Sirolimus for Cowden Syndrome With Colon Polyposis

NCT ID: NCT04094675

Last Updated: 2025-06-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 5 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-09-16
• Study Completion Date: 2025-06-05

Brief Summary

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.

Detailed Description

PTEN is a tumor suppressor gene that regulates the cell cycle through the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway. When germline mutations in PTEN occur, the result is Cowden syndrome (or less commonly one of several related disorders collectively called the PTEN hamartoma tumor syndrome). This is characterized by the growth of hamartomas and a high risk of cancer in multiple organ systems. This includes colon polyps in 92.5% of Cowden syndrome patients and 64% with an estimated 50 or more polyps. Although outcomes of this are under reported, series suggest 20-38% of patients will receive colectomy.

Current clinical practice for Cowden syndrome is based on close surveillance for the development of cancers. Sirolimus (also known as rapamycin) is a specific inhibitor of mTOR that is FDA-approved for immunosuppression and use in several types of cancers as chemotherapy. It has also been used successfully in other hamartomatous syndromes including lymphangioleiomyomatosis. There is also a completed pilot clinical trial for adults with Cowden syndrome in which some had reduction in the number of colon polyps with the use of the medication sirolimus for a very short time period.

This will be an open-label pilot trial to determine whether sirolimus reduces colon polyp burden in Cowden syndrome. Sirolimus will be administered for one year. Colonoscopy with polyp estimation will be performed at trial entrance and at study completion.

Conditions

PTEN Gene Mutation; PTEN Hamartoma Tumor Syndrome; PTEN Hamartoma Syndrome; Cowden Syndrome; Bannayan Syndrome; Bannayan Zonana Syndrome; Polyposis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment arm

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.

Group Type: EXPERIMENTAL

Sirolimus

Intervention Type: DRUG

Use of sirolimus 2 mg by mouth daily for 1 year

Interventions

Sirolimus

Use of sirolimus 2 mg by mouth daily for 1 year

Intervention Type: DRUG

Other Intervention Names

Rapamycin; Rapamune

Eligibility Criteria

Inclusion Criteria

• Cowden syndrome or other PTEN hamartoma tumor syndrome spectrum disorder
• Confirmed pathogenic or likely pathogenic PTEN germline mutation on genetic testing
• Previous colonoscopy with colon polyposis. This is defined for the study as either too many polyps to remove endoscopically as judged by the performing physician at the last colonoscopy or findings indicating at least an InSIGHT stage 1 score (over 20 polyps).
• Age 18 or greater
• Capacity to consent to study

Exclusion Criteria

• Pregnancy or plans for pregnancy while on treatment or within 3 months of stopping treatment (for both women and men)
• Chronic kidney disease
• Chronic renal disease
• History of colon cancer or colon adenoma with high grade dysplasia
• History of colectomy

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

PTEN Research

UNKNOWN

Sponsor Role: collaborator

Pfizer

INDUSTRY

Sponsor Role: collaborator

Ohio State University

OTHER

Sponsor Role: lead

Responsible Party

Peter P Stanich

Associate Professor, Division of Gastroenterology, Hepatology & Nutrition

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Peter P Stanich, MD

Role: PRINCIPAL_INVESTIGATOR

Ohio State University

Locations

The Ohio State University Wexner Medical Center

Columbus, Ohio, United States

Countries

United States

References

Stanich PP, Pilarski R, Rock J, Frankel WL, El-Dika S, Meyer MM. Colonic manifestations of PTEN hamartoma tumor syndrome: case series and systematic review. World J Gastroenterol. 2014 Feb 21;20(7):1833-8. doi: 10.3748/wjg.v20.i7.1833.

Reference Type: BACKGROUND

PMID: 24587660 (View on PubMed)

Stanich PP, Owens VL, Sweetser S, Khambatta S, Smyrk TC, Richardson RL, Goetz MP, Patnaik MM. Colonic polyposis and neoplasia in Cowden syndrome. Mayo Clin Proc. 2011 Jun;86(6):489-92. doi: 10.4065/mcp.2010.0816.

Reference Type: BACKGROUND

PMID: 21628613 (View on PubMed)

Heald B, Mester J, Rybicki L, Orloff MS, Burke CA, Eng C. Frequent gastrointestinal polyps and colorectal adenocarcinomas in a prospective series of PTEN mutation carriers. Gastroenterology. 2010 Dec;139(6):1927-33. doi: 10.1053/j.gastro.2010.06.061. Epub 2010 Jun 27.

Reference Type: BACKGROUND

PMID: 20600018 (View on PubMed)

Komiya T, Blumenthal GM, DeChowdhury R, Fioravanti S, Ballas MS, Morris J, Hornyak TJ, Wank S, Hewitt SM, Morrow B, Memmott RM, Rajan A, Dennis PA. A Pilot Study of Sirolimus in Subjects with Cowden Syndrome or Other Syndromes Characterized by Germline Mutations in PTEN. Oncologist. 2019 Dec;24(12):1510-e1265. doi: 10.1634/theoncologist.2019-0514. Epub 2019 Jul 26.

Reference Type: BACKGROUND

PMID: 31350329 (View on PubMed)

Lynch PM, Morris JS, Wen S, Advani SM, Ross W, Chang GJ, Rodriguez-Bigas M, Raju GS, Ricciardiello L, Iwama T, Rossi BM, Pellise M, Stoffel E, Wise PE, Bertario L, Saunders B, Burt R, Belluzzi A, Ahnen D, Matsubara N, Bulow S, Jespersen N, Clark SK, Erdman SH, Markowitz AJ, Bernstein I, De Haas N, Syngal S, Moeslein G. A proposed staging system and stage-specific interventions for familial adenomatous polyposis. Gastrointest Endosc. 2016 Jul;84(1):115-125.e4. doi: 10.1016/j.gie.2015.12.029. Epub 2016 Jan 6.

Reference Type: BACKGROUND

PMID: 26769407 (View on PubMed)

Stanich PP, Gofar K, Roberts ME, Hussan H. Sirolimus for Colon Polyposis in PTEN Hamartoma Tumor Syndrome. Clin Transl Gastroenterol. 2025 Jun 6;16(8):e00871. doi: 10.14309/ctg.0000000000000871. eCollection 2025 Aug 1.

Reference Type: DERIVED

PMID: 40478255 (View on PubMed)

Provided Documents

Document Type: Informed Consent Form

View Document

Other Identifiers

2018H0179

Identifier Type: -

Identifier Source: org_study_id