PTEN Gene Mutation, PTEN Hamartoma Syndrome, PTEN Hamartoma Tumor Syndrome
Conditions
Keywords
Sirolimus, Rapamune
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.
Interventions
DRUGSirolimus
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.
DRUGPlacebo
matching placebo
Sponsors
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-Blind
Eligibility
Sex/Gender
ALL
Age
5 Years to 45 Years
Healthy volunteers
No
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 at least 4 weeks with the exception of fluoxetine which should be stable for at least 8 weeks * 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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 Brief Observation of Social Communication Change (BOSCC) | 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 |
| 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 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 |
Countries
United States
Outcome results
None listed