RAD001 and Neurocognition in PTEN Hamartoma Tumor Syndrome
Condition: PTEN Gene Mutation; PTEN Hamartoma Tumor Syndrome
MeSH terms: Hamartoma; Neoplasms; Hamartoma Syndrome, Multiple; Syndrome
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): RAD001; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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.
Other intervention name(s): Everolimus; Afinitor
Intervention MeSH terms: Everolimus
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: PTEN; PTEN Gene Mutation; PTEN Hamartoma Tumor Syndrome; Autism; Intellectual Disability; Neurocognition; Afinitor; Everolimus; RAD001