A Pilot Study To Evaluate The Effects of Everolimus on Brain mTOR Activity and Cortical Hyperexcitability in TSC and FCD
Condition: Epilepsy; Tuberous Sclerosis Complex; Focal Cortical Dysplasia
MeSH terms: Tuberous Sclerosis; Malformations of Cortical Development; Focal Cortical Dysplasia
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to measure if the drug called Everolimus effects mTOR signaling
      (an electrical activity signal in the brain) in patients with Tuberous Sclerosis Complex
      (TSC) and Focal Cortical Dysplasia (FCD) with treatment resistant epilepsy (TRE) who will be
      undergoing brain surgery. One group of patients will be treated with Everolimus, and another
      will not. Researchers will determine if there is a difference in mTOR signaling between the
      patients who were treated with Everolimus and those who were not. Previous studies have
      suggested that Everolimus may reduce seizure activity in TSC patients by decreasing mTOR
      signaling. Since patients with FCD may also have excess mTOR signaling brain activity,
      Everolimus may also reduce seizure activity in these patients.

      The drug Everolimus is approved by the Food and Drug Administration to treat specific types
      of breast, pancreatic, and kidney cancer, a kidney tumor called an angiomyolipoma (common in
      patients with TSC), and TSC patients who have a brain tumor called a subependymal giant cell
      astrocytoma (SEGA). However, in this research it is considered to be an investigational since
      it is not approved for reduction in mTOR signaling and a decrease in seizure frequency.
      Researchers believe that Everolimus may be useful in reducing something called cortical
      hyperexcitability, which is the excess brain activity that can contribute to seizures.
    

Detailed description: 
      This is a single center open-label pilot clinical trial of patients with TRE, ages 1 to 40
      years old, with TSC or FCD who are scheduled for epilepsy surgery. Patients will be treated
      with everolimus for 7 to 28 days prior to epilepsy surgery with extension of time from 7 to
      28 days in successive cohorts of patients. The initial cohort of at least three patients will
      be treated for 7 days and after the safety of therapy is assured for this group, there will
      be an extension of the treatment to 14 days for at least three patients. This will be
      extended at one week intervals/three patient groups to a maximum treatment duration of 28
      days. Resected brain tissue will be analyzed for activation of mTORC1 and mTORC2 signaling
      pathways, glutamatergic and GABA-ergic neurotransmission using histochemistry, genetic
      analysis, as well as extracellular field recordings in acute ex-vivo brain slices from
      surgery. A blood sample, collected at the time of surgery, will be analyzed for everolimus
      levels and VEGF-D. All patients will undergo standardized intra-operative ECoG recordings
      over the primary epileptogenic region and reviewed blindly.

      Subjects will be in the study for 7-28 days. The investigators will study variables listed in
      specific aims 1 and 2 in TSC and FCD patients treated with 7 to 28 days of everolimus and
      compare these to untreated control patients with TRE and TSC or FCD. A concurrent comparison
      group of 12 subjects will also be enrolled. They will all be undergoing routine surgery for
      the diagnosis of TRE with TSC or FCD.

      All study procedures will be performed at the Comprehensive Epilepsy Center (CEC) with the
      exception of the surgery, which will be performed at Tisch Hospital.
    

Intervention name(s): Everolimus
Intervention type(s): Drug
Intervention description(s): This study will measure if the drug called Everolimus effects mTOR signaling (an electrical activity signal in the brain) in patients with Tuberous Sclerosis Complex (TSC) and Focal Cortical Dysplasia (FCD) with treatment resistant epilepsy (TRE) who will be undergoing brain surgery. One group of patients will be treated with Everolimus, for 7-28 days prior to epilepsy surgery and another will not. We will determine if there is a difference in mTOR signaling between the patients who were treated with Everolimus and those who were not
Other intervention name(s): Trade Name: Afinitor®
Intervention MeSH terms: Everolimus
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment