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Sirolimus for Cowden Syndrome With Colon Polyposis

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ClinicalTrials.gov Identifier: NCT04094675
Recruitment Status : Recruiting
First Posted : September 19, 2019
Last Update Posted : November 22, 2021
Sponsor:
Collaborator:
PTEN Research
Information provided by (Responsible Party):
Peter P Stanich, Ohio State University

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.

Condition or disease Intervention/treatment Phase
PTEN Gene Mutation PTEN Hamartoma Tumor Syndrome PTEN Hamartoma Syndrome Cowden Syndrome Bannayan Syndrome Bannayan Zonana Syndrome Polyposis Drug: Sirolimus Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Open-label pilot trial
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Sirolimus for Cowden Syndrome With Colon Polyposis
Actual Study Start Date : September 16, 2019
Estimated Primary Completion Date : August 2023
Estimated Study Completion Date : August 2024


Arm Intervention/treatment
Experimental: 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.

Drug: Sirolimus
Use of sirolimus 2 mg by mouth daily for 1 year
Other Names:
  • Rapamycin
  • Rapamune




Primary Outcome Measures :
  1. Change in colon polyp burden by number [ Time Frame: 1 year ]
    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.

  2. Change in colon polyp burden by staging [ Time Frame: 1 year ]
    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 :
  1. Change in well-being assessment [ Time Frame: 1 year ]
    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.



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04094675


Contacts
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Contact: Peter P Stanich, MD (614) 293-6255 peter.stanich@osumc.edu
Contact: Ahmad Abusharkh (614) 293-8400 ahmad.abusharkh@osumc.edu

Locations
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United States, Ohio
The Ohio State University Wexner Medical Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Peter P Stanich, MD    614-293-6255    peter.stanich@osumc.edu   
Contact: Ahmad Abusharkh    (614) 293-8400    ahmad.abusharkh@osumc.edu   
Sponsors and Collaborators
Ohio State University
PTEN Research
Investigators
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Principal Investigator: Peter P Stanich, MD The Ohio State University Wexner Medical Center
  Study Documents (Full-Text)

Documents provided by Peter P Stanich, Ohio State University:
Informed Consent Form  [PDF] September 24, 2021

Publications:

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Responsible Party: Peter P Stanich, Associate Professor, Division of Gastroenterology, Hepatology & Nutrition, Ohio State University
ClinicalTrials.gov Identifier: NCT04094675    
Other Study ID Numbers: 2018H0179
First Posted: September 19, 2019    Key Record Dates
Last Update Posted: November 22, 2021
Last Verified: November 2021

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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
Keywords provided by Peter P Stanich, Ohio State University:
PTEN
Cowden syndrome
PHTS
Colon polyposis
sirolimus
Rapamycin
mTOR inhibitor
Additional relevant MeSH terms:
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Colorectal Neoplasms
Nasopharyngeal Neoplasms
Hamartoma
Neoplasms
Hamartoma Syndrome, Multiple
Syndrome
Disease
Pathologic Processes
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Pharyngeal Neoplasms
Otorhinolaryngologic Neoplasms
Head and Neck Neoplasms
Nasopharyngeal Diseases
Pharyngeal Diseases
Stomatognathic Diseases
Otorhinolaryngologic Diseases
Neoplasms, Multiple Primary
Neoplastic Syndromes, Hereditary
Genetic Diseases, Inborn
Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents