Neoplasms

Nervous System Diseases

All Conditions

Symptoms and General Pathology

Respiratory Tract (Lung and Bronchial) Diseases

Blood and Lymph Conditions

Immune System Diseases

Diseases and Abnormalities at or Before Birth

Skin and Connective Tissue Diseases

Rare Diseases

Brain Neoplasms

Astrocytoma

Sclerosis

Lung Diseases

Seizures

Lymphangioleiomyomatosis

Tuberous Sclerosis

Angiomyolipoma

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

Lymphangiomyoma

Neoplasms by Histologic Type

Perivascular Epithelioid Cell Neoplasms

Neoplasms, Connective and Soft Tissue

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Neoplasms, Adipose Tissue

Tuberous Sclerosis Complex

Subependymal Giant Cell Astrocytoma

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Everolimus

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

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

Novartis Pharmaceuticals

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

Placebo

Total

Age, Continuous

<30 years

≥ 30 years

Age, Customized

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.

Everolimus Trough Concentrations (Cmin)

2 hours post dose administration at Week 2 (n:55)

2 hours post dose administration at Week 4 (n:49)

2 hours post dose administration at Week 12 (n:56)

2 hours post dose administration at Week 24 (n:50)

2 hours post dose administration at Week 48 (n:14)

Everolimus Blood Concentrations (C2h) at 2 Hours Post-dose

The analysis was performed on the Full analysis Set for patients in Everolimus arm and who experienced an angiomyolipoma response.

Time to Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response

Duration of Angiomyolipoma Response - Only Everolimus Patients With Angiomyolipoma Response

The analysis was performed on the Full analysis Set for patients in Everolimus arm and who experienced a best overall skin lesion response CCR or PR.

Duration of Skin Lesion Response - Only Everolimus Patients With Best Overall Skin Lesion Response of Complete Clinical Response (CCR) or Partial Response (PR)

Spots Global Cancer Trial Database for tuberin, tumor growth suppressors