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

Learn more about:
Related Clinical Trial
Doxycycline In Lymphangioleiomyomatosis (LAM) Effect of Fasting on the Size of Abdominal Lymphatic Tumors in Women Turmeric as Treatment in Epilepsy Study of the Disease Process of Lymphangioleiomyomatosis RAD001 Therapy of Angiomyolipomata in Patients With TS Complex and Sporadic LAM The Effectiveness and Safety of Vagus Nerve Stimulation for TRE The Effectiveness and Safety of Resective Epilepsy Surgery for TRE Roll-over Study to Collect and Assess Long-term Safety of Everolimus in Patients With TSC and Refractory Seizures Who Have Completed the EXIST-3 Study [CRAD001M2304] and Who Are Benefitting From Continued Treatment Adjunctive Ganaxolone Treatment (Part A) in TSC Followed by Long-term Treatment (Part B) Safety of Simvastatin in LAM and TSC Studies of Autistic Patients: Gene Networks and Clinical Subtypes Topical Rapamycin to Erase Angiofibromas in TSC Rapalogues for Autism Phenotype in TSC: A Feasibility Study A Pilot Study To Evaluate The Effects of Everolimus on Brain mTOR Activity and Cortical Hyperexcitability in TSC and FCD Everolimus for Cancer With TSC1 or TSC2 Mutation Topical Sirolimus Ointment for Cutaneous Angiofibromas in Subjects With Tuberous Sclerosis Complex The Cognitive Variability in NF1 and TSC Monozygotic Twins Long-term Trial of Topical Sirolimus to Angiofibroma in Patient With Tuberous Sclerosis Complex Efficacy of RAD001/Everolimus in Autism and NeuroPsychological Deficits in Children With Tuberous Sclerosis Complex Phase III Trial of Topical Formulation of Sirolimus to Skin Lesions in Patients With Tuberous Sclerosis Complex (TSC) Topical Rapamycin Therapy to Alleviate Cutaneous Manifestations of Tuberous Sclerosis Complex (TSC) and Neurofibromatosis I (NF1) Trial of Efficacy and Safety of Sirolimus in Tuberous Sclerosis and LAM Long-term, Prospective Study Evaluating Clinical and Molecular Biomarkers of Epileptogenesis in a Genetic Model of Epilepsy – Tuberous Sclerosis Complex A Randomized Controlled Trial of Cannabidiol (GWP42003-P, CBD) for Seizures in Tuberous Sclerosis Complex (GWPCARE6) An Open-label Extension Trial of Cannabidiol (GWP42003-P, CBD) for Seizures in Tuberous Sclerosis Complex (GWPCARE6) Aspirin as an add-on Treatment of Refractory Epilepsy in Tuberous Sclerosis Complex Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC) Clinical Presentation and Renal Outcome of Patients With Tuberous Sclerosis Complex and/or Renal Angiomyolipoma in the Great West Region of France Preventing Epilepsy Using Vigabatrin In Infants With Tuberous Sclerosis Complex Early Behavioral Intervention to Improve Social Communication Function in Infants With Tuberous Sclerosis Complex Characterization of Patients With Tuberous Sclerosis Complex, Lymphangioleiomyomatosis and Angiomyolipoma Everolimus (RAD001) Therapy for Epilepsy in Patients With Tuberous Sclerosis Complex (TSC) Everolimus (RAD001) Therapy of Giant Cell Astrocytoma in Patients With Tuberous Sclerosis Complex JASPER Early Intervention for Tuberous Sclerosis Studies in Patients With Tuberous Sclerosis Complex Treatment of Renal Angiomyolipomas in Tuberous Sclerosis by Beta-blockers Efficacy and Safety of RAD001 in Patients Aged 18 and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM) Efficacy and Safety of Everolimus (RAD001) in Patients of All Ages With Subependymal Giant Cell Astrocytoma Associated With Tuberous Sclerosis Complex (TSC)(EXIST-1) Long Term Follow Up for RAD001 Therapy of Angiomyolipomata in Patients With Tuberous Sclerosis (TSC) and Sporadic Lymphangioleiomyomatosis (LAM) Dose-Ranging Efficacy and Safety Study of Topical Rapamycin Cream for Facial Angiofibroma Associated With Tuberous Sclerosis Complex Dermatologic Patterns of Tuberous Sclerosis Patients and Somatic Mutation Relationship Genetic Heterogeneity and Genotype-phenotype Correlation of Children and Adults With Tuberous Sclerosis Complex (TuScCom) Early Biomarkers of Autism in Infants With Tuberous Sclerosis Complex (TSC) Tuberous Sclerosis Complex Natural History Study: Renal Manifestations Rapamycin Therapy for Patients With Tuberous Sclerosis Complex and Sporadic LAM A Study of Everolimus in the Treatment of Neurocognitive Problems in Tuberous Sclerosis Trial of RAD001 and Neurocognition in Tuberous Sclerosis Complex (TSC) Study of Skin Tumors in Tuberous Sclerosis

Brief Title

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

Official Title

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

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.
    

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 Phase

Phase 2

Study Type

Interventional


Primary Outcome

Number of patients with adverse events

Secondary Outcome

 Number of participants with reduced mTOR signaling

Condition

Epilepsy

Intervention

Everolimus

Study Arms / Comparison Groups

 Treated Subjects
Description:  This group will be treated with everolimus 7-28 days prior to surgery

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

15

Start Date

January 2014

Completion Date

December 28, 2017

Primary Completion Date

December 8, 2017

Eligibility 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;
      

Gender

All

Ages

2 Years - 40 Years

Accepts Healthy Volunteers

No

Contacts

Orrin Devinsky, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02451696

Organization ID

14-00245


Responsible Party

Sponsor

Study Sponsor

NYU Langone Health


Study Sponsor

Orrin Devinsky, MD, Principal Investigator, NYU Langone Health


Verification Date

September 2020