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Poor patients' accrual
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This study was to evaluate the antitumor activity and safety of RAD001 in patients with Plexiform neurofibromas (PN) associated with Neurofibromatosis Type 1 (NF1).
The aim of the study was to :
determine whether RAD001, administrated orally daily on a continuous dosing schedule might:
To evaluate the tolerability and toxicity of chronic RAD001 administration in this patient population as assessed by the NCI Common Toxicity Criteria, version 4.0.
Approximately 20 patients were to be enrolled to receive everolimus in an open label manner. A total of 9 patients were enrolled to either Stratum 1 or Stratum 2.
The study was open for enrollment up to 2 years. Because the target enrollment was not achieved in this period, study was terminated with less patient than planned.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Everolimus (RAD001) | Experimental | enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Everolimus (RAD001) | Drug | oral daily dosing of tablet starting with 2.5 mg |
|
| Measure | Description | Time Frame |
|---|---|---|
| Time to Disease Progression (TTP) Based on Change in Volumetric MRI Measurements in Children and Adults (In Stratum I Only) | This endpoint was planned to be analyzed for only Stratum 1 patients. Progression of disease defined as a ≥ 20% increase in the volume (by volumetric MRI) of at least one of the index plexiform neurofibromas (PN) compared to the pretreatment volume measured prior to the start of the current treatment phase. | Screening, after course #6, #12, #18, #24, End of Treatment(1 course=28days) |
| Number of Patients With Objective Radiographic Responses Based on Volumetric MRI Measurements (In Stratum 2 Only) | Response was assessed at the time that a follow up volumetric MRI scan is performed (after course 6 and then every 6 months and at the end of treatment).
| Screening, after course #6, then every 6 months and end of treatment(1 course=28days) |
| Number of Patients With Adverse Events Assessed by Common Toxicity Criteria for Adverse Events (CTCAE) V.04 | Adverse events were assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0. If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, and life-threatening, corresponding to grades 1 - 4 respectively, were used. CTCAE grade 5 (death) was not used in this study. | From the time ICF was signed until 28 days after End of Treatment (up to a maximum of 25 months) |
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| Measure | Description | Time Frame |
|---|---|---|
| Number of Patients With Clinical Response | Clinical response is defined as improvement of function, performance status, or decrease in PN related pain persisting for at least 28 days on treatment. | Screening, Day 1, after course #3, #6, #12, #18, #24, End of Treatment (1 course = 28 days) |
| Physician's Global Assessment of Clinical Condition (PGA) of Skin Lesions |
Inclusion Criteria:
Exclusion Criteria:
Other protocol-defined inclusion/exclusion criteria may apply
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| Name | Affiliation | Role |
|---|---|---|
| Novartis Pharmaceuticals | Novartis Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Novartis Investigative Site | Tel Aviv | 6423906 | Israel | |||
| Novartis Investigative Site |
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| ID | Title | Description |
|---|---|---|
| FG000 | Stratum 1 | Adults and children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) with the potential to cause significant morbidity with documented progressive PN prior to study entry wereenrolled in this stratum. Enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. |
| FG001 | Stratum 2 | Adults and children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) with the potential to cause significant morbidity that do not have documented progression of the PN at the time of study entry were enrolled in this stratum. Enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Stratum 1 | Adults and children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) with the potential to cause significant morbidity with documented progressive PN prior to study entry wereenrolled in this stratum. Enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Time to Disease Progression (TTP) Based on Change in Volumetric MRI Measurements in Children and Adults (In Stratum I Only) | This endpoint was planned to be analyzed for only Stratum 1 patients. Progression of disease defined as a ≥ 20% increase in the volume (by volumetric MRI) of at least one of the index plexiform neurofibromas (PN) compared to the pretreatment volume measured prior to the start of the current treatment phase. | The Full Analysis Set (FAS) consisted of all enrolled patients. | Posted | Median | 95% Confidence Interval | Days | Screening, after course #6, #12, #18, #24, End of Treatment(1 course=28days) |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Stratum 1 | Adults and children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) with the potential to cause significant morbidity with documented progressive PN prior to study entry wereenrolled in this stratum. Enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypersensitivity | Immune system disorders | MedDRA | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Ear pain | Ear and labyrinth disorders | MedDRA | Systematic Assessment |
Study got terminated because of poor patient's accrual.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Novartis Pharmaceuticals | 862-778-8300 | trialandresults.registries@novartis.com |
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| ID | Term |
|---|---|
| D018318 | Neurofibroma, Plexiform |
| D009456 | Neurofibromatosis 1 |
| ID | Term |
|---|---|
| D009455 | Neurofibroma |
| D018317 | Nerve Sheath Neoplasms |
| D009380 | Neoplasms, Nerve Tissue |
| D009370 | Neoplasms by Histologic Type |
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| ID | Term |
|---|---|
| D000068338 | Everolimus |
| ID | Term |
|---|---|
| D020123 | Sirolimus |
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
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The Physician"s Global Assessment of Clinical Condition (PGA) is a 7-point grading scale for the investigator's assessment of the overall extent of improvement or worsening of the patient"s skin disease as compared to baseline. Responses must be confirmed by at least two assessments separated in time by at least 4 weeks. The grading ranges from 0 to 6; 0 is Completely clear where as 6 is for worse condition. 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. |
| Screening, after course #3, #6, #12, #18, #24, End of Treatment (1 course = 28 days) |
| Tel Litwinsky |
| 52621 |
| Israel |
| Lost to Follow-up |
|
| BG001 | Stratum 2 | Adults and children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) with the potential to cause significant morbidity that do not have documented progression of the PN at the time of study entry were enrolled in this stratum. Enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. |
| BG002 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
|
|
| Primary | Number of Patients With Objective Radiographic Responses Based on Volumetric MRI Measurements (In Stratum 2 Only) | Response was assessed at the time that a follow up volumetric MRI scan is performed (after course 6 and then every 6 months and at the end of treatment).
| The Full Analysis Set (FAS) consisted of all enrolled patients. | Posted | Number | Patients | Screening, after course #6, then every 6 months and end of treatment(1 course=28days) |
|
|
|
| Primary | Number of Patients With Adverse Events Assessed by Common Toxicity Criteria for Adverse Events (CTCAE) V.04 | Adverse events were assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0. If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, and life-threatening, corresponding to grades 1 - 4 respectively, were used. CTCAE grade 5 (death) was not used in this study. | The Safety Population consisted of all patients who received at least one dose of study treatment and had at least one post-baseline safety assessment. | Posted | Number | Patients | From the time ICF was signed until 28 days after End of Treatment (up to a maximum of 25 months) |
|
|
|
| Other Pre-specified | Number of Patients With Clinical Response | Clinical response is defined as improvement of function, performance status, or decrease in PN related pain persisting for at least 28 days on treatment. | Study got terminated because of poor patient's accrual. Enrolled patients were less than planned number of patients required for analysis. Hence, planned analysis was not done. | Posted | Screening, Day 1, after course #3, #6, #12, #18, #24, End of Treatment (1 course = 28 days) |
|
|
| Other Pre-specified | Physician's Global Assessment of Clinical Condition (PGA) of Skin Lesions | The Physician"s Global Assessment of Clinical Condition (PGA) is a 7-point grading scale for the investigator's assessment of the overall extent of improvement or worsening of the patient"s skin disease as compared to baseline. Responses must be confirmed by at least two assessments separated in time by at least 4 weeks. The grading ranges from 0 to 6; 0 is Completely clear where as 6 is for worse condition. 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. | Study got terminated because of poor patient's accrual. Enrolled patients were less than planned number of patients required for analysis. Hence, planned analysis was not done. | Posted | Screening, after course #3, #6, #12, #18, #24, End of Treatment (1 course = 28 days) |
|
|
| 1 |
| 4 |
| 4 |
| 4 |
| EG001 | Stratum 2 | Adults and children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) with the potential to cause significant morbidity that do not have documented progression of the PN at the time of study entry were enrolled in this stratum. Enrolled patients received everolimus (RAD001) in an open label manner. Recommended starting dose of everolimus depend on body surface area, starting from 2.5 mg once daily to 7.5 mg once daily. | 0 | 5 | 5 | 5 |
| External ear inflammation | Ear and labyrinth disorders | MedDRA | Systematic Assessment |
|
| Ocular hyperaemia | Eye disorders | MedDRA | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Flatulence | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Mouth ulceration | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Toothache | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Asthenia | General disorders | MedDRA | Systematic Assessment |
|
| Chest pain | General disorders | MedDRA | Systematic Assessment |
|
| Discomfort | General disorders | MedDRA | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA | Systematic Assessment |
|
| Influenza like illness | General disorders | MedDRA | Systematic Assessment |
|
| Mucosal inflammation | General disorders | MedDRA | Systematic Assessment |
|
| Oedema peripheral | General disorders | MedDRA | Systematic Assessment |
|
| Pain | General disorders | MedDRA | Systematic Assessment |
|
| Peripheral swelling | General disorders | MedDRA | Systematic Assessment |
|
| Eye infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA | Systematic Assessment |
|
| Skin infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Tendonitis | Injury, poisoning and procedural complications | MedDRA | Systematic Assessment |
|
| Blood cholesterol increased | Investigations | MedDRA | Systematic Assessment |
|
| Blood creatine phosphokinase increased | Investigations | MedDRA | Systematic Assessment |
|
| Blood triglycerides increased | Investigations | MedDRA | Systematic Assessment |
|
| Drug level increased | Investigations | MedDRA | Systematic Assessment |
|
| Eosinophil count increased | Investigations | MedDRA | Systematic Assessment |
|
| Low density lipoprotein increased | Investigations | MedDRA | Systematic Assessment |
|
| Lymphocyte count decreased | Investigations | MedDRA | Systematic Assessment |
|
| Platelet count decreased | Investigations | MedDRA | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Hypertriglyceridaemia | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Fibroma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Paraesthesia | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Anxiety | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Sleep disorder | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Tic | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Breast mass | Reproductive system and breast disorders | MedDRA | Systematic Assessment |
|
| Metrorrhagia | Reproductive system and breast disorders | MedDRA | Systematic Assessment |
|
| Vaginal haemorrhage | Reproductive system and breast disorders | MedDRA | Systematic Assessment |
|
| Dysphonia | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Pharyngeal erythema | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Alopecia | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Dermatitis acneiform | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
| Cytoreductive surgery | Surgical and medical procedures | MedDRA | Systematic Assessment |
|
| Tooth extraction | Surgical and medical procedures | MedDRA | Systematic Assessment |
|
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
| D009369 | Neoplasms |
| D010524 | Peripheral Nervous System Neoplasms |
| D009423 | Nervous System Neoplasms |
| D009422 | Nervous System Diseases |
| D010523 | Peripheral Nervous System Diseases |
| D009468 | Neuromuscular Diseases |
| D017253 | Neurofibromatoses |
| D009386 | Neoplastic Syndromes, Hereditary |
| D020752 | Neurocutaneous Syndromes |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| Title | Measurements |
|---|---|
|
| At least one Grade 3 AE |
|
| At least one Grade 4 AE |
|