A Pilot Study To Evaluate The Effects of Everolimus on Brain mTOR Activity and Cortical Hyperexcitability in TSC and FCD
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
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:
|
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
- 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
- Blood Everolimus Levels [28 days]
mTOR signaling in blood
- Blood Total VEGF Levels (Not Only VEGF-D) [28 days]
- mTOR Brain Tissue-S6 Phosphate by Western Blot [28 days]
- 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
Inclusion Criteria
-
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)
-
Patients: 1 year to 40 years. Matched for age (+/- 7 years) and sex of subjects in the treatment group.
-
Diagnosis: treatment resistant due to TSC or FCD. Matched for diagnosis of TSC and FCD.
-
Brain surgery for seizure control in which tissue is banked for research utilizing an existing IRB-approved study.
Exclusion Criteria
-
Treatment with an mTOR inhibitor (everolimus, sirolimus) during the past four weeks.
-
Known hypersensitivity to an mTOR inhibitor (everolimus, sirolimus)
-
Failure to establish diagnosis of treatment resistant epilepsy (i.e., adequate trials of two appropriately-chosen, tolerated and adequate trials of antiepileptic drugs) [32].
-
Exposure to any investigational agent in the month prior to study entry.
-
History of malignancy patients who are receiving anti-cancer treatments, such as radiation therapy and/or chemotherapy.
-
Patients with severe and/or uncontrolled medical conditions,
-
Patients on chronic corticosteroid therapy
-
A history of HIV seropositivity
-
Patients who have received live attenuated vaccines within 1 week of start of everolimus and during the study;
-
Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus;
-
Uncontrolled diabetes mellitus
-
Patients who have any severe and/or uncontrolled medical conditions
-
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.- 14-00245
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
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%
|
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)
|
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)
|
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)
|
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
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 |
od4@nyu.edu |
- 14-00245