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

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ClinicalTrials.gov Identifier: NCT02451696
Recruitment Status : Recruiting
First Posted : May 22, 2015
Last Update Posted : July 12, 2018
Sponsor:
Information provided by (Responsible Party):
New York University School of Medicine

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
Epilepsy Tuberous Sclerosis Complex Focal Cortical Dysplasia Drug: Everolimus 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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 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 : January 2014
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : June 2020


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 Name: 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.



Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. Number of participants with reduced mTOR signaling [ Time Frame: 28 days ]
    MTor signaling is measured by peripheral VEGF-D levels, Blood and brain levels of cytokines (and TNF-α) and inflammatory proteins (HMGB1)at the time of surgery, Brain glutamate and GABA receptor expression at the time of surgery, and Blood levels of everolimus at the time of surgery



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 40 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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;

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02451696


Contacts
Contact: Maria Hopkins 646-558-0843 maria.hopkins@nyumc.org
Contact: Sherry Ann Santarina 646-558-0843 SherryAnn.Santarina@nyumc.org

Locations
United States, New York
New York University Langone Medical Center Recruiting
New York, New York, United States, 10016
Contact: Maria Hopkins    646-558-0842    Maria.Hopkins@nyumc.org   
Contact: Anjanette Burns    347-578-4066    anjanette.burns@nyumc.org   
Sub-Investigator: Howard Weiner, MD         
Sub-Investigator: Maria Hopkins, RN         
Sub-Investigator: Erin Conway, RN         
Sub-Investigator: Spiros Manolatos         
Sponsors and Collaborators
New York University School of Medicine
Investigators
Principal Investigator: Orrin Devinsky, MD New York University School of Medicine

Responsible Party: New York University School of Medicine
ClinicalTrials.gov Identifier: NCT02451696     History of Changes
Other Study ID Numbers: 14-00245
First Posted: May 22, 2015    Key Record Dates
Last Update Posted: July 12, 2018
Last Verified: July 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Tuberous Sclerosis
Malformations of Cortical Development
Hamartoma
Neoplasms
Neoplasms, Multiple Primary
Neoplastic Syndromes, Hereditary
Malformations of Cortical Development, Group I
Nervous System Malformations
Nervous System Diseases
Neurocutaneous Syndromes
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Congenital Abnormalities
Genetic Diseases, Inborn
Everolimus
Sirolimus
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents