Sirolimus for Improving Social Abilities in People With PTEN Germline Mutations

Sponsor

Stanford University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06080165

Collaborator

(none)

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
PTEN Gene Mutation PTEN Hamartoma Tumor Syndrome PTEN Hamartoma Syndrome	Drug: Sirolimus Drug: Placebo	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Double-Blind

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Jul 1, 2024

Anticipated Primary Completion Date :

Jun 1, 2028

Anticipated Study Completion Date :

Jun 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
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 sirolimus levels obtained every 2 to 3 weeks after every dose change.	Drug: Sirolimus 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. Other Names: Rapamune
Placebo Comparator: Placebo matching placebo	Drug: Placebo matching placebo

Arm

Intervention/Treatment

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 sirolimus levels obtained every 2 to 3 weeks after every dose change.

Drug: Sirolimus

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.

Other Names:

Rapamune

Placebo Comparator: Placebo

matching placebo

Drug: Placebo

matching placebo

Outcome Measures

Primary Outcome Measures

Change from baseline in parent rated Social Responsiveness Scale, Second Edition Total Scores (SRS-2) total scores during treatment. [Month 1, Month 2, Month 3, Month 4, Month 5, Month 6]

Secondary Outcome Measures

Clinical Global Impression Improvement (CGI-I) Scale changes during treatment. [Month 1, Month 2, Month 3, Month 4, Month 5, Month 6]
Change from baseline on parent rated Stanford Social Dimensions Scale (SSDS) [Month 1, Month 2, Month 3, Month 4, Month 5, Month 6]

Other Outcome Measures

Change from baseline on Brief Observation of Social Communication Change (BOSCC) [Month 6]
Change from baseline on Neurobehavioral Evaluation Tool (NET) Social Communication and Interaction subscale [Month 3, Month 6]
Change from baseline on the Reading the Mind in the Eyes Test (RMET) [Month 6]
Change from baseline on Purdue Pegboard (PP) Test [Month 6]
Change from baseline on parent rated Dimensional Assessment of Restricted/Repetitive Behaviors (DARB) [Month 3, Month 6]
Change from baseline on Vineland Adaptive Behavior Scales (VABS-III) [Month 3, Month 6]
Change from baseline on Wide Range Assessment of Memory and Learning-2 (WRAML-2) [Month 6]
Change from baseline on parent reported Sensory Profile Questionnaire - Short Form [Month 3, Month 6]
Change from baseline on Clinical Global Impression Improvement (CGI-I) Scale changes during treatment. [Month 1, Month 2, Month 3, Month 4, Month 5, Month 6]
Change from baseline on parent reported Child or Adult Behavioral Checklist [Month 3, Month 6]
Change from baseline on complete blood count (CBC) with differential as measured by peripheral blood [Month 1, Month 3, Month 5, Month 6]
Change from baseline on comprehensive metabolic panel as measured by peripheral blood [Month 1, Month 3, Month 5, Month 6]
Change from baseline on lipid profile as measured by peripheral blood. [Month 1, Month 3, Month 5, Month 6]

Eligibility Criteria

Criteria

Ages Eligible for Study:

5 Years to 45 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Inclusion Criteria: All participants will meet the following selection criteria:
Male or female outpatients between 5.00 and 45.99 years of age
PHTS confirmed by genetic testing;
Fluent in English
at least moderate severity of social skill deficits based on a social responsiveness scale t score ≥ 60
Stable psychotropic and anti-epileptic medications for ≥ 2months;
Adequate Liver function (SGOT, SGPT, TBili, Alk Phos all<3x normal); HCT>27%; WBC > 3.0, ANC >1,500, and platelets >100,000
adequate renal function with a GFR ≥ 50 ml/min/m2 as determined by the Schwartz Formula for children and MDRD for adults (www.nkdep.nih.gov/professionals/gfr_calculators/index)
Negative urine pregnancy test for females and no plans to become pregnant or conceive a child while participating in the study. The effects of mTOR inhibitors on the developing fetus at the doses used in this study are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of the study. Because of the possibility of drug interactions and the potential effect of female hormones on the growth of kidney angiomyolipomas and lymphangioleiomyomatosis, estrogen-containing oral contraceptives are not recommended in women enrolled in this study, so an effective non-estrogen or barrier method of contraception must be used.
Medically stable with no active medical problems such as unstable seizures or cardiovascular disease or cancer that is not in remission as evidenced by medical history; -No anticipated changes in frequency and intensity of existing interventions such as behavioral and developmental treatments, in home services, or speech therapy;
No planned changes in school placement in children and adolescents;
Availability of reliable transportation to attend clinic visits;
availability of a trustworthy informant who interacts with subject on a regular basis;
Ability to participate in the testing procedures to the extent that valid standard scores and biological samples can be obtained.

Exclusion Criteria:

Participants will be excluded if one of the following is met:
Significant medical illness, such as endocrinopathies, cardiovascular disease, or severe chronic malnutrition;
Pregnancy, planned pregnancy, or unwillingness to use adequate contraception;
Planned changes to concomitant medications;
Concomitant therapy, or prior use within 3 months of the baseline visit, with an agent with known or possible anti-mTOR activity or concomitant therapy with strong inhibitors (e.g., cyclosporine and ketoconazole) or inducers of CYP3A;
Active infection at time of enrollment;
Participation in a clinical trial in the 30 days prior to study entry;
Major surgery, radiation therapy or stereotactic radio-surgery within previous 4 weeks at time of enrollment; and
Neurosurgery within prior 6 months at time of enrollment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University	Stanford	California	United States	94305
2	Boston Children's Hospital	Boston	Massachusetts	United States	02115
3	Cleveland Clinic	Cleveland	Ohio	United States	44195