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

A Phase II Study of RAD001 in the Treatment of Patients With Plexiform Neurofibromas (PN) Associated With Neurofibromatosis Type 1 (NF1)

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.

Study Overview

• Status: Terminated
• Conditions: Plexiform Neurofibroma Associated With Neurofibromatosis Type 1
• Intervention / Treatment: Drug: Everolimus (RAD001)

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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2

Contacts and Locations

Study Locations

• Israel
  • Tel-Aviv, Israel, 6423906
    • Novartis Investigative Site
  • Tel-Hashomer, Israel, 52621
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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).; 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.	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)

Other Outcome Measures

Outcome Measure	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	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)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): April 1, 2015
• Study Completion (Actual): April 1, 2015

Study Registration Dates

• First Submitted: May 27, 2011
• First Submitted That Met QC Criteria: June 2, 2011
• First Posted (Estimate): June 3, 2011

Study Record Updates

• Last Update Posted (Estimate): May 12, 2016
• Last Update Submitted That Met QC Criteria: May 10, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: Neurofibromatosis Type 1; RAD001,; Everolimus,; Plexiform Neurofibroma,
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Genetic Diseases, Inborn; Neuromuscular Diseases; Neurodegenerative Diseases; Neoplasms, Nerve Tissue; Peripheral Nervous System Diseases; Nervous System Neoplasms; Heredodegenerative Disorders, Nervous System; Neoplastic Syndromes, Hereditary; Nerve Sheath Neoplasms; Neurocutaneous Syndromes; Peripheral Nervous System Neoplasms; Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurofibroma, Plexiform; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: CRAD001MIL04T