Bannayan Syndrome, Bannayan Zonana Syndrome, Cowden Syndrome, Polyposis, PTEN Gene Mutation, PTEN Hamartoma Syndrome, PTEN Hamartoma Tumor Syndrome
Conditions
Keywords
PTEN, Cowden syndrome, PHTS, Colon polyposis, sirolimus, Rapamycin, mTOR inhibitor
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.
Interventions
DRUGSirolimus
Use of sirolimus 2 mg by mouth daily for 1 year
Sponsors
PTEN Research
Pfizer
Ohio State University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label pilot trial
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
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 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in colon polyp burden by number | 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in well-being assessment | 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. |
Countries
United States
Outcome results
None listed