Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Lymphangioleiomyomatosis

Lymphangiomyoma

Neoplasms by Histologic Type

Perivascular Epithelioid Cell Neoplasms

Neoplasms, Connective and Soft Tissue

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Everolimus

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

All patients received a starting dose of everolimus 2.5mg/day for 4 weeks, followed by a dose of 5 mg/day for 4 weeks and finally a dose of 10mg/day for 18 weeks.

The 26 week treatment period was followed by an optional extension period wherein patients continued therapy until the last patient had completed 26-weeks of treatment. The longest period a patient participated in the study was 62 weeks.

Everolimus was formulated as tablets in strengths of 2.5mg, 5mg and 10mg.

Novartis

This was an exploratory study to determine whether escalating doses of RAD001 (everolimus) were safe and effective in patients with Lymphangioleiomyomatosis

In addition to the data collected in this study, historical data from 43 patients treated with placebo from the multicenter trial of sirolimus in LAM (MILES) study (NCT00414648) were down weighted to an effective sample size of 18 for comparison of FEV1 and FVC endpoints. Reference to the publication of the MILES study has been provided under "Result Publication".

A Study to Determine the Safety and Effectiveness of RAD001 (Everolimus) in Patients With Lymphangioleiomyomatosis

An Exploratory, Open-label, Non-randomized, Within-patient Multiple Dose-escalation Safety, Tolerability, PK and Efficacy Trial of RAD001 (Everolimus) in Patients With Lymphangioleiomyomatosis

Blood samples (1 mL) for determination of VEGF-D were collected from a forearm vein (direct venipuncture or from an indwelling cannula) and 2 aliquots of serum were collected. VEGF-D levels were determined from only 1 of the 2 serum aliquots, with the second acting as a back-up. A serum VEGF-D \>800 pg/mL level supports a diagnosis of Lymphangioleiomyomatosis (LAM)

Venous blood samples (2 mL) for pharmacokinetic evaluation were collected pre dose and 2 hours post dose at preselected visits.

All spirometry evaluation followed recommendations of the Standardization of Lung Function Testing. All spirometry maneuvers were performed in sitting position whilst wearing nose clips. At least three acceptable maneuvers were performed for each time point, and results met within-test and between-test criteria for acceptability. The highest value was obtained of FVC from any of the three maneuvers that met acceptability criteria. Change from baseline in FVC was compared between everolimus and historical placebo data from multicenter trial of sirolimus in LAM. (MILES NCT00414648) due to absence of placebo group in this current study on a rare lung disease. These two studies had different study designs, so the change from baseline to 6 months (26 weeks) in MILES study was estimated from the publicly reported rate of change per month to provide a meaningful comparison. This historical control be can be viewed on the Novartis Clinical Trial Results website.

All spirometry evaluation followed the recommendations of the Standardization of Lung Function Testing. All spirometry maneuvers were performed in the sitting position whilst wearing nose clips. At least three acceptable maneuvers were performed for each time point, and the results met within-test and between-test criteria for acceptability. The highest value was obtained of FEV1 from any of the three maneuvers that met acceptability criteria.

Change from baseline in FEV1 was compared between everolimus and historical placebo data from the MILES study (NCT00414648) due to the absence of a placebo group in this current study on a rare lung disease. These two studies had different study designs, so the change from baseline to 6 months (26 weeks) in MILES study was estimated from the publicly reported rate of change per month in order to provide a meaningful comparison. This historical control can be viewed on the Novartis Clinical Trial Results website.

Extended pulmonary function testing such as Total Lung Capacity (TLC), Thoracic Gas Volume (TGV), Residual Volume (RV) were measured using a body plethysmograph

Carbon Monoxide Diffusing Capacity (DLCO) one of the extended pulmonary function testing which was also measured using a body plethysmograph.

A standardized 6-minute walk test (6MWT) was performed in accordance with the guidelines of the American Thoracic Society 2002. The test was done about the same time of day to avoid diurnal variation in an environment that had an adequate temperature to avoid additional burden to the patient due to heat or cold air. The distance walked in six minutes (6MWD) was recorded.

Oxygen saturation means the amount of oxygen in blood stream. Oxygen saturation was measured by using a Pulse Oximeter.

Novartis Pharmaceuticals

Safety set includes all the patients who had received at least one dose of study drug.

All patients received a starting dose of everolimus 2.5mg/day for 4 weeks, followed by a dose of 5 mg/day for 4 weeks and finally a dose of 10mg/day for 18 weeks. The 26 week treatment period was followed by an optional extension period wherein patients continued therapy until the last patient had completed 26-weeks of treatment. The longest period a patient participated in the study was 62 weeks.

All patients received a starting dose of everolimus 2.5mg/day for 4 weeks, followed by a dose of 5 mg/day for 4 weeks and finally a dose of 10mg/day for 18 weeks.

The 26 week treatment period was followed by an optional extension period wherein patients continued therapy until the last patient had completed 26-weeks of treatment. The longest period a patient participated in the study was 62 weeks.

Everolimus : Everolimus was formulated as tablets in strengths of 2.5mg, 5mg and 10mg.

Age, Continuous

Sex: Female, Male

Everolimus arm has all patients who received study drug that is the safety analysis set.

Study Director

All patients received a starting dose of everolimus 2.5mg/day for first 4 weeks.

Everolimus 2.5 mg/Day

Patients from 2.5 mg/day up-titrated after 4 weeks and followed by a dose of 5 mg/day for another 4 weeks.

Everolimus 5 mg/Day

Patients who had received 2.5 mg/day for first 4 weeks, up titrated to 5 mg/day and continued for another 4 weeks, again up-titrated to 10 mg/day for 18 weeks.

Everolimus 10 mg/Day

Pharmacodynamic analysis included patients who received study drug without any major protocol violation. Same patients in different dose groups were included in this analysis with available data.

Change From Baseline in Vascular Endothelial Growth Factor-D (VEGF-D) Concentrations

Trough (C0, ss)

Peak (C2, ss)

Pharmacokinetics analysis set. Patients with measurable data at particular time points were included in this analysis.

Mean Trough (C0,ss) and Peak (C2,ss) Drug Concentration at Steady State

Proof of Concept was proposed as follows:

* 90% level of proof that difference in FVC change from baseline everolimus vs. Historical Placebo Control arm from MILES study \> 0 mL
* 50% level of proof that difference in FVC change from baseline everolimus vs. Historical Placebo Control arm from MILES study \>= 100 mL

Historical data from 43 patients treated with placebo from the MILES study were down weighted to an effective sample size of 18 for comparison.

All patients received a starting dose of everolimus 2.5mg/day for 4 weeks, followed by a dose of 5 mg/day for 4 weeks and finally a dose of 10mg/day for 18 weeks.

Everolimus : Everolimus was formulated as tablets in strengths of 2.5mg, 5mg and 10mg.

Pharmacodynamic analysis set for everolimus reporting arm. Patients with both baseline and 26 weeks assessment were included in this analysis.

Change From Baseline in Forced Vital Capacity (FVC)

Proof of Concept was proposed as follows:

* 90% level of proof that difference in FEV1 change from baseline everolimus vs. Historical Placebo Control arm from MILES study \> 0 mL
* 50% level of proof that difference in FEV1 change from baseline everolimus vs. Historical Placebo Control arm from MILES study \>= 100 mL

Historical data from 43 patients treated with placebo from the MILES study were down weighted to an effective sample size of 18 for comparison.

Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1)

Pharmacodynamic analysis set. Patients with both baseline and 26 weeks assessment were included in the analysis.

Change From Baseline in Extended Pulmonary Function Testing

Change From Baseline in Carbon Monoxide Diffusing Capacity (DLCO)

Change From Baseline in 6-minute Walk Test Score to Measure Exercise Capacity

Change From Baseline in Oxygen Saturation

All patients received a starting dose of everolimus 2.5mg/day for 4 weeks, followed by a dose of 5 mg/day for 4 weeks and finally a dose of 10mg/day for 18 weeks. The 26 week treatment period was followed by an optional extension period wherein patients continued therapy until the last patient had completed 26-weeks of treatment. The longest period a patient participated in the study was 62 weeks.

Everolimus : Everolimus was formulated as tablets in strengths of 2.5mg, 5mg and 10mg.

Spots Global Cancer Trial Database for 6 minute walk test,