Plexiform Neurofibroma Associated With Neurofibromatosis Type 1
Conditions
Keywords
RAD001,, Everolimus,, Plexiform Neurofibroma,, Neurofibromatosis Type 1
Brief summary
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 : 1. determine whether RAD001, administrated orally daily on a continuous dosing schedule might: 1. Increases time to disease progression (TTP) based on volumetric MRI measurements in children and adults with NF1 in inoperable documented progressive PN (stratum 1). 2. Results in objective radiographic responses based on volumetric MRI measurements in children and adults with NF1 and inoperable PN in the absence of documented radiographic progression at the trail entry (stratum 2. 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.
Detailed description
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.
Interventions
DRUGEverolimus (RAD001)
oral daily dosing of tablet starting with 2.5 mg
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Clinically definite diagnosis of NF1 according to the NIH consensus conference criteria. 2. Patients must have PN that have the potential to cause significant morbidity, such as lesions that could compromise the airway or the great vessels, lesions that could cause nerve compression, lesions that could result in major deformity or significant cosmetic problems 3. Measurable disease: patient must have at least one measurable PN amenable to volumetric MRI analysis.
Exclusion criteria
1. Chronic treatment with systemic steroids or another immunosuppressive agent. 2. Evidence of an active optic glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancer requiring treatment with chemotherapy or radiation therapy. 3. Clinical evidence of significantly impaired lung function 4. Pregnancy or breast feeding. 5. Prior therapy with mTOR inhibitors (e.g.sirolimus, temsirolimus, everolimus). 6. No contraindications for MRI assessments Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Disease Progression (TTP) Based on Change in Volumetric MRI Measurements in Children and Adults (In Stratum I Only) | Screening, after course #6, #12, #18, #24, End of Treatment(1 course=28days) | 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. |
| Number of Patients With Objective Radiographic Responses Based on Volumetric MRI Measurements (In Stratum 2 Only) | Screening, after course #6, then every 6 months and end of treatment(1 course=28days) | 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. |
| Number of Patients With Adverse Events Assessed by Common Toxicity Criteria for Adverse Events (CTCAE) V.04 | From the time ICF was signed until 28 days after End of Treatment (up to a maximum of 25 months) | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Clinical Response | Screening, Day 1, after course #3, #6, #12, #18, #24, End of Treatment (1 course = 28 days) | Clinical response is defined as improvement of function, performance status, or decrease in PN related pain persisting for at least 28 days on treatment. |
| Physician's Global Assessment of Clinical Condition (PGA) of Skin Lesions | Screening, after course #3, #6, #12, #18, #24, End of Treatment (1 course = 28 days) | The Physicians 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 patients 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. |
Countries
Israel
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 4 |
| 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. | 5 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Disease progression | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
Baseline characteristics
| Characteristic | Stratum 1 | Stratum 2 | Total |
|---|---|---|---|
| Age, Continuous | 22.7 Years STANDARD_DEVIATION 14.3 | 16.9 Years STANDARD_DEVIATION 9.8 | 19.5 Years STANDARD_DEVIATION 11.6 |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 1 Participants | 4 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 5 / 5 |
| serious Total, serious adverse events | 1 / 4 | 0 / 5 |
Outcome results
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.
Time frame: From the time ICF was signed until 28 days after End of Treatment (up to a maximum of 25 months)
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stratum 1 | Number of Patients With Adverse Events Assessed by Common Toxicity Criteria for Adverse Events (CTCAE) V.04 | At least one Grade 1 AE | 4 Patients |
| Stratum 1 | Number of Patients With Adverse Events Assessed by Common Toxicity Criteria for Adverse Events (CTCAE) V.04 | At least one Grade 2 AE | 4 Patients |
| Stratum 1 | Number of Patients With Adverse Events Assessed by Common Toxicity Criteria for Adverse Events (CTCAE) V.04 | At least one Grade 3 AE | 1 Patients |
| Stratum 1 | Number of Patients With Adverse Events Assessed by Common Toxicity Criteria for Adverse Events (CTCAE) V.04 | At least one Grade 4 AE | 1 Patients |
| Stratum 2 | Number of Patients With Adverse Events Assessed by Common Toxicity Criteria for Adverse Events (CTCAE) V.04 | At least one Grade 4 AE | 0 Patients |
| Stratum 2 | Number of Patients With Adverse Events Assessed by Common Toxicity Criteria for Adverse Events (CTCAE) V.04 | At least one Grade 1 AE | 5 Patients |
| Stratum 2 | Number of Patients With Adverse Events Assessed by Common Toxicity Criteria for Adverse Events (CTCAE) V.04 | At least one Grade 3 AE | 0 Patients |
| Stratum 2 | Number of Patients With Adverse Events Assessed by Common Toxicity Criteria for Adverse Events (CTCAE) V.04 | At least one Grade 2 AE | 5 Patients |
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). * 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)
Population: The Full Analysis Set (FAS) consisted of all enrolled patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stratum 1 | Number of Patients With Objective Radiographic Responses Based on Volumetric MRI Measurements (In Stratum 2 Only) | Complete Response | 0 Patients |
| Stratum 1 | Number of Patients With Objective Radiographic Responses Based on Volumetric MRI Measurements (In Stratum 2 Only) | Partial Response | 0 Patients |
| Stratum 1 | Number of Patients With Objective Radiographic Responses Based on Volumetric MRI Measurements (In Stratum 2 Only) | Stable Disease | 5 Patients |
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.
Time frame: Screening, after course #6, #12, #18, #24, End of Treatment(1 course=28days)
Population: The Full Analysis Set (FAS) consisted of all enrolled patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum 1 | Time to Disease Progression (TTP) Based on Change in Volumetric MRI Measurements in Children and Adults (In Stratum I Only) | NA Days |
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.
Time frame: Screening, Day 1, after course #3, #6, #12, #18, #24, End of Treatment (1 course = 28 days)
Population: 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.
Other Pre-specified
Physician's Global Assessment of Clinical Condition (PGA) of Skin Lesions
The Physicians 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 patients 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)
Population: 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.