Sirolimus for Cowden Syndrome with Colon Polyposis

Overseen By Kebire Gofar, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Ohio State University

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 52 weeks

10 Participants Needed

Trial Summary

What is the purpose of this trial?

Colon polyposis (the presence of multiple colon polyps) is very common with Cowden syndrome, as over 60% of patients have 50 or more polyps. In a previous clinical trial, some participants had reduction in the number of colon polyps with the use of the medication sirolimus for a very short time period. This study is investigating sirolimus and its effect on the number of colon polyps in patients with Cowden syndrome and polyposis over a 1 year period.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Sirolimus for Cowden Syndrome with Colon Polyposis?

Research shows that Sirolimus, which is an mTOR inhibitor, has been effective in reducing disease symptoms in conditions similar to Cowden Syndrome, such as juvenile polyposis syndrome. It helped decrease the number of polyps and improved overall health without significant side effects. ^{1 2 3 4 5}

Is sirolimus safe for humans?

Sirolimus, also known as Rapamune, has been studied in humans for conditions like Cowden syndrome and has shown no significant toxicity in these studies. It has been used safely in other conditions as well, suggesting it is generally safe for human use. ^{1 2 3 6 7}

How is the drug Sirolimus unique for treating Cowden Syndrome with Colon Polyposis?

Sirolimus is unique because it works by inhibiting a specific protein called mTOR, which helps control cell growth and immune response. This mechanism is different from other treatments and may help manage the growth of polyps in Cowden Syndrome. ^{8 9 10 11 12}

Research Team

Peter P. Stanich

Principal Investigator

Ohio State University

Eligibility Criteria

This trial is for adults over 18 with Cowden syndrome or related disorders, who have a genetic mutation called PTEN and more than 50 colon polyps that can't be removed endoscopically. It's not for those with chronic kidney disease, past high-grade colon tumors, colectomy history, or current/pending pregnancy.

Inclusion Criteria

I have a confirmed PTEN gene mutation.

I have Cowden syndrome or a related genetic condition.

I am able to understand and agree to participate in the study.

Exclusion Criteria

I have had colon cancer or a serious type of colon polyp.

I have long-term kidney disease.

You are pregnant, planning to become pregnant, or planning to father a child within 3 months after treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive sirolimus 2 mg by mouth daily for 1 year. Colonoscopy with polyp estimation at trial entrance and study completion.

52 weeks

Clinic visits at 3, 6, 9, and 12 months; Laboratories checked at 4 days, 2 weeks, then every 4 weeks for 3 months, then every 3 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Sirolimus

Trial Overview The study tests Sirolimus on patients with Cowden syndrome to see if it reduces the number of colon polyps over one year. Participants must have many polyps and a specific genetic mutation linked to their condition.

Participant Groups

Group I: Treatment arm Experimental Treatment 1 Intervention

There will be a clinic visit and colonoscopy at study entrance with standard of care sampling and assessment of polyps, including resection of concerning polyps. The investigators will also collect data on well-being via the SF-36 health survey (a validated questionnaire to help monitor this aspect given anecdotal patient-level reports of improvement while on therapy). Study subjects will then begin sirolimus 2 mg by mouth daily for 1 year. Laboratories will be checked at 4 days after initiation, at 2 weeks after initiation, then every 4 weeks for 3 months, then every 3 months to complete the year of therapy Participants will have a clinic visit at 3, 6 and 9 months and include well-being assessment with the SF-36 health survey. Participants will have a clinic visit with well-being assessment and perform colonoscopy at study closure at 12 months. The investigators will perform standard of care sampling and assessment of polyps, including resection of concerning polyps.

Sirolimus is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Rapamune for:

• Prevention of organ rejection in kidney transplant patients
• Treatment of lymphangioleiomyomatosis (LAM)

Approved in European Union as Rapamune for:

• Prevention of organ rejection in kidney transplant patients
• Treatment of lymphangioleiomyomatosis (LAM)

Approved in Canada as Rapamune for:

• Prevention of organ rejection in kidney transplant patients
• Treatment of lymphangioleiomyomatosis (LAM)

Approved in Japan as Rapamune for:

• Prevention of organ rejection in kidney transplant patients

Who Is Running the Clinical Trial?

Ohio State University

Lead Sponsor

Trials

891

Recruited

2,659,000+

PTEN Research

Collaborator

Trials

2

Recruited

60+

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Findings from Research

Sirolimus is a powerful immunosuppressant used in kidney transplantation that works by inhibiting the mTOR pathway, which is crucial for cell growth and proliferation, leading to reduced rates of acute rejection episodes to less than 10% when combined with cyclosporin A (CsA).

In clinical trials, using sirolimus at doses of 2 or 5 mg/day alongside CsA and steroids resulted in acute rejection rates of only 19% and 14% within 12 months, while also potentially reducing the need for nephrotoxic calcineurin inhibitors, although it may cause side effects like myelosuppression and increased lipid levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus: a comprehensive review. Kahan, BD.[2019]

Sirolimus (rapamycin) is an effective immunosuppressant approved for preventing graft rejection in kidney transplants, with a lower risk of complications compared to other immunosuppressants.

Recent findings suggest that sirolimus may also have potential in treating skin disorders and extending lifespan, making it a promising candidate for addressing age-related diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. Peters, T., Traboulsi, D., Tibbles, LA., et al.[2014]

References

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

A Pilot Study of Sirolimus in Subjects with Cowden Syndrome or Other Syndromes Characterized by Germline Mutations in PTEN. [2020]

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

Colonic polyposis and neoplasia in Cowden syndrome. [2021]

3. Canada pubmed.ncbi.nlm.nih.gov

Polygenic Infantile Juvenile Polyposis Syndrome Managed With Sirolimus and Endoscopic Polypectomy. [2022]

4. Greece pubmed.ncbi.nlm.nih.gov

Multiple colon carcinomas in a patient with Cowden syndrome. [2006]

5. England pubmed.ncbi.nlm.nih.gov

mTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in patients with juvenile polyposis of infancy with PTEN-BMPR1A deletion. [2022]

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

Chemoprevention and treatment of experimental Cowden's disease by mTOR inhibition with rapamycin. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Sirolimus for the treatment of polyposis of the rectal remnant and ileal pouch in four patients with familial adenomatous polyposis: a pilot study. [2021]

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

Sirolimus: a comprehensive review. [2019]

9. Canada pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. [2014]

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

Switching from tacrolimus to sirolimus halts the appearance of new sebaceous neoplasms in Muir-Torre syndrome. [2023]

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

Interstitial pneumonitis associated with sirolimus: a dilemma for lung transplantation. [2019]

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

Treatment of childhood kaposiform hemangioendothelioma with sirolimus. [2022]