Efficacy and Safety of Everolimus (RAD001) in Patients of All Ages With Subependymal Giant Cell Astrocytoma Associated With Tuberous Sclerosis Complex (TSC)(EXIST-1)

NCT00789828 | Completed Phase 3 Results

• 2 other identifiers: CRAD001M23012007-006997-27
• Study Type: interventional
• Target: 117
• Locations: 10 countries
• Sites: 24

Brief Summary

This study evaluated the efficacy and safety of Everolimus in treating patients with Subependymal Giant Cell Astrocytomas associated with Tuberous Sclerosis Complex.

Conditions

Tuberous Sclerosis; Subependymal Giant Cell Astrocytoma

Keywords

SEGA; Tuberous Sclerosis; Subependymal Giant Cell Astrocytoma; mTOR; RAD001; Mamalian Target Rapamycin; Everolimus; TSC

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With Best Overall Subependymal Giant Cell Astrocytomas (SEGA) Response

  Participants were assessed for SEGA response, defined as 50% reduction from baseline in SEGA volume (where SEGA volume was the sum of the volumes of all target SEGA lesions identified at baseline, and confirmed with a second scan performed approximately 12 weeks later), no unequivocal worsening of non-target SEGA lesions, no new SEGA lesions (≥ 1 cm in longest diameter), and no new or worsening hydrocephalus. Multi-phase brain MRI was utilized to identify SEGA lesions. SEGA response rate was defined as the percentage of participants whose best overall status was SEGA response as determined by Independent Central Radiology Review. The Kaplan-Meier estimate was used for determining time to SEGA response.

  End of core period (Week 48), and end of extension period (up to 4 years)

Secondary Outcomes (10)

• Change From Baseline in Frequency of Total Seizure Events Per 24 Hours at Week 24 in Both Core and Extension Period

  Baseline (Core period) to Week 24 (Core period), Baseline (Extension period, Week 24 post-core baseline) to Week 24 (Extension period, Week 48 post-core baseline)

• Time to SEGA Progression

  Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)

• Time to SEGA Response

  Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)

• Duration of SEGA Response

  Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)

• Time to SEGA Worsening

  Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)

Study Arms (2)

Everolimus

EXPERIMENTAL

Everolimus was administered orally at a starting dose of 4.5mg/m\^2 daily and subsequently titrated to attain whole blood trough concentration of 5 to 15 ng/mL. Dose adjustments were permitted based on safety and whole blood trough concentrations.

Drug: Everolimus

Placebo

PLACEBO COMPARATOR

Matching Placebo administered orally.

Drug: Placebo

Interventions

Everolimus DRUG

Everolimus was formulated as tablets of 1.0-mg strength and was blisterpacked under aluminum foil in units of 10 tablets.

Also known as: RAD001

Everolimus

Placebo DRUG

Placebo was provided as a matching tablet and was blisterpacked under aluminum foil in units of 10.

Placebo

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• All Ages
• Definite diagnosis of Tuberous Sclerosis according to the modified Gomez criteria
• At least one Subependymal Giant Cell Astrocytoma of at least 1 cm in diameter
• Evidence of SEGA worsening as compared to prior MRI scans
• Females of child bearing potential must use birth control
• Written informed consent

You may not qualify if:

• SEGA related surgery is likely to be required in the opinion of the investigator
• Recent heart attack, cardiac related chest pain or stroke
• Severely impaired lung function
• Severe liver dysfunction
• Severe kidney dysfunction
• Pregnancy or breast feeding
• Current infection
• History of organ transplant
• Surgery within two months prior to study enrollment
• Prior therapy with a medication in the same class as Everolimus
• Uncontrolled high cholesterol
• Uncontrolled diabetes
• HIV
• Patients with metal implants thus prohibiting MRI evaluations

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (24)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

Barrow Tuberous Sclerosis Center

Phoenix, Arizona, 85013, United States

Location

University of California at Los Angeles

Los Angeles, California, 90048, United States

Location

Children's Hospital Oakland Hematology/Oncology Dept

Oakland, California, 94609-1809, United States

Location

Children's Healthcare of Atlanta

Atlanta, Georgia, 30342, United States

Location

University of CHicago Comer Children's Hospital

Chicago, Illinois, 60637-1470, United States

Location

Massachusetts General Hospital Mass General

Boston, Massachusetts, 02114, United States

Location

Children's Hospital Boston SC-1

Boston, Massachusetts, 02115, United States

Location

Minnesota Epilepsy Group - PA

Saint Paul, Minnesota, 55102-2383, United States

Location

Cincinnati Children's Hospital Medical Center Cincinnati Children's Hosp

Cincinnati, Ohio, 45229-3039, United States

Location

Texas Scottish Rite Hospital for Children

Dallas, Texas, 75219, United States

Location

Children's Regional Outpatients Center SC

Fairfax, Virginia, 22031, United States

Location

Novartis Investigative Site

Randwick, New South Wales, 2130, Australia

Location

Novartis Investigative Site

Brussels, 1090, Belgium

Location

Novartis Investigative Site

Toronto, Ontario, M5G 1X8, Canada

Location

Novartis Investigative Site

Québec, H3T IC5, Canada

Location

Novartis Investigative Site

Berlin, 13353, Germany

Location

Novartis Investigative Site

Heidelberg, 69120, Germany

Location

Novartis Investigative Site

Genova, GE, 16147, Italy

Location

Novartis Investigative Site

Roma, 00137, Italy

Location

Novartis Investigative Site

Utrecht, Netherlands, 3584CX, Netherlands

Location

Novartis Investigative Site

Warsaw, 04-730, Poland

Location

Novartis Investigative Site

Moscow, 127412, Russia

Location

Novartis Investigative Site

Bristol, BS1 3NU, United Kingdom

Location

Related Publications (9)

• Bissler JJ, Budde K, Sauter M, Franz DN, Zonnenberg BA, Frost MD, Belousova E, Berkowitz N, Ridolfi A, Christopher Kingswood J. Effect of everolimus on renal function in patients with tuberous sclerosis complex: evidence from EXIST-1 and EXIST-2. Nephrol Dial Transplant. 2019 Jun 1;34(6):1000-1008. doi: 10.1093/ndt/gfy132.

  PMID: 30053159 DERIVED

• Sparagana S, Franz DN, Krueger DA, Bissler JJ, Berkowitz N, Burock K, Kingswood JC. Pooled analysis of menstrual irregularities from three major clinical studies evaluating everolimus for the treatment of tuberous sclerosis complex. PLoS One. 2017 Oct 12;12(10):e0186235. doi: 10.1371/journal.pone.0186235. eCollection 2017.

  PMID: 29023494 DERIVED

• Franz DN, Belousova E, Sparagana S, Bebin EM, Frost MD, Kuperman R, Witt O, Kohrman MH, Flamini JR, Wu JY, Curatolo P, de Vries PJ, Berkowitz N, Niolat J, Jozwiak S. Long-Term Use of Everolimus in Patients with Tuberous Sclerosis Complex: Final Results from the EXIST-1 Study. PLoS One. 2016 Jun 28;11(6):e0158476. doi: 10.1371/journal.pone.0158476. eCollection 2016.

  PMID: 27351628 DERIVED

• Jozwiak S, Kotulska K, Berkowitz N, Brechenmacher T, Franz DN. Safety of Everolimus in Patients Younger than 3 Years of Age: Results from EXIST-1, a Randomized, Controlled Clinical Trial. J Pediatr. 2016 May;172:151-155.e1. doi: 10.1016/j.jpeds.2016.01.027. Epub 2016 Feb 6.

  PMID: 26858193 DERIVED

• Goyer I, Dahdah N, Major P. Use of mTOR inhibitor everolimus in three neonates for treatment of tumors associated with tuberous sclerosis complex. Pediatr Neurol. 2015 Apr;52(4):450-3. doi: 10.1016/j.pediatrneurol.2015.01.004. Epub 2015 Jan 14.

  PMID: 25682485 DERIVED

• Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, Witt O, Kohrman MH, Flamini JR, Wu JY, Curatolo P, de Vries PJ, Berkowitz N, Anak O, Niolat J, Jozwiak S. Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. Lancet Oncol. 2014 Dec;15(13):1513-1520. doi: 10.1016/S1470-2045(14)70489-9. Epub 2014 Nov 10.

  PMID: 25456370 DERIVED

• Kingswood JC, Jozwiak S, Belousova ED, Frost MD, Kuperman RA, Bebin EM, Korf BR, Flamini JR, Kohrman MH, Sparagana SP, Wu JY, Brechenmacher T, Stein K, Berkowitz N, Bissler JJ, Franz DN. The effect of everolimus on renal angiomyolipoma in patients with tuberous sclerosis complex being treated for subependymal giant cell astrocytoma: subgroup results from the randomized, placebo-controlled, Phase 3 trial EXIST-1. Nephrol Dial Transplant. 2014 Jun;29(6):1203-10. doi: 10.1093/ndt/gfu013. Epub 2014 Apr 11.

  PMID: 24729041 DERIVED

• Kotulska K, Borkowska J, Jozwiak S. Possible prevention of tuberous sclerosis complex lesions. Pediatrics. 2013 Jul;132(1):e239-42. doi: 10.1542/peds.2012-3607. Epub 2013 Jun 3.

  PMID: 23733802 DERIVED

• Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, Witt O, Kohrman MH, Flamini JR, Wu JY, Curatolo P, de Vries PJ, Whittemore VH, Thiele EA, Ford JP, Shah G, Cauwel H, Lebwohl D, Sahmoud T, Jozwiak S. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2013 Jan 12;381(9861):125-32. doi: 10.1016/S0140-6736(12)61134-9. Epub 2012 Nov 14.

  PMID: 23158522 DERIVED

Related Links

• Visit EXIST-1 NovartisClinicalTrials.com: Pre-qualify for a trial, and view a list of trials and participating study centers.

MeSH Terms

Conditions

Tuberous Sclerosis; Astrocytoma

Interventions

Everolimus

Condition Hierarchy (Ancestors)

Hamartoma; Neoplasms; Neoplasms, Multiple Primary; Neoplastic Syndromes, Hereditary; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Nervous System Diseases; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

862-778-8300

Study Officials

• Novartis Pharmaceuticlas

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 12, 2008
• First Posted: November 13, 2008
• Study Start: August 1, 2009
• Primary Completion: March 1, 2011
• Study Completion: October 1, 2014
• Last Updated: February 3, 2016
• Results First Posted: May 1, 2012

Record last verified: 2016-01

Locations

CA (2); DE (2); IT (2); PL (1); US (12); GB (1); AU (1); NL (1); BE (1); RU (1)