Clinical trial NCT00789828: Efficacy and Safety of Everolimus (RAD001) in Patients of All Ages With Subependymal Giant Cell Astrocytoma Associated With Tuberous Sclerosis Complex (TSC)(EXIST-1)
Official title: A Randomized, Double-blind, Placebo-controlled Study of Everolimus in the Treatment of Patients With Subependymal Giant Cell Astrocytomas (SEGA) Associated With Tuberous Sclerosis Complex (TSC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Tuberous Sclerosis
Subependymal Giant Cell Astrocytoma
Keywords: SEGA
Tuberous Sclerosis
Subependymal Giant Cell Astrocytoma
mTOR
RAD001
Mamalian Target Rapamycin
Everolimus
TSC
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2008-11-13
Enrollment: 117
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Other protocol-defined inclusion/exclusion criteria may apply

Primary outcomes:
measure: Percentage of Participants With Best Overall Subependymal Giant Cell Astrocytomas (SEGA) Response
timeFrame: End of core period (Week 48), and end of extension period (up to 4 years)
Secondary outcomes:
measure: Change From Baseline in Frequency of Total Seizure Events Per 24 Hours at Week 24 in Both Core and Extension Period
timeFrame: 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)
measure: Time to SEGA Progression
timeFrame: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)
measure: Time to SEGA Response
timeFrame: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)
measure: Duration of SEGA Response
timeFrame: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)
measure: Time to SEGA Worsening
timeFrame: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)
measure: Percentage of Participants With Skin Lesions Assessed Using Physician's Global Assessement Overall Score
timeFrame: End of core period (Week 48), and end of extension period (up to 4 years)
measure: Duration of Skin Lesion Response in Everolimus Treated Participants
timeFrame: Baseline up to week 48 (end of core period), and end of extension period (up to 4 years)
measure: Everolimus Blood Concentration (C2h) at 2 Hours Post Dose
timeFrame: 2 hours post dose on Week 6, Week 24, Week 48, Week 96, Week 144, and Week 240
measure: Everolimus Trough Concentrations (Cmin) at 24 Hours After Last Dose
timeFrame: 24 hours post dose on Week 6, Week 24, Week 48, Week 72, Week 96, Week 144, and Week 240
measure: Percentage of Participants With Renal Impairment During Core Period
timeFrame: Day 1 up to 28 days after end of treatment (Core period)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Barrow Tuberous Sclerosis Center
state: Arizona
city: Los Angeles
country: United States
facility: University of California at Los Angeles
state: California
city: Oakland
country: United States
facility: Children's Hospital Oakland Hematology/Oncology Dept
state: California
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Chicago
country: United States
facility: University of CHicago Comer Children's Hospital
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital Mass General
state: Massachusetts
city: Boston
country: United States
facility: Children's Hospital Boston SC-1
state: Massachusetts
city: St. Paul
country: United States
facility: Minnesota Epilepsy Group - PA
state: Minnesota
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center Cincinnati Children's Hosp
state: Ohio
city: Dallas
country: United States
facility: Texas Scottish Rite Hospital for Children
state: Texas
city: Fairfax
country: United States
facility: Children's Regional Outpatients Center SC
state: Virginia
city: Randwick
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Brussel
country: Belgium
facility: Novartis Investigative Site
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Quebec
country: Canada
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Roma
country: Italy
facility: Novartis Investigative Site
city: Utrecht
country: Netherlands
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Bristol
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticlas
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.