Neoplasms

All Conditions

Symptoms and General Pathology

Nervous System Diseases

Diseases and Abnormalities at or Before Birth

Skin and Connective Tissue Diseases

Rare Diseases

Astrocytoma

Sclerosis

Tuberous Sclerosis

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Hamartoma

Neoplasms, Multiple Primary

Syndrome

Neoplastic Syndromes, Hereditary

Congenital Abnormalities

Malformations of Cortical Development

Nervous System Malformations

Neurocutaneous Syndromes

Heredodegenerative Disorders, Nervous System

Neurodegenerative Diseases

Genetic Diseases, Inborn

Tuberous Sclerosis Complex

Subependymal Giant Cell Astrocytoma

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Everolimus

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

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.

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

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

Placebo

Novartis Pharmaceuticlas

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

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

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)

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.

Seizure frequency per 24 hours was defined as the number of seizures in the electroencephalography (EEG) divided by the number of hours in the EEG, multiplied by 24. Seizure frequency was evaluated using a 24-hour video-EEG. Seizure frequency was listed as missing if the actual EEG recording duration was \< 18 hours.

Time to SEGA progression was defined as time between randomisation to time to first SEGA progression. SEGA progression was defined as either one or more of the following criteria: 1. increase from nadir of ≥ 25% in SEGA volume to a value greater than baseline SEGA volume (where SEGA volume is the sum of the volumes of all target SEGA lesions identified at baseline, and nadir is the lowest SEGA volume obtained for the participant previously in the trial), 2. unequivocal worsening of non-target SEGA lesions, 3. appearance of new SEGA lesion ≥ 1.0 cm in longest diameter, 4. new or worsening hydrocephalus. The median TTSP based on central radiology review was not reached in any treatment arms; Only 6 events of SEGA progressions were observed in the placebo group of core period.

Participants were assessed for time to 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 utilised 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.

Duration of SEGA response was defined as time from the date of the first documented SEGA response until the date of the first documented SEGA progression. Duration of SEGA response was evaluated only for participants who achieved a SEGA response. The time to SEGA progression was censored if SEGA progression was not observed before the first to occur out of (i) analysis cut-off date (ii) the date when systemic anti-SEGA medication is started, (iii) the date of a SEGA-related surgery or (iv) the date of death. Since, no case of SEGA progression was observed in core study which resulted in censored duration of SEGA response. Only 5 SEGA responders experienced a SEGA progression in extension period.

Time to SEGA worsening was defined as the time from the start of everolimus to date of the first SEGA worsening. SEGA worsening was defined as either; increase from nadir of ≥ 25% in SEGA volume or unequivocal worsening of non-target SEGA lesions, or appearance of new SEGA lesion ≥ 1.0 cm in longest diameter, or new or worsening hydrocephalus. The median value was not reached in either treatment arm of core period as SEGA worsening was observed in less participants (everolimus - 7 and placebo - 8).

Skin lesions included hypomelanotic macules, the shagreen patch, periungual or subungual fibromas, facial angiofibromas and/or forehead plaques. Response was evaluated using the Physician's Global Assessment of Clinical Condition (PGA) on a 7-point scale: Grade 0 = complete clinical response, indicated absence of disease, Grade 1, 2, and 3 = partial response, indicated improvements of ≥ 50% but \< 100%, Grade 4, 5 = stable disease, indicated some or no improvements of 25% - \< 50% and 6 = progressive disease, indicated worse than at baseline evaluation by \> 25%. Response rate was determined for participants with ≥ 1 skin lesion at baseline, defined as the percentage of participants with overall status as complete clinical response or partial response.

Duration of skin lesion response was defined as the time from the first skin lesion response until the first skin lesion progression, defined as worsening of lesion by \> 25% or more from baseline.

The participants were assessed for everolimus blood concentration at 2 hours time point after dose administration on the same day, if the participant did not vomit between previous dose and blood sample collection. Tandem liquid chromatography-mass spectrometry method was used for evaluation. C2h values were categorized as \< 20 ng/mL, 20-50 ng/mL, and \> 50 ng/mL, concentrations below the lower limit of quantification were entered as 0 ng/mL.

The participants were assessed for everolimus trough concentration (Cmin) at 24 hours time point after previous dose administration, at a steady state following 5 days of consistent dosing, if the participant did not vomit within 4 hours of previous dose. Tandem liquid chromatography-mass spectrometry method was used for evaluation. Cmin values were categorized as \<5 ng/mL, 5-10 ng/mL, and \>10 ng/mL, concentrations below the lower limit of quantification were entered as 0 ng/mL.

Renal function was assessed using glomerular filtration rate (GFR) based on age measure; Modification of Diet in Renal Disease (MDRD) formula for participants aged 18 years or older, defined as GFR equal to 32788\*(serum creatinine (micromol/L)\^-1.154)\*(age\^-0.203 )\*(0.742, if female)\*(1.210, if black), and Schwartz formula for participants less than 18 years defined as GFR equal to 0.41\*height (cm)/ Serum creatinine (mg/dL). Participants with severe renal impairment defined as GFR \< 30 mL/min/1.73 m\^2 and participants with National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) grade 3/4 serum creatinine were reported.

Novartis Pharmaceuticals

For safety, the reporting arms have been created on the basis of actual exposure to study treatment

Participants who received everolimus treatment in core period and continued to receive evrolimus treatment in extension period.

Everolimus Treated (Core and Extension Period)

Participants who received placebo in core period and then received evrolimus treatment in extension period.

Placebo (Core) Then Everolimus Treated (Extension Period)

Participants who received placebo in core period.

Placebo Treated (Core Period)

Participants received oral dose of everolimus 4.5 mg/m\^2 daily as an initial starting dose to attain the whole blood trough concentrations in range of 5-15 ng/mL. Dose adjustments were permitted based on safety and whole blood trough concentrations.

Everolimus (Core Period)

Participants received oral dose of placebo matching to everolimus daily.

Placebo (Core Period)

Total

Age, Continuous

<3 years

3-18 years

≥18 years

Age, Customized

Sex: Female, Male

Study Director

Participants received oral dose of everolimus 4.5 mg/m\^2 daily as an initial starting dose to attain blood trough concentrations in range of 5-15 ng/mL.

Everolimus (Extension Period)

The primary analysis was performed in Full Analysis Set (FAS) population, defined as all randomized participants involved in the study.

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

The analysis was performed in the FAS population. Missing values were imputed using last observation carried forward approach for core period while raw count for extension period.

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

The analysis was performed in the FAS population. Here "Number of participants analysed" signifies the participants assessed for time to SEGA progression during the study for each arm, respectively.

Time to SEGA Progression

The analysis was performed in the FAS population.

Time to SEGA Response

The analysis was performed in the FAS population. Here, "Number of participants analysed" signifies the participants assessed for SEGA progression during the study for each arm, respectively.

Duration of SEGA Response

The analysis was performed in the FAS population. Here, "Number of participants analysed" signifies the participants assessed for time to SEGA worsening during the study for each arm, respectively.

Time to SEGA Worsening

The analysis was performed in the FAS population. Here, "Number of participants analysed" signifies the participants assessed for skin lesion response during the study for each arm, respectively.

Percentage of Participants With Skin Lesions Assessed Using Physician's Global Assessement Overall Score

The analysis was performed in the FAS population. Here, "Number of participants analysed" signifies everolimus treated responders with best overall skin lesion response during the core and extension period, respectively.

Duration of Skin Lesion Response in Everolimus Treated Participants

Week 6 (n= 37, 47)

Week 24 (n= 11, 13)

Week 48 (n= 1, 3)

Week 96 (n= 0, 6)

Week 144 (n= 0, 6)

Week 240 (n= 0, 0)

The analysis was performed in the Safety Set population (Only evaluable PK Samples), defined as participants who received at least one dose of the double-blind study drug, with a valid post baseline assessment. The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.

Everolimus Blood Concentration (C2h) at 2 Hours Post Dose

Week 6 (n= 64, 94)

Week 24 (n= 64, 89)

Week 48 (n= 23, 86)

Week 72 (n= 4, 92)

Week 96 (n= 0, 83)

Week 144 (n= 0, 69)

Week 240 (n= 0, 13)

The analysis was performed in the Safety Set population. The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.

Everolimus Trough Concentrations (Cmin) at 24 Hours After Last Dose

Grade 3 or 4

Grade 1 or 2

Grade 0

The analysis was performed in the SAF population. Here, "Number of participants analysed" signifies the participants assessed for renal function during the study for each arm, respectively.

Percentage of Participants With Renal Impairment During Core Period

Participants received oral dose of everolimus 4.5 milligram/square meter (mg/m\^2) daily as an initial starting dose to attain the whole blood trough concentrations in range of 5-15 nanogram/millilitre (ng/mL). Dose adjustments were permitted based on safety and whole blood trough concentrations.

Core Period (48 Weeks)

Open-label Extension Period (4 Years)

Respiratory Tract (Lung and Bronchial) Diseases

Blood and Lymph Conditions

Immune System Diseases

Brain Neoplasms

Lung Diseases

Seizures

Lymphangioleiomyomatosis

Angiomyolipoma

Lymphangiomyoma

Perivascular Epithelioid Cell Neoplasms

Neoplasms, Connective and Soft Tissue

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Neoplasms, Adipose Tissue

Study drug was given by continuous oral daily dosing of two 5 mg tablets.

Placebo was given by continuous oral daily dosing of two 5 mg tablets.

Everolimus is used in 5 mg strength tablets, blister-packed under aluminum foil in units of ten tablets and dosed on a daily basis. 10mg daily dosing throughout the trial.

Everolimus (RAD001)

Matching placebo was provided as a matching tablet and was also blister-packed under aluminum foil in units of ten.

Everolimus Placebo

This study will evaluate the safety and efficacy of RAD001 in treating patients with Angiomyolipoma associated with Tuberous Sclerosis Complex or Sporadic Lymphangioleiomyomatosis.

Efficacy and Safety of RAD001 in Patients Aged 18 and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)

A Randomized, Double-blind, Placebo-controlled Study of RAD0001 in the Treatment of Angiomyolipoma in Patients With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)

Angiomyolipoma response defined as the combination of the following criteria: reduction in angiomyolipoma volume of ≥ 50% relative to baseline, where angiomyolipoma volume was sum of volumes of all target lesions identified at baseline, and with a confirmatory scan performed approximately 12 weeks later (no sooner than 8 weeks later); no new angiomyolipoma lesions ≥ 1.0 cm in longest diameter were identified; there were no kidney increases in volume \> 20% from nadir. The patient did not have any angiomyolipoma-related bleeding of ≥ grade 2.

For the everolimus (core/extension periods) treatment group, the baseline means the latest value on or before starting everolimus.

Time to angiomyolipoma progression (TTAP) is defined as time from date of randomization to date of first documented angiomyolipoma progression. Angiomyolipoma progression was defined as one or more of the following: Increase from nadir of ≥ 25% in angiomyolipoma volume to value greater than baseline; the appearance of a new angiomyolipoma ≥ 1.0 cm in longest diameter; an increase from nadir of 20% or more in the volume of either kidney to a value greater than baseline; angiomyolipoma-related bleeding grade ≥ 2.

For the everolimus (core/extension periods) treatment group, the time to angiomyolipoma progression is defined starting from the start of everolimus. The baseline means the latest value on or before starting everolimus.

Skin lesion response rate in the double-blind period was determined only among patients with at least one skin lesion at baseline, and is the percentage of this group of patients with a best overall skin lesion response on the Physician's Global Assessment of Clinical Condition (PGA) of either complete clinical response (CCR) or partial response (PR). A complete clinical response (CCR) requires a grading of 0 indicating the absence of disease (histological confirmation is not required). Grades 1, 2, and 3 constitute partial response, indicating improvement of at least 50 percent, but less than 100 percent improvement. For the everolimus (core/extension periods) treatment group, the baseline means the latest value on or before starting everolimus.

Renal Impairment was measured by glomerular filtration rate which was calculated using the Modification of Diet in Renal Disease formula. Percentage of participants with renal impairment was reported. Severe renal impairment was defined as a GFR of \<30ml/min/1.73m2.

Blood samples for biomarker assessment were collected immediately prior to study administration. On-treatment samples was compared to baseline samples with the change from baseline.

Cmin values collected prior to dose administration on the same study day and at 20-28 hours after previous dose, at steady state, and patient did not vomit within 4 hours of previous dose. Samples collected during the first 4 days of dosing were excluded from all analyses.

C2h values collected 1-3 hours after dose administration on the same study day, at steady state, and patient did not vomit between taking previous dose and blood collection. Samples collected during the first 4 days of dosing will be excluded from all analyses.

Time to angiomyolipoma response was defined as the time from the date of randomization until the date of the first documented angiomyolipoma response. Angiomyolipoma response defined as the combination of the following criteria: reduction in angiomyolipoma volume of ≥ 50% relative to baseline, where angiomyolipoma volume was sum of volumes of all target lesions identified at baseline, and with a confirmatory scan performed approximately 12 weeks later (no sooner than 8 weeks later); no new angiomyolipoma lesions ≥ 1.0 cm in longest diameter were identified; no kidney increases in volume \> 20% from nadir; no angiomyolipoma-related bleeding of ≥ grade 2.

For the everolimus (core/extension periods) treatment group, the time to angiomyolipoma response is from the start of everolimus. The baseline in the response definition means the latest value on or before starting everolimus.

Duration of angiomyolipoma response was defined as the time from the date of the first documented angiomyolipoma response until the date of the first documented angiomyolipoma progression . Angiomyolipoma response was defined as the combination of the following criteria: reduction in angiomyolipoma volume of ≥ 50% relative to baseline, where angiomyolipoma volume was sum of volumes of all target lesions identified at baseline, and with a confirmatory scan performed approximately 12 weeks later (no sooner than 8 weeks later); no new angiomyolipoma lesions ≥ 1.0 cm in longest diameter were identified; there were no kidney increases in volume \> 20% from nadir. The patient did not have any angiomyolipoma-related bleeding of ≥ grade 2.

Duration of skin lesion response is defined as the time from the date of the first skin lesion response until the date of the first skin lesion progression, according to the PGA (physician's global assessment of clinical condition). A progression is when the disease is worse than at baseline evaluation by \>=25% or more.

Patients who were randomized and treated with Everolimus during the Core and Extension phase

Everolimus Randomized (Core & Ext)

Patients who were randomized to placebo in the Core phase and who crossed-over to Everolimus in the Extension phase

Placebo Randomized/Crossed Over to Everolimus

Patients randomized to placebo who never crossed-over to Everolimus

Placebo Randomized/Never Crossed-over

<30 years

≥ 30 years

Gender

Everolimus Randomized (Core Period)

Placebo Randomized (Core Period)

Patients initially randomized in everolimus and patients initially randomized in placebo but who crossed-over to everolimus during extension.

Everolimus (Core and/or Extension Period)

The Full Analysis Set (FAS) is defined according to the Intention-to-Treat principle and consists of all randomized patients.

Angiomyolipoma Response Rate as Per Central Radiology Review

Time to Angiomyolipoma Progression as Per Central Radiology Review

The Full Analysis Set (FAS) is defined according to the Intention-to-Treat principle and consists of all randomized patients. Only patients with at least one skin lesion at baseline are included in the analysis.

Skin Lesion Response Rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline)

Glomerular filtration rate <30 ml/min/1.73m^2

Glomerular filtration rate≥ 30 ml/min/1.73m^2

Safety set consists of all patients who received at least 1 dose of the double-blind study drug with a valid post-baseline assessment. For the everolimus (core/extension) treatment arm, patients received at least 1 dose of everolimus with a valid post-baseline assessment, where baseline was defined as the assessment just before start of everolimus.

Percentage of Participants With Renal Impairment

Week 4 (n:56, 28)

Week 12 (n:56, 29)

Week 24 (n:53, 29)

Week 36 (n:26, 18)

Week 48 (n:16, 8)

Week 60 (n:0, 1)

Week 72 (n:0, 1)

The Full Analysis Set (FAS) is defined according to the Intention-to-Treat principle and consists of all randomized patients. The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.

Change From Baseline in Plasma Angiogenic Molecules - Vascular Endothelial Growth Factor (VEGF) Marker

Prior to dosing at Week 2 (n:43)

Prior to dosing Week 4 (n:44)

Prior to dosing Week 12 (n:49)

Prior to dosing Week 24 (n:46)

Prior to dosing Week 48 (n:15)

The analysis was performed in the Safety Set population for patients treated only with Everolimus and with a confirmed PK sample.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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	Tuberous Sclero... Subependymal Gi...	Everolimus Placebo	-	Novartis
Efficacy and Safety of RAD001 in Patients Aged 18 and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)	NCT00790400	Tuberous Sclero... Lymphangioleiom...	Everolimus (RAD... Everolimus Plac...	18 Years -	Novartis
Everolimus (RAD001) Therapy of Giant Cell Astrocytoma in Patients With Tuberous Sclerosis Complex	NCT00411619	Tuberous Sclero... Subependymal Gi...	Everolimus	3 Years -	Children's Hospital Medical Center, Cincinnati
Biomarkers for Tuberous Sclerosis Complex (BioTuScCom)	NCT02654340	Hypomelanotic M... Facial Angiofib... Shagreen Patche... Ungual Fibromas Cortical Dyspla... Cardiac Rhabdom... Lymphangioleiom... Renal Angiomyol... Subependymal Gi...		2 Years - 50 Years	CENTOGENE GmbH Rostock
Biomarkers for Tuberous Sclerosis Complex (BioTuScCom)	NCT02654340	Hypomelanotic M... Facial Angiofib... Shagreen Patche... Ungual Fibromas Cortical Dyspla... Cardiac Rhabdom... Lymphangioleiom... Renal Angiomyol... Subependymal Gi...		2 Years - 50 Years	CENTOGENE GmbH Rostock
Everolimus (RAD001) Therapy of Giant Cell Astrocytoma in Patients With Tuberous Sclerosis Complex	NCT00411619	Tuberous Sclero... Subependymal Gi...	Everolimus	3 Years -	Children's Hospital Medical Center, Cincinnati
Biomarkers for Tuberous Sclerosis Complex (BioTuScCom)	NCT02654340	Hypomelanotic M... Facial Angiofib... Shagreen Patche... Ungual Fibromas Cortical Dyspla... Cardiac Rhabdom... Lymphangioleiom... Renal Angiomyol... Subependymal Gi...		2 Years - 50 Years	CENTOGENE GmbH Rostock

Spots Global Cancer Trial Database for subependymal giant cell astrocytoma