Symptoms and General Pathology

All Conditions

Neoplasms

Diseases and Abnormalities at or Before Birth

Rare Diseases

Syndrome

Hamartoma Syndrome, Multiple

Hamartoma

Neoplasms, Multiple Primary

Neoplastic Syndromes, Hereditary

Genetic Diseases, Inborn

Cowden Syndrome

Bannayan-Riley-Ruvalcaba Syndrome

PTEN Hamartoma Tumor Syndrome

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Sirolimus

Temsirolimus

MTOR Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

Immunosuppressive Agents

Immunologic Factors

Participants that are 5 to 12.99 years old will start at 1 mg/m2/dose. Participants that are 13 to 45.99 years old and \< 39.99 kg in weight will also start on 1 mg/day. Participants that are 13 to 45.99 years old and \> 40 kg in weight will start on 2 mg/day. The target blood level will be 5-15 ng/ml with dose adjustment based on sirolimus levels obtained every 2 to 3 weeks after every dose change.

Experimental: Sirolimus Participants that are 5 to 12.99 years old will start at 1 mg/m2/dose. Participants that are 13 to 45.99 years old and \< 39.99 kg in weight will also start on 1 mg/day. Participants that are 13 to 45.99 years old and \> 40 kg in weight will start on 2 mg/day. The target blood level will be 5-15 ng/ml with dose adjustment based on clinical labs of sirolimus levels. The target blood level will be 5-15 ng/ml with dose adjustment based on sirolimus levels obtained every 2 to 3 weeks after every dose change.

Placebo

John Hegarty, PhD

Robin Libove

Antonio Hardan, MD

Emine Arcasoy

Mustafa Sahin, MD

Xiangling Wang, MD

Beth Crouser

The goal of this study is to examine the safety and treatment effects of sirolimus for targeting social communication deficits in people with genetic disorders associated with PTEN germline mutations, which are often referred to as PTEN Harmartoma Tumor Syndrome (PHTS). The mechanism of sirolimus in the body has shown promise for helping to improve social communication skills in case reports of people with PHTS. Everolimus, a closely related compound, also showed benefits in social communication skills in a previous pilot trial in people with PHTS. This is a 6 month double-blind trial followed by at 6 month open label extension trial.

Sirolimus for Improving Social Abilities in People With PTEN Germline Mutations

A Randomized Controlled Double-Blind Trial of Sirolimus for Improving Social Abilities in People With PTEN Germline Mutations

Data will be on the National Institute of Mental Health Data Archive (NDA).

Stanford University

Professor

Virginie Dr BUBIEN

Simone Pr MATHOULIN-PELISSIER

This is a multicentric, observational, retrospective and prospective study, aiming to estimate the risk of cancer occurrence in subjects carrying a PTEN mutation, based on the constitution of a national cohort.

After collection of the non objection and verification of the eligibility criteria, a first clinical questionnaire will be completed by the participant and the prescribing physician to collect the main medical events including the history of malignant tumor pathologies until the date of inclusion in the study.

Thereafter, an annual questionnaire will be sent to the participants to update the elements related to a tumor pathology.

For the case of patients who have died or been lost to follow-up, only the information from the first clinical questionnaire will be collected from the data available from the prescribing physician without informing the relatives. However, the investigating center will have to check that these patients have not objected, during their lifetime, to the use of their data.

Cancer Risk Assessment in Patients With a Constitutional Alteration of the PTEN Gene

National Cohort of Patients With Cowden's Disease and With a Constitutional Alteration of the PTEN Gene for the Prospective Assessment of the Risk of Cancer.

Number of subjects with a cancer event (any cancer) observed in the population of subjects presenting a constitutional alteration of the PTEN gene.

Number of subjects with a breast cancer event (any cancer) observed in the population of subjects presenting a constitutional alteration of the PTEN gene.

Number of subjects with a thyroid cancer event (any cancer) observed in the population of subjects presenting a constitutional alteration of the PTEN gene.

Number of subjects with an endometrial cancer event (any cancer) observed in the population of subjects presenting a constitutional alteration of the PTEN gene.

Number of subjects with a renal cancer event (any cancer) observed in the population of subjects presenting a constitutional alteration of the PTEN gene.

Number of subjects with a colorectal cancer event (any cancer) observed in the population of subjects presenting a constitutional alteration of the PTEN gene.

Number of subjects with a melanoma cancer event (any cancer) observed in the population of subjects presenting a constitutional alteration of the PTEN gene.

Institut Bergonié

Behaviors and Mental Disorders

Nervous System Diseases

Autistic Disorder

Intellectual Disability

Everolimus

Protein Kinase Inhibitors

Enzyme Inhibitors

RAD001 is formulated as tablets of 5.0 mg or 2.5mg strength, blister-packed under aluminum foil in units of 10 tablets and dosed on a regular basis.

Matching placebo will be provided as a matching tablet and will also be blister packed under aluminum foil in units of 10.

RAD001 is formulated as tablets of 5.0 mg strength, blister-packed under aluminum foil in units of 10 tablets and dosed on a regular basis. RAD001 tablets should be opened only at the time of administration as drug is both hygroscopic and light-sensitive.

Patients will be instructed to take 4.5 mg/m2 of RAD001 orally with a glass of water at regular intervals at the same time (delete: each day) in the morning after a light, nonfat breakfast.

RAD001

Matching placebo will be provided as a matching tablet and will also be blister packed under aluminum foil in units of 10. Matching placebo tablets should be opened only at the time of administration as drug is both hygroscopic and light-sensitive.

Patients will be instructed to take 4.5 mg/m2 of the matching placebo orally with a glass of water at regular intervals at the same time (delete: each day) in the morning after a light, nonfat breakfast.

Mustafa Sahin, MD, PhD

Phosphatase and TENsin homolog (PTEN) gene germline mutations are associated with a spectrum of clinical manifestations characterized by neurocognitive deficits, intellectual disability, autism symptomatology, skin lesions, macrocephaly, hamartomatous overgrowth of tissues, and an increased risk of cancers. Investigators are conducting research to evaluate the potential safety and efficacy of RAD001 (everolimus) in this patient population, and the potential neurocognitive benefits from treatment with RAD001 or placebo for a six month period. The investigators hope this trial will lead to a better understanding of PTEN and to new forms of treatment that may benefit children and adults with PTEN in the future.

This is a signal seeking Phase I/II 6-month, randomized, double-blind placebo-controlled trial of everolimus in individuals, ages 5 to 45 years with a PTEN mutation, with safety and neurocognition as the primary endpoints.

Participant's or a legal guardian will need to sign an informed consent prior to enrollment in the study. To determine eligibility participants will undergo a series of screening tests and safety measures. If determined to be eligible for the blinded phase of the study, participants will be randomly assigned to take either the study drug or a placebo (pill with no medicine).

The blinded phase of the study involves about eight visits, five of which will occur at the study site, and three of which will be conducted over the phone. These visits will take place over a six month period. Study visits will vary in length. Baseline, three month and six month visits may last up to 8 hours, if optional measures are done, while all other visits will be less than 2 hours. The study visits include blood draws, general health exams, and neuropsychological assessments. The study will also include optional eye-tracking, EEG and auditory evoked potential (AEP) measures, and the collection of microbiome/mycobiome and biomarker blood sample. There is no fee to participate in this study. The study drug will be provided at no charge during the study.

After the 6 month treatment phase, individuals who were randomly assigned to take placebo will be offered inclusion in a 6 month open label phase where the study drug will be provided at no charge. The open label phase assessments will be similar to those done in the blinded phase, but patients/families will only need to return to the study site three times during this phase.

Participants will receive a developmental assessments report after completing the study. After all study data has been analyzed, patients and families will also be informed of the overall results. Treatment on this study may or may not improve an individual's learning skills (neurocognition) or behavior. We hope that future patients and families will benefit from what is learned by this study.

Specific Aims /Objectives Primary objective

-To evaluate the safety of everolimus compared with placebo in patients with PTEN mutations focusing on NCI CTCAE Grade 3 and 4 adverse events, serious adverse events, and Grade 3 and 4 laboratory toxicities.

Secondary objectives

-To evaluate the efficacy of everolimus on neurocognition and behavior in inividuals with PTEN mutations compared to placebo as measured by standardized, direct and indirect neurocognitive tools and behavioral measures.

RAD001 and Neurocognition in PTEN Hamartoma Tumor Syndrome

A Randomized Double-Blind Controlled Trial of Everolimus in Individuals With PTEN Mutations (RAD001XUS257T)

Data will be shared with the National Database of Autism Research (NDAR)

The primary endpoint will be safety as measured by study drop-out rate due to side effects, comparing everolimus vs. placebo. We will also determine the frequency of adverse events by type and severity.

Working memory will be evaluated using the Stanford Binet 5 or Mullen Scales of Early Learning at 6 months

Processing speed will be evaluated using mean reaction time on the Conner's Continuous Performance Test (CPT)-3.

Fine motor skills will be evaluated using the Purdue Pegboard sub-tests average of both hands

Attention will be measured by Conners' Continuous Performance Test - 3 - Discriminability index (d') and Omissions

Impulsivity will be measured by Conners' Continuous Performance Test-3- Commissions and Bias (B').

Change in global cognitive ability will be measured by Stanford-Binet 5 or Mullen; Full scale, verbal and nonverbal ability (IQ)

Motor functioning will be measured by the Purdue Pegboard (Pegs): Dominant and non-dominant hand combined standard scores and Developmental Coordination Disorder Questionnaire (DCDQ): Total score.

Communication ability will be measured by using standard scores of the Peabody Picture Vocabulary Test (PPVT-4), Expressive Vocabulary Test (EVT-2)

National Institutes of Health (NIH)

National Institute of Neurological Disorders and Stroke (NINDS)

Office of Rare Diseases (ORD)

National Center for Advancing Translational Sciences (NCATS)

Novartis Pharmaceuticals

PTEN Research

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Boston Children's Hospital

Director, Translational Neuroscience Center/ Professor of Neurology, Harvard Medical School

Digestive System Diseases

Mouth and Tooth Diseases

Ear, Nose, and Throat Diseases

Colorectal Neoplasms

Nasopharyngeal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Pharyngeal Neoplasms

Otorhinolaryngologic Neoplasms

Head and Neck Neoplasms

Nasopharyngeal Diseases

Pharyngeal Diseases

Stomatognathic Diseases

Otorhinolaryngologic Diseases

Herbal and Botanical

Cola

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.

Use of sirolimus 2 mg by mouth daily for 1 year

Peter P Stanich, MD

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.

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.

Sirolimus for Cowden Syndrome With Colon Polyposis

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.

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.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Sirolimus for Improving Social Abilities in People With PTEN Germline Mutations	NCT06080165	PTEN Gene Mutat... PTEN Hamartoma ... PTEN Hamartoma ...	Sirolimus Placebo	5 Years - 45 Years	Stanford University
Cancer Risk Assessment in Patients With a Constitutional Alteration of the PTEN Gene	NCT05630105	PTEN Gene Mutat...		-	Institut Bergonié
RAD001 and Neurocognition in PTEN Hamartoma Tumor Syndrome	NCT02991807	PTEN Gene Mutat... PTEN Hamartoma ...	RAD001 Placebo	5 Years - 45 Years	Boston Children's Hospital
Sirolimus for Cowden Syndrome With Colon Polyposis	NCT04094675	PTEN Gene Mutat... PTEN Hamartoma ... PTEN Hamartoma ... Cowden Syndrome Bannayan Syndro... Bannayan Zonana... Polyposis	Sirolimus	18 Years - 80 Years	Ohio State University
Sirolimus for Cowden Syndrome With Colon Polyposis	NCT04094675	PTEN Gene Mutat... PTEN Hamartoma ... PTEN Hamartoma ... Cowden Syndrome Bannayan Syndro... Bannayan Zonana... Polyposis	Sirolimus	18 Years - 80 Years	Ohio State University

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