Sirolimus for Improving Social Abilities in People With PTEN Germline Mutations

NCT ID: NCT06080165

Last Updated: 2024-07-10

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE1/PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-07-31
• Study Completion Date: 2028-06-30

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.

Conditions

PTEN Gene Mutation; PTEN Hamartoma Tumor Syndrome; PTEN Hamartoma Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Sirolimus

Intervention Type: DRUG

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

matching placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

matching placebo

Interventions

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.

Intervention Type: DRUG

Placebo

matching placebo

Intervention Type: DRUG

Other Intervention Names

Rapamune

Eligibility Criteria

Inclusion 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.

• Minimum Eligible Age: 5 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Stanford University

OTHER

Sponsor Role: lead

Responsible Party

Antonio Hardan

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Antonio Hardan, MD

Role: PRINCIPAL_INVESTIGATOR

Stanford University

Locations

Stanford University

Stanford, California, United States

Boston Children's Hospital

Boston, Massachusetts, United States

Cleveland Clinic

Cleveland, Ohio, United States

Countries

United States

Other Identifiers

IRB-72157

Identifier Type: -

Identifier Source: org_study_id