A Pilot Study To Evaluate The Effects of Everolimus on Brain mTOR Activity and Cortical Hyperexcitability in TSC and FCD

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.

Inclusion Criteria

1. Patients: 1 year to 40 years. 2. Diagnosis: treatment resistant epilepsy due to Tuberous
Sclerosis Complex or Focal Cortical Dysplasia Inclusion Criteria (Concurrent Comparison
Group)

1. Patients: 1 year to 40 years. Matched for age (+/- 7 years) and sex of subjects in the
treatment group.

2. Diagnosis: treatment resistant due to TSC or FCD. Matched for diagnosis of TSC and
FCD.

3. Brain surgery for seizure control in which tissue is banked for research utilizing an
existing IRB-approved study.

Exclusion Criteria

1. Treatment with an mTOR inhibitor (everolimus, sirolimus) during the past four weeks.

2. Known hypersensitivity to an mTOR inhibitor (everolimus, sirolimus)

3. Failure to establish diagnosis of treatment resistant epilepsy (i.e., adequate trials
of two appropriately-chosen, tolerated and adequate trials of antiepileptic drugs)
[32].

4. Exposure to any investigational agent in the month prior to study entry.

5. History of malignancy patients who are receiving anti-cancer treatments, such as
radiation therapy and/or chemotherapy.

6. Patients with severe and/or uncontrolled medical conditions,

7. Patients on chronic corticosteroid therapy

8. A history of HIV seropositivity

9. Patients who have received live attenuated vaccines within 1 week of start of
everolimus and during the study;

10. Known impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of oral everolimus;

11. Uncontrolled diabetes mellitus

12. Patients who have any severe and/or uncontrolled medical conditions

13. Known impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of oral everolimus;