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

Sponsor
NYU Langone Health (Other)
Overall Status
Completed
CT.gov ID
NCT02451696
Collaborator
(none)
15
1
2
47.9
0.3

Study Details

Study Description

Brief 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.

Condition or Disease Intervention/Treatment Phase
Phase 2

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 Design

Study Type:
Interventional
Actual Enrollment :
15 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Pilot Study To Evaluate The Effects of Everolimus on Brain mTOR Activity and Cortical Hyperexcitability in TSC and FCD
Study Start Date :
Jan 1, 2014
Actual Primary Completion Date :
Dec 8, 2017
Actual Study Completion Date :
Dec 28, 2017

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treated Subjects

This group will be treated with everolimus 7-28 days prior to surgery

Drug: Everolimus
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.

    Outcome Measures

    Primary Outcome Measures

    1. Number of Patients With Adverse Events [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

    Secondary Outcome Measures

    1. Blood Everolimus Levels [28 days]

      mTOR signaling in blood

    2. Blood Total VEGF Levels (Not Only VEGF-D) [28 days]

    3. mTOR Brain Tissue-S6 Phosphate by Western Blot [28 days]

    4. HMGB1 Expression in Brain Tissue [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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    2 Years to 40 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No

    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)

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

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

    4. 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;

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 New York University Langone Medical Center New York New York United States 10016

    Sponsors and Collaborators

    • NYU Langone Health

    Investigators

    • Principal Investigator: Orrin Devinsky, MD, NYU Langone Health

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    NYU Langone Health
    ClinicalTrials.gov Identifier:
    NCT02451696
    Other Study ID Numbers:
    • 14-00245
    First Posted:
    May 22, 2015
    Last Update Posted:
    Sep 1, 2021
    Last Verified:
    Aug 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Treated Subjects Reference Subjects
    Arm/Group Description This group will be treated with everolimus 7-28 days prior to surgery Everolimus: 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 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
    Period Title: Overall Study
    STARTED 5 10
    COMPLETED 4 10
    NOT COMPLETED 1 0

    Baseline Characteristics

    Arm/Group Title Treated Subjects Reference Subjects Total
    Arm/Group Description This group will be treated with everolimus 7-28 days prior to surgery Everolimus: 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 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. Total of all reporting groups
    Overall Participants 4 10 14
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    18.25
    (10.1)
    13.1
    (12.3)
    14.6
    (11.6)
    Sex: Female, Male (Count of Participants)
    Female
    3
    75%
    6
    60%
    9
    64.3%
    Male
    1
    25%
    4
    40%
    5
    35.7%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    0
    0%
    White
    0
    0%
    0
    0%
    0
    0%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    4
    100%
    10
    100%
    14
    100%
    Region of Enrollment (participants) [Number]
    United States
    4
    100%
    10
    100%
    14
    100%

    Outcome Measures

    1. Primary Outcome
    Title Number of Patients With Adverse Events
    Description .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
    Time Frame 6 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treated Subjects Reference Subjects
    Arm/Group Description This group will be treated with everolimus 7-28 days prior to surgery Everolimus: 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 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.
    Measure Participants 4 10
    Count of Participants [Participants]
    0
    0%
    0
    0%
    2. Secondary Outcome
    Title Blood Everolimus Levels
    Description mTOR signaling in blood
    Time Frame 28 days

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treated Subjects Reference Subjects
    Arm/Group Description This group will be treated with everolimus 7-28 days prior to surgery Everolimus: 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 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.
    Measure Participants 4 10
    Mean (Standard Deviation) [ng/ml]
    12.35
    (5.36)
    2
    (0)
    3. Secondary Outcome
    Title Blood Total VEGF Levels (Not Only VEGF-D)
    Description
    Time Frame 28 days

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treated Subjects Reference Subjects
    Arm/Group Description This group will be treated with everolimus 7-28 days prior to surgery Everolimus: 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 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
    Measure Participants 4 10
    Mean (Standard Deviation) [pg/ml]
    56.5
    (46.9)
    50.85
    (54.1)
    4. Secondary Outcome
    Title mTOR Brain Tissue-S6 Phosphate by Western Blot
    Description
    Time Frame 28 days

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treated Subjects Reference Subjects
    Arm/Group Description This group will be treated with everolimus 7-28 days prior to surgery Everolimus: 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 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
    Measure Participants 4 10
    Mean (Standard Deviation) [normalized val-protein relative to actin]
    0.49
    (0.54)
    0.81
    (0.22)
    5. Secondary Outcome
    Title HMGB1 Expression in Brain Tissue
    Description 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.
    Time Frame 28 days

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treated Subjects Reference Subjects
    Arm/Group Description This group will be treated with everolimus 7-28 days prior to surgery Everolimus: 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 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
    Measure Participants 4 10
    Mean (Standard Deviation) [LFQ intensity]
    14.85
    (0.6)
    15.06
    (0.35)

    Adverse Events

    Time Frame 30 days
    Adverse Event Reporting Description
    Arm/Group Title Treated Subject Reference Subject
    Arm/Group Description This group will be treated with everolimus 7-28 days prior to surgery Everolimus: 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 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.
    All Cause Mortality
    Treated Subject Reference Subject
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/4 (0%) 0/10 (0%)
    Serious Adverse Events
    Treated Subject Reference Subject
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/4 (0%) 0/10 (0%)
    Other (Not Including Serious) Adverse Events
    Treated Subject Reference Subject
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/4 (0%) 0/10 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Orrin Devinsky
    Organization NYU Langone
    Phone 646-558-0800
    Email od4@nyu.edu
    Responsible Party:
    NYU Langone Health
    ClinicalTrials.gov Identifier:
    NCT02451696
    Other Study ID Numbers:
    • 14-00245
    First Posted:
    May 22, 2015
    Last Update Posted:
    Sep 1, 2021
    Last Verified:
    Aug 1, 2021