP or MRP2 inhibitors before starting the study.

What data supports the effectiveness of the drug REC-4881 for treating Familial Adenomatous Polyposis?

Research shows that non-steroidal anti-inflammatory drugs (NSAIDs) like sulindac and celecoxib can reduce colorectal adenoma burden in familial adenomatous polyposis (FAP), suggesting that similar drugs might be effective in managing this condition. ^{1 2 3 4 5}

How does the drug REC-4881 differ from other treatments for familial adenomatous polyposis?

REC-4881 is unique because it is being studied specifically for its effects on familial adenomatous polyposis, whereas other treatments like sulindac and meloxicam are non-steroidal anti-inflammatory drugs (NSAIDs) used to manage polyps by targeting inflammation pathways. The novelty of REC-4881 lies in its potential to offer a new mechanism of action or treatment approach for this condition. ^{1 5 6 7 8}

Eligibility Criteria

Adults over 18 with Familial Adenomatous Polyposis (FAP) who've had a colectomy can join this trial. They must not use strong CYP3A affecting drugs, NSAIDs (except low-dose aspirin), or have had recent cancer treatments. Those with certain GI diseases or difficulty swallowing pills are excluded.

Inclusion Criteria

Have provided written informed consent to participate in the study

I am 55 years old or older.

My blood counts are normal.

Exclusion Criteria

I am currently being treated for desmoid tumors.

I haven't taken any FAP-targeted drugs in the last 8 weeks.

Has received treatment with other investigational agents prior to Study Day 1

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part 1

Participants receive either REC-4881 4mg or placebo once daily post-colectomy/proctocolectomy

43 days

Treatment Part 2

Participants receive escalating doses of REC-4881 (4mg, 8mg, or 12mg) to determine the RP2D

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Placebo (Placebo)
• REC-4881 (Unknown)

Trial Overview The study tests REC-4881 against a placebo in people with FAP to see if it's effective and safe. It's conducted at multiple centers and includes two parts, focusing on patients who've undergone colon surgery due to their condition.

Participant Groups

Group I: REC-4881 8mg (Part 2) Experimental Treatment 1 Intervention

Participants will receive REC-4881 8mg PO dosed once daily

Group II: REC-4881 4mg (Part 2) Experimental Treatment 1 Intervention

Participants will receive REC-4881 4mg PO dosed once daily

Group III: REC-4881 4mg (Part 1) Experimental Treatment 1 Intervention

Participants will receive REC-4881 4mg PO dosed once daily

Group IV: Placebo (Part 1) Placebo Group 1 Intervention

Participants will receive placebo PO dosed once daily

Who Is Running the Clinical Trial?

Recursion Pharmaceuticals Inc.

Lead Sponsor

Trials

6

Recruited

450+

Findings from Research

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 Phase III trial involving 106 children with familial adenomatous polyposis (FAP), celecoxib treatment resulted in a lower rate of colorectal polyps and a longer time to disease progression compared to placebo, with 12.7% of celecoxib patients showing disease progression versus 25.5% in the placebo group.

Celecoxib was well-tolerated, with similar rates of adverse events between the treatment and placebo groups, although three patients on celecoxib experienced serious adverse events, indicating a need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Children's International Polyposis (CHIP) study: a randomized, double-blind, placebo-controlled study of celecoxib in children with familial adenomatous polyposis. Burke, CA., Phillips, R., Berger, MF., et al.[2020]

A new staging and intervention classification system for familial adenomatous polyposis (FAP) was developed, showing high agreement among 26 expert reviewers in assessing polyp stages and recommending interventions, which is crucial for future clinical trials.

The high concordance rate (ρ = 0.710) indicates that this system can reliably measure treatment outcomes, although cases with significant disagreement may need special consideration before being included in clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A proposed staging system and stage-specific interventions for familial adenomatous polyposis. Lynch, PM., Morris, JS., Wen, S., et al.[2020]

In a randomized trial involving 112 subjects with familial adenomatous polyposis, the combination of celecoxib (CXB) and diflouromethylornithine (DFMO) showed a moderate synergy in reducing adenoma burden, but no significant difference in adenoma count compared to celecoxib alone after 6 months.

The study found that while fatigue was a significant adverse event associated with celecoxib, there were no major cardiovascular risks or DFMO-related ototoxicity observed, indicating a relatively safe profile for the combination treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An international randomised trial of celecoxib versus celecoxib plus difluoromethylornithine in patients with familial adenomatous polyposis. Lynch, PM., Burke, CA., Phillips, R., et al.[2016]

Familial adenomatous polyposis (FAP) is a genetic condition that leads to the early development of numerous polyps in the colon and rectum, with an incidence of 1 in 10,000 newborns, and can result in cancer if not monitored and treated.

The condition is primarily caused by mutations in the APC tumor suppressor gene, and a DNA Bank has been established in Poland to study FAP, collecting samples from 600 families to better understand the genetic factors involved.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Familial adenomatous polyposis of the colon. Plawski, A., Banasiewicz, T., Borun, P., et al.[2022]

Patients with familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) require frequent endoscopic surveillance and may need prophylactic colectomy to prevent colorectal cancer, with ongoing management focusing on both colorectal and upper gastrointestinal adenomas.

Recent advancements allow for endoscopic treatment of premalignant lesions in the upper gastrointestinal tract, shifting the focus from solely diagnostic surveillance to active intervention, while research into chemopreventive agents aims to further reduce polyp burden.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of familial adenomatous polyposis and MUTYH-associated polyposis; new insights. Aelvoet, AS., Buttitta, F., Ricciardiello, L., et al.[2022]

References

1. 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]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Children's International Polyposis (CHIP) study: a randomized, double-blind, placebo-controlled study of celecoxib in children with familial adenomatous polyposis. [2020]

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

A proposed staging system and stage-specific interventions for familial adenomatous polyposis. [2020]

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

An international randomised trial of celecoxib versus celecoxib plus difluoromethylornithine in patients with familial adenomatous polyposis. [2016]

5. Poland pubmed.ncbi.nlm.nih.gov

Familial adenomatous polyposis of the colon. [2022]

6. Korea (South) pubmed.ncbi.nlm.nih.gov

A Novel Germline Mutation in Exon 15 of the APC Gene in Attenuated Familial Adenomatous Polyposis: A Report of Two Cases. [2021]

7. Greece pubmed.ncbi.nlm.nih.gov

Expression of COX-2 and Wnt pathway genes in adenomas of familial adenomatous polyposis patients treated with meloxicam. [2018]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Management of familial adenomatous polyposis and MUTYH-associated polyposis; new insights. [2022]