Sirolimus for Cowden Syndrome With Colon Polyposis

NCT04094675 | Completed Phase 2 FDA Drug

• 1 other identifier: 2018H0179
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

PTEN; Cowden syndrome; PHTS; Colon polyposis; sirolimus; Rapamycin; mTOR inhibitor

Outcome Measures

Primary Outcomes (2)

• Change in colon polyp burden by number

  Assessment of change in number of colon polyps. This will be assessed for each segment of colon (ascending, transverse, descending, sigmoid, rectum) and then aggregated into a total number of colon polyps. The entrance result will be compared to the final result for each participant.

  1 year

• Change in colon polyp burden by staging

  Assessment of change in staging of colon polyps by using the International Society for Gastrointestinal Hereditary Tumors (InSIGHT) polyposis staging system. The InSight staging system divides colorectal polyposis into 5 progressive stages based on polyp number and size (Stage 0: \<20 polyps, all \<5 mm; Stage 1: 20-200 polyps, most \<5 mm, none, \>1 cm; Stage 2: 200-500 polyps, \<10 that are \>1 cm; Stage 3: 500-1000 polyps or any number if there are 10-50 that are \>1 cm and amenable to complete polypectomy; Stage 4: \>1000 polyps and/or any polyps grown to confluence and not amenable to simple polypectomy; any high-grade dysplasia or invasive cancer). The entrance result will be compared to the final result for each participant.

  1 year

Secondary Outcomes (1)

• Change in well-being assessment

  1 year

Study Arms (1)

Treatment arm

EXPERIMENTAL

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.

Drug: Sirolimus

Interventions

Sirolimus DRUG

Use of sirolimus 2 mg by mouth daily for 1 year

Also known as: Rapamycin, Rapamune

Treatment arm

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Ohio State University: lead
• PTEN Research: collaborator
• Pfizer: collaborator

Study Sites (1)

The Ohio State University Wexner Medical Center

Columbus, Ohio, 43210, United States

Location

Related Publications (6)

• 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.

  PMID: 24587660 BACKGROUND

• 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.

  PMID: 21628613 BACKGROUND

• 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.

  PMID: 20600018 BACKGROUND

• 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.

  PMID: 31350329 BACKGROUND

• 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.

  PMID: 26769407 BACKGROUND

• 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.

  PMID: 40478255 DERIVED

MeSH Terms

Conditions

Hamartoma Syndrome, Multiple

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Hamartoma; Neoplasms; Neoplasms, Multiple Primary; Neoplastic Syndromes, Hereditary; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Peter P Stanich, MD

  Ohio State University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor, Division of Gastroenterology, Hepatology & Nutrition

Model Details: Open-label pilot trial

Study Record Dates

• First Submitted: May 13, 2019
• First Posted: September 19, 2019
• Study Start: September 16, 2019
• Primary Completion: February 1, 2025
• Study Completion: June 5, 2025
• Last Updated: June 10, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)