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

NCT02451696 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 14-00245
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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.

Conditions

Epilepsy; Tuberous Sclerosis Complex; Focal Cortical Dysplasia

Outcome Measures

Primary Outcomes (1)

• Number of Patients With Adverse Events

  .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 Outcomes (4)

• Blood Everolimus Levels

  28 days

• 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

Study Arms (2)

Treated Subjects

EXPERIMENTAL

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

Drug: Everolimus

Reference Subjects

NO INTERVENTION

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.

Interventions

Everolimus DRUG

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

Also known as: Trade Name: Afinitor®

Treated Subjects

Eligibility Criteria

• Age: 2 Years - 40 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• NYU Langone Health: lead

Study Sites (1)

New York University Langone Medical Center

New York, New York, 10016, United States

Location

Related Publications (1)

• Leitner DF, Kanshin E, Askenazi M, Siu Y, Friedman D, Devore S, Jones D, Ueberheide B, Wisniewski T, Devinsky O. Pilot study evaluating everolimus molecular mechanisms in tuberous sclerosis complex and focal cortical dysplasia. PLoS One. 2022 May 19;17(5):e0268597. doi: 10.1371/journal.pone.0268597. eCollection 2022.

  PMID: 35587487 DERIVED

MeSH Terms

Conditions

Epilepsy; Tuberous Sclerosis; Focal Cortical Dysplasia

Interventions

Everolimus

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hamartoma; Neoplasms; Neoplasms, Multiple Primary; Neoplastic Syndromes, Hereditary; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Dr. Orrin Devinsky
• Organization: NYU Langone

od4@nyu.edu

646-558-0800

Study Officials

• Orrin Devinsky, MD

  NYU Langone Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 8, 2014
• First Posted: May 22, 2015
• Study Start: January 1, 2014
• Primary Completion: December 8, 2017
• Study Completion: December 28, 2017
• Last Updated: September 1, 2021
• Results First Posted: September 1, 2021

Record last verified: 2021-08

Locations

US (1)