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)

Double-blind Period (Core Phase)

Everolimus Period (Core or Extension)

Amino Acids

Glutamine

To compare images from subjects prior to use of sirolimus or everolimus to images produced after use of sirolimus or everolimus.

Glutamine will be administered by IV injection prior to PET imaging.

Timothy S Blackwell, MD

In this study, subjects with spontaneous or tuberous sclerosis complex associated lymphangioleiomyomatosis (LAM) who have not been started on therapy with mTOR inhibitors such as sirolimus or everolimus to undergo a PET/CT scan using an novel PET tracer that may better evaluate disease activity in LAM subjects both before and after the initiation of mTOR inhibitor therapy will be enrolled. The procedure for each scan will be similar, involving one administration of the novel tracer C11-glutamine followed by a whole body PET/CT scan.

Objectives This is a hypothesis-driven prospective pilot study of the targeted PET reagent 11C-Glutamine in LAM.

The objective is to test the hypothesis that 11C-Glutamine PET/CT will demonstrate uptake within the lungs and/or associated neoplasm of patients with LAM and that this effect will be modified by treatment with mTOR inhibitors.

Rationale Our rationale is that 11C-Glutamine PET/CT may provide an improved ability to diagnose LAM, as well as predict and monitor treatment response to mTOR inhibitors.

Aims Test the hypothesis that 11C-Gln PET imaging of the lungs in humans will reflect the known "glutamine addiction" seen in mechanistic preclinical studies of LAM. As a result, PET imaging will show increased tracer uptake in affected areas of diseased lungs and will show reduced uptake after initiating treatment with mTOR inhibitors.

Approach: We will evaluate 11C-Glutamine PET/CT uptake in patients with known LAM, and if possible, we will test subjects again after 8 weeks of mTOR inhibitor therapy (either sirolimus or everolimus).

Test subjects with spontaneous or tuberous sclerosis complex associated lymphangioleiomyomatosis (LAM) who have not been started on therapy with mTOR inhibitors such as sirolimus or everolimus to undergo a PET/CT scan using an novel PET tracer that may better evaluate disease activity in LAM subjects both before and after the initiation of mTOR inhibitor therapy.

Because LAM is a disease that occurs essentially only in females, the study population will consist of only females.

Glutamine PET Imaging in LAM

While these imaging techniques have not been used in normal populations, the pulmonary uptake of patients with known intraabdominal malignancy will serve as control for evaluation of any potential uptake. When comparing treatment effects, each patient can serve as their own control as they will have already had imaging completed prior to the initiation of therapy. VEGF-D levels will be collected from clinical laboratory assessment or will be collected at time of enrollment, and relative elevation of VEGF-D will be compared to the relative uptake of tracer within the pulmonary parenchyma of each individual patient.

The LAM Foundation

Vanderbilt University Medical Center

Principal Investigator

Pleural Effusion

Ascites

Chylothorax

Pleural Diseases

Respiratory Tract Diseases

Gastrointestinal Agents

Somatostatin

Octreotide

Antineoplastic Agents, Hormonal

Patients with lymphangioleiomyomatosis and lymphatic tumors, ascites or pleural effusions who are symptomatic will receive subcutaneous injections of octreotide starting at a dose of 100 micrograms per day. Doses will be gradually increased to a maximum of 800 micrograms per day, two months after enrollment, if there is no response to lower doses.

Treatment with octreotide starts at a dose of 50 micrograms(ug) twice a day which is increased to 100 ug twice a day after two weeks and to 200 ug twice a day two weeks later. After two months, if there is no response the dose shall be increased to 400 ug twice a day.

Lymphangioleiomyomatosis (LAM), a disease primarily of women of child-bearing age, is characterized by cystic lung disease and abdominal tumors (e.g., angiomyolipomas). Within the LAM patient population is a subset of patients who develop chylous effusions and lymphangioleiomyomas. Treatment of many of these symptoms has been ineffective. Previous studies with somatostatin and octreotide in other clinical settings have shown reduction in chylous effusions. This study assesses the effectiveness of octreotide in symptomatic patients with LAM, lymphangioleiomyomas and/or chylous effusions/ascites, peripheral lymphedema and chyluria.

Lymphangioleiomyomatosis (LAM), a disease primarily of women of child-bearing age, is characterized by cystic lung disease and abdominal tumors (e.g., angiomyolipomas). Within the LAM patient population is a subset of patients who develop chylous ascites, chylous pleural effusions, chyluria, peripheral lymphedema, and/or lymphangioleiomyomas. Lymphangioleiomyomas are believed to result from a proliferation of abnormal smooth muscle cells within the lymphatic system, which appears to obstruct fluid outflow, leading to fluid accumulation and an increase in size. The lymphangioleiomyomas may occur anywhere along the axial lymphatic chain. In patients with LAM, they occur most frequently in the thorax, abdomen and pelvis and may give rise to a myriad of symptoms (e.g., paresthesias, palpitations, peripheral edema). In some patients, treatment of many of these symptoms, i.e., elevation of lower extremities, paracentesis, thoracentesis, diuretics, and/or surgery, has been ineffective. Previous studies with somatostatin and octreotide in other clinical settings (e.g., traumatic damage to the lymphatics) have shown a successful reduction in chylous effusions, chyluria, ascites, and peripheral lymphedema, when other therapies were less effective. This study will assess the effectiveness of octreotide in symptomatic patients with LAM, lymphangioleiomyomas and/or chylous effusions/ascites, peripheral lymphedema and chyluria. The dose of octreotide starts at 50 micrograms (ug) by the subcutaneous route twice a day. After two weeks the dose will be increased to 200 ug per day and two weeks later to 400 ug/day. Maximal dose is 400 ug twice a day.

Treatment With Octreotide in Patients With Lymphangioleiomyomatosis

Octreotide treatment will be considered successful if the patient receiving treatment for six months shows a reduction in total tumor mass/ fluid collection or reaccumulation of at least 20%.

Octreotide treatment will be considered successful if the reported pain/symptom score is reduced by at least 2 levels at termination of treatment.

A simple visual numeric distress scale ranging from zero to 10 will be employed to rate the severity of individual symptoms. The best score is zero, which means absence of symptoms and the maximal is 10, meaning that the symptoms are very severe.

One or more abnormality of the following liver function tests:

1. Alkaline phosphatase above 116 i.u.
2. SGPT above 41 i.u.
3. SGOT from 34 i.u.
4. Total bilirubin above 1.0 mg/dl

National Heart, Lung, and Blood Institute (NHLBI)

Joel Moss, M.D./National Heart, Lung and Blood Institute

Patients with lymphangioleiomyomatosis and lymphatic tumors causing chylous effusions and abdominal pain

Age, Categorical

Age Continuous

Sex: Female, Male

United States

Region of Enrollment

Joel Moss

Number of Participants With a Reduction in Total Tumor Volume of at Least 20%.

Four patients with lymphangioleiomyomatosis and lymphangioleiomyomas and chylous effusions treated with octreotide injections by the subcutaneous route to determine whether the size of the tumors and effusions decrease with the therapy

Number of Participants With a Reduction of Pain/Symptoms as Measured by a Simple Numeric Symptom Distress Scale (NDS) to Rate the Severity of Individual Symptoms.

Number of Participants With Liver Function Abnormalities

Overall Study

Lipid Regulating Agents

Simvastatin

Anti-Bacterial Agents

Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

Anticholesteremic Agents

Hypolipidemic Agents

Antimetabolites

Hydroxymethylglutaryl-CoA Reductase Inhibitors

Eligible patients on sirolimus or everolimus will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4.

Eligible patients on sirolimus will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4.

Sirolimus Oral Product

Eligible patients on everolimus will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4.

Everolimus Oral Product

Vera P Krymskaya, PhD, MBA

Maryl Kreider, MD, MSCE

Frank McCormack, MD

The purpose of this research study is to see if simvastatin can be taken safely in patients with either LAM or TSC, who are already being treated with everolimus or sirolimus. This is the first step in looking at simvastatin as a drug that may help patients, by impacting the growth and survival of cells that make up the lung lesions that cause problems in LAM and TSC patients. The study also seeks to learn more about how simvastatin works, when given to patients being treated with everolimus or sirolimus, and to evaluate the safety and any potential benefit to patients taking this 2-drug combination.

The primary objective of this study is to determine the safety of simvastatin in the treatment of LAM-S or LAM-TS in patients on a stable (for at least 3 months) dose of sirolimus or everolimus.

Secondary objectives include:

* To assess the effect of simvastatin on forced expiratory volume in 1 second (FEV1).
* To assess the effect of simvastatin on forced vital capacity (FVC).
* To assess the effect of simvastatin on diffusing lung capacity (DLCO).
* To assess the effect of simvastatin on vascular endothelial growth factor -D (VEGF-D) serum levels.
* To assess the effect of simvastatin with questionnaire- based assessments of dyspnea, fatigue, and quality of life (QOL).
* Assess signs of clinical benefit.

After providing written informed consent, study related tests/procedures will be done to ensure eligibility for the study. If found to be eligible, the participant will be given simvastatin at a starting dose of 20 mg, to be taken each evening by mouth. If after 2 months the simvastatin 20 mg dose is tolerated, the dose of simvastatin will be increased to 40 mg each evening by mouth. Doses may be adjusted as needed, should the participant experience side effects from simvastatin. The participant's dose of everolimus or sirolimus is not expected to change, as this is a dose that has been previously tolerated. If side effects occur as a result of the combination of drugs, the dosages may be adjusted by the study physician (investigator).

Safety of Simvastatin in LAM and TSC

The Safety of Simvastatin (SOS) in Patients With Pulmonary Lymphangioleiomyomatosis (LAM) and With Tuberous Sclerosis Complex (TSC)

Safety is a primary outcome measure which will be assessed by any major changes or deterioration in patient health.

Lung function will be measured by FEV1: forced expiratory volume in 1s mean and calculated as % predicted +_ SD (standard deviation).

University of Pennsylvania

Simvastatin 20 mg oral daily for 2 months; if tolerated, followed by simvastatin 40 mg oral daily for 2 months

Simvastatin: Eligible patients will be assigned to receive 20 mg of simvastatin once daily for a period of two months. If tolerated, the dosage of simvastatin will be advanced to 40 mg once daily in months 3 and 4.

Single Simvastatin Treatment Arm

Race (NIH/OMB)

The baseline measure was lung function accessed as the forced expiratory volumes (unit ml) in 1 second (FEV1) response and was calculated as the rate of change in FEV1, which was calculated as percentage of predicted.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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
Glutamine PET Imaging in LAM	NCT04388371	Lymphangioleiom...	Glutamine	18 Years -	Vanderbilt University Medical Center
Treatment With Octreotide in Patients With Lymphangioleiomyomatosis	NCT00005906	Lymphangioleiom... Lymphangiomyoma... Pleural Effusio... Ascites	Octreotide	18 Years - 65 Years	National Institutes of Health Clinical Center (CC)
Safety of Simvastatin in LAM and TSC	NCT02061397	Lymphangioleiom... Tuberous Sclero...	Simvastatin Sirolimus Oral ... Everolimus Oral...	18 Years -	University of Pennsylvania
Treatment With Octreotide in Patients With Lymphangioleiomyomatosis	NCT00005906	Lymphangioleiom... Lymphangiomyoma... Pleural Effusio... Ascites	Octreotide	18 Years - 65 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for lymphangioleiomyomatosis (lam)