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

August 31, 2021 updated by: NYU Langone Health

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.

Study Overview

Status

Completed

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

15

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • New York
      • New York, New York, United States, 10016
        • New York University Langone Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

8 months to 38 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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;

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treated Subjects
This group will be treated with everolimus 7-28 days prior to surgery
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 Names:
  • Trade Name: Afinitor®
No Intervention: Reference Subjects
This group will be enrolled as reference subjects, and will be undergoing routine surgery as part of standard of care treatment. No intervention will be provided to these subjects as part of the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Patients With Adverse Events
Time Frame: 6 weeks
.Adverse event monitoring should be continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose of study treatment
6 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Blood Everolimus Levels
Time Frame: 28 days
mTOR signaling in blood
28 days
Blood Total VEGF Levels (Not Only VEGF-D)
Time Frame: 28 days
28 days
mTOR Brain Tissue-S6 Phosphate by Western Blot
Time Frame: 28 days
28 days
HMGB1 Expression in Brain Tissue
Time Frame: 28 days
HMGB1 expression is measured through label-free quantification (LFQ). LFQ is a method in mass spectroscopy that determines the relative amount of proteins in biological samples. The unit of measure is LFQ intensity; a higher LFQ intensity indicates greater HMGB1 expression.
28 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2014

Primary Completion (Actual)

December 8, 2017

Study Completion (Actual)

December 28, 2017

Study Registration Dates

First Submitted

October 8, 2014

First Submitted That Met QC Criteria

May 21, 2015

First Posted (Estimate)

May 22, 2015

Study Record Updates

Last Update Posted (Actual)

September 1, 2021

Last Update Submitted That Met QC Criteria

August 31, 2021

Last Verified

August 1, 2021

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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