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

This study has been terminated.
(Poor patients' accrual)
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01365468
First received: May 27, 2011
Last updated: May 10, 2016
Last verified: May 2016
  Purpose

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.

Condition Intervention Phase
Plexiform Neurofibroma Associated With Neurofibromatosis Type 1
Drug: Everolimus (RAD001)
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of RAD001 in the Treatment of Patients With Plexiform Neurofibromas (PN) Associated With Neurofibromatosis Type 1 (NF1)

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Time to Disease Progression (TTP) Based on Change in Volumetric MRI Measurements in Children and Adults (In Stratum I Only) [ Time Frame: Screening, after course #6, #12, #18, #24, End of Treatment(1 course=28days) ] [ Designated as safety issue: No ]
    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) [ Time Frame: Screening, after course #6, then every 6 months and end of treatment(1 course=28days) ] [ Designated as safety issue: Yes ]

    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 [ Time Frame: From the time ICF was signed until 28 days after End of Treatment (up to a maximum of 25 months) ] [ Designated as safety issue: Yes ]
    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 Outcome Measures:
  • Number of Patients With Clinical Response [ Time Frame: Screening, Day 1, after course #3, #6, #12, #18, #24, End of Treatment (1 course = 28 days) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Screening, after course #3, #6, #12, #18, #24, End of Treatment (1 course = 28 days) ] [ Designated as safety issue: No ]
    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.


Enrollment: 9
Study Start Date: April 2012
Study Completion Date: April 2015
Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Everolimus (RAD001)
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.
Drug: Everolimus (RAD001)
oral daily dosing of tablet starting with 2.5 mg

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.

  Eligibility

Ages Eligible for Study:   6 Years and older   (Child, Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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/exclusion criteria may apply

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01365468

Locations
Israel
Novartis Investigative Site
Tel-Aviv, Israel, 6423906
Novartis Investigative Site
Tel-Hashomer, Israel, 52621
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01365468     History of Changes
Other Study ID Numbers: CRAD001MIL04T 
Study First Received: May 27, 2011
Results First Received: March 15, 2016
Last Updated: May 10, 2016
Health Authority: Israel: Ministry of Health

Keywords provided by Novartis:
RAD001,
Everolimus,
Plexiform Neurofibroma,
Neurofibromatosis Type 1

Additional relevant MeSH terms:
Neurofibromatoses
Neurofibroma
Neurofibromatosis 1
Nerve Sheath Neoplasms
Neurofibroma, Plexiform
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Peripheral Nervous System Diseases
Neuromuscular Diseases
Everolimus
Sirolimus
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents

ClinicalTrials.gov processed this record on December 07, 2016