Sirolimus for Cowden Syndrome With Colon Polyposis
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| ClinicalTrials.gov Identifier: NCT04094675 |
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Recruitment Status :
Recruiting
First Posted : September 19, 2019
Last Update Posted : November 22, 2021
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| 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 |
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.
| 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 |
|---|---|
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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:
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- 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.
- 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.
- 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 |
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
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
| Contact: Peter P Stanich, MD | (614) 293-6255 | peter.stanich@osumc.edu | |
| Contact: Ahmad Abusharkh | (614) 293-8400 | ahmad.abusharkh@osumc.edu |
| 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 | |
| Principal Investigator: | Peter P Stanich, MD | The Ohio State University Wexner Medical Center |
Documents provided by Peter P Stanich, Ohio State University:
| 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 |
| 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 |
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PTEN Cowden syndrome PHTS Colon polyposis |
sirolimus Rapamycin mTOR inhibitor |
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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 |