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Efficacy and Safety of RAD001 in Treating Plexiform Neurofibromas (PN) Associated With Neurofibromatosis (NF1)

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ClinicalTrials.gov Identifier: NCT01365468
Recruitment Status : Terminated (Poor patients' accrual)
First Posted : June 3, 2011
Results First Posted : May 12, 2016
Last Update Posted : May 12, 2016
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Plexiform Neurofibroma Associated With Neurofibromatosis Type 1
Intervention Drug: Everolimus (RAD001)
Enrollment 9

Recruitment Details  
Pre-assignment Details  
Arm/Group Title Stratum 1 Stratum 2
Hide Arm/Group Description 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. 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.
Period Title: Overall Study
Started 4 5
Completed 0 5
Not Completed 4 0
Reason Not Completed
Physician Decision             1             0
Disease progression             1             0
Lost to Follow-up             2             0
Arm/Group Title Stratum 1 Stratum 2 Total
Hide Arm/Group Description 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. 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. Total of all reporting groups
Overall Number of Baseline Participants 4 5 9
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 4 participants 5 participants 9 participants
22.7  (14.3) 16.9  (9.8) 19.5  (11.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 4 participants 5 participants 9 participants
Female
3
  75.0%
1
  20.0%
4
  44.4%
Male
1
  25.0%
4
  80.0%
5
  55.6%
1.Primary Outcome
Title Time to Disease Progression (TTP) Based on Change in Volumetric MRI Measurements in Children and Adults (In Stratum I Only)
Hide Description 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.
Time Frame Screening, after course #6, #12, #18, #24, End of Treatment(1 course=28days)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) consisted of all enrolled patients.
Arm/Group Title Stratum 1
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 4
Median (95% Confidence Interval)
Unit of Measure: Days
NA [1] 
(NA to NA)
[1]
Median was not achieved because only one progression event occurred.
2.Primary Outcome
Title Number of Patients With Objective Radiographic Responses Based on Volumetric MRI Measurements (In Stratum 2 Only)
Hide Description

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).

  • Complete response (CR): complete resolution of all measurable or palpable PN for ≥ 28days and no appearance of new lesions.
  • Partial response (PR): A ≥ 20% reduction in the sum of the volume of all index PN lesions for ≥ 28days.
  • Stable disease (SD): A ‹ 20% increase and ‹ 20% decrease in the sum of the volume of all index PN lesions for ≥ 28days.
Time Frame Screening, after course #6, then every 6 months and end of treatment(1 course=28days)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) consisted of all enrolled patients.
Arm/Group Title Stratum 2
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 5
Measure Type: Number
Unit of Measure: Patients
Complete Response 0
Partial Response 0
Stable Disease 5
3.Primary Outcome
Title Number of Patients With Adverse Events Assessed by Common Toxicity Criteria for Adverse Events (CTCAE) V.04
Hide Description 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.
Time Frame From the time ICF was signed until 28 days after End of Treatment (up to a maximum of 25 months)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Stratum 1 Stratum 2
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 4 5
Measure Type: Number
Unit of Measure: Patients
At least one Grade 1 AE 4 5
At least one Grade 2 AE 4 5
At least one Grade 3 AE 1 0
At least one Grade 4 AE 1 0
4.Other Pre-specified Outcome
Title Number of Patients With Clinical Response
Hide Description Clinical response is defined as improvement of function, performance status, or decrease in PN related pain persisting for at least 28 days on treatment.
Time Frame Screening, Day 1, after course #3, #6, #12, #18, #24, End of Treatment (1 course = 28 days)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Stratum 1 Stratum 2
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
5.Other Pre-specified Outcome
Title Physician’s Global Assessment of Clinical Condition (PGA) of Skin Lesions
Hide Description 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.
Time Frame Screening, after course #3, #6, #12, #18, #24, End of Treatment (1 course = 28 days)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Stratum 1 Stratum 2
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Stratum 1 Stratum 2
Hide Arm/Group Description 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. 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.
All-Cause Mortality
Stratum 1 Stratum 2
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Stratum 1 Stratum 2
Affected / at Risk (%) Affected / at Risk (%)
Total   1/4 (25.00%)   0/5 (0.00%) 
Immune system disorders     
Hypersensitivity  1  1/4 (25.00%)  0/5 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Stratum 1 Stratum 2
Affected / at Risk (%) Affected / at Risk (%)
Total   4/4 (100.00%)   5/5 (100.00%) 
Ear and labyrinth disorders     
Ear pain  1  2/4 (50.00%)  0/5 (0.00%) 
External ear inflammation  1  0/4 (0.00%)  1/5 (20.00%) 
Eye disorders     
Ocular hyperaemia  1  1/4 (25.00%)  0/5 (0.00%) 
Gastrointestinal disorders     
Abdominal pain  1  1/4 (25.00%)  2/5 (40.00%) 
Diarrhoea  1  2/4 (50.00%)  0/5 (0.00%) 
Dysphagia  1  2/4 (50.00%)  0/5 (0.00%) 
Flatulence  1  0/4 (0.00%)  1/5 (20.00%) 
Mouth ulceration  1  0/4 (0.00%)  1/5 (20.00%) 
Nausea  1  1/4 (25.00%)  0/5 (0.00%) 
Stomatitis  1  0/4 (0.00%)  1/5 (20.00%) 
Toothache  1  1/4 (25.00%)  1/5 (20.00%) 
Vomiting  1  1/4 (25.00%)  1/5 (20.00%) 
General disorders     
Asthenia  1  0/4 (0.00%)  1/5 (20.00%) 
Chest pain  1  1/4 (25.00%)  0/5 (0.00%) 
Discomfort  1  1/4 (25.00%)  0/5 (0.00%) 
Fatigue  1  2/4 (50.00%)  2/5 (40.00%) 
Influenza like illness  1  3/4 (75.00%)  1/5 (20.00%) 
Mucosal inflammation  1  2/4 (50.00%)  2/5 (40.00%) 
Oedema peripheral  1  1/4 (25.00%)  0/5 (0.00%) 
Pain  1  1/4 (25.00%)  1/5 (20.00%) 
Peripheral swelling  1  1/4 (25.00%)  0/5 (0.00%) 
Infections and infestations     
Eye infection  1  0/4 (0.00%)  1/5 (20.00%) 
Pneumonia  1  0/4 (0.00%)  1/5 (20.00%) 
Skin infection  1  0/4 (0.00%)  1/5 (20.00%) 
Injury, poisoning and procedural complications     
Tendonitis  1  1/4 (25.00%)  0/5 (0.00%) 
Investigations     
Blood cholesterol increased  1  1/4 (25.00%)  2/5 (40.00%) 
Blood creatine phosphokinase increased  1  0/4 (0.00%)  1/5 (20.00%) 
Blood triglycerides increased  1  1/4 (25.00%)  1/5 (20.00%) 
Drug level increased  1  1/4 (25.00%)  0/5 (0.00%) 
Eosinophil count increased  1  0/4 (0.00%)  1/5 (20.00%) 
Low density lipoprotein increased  1  1/4 (25.00%)  0/5 (0.00%) 
Lymphocyte count decreased  1  1/4 (25.00%)  0/5 (0.00%) 
Platelet count decreased  1  1/4 (25.00%)  1/5 (20.00%) 
Metabolism and nutrition disorders     
Decreased appetite  1  1/4 (25.00%)  1/5 (20.00%) 
Hypertriglyceridaemia  1  1/4 (25.00%)  1/5 (20.00%) 
Musculoskeletal and connective tissue disorders     
Musculoskeletal chest pain  1  1/4 (25.00%)  0/5 (0.00%) 
Pain in extremity  1  2/4 (50.00%)  0/5 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Fibroma  1  1/4 (25.00%)  0/5 (0.00%) 
Nervous system disorders     
Dizziness  1  1/4 (25.00%)  1/5 (20.00%) 
Headache  1  3/4 (75.00%)  4/5 (80.00%) 
Paraesthesia  1  1/4 (25.00%)  0/5 (0.00%) 
Psychiatric disorders     
Anxiety  1  0/4 (0.00%)  1/5 (20.00%) 
Insomnia  1  0/4 (0.00%)  1/5 (20.00%) 
Sleep disorder  1  0/4 (0.00%)  1/5 (20.00%) 
Tic  1  1/4 (25.00%)  0/5 (0.00%) 
Reproductive system and breast disorders     
Breast mass  1  1/4 (25.00%)  0/5 (0.00%) 
Metrorrhagia  1  1/4 (25.00%)  0/5 (0.00%) 
Vaginal haemorrhage  1  1/4 (25.00%)  0/5 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Dysphonia  1  0/4 (0.00%)  1/5 (20.00%) 
Dyspnoea  1  1/4 (25.00%)  0/5 (0.00%) 
Oropharyngeal pain  1  1/4 (25.00%)  2/5 (40.00%) 
Pharyngeal erythema  1  1/4 (25.00%)  0/5 (0.00%) 
Skin and subcutaneous tissue disorders     
Alopecia  1  0/4 (0.00%)  1/5 (20.00%) 
Dermatitis acneiform  1  0/4 (0.00%)  1/5 (20.00%) 
Rash  1  2/4 (50.00%)  0/5 (0.00%) 
Surgical and medical procedures     
Cytoreductive surgery  1  0/4 (0.00%)  1/5 (20.00%) 
Tooth extraction  1  0/4 (0.00%)  1/5 (20.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Study got terminated because of poor patient's accrual.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01365468     History of Changes
Other Study ID Numbers: CRAD001MIL04T
First Submitted: May 27, 2011
First Posted: June 3, 2011
Results First Submitted: March 15, 2016
Results First Posted: May 12, 2016
Last Update Posted: May 12, 2016