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Sirolimus for Cowden Syndrome With Colon Polyposis

Primary Purpose

PTEN Gene Mutation, PTEN Hamartoma Tumor Syndrome, PTEN Hamartoma Syndrome

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Sirolimus
Sponsored by
Ohio State University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for PTEN Gene Mutation focused on measuring PTEN, Cowden syndrome, PHTS, Colon polyposis, sirolimus, Rapamycin, mTOR inhibitor

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 a burden of colon polyps that are too numerous to clear endoscopically (this is usually when polyp burden is estimated to be over 50 colon 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

Sites / Locations

  • The Ohio State University Wexner Medical CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment arm

Arm Description

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.

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

Change in well-being assessment
Assessment in change in overall health and quality of life as quantified by the SF-36 (Short Form) Health Survey. The SF-36 is a widely-used and standardized survey of participant responses to 36 questions that measures health-related quality of life. Each question has answers that are given a correlating score from 0 to 100, with a high score representing a more favorable health state. Through the combination of specific questions and averaging the scores, there are 8 scales (physical functioning, role limitations due to physical health, role limitations due to emotional problems, vitality, mental health, social functioning, bodily pain, and general health) that are reported with scores from 0 to 100, with a high score representing a more favorable health state. These can also be averaged into a physical component summary score and mental component summary score that is again from 0 to 100, with a high score representing a more favorable health state.

Full Information

First Posted
May 13, 2019
Last Updated
June 12, 2023
Sponsor
Ohio State University
Collaborators
PTEN Research, Pfizer
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1. Study Identification

Unique Protocol Identification Number
NCT04094675
Brief Title
Sirolimus for Cowden Syndrome With Colon Polyposis
Official Title
Sirolimus for Cowden Syndrome With Colon Polyposis
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 16, 2019 (Actual)
Primary Completion Date
September 2024 (Anticipated)
Study Completion Date
September 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Ohio State University
Collaborators
PTEN Research, Pfizer

4. Oversight

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.
Yes
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Open-label pilot trial
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment arm
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
Rapamycin, Rapamune
Intervention Description
Use of sirolimus 2 mg by mouth daily for 1 year
Primary Outcome Measure Information:
Title
Change in colon polyp burden by number
Description
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.
Time Frame
1 year
Title
Change in colon polyp burden by staging
Description
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.
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Change in well-being assessment
Description
Assessment in change in overall health and quality of life as quantified by the SF-36 (Short Form) Health Survey. The SF-36 is a widely-used and standardized survey of participant responses to 36 questions that measures health-related quality of life. Each question has answers that are given a correlating score from 0 to 100, with a high score representing a more favorable health state. Through the combination of specific questions and averaging the scores, there are 8 scales (physical functioning, role limitations due to physical health, role limitations due to emotional problems, vitality, mental health, social functioning, bodily pain, and general health) that are reported with scores from 0 to 100, with a high score representing a more favorable health state. These can also be averaged into a physical component summary score and mental component summary score that is again from 0 to 100, with a high score representing a more favorable health state.
Time Frame
1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Peter P Stanich, MD
Phone
(614) 293-6255
Email
peter.stanich@osumc.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Kebire Gofar, MPH
Phone
(614) 293-8400
Email
gofa01@osumc.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter P Stanich, MD
Organizational Affiliation
The Ohio State University Wexner Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Ohio State University Wexner Medical Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Peter P Stanich, MD
Phone
614-293-6255
Email
peter.stanich@osumc.edu
First Name & Middle Initial & Last Name & Degree
Kebire Gofar, MPH
Phone
(614) 293-8400
Email
gofa01@osumc.edu

12. IPD Sharing Statement

Citations:
PubMed Identifier
24587660
Citation
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.
Results Reference
background
PubMed Identifier
21628613
Citation
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.
Results Reference
background
PubMed Identifier
20600018
Citation
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.
Results Reference
background
PubMed Identifier
31350329
Citation
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.
Results Reference
background
PubMed Identifier
26769407
Citation
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.
Results Reference
background

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Sirolimus for Cowden Syndrome With Colon Polyposis

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