Use of RAD001 as Monotherapy in the Treatment of Neurofibromatosis 1 Related Internal Plexiform Neurofibromas
Condition: Neurofibromatosis Type 1; Plexiform Neurofibroma; Neurofibromatoses
MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurofibroma, Plexiform
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

      Patients with the genetic disorder neurofibromatosis Type 1 (NF1) are at increased risk of
      developing tumors of the central and peripheral nervous system. These include plexiform
      neurofibromas. The conventional treatment of these internal plexiform neurofibromas is
      surgery. This surgery can be possible on a single and limited tumor. On the other hand these
      tumors are often surgically intractable due to their multiplicity and their infiltrating
      characteristics Increased activity of mammalian target of rapamycin(mTOR) protein is seen in
      neurofibromas. mTOR inhibitor rapamycin , or its derivatives such as everolimus may slow or
      stop tumor growth in patients with NF1.

      Objectives:

      Primary objectives To determine whether everolimus has an effect on the volume of surgically
      intractable and life-threatening internal plexiform neurofibromas in patients with
      neurofibromatosis 1.

      Secondary objectives To determine whether everolimus has an effect on the number and the
      volume of cutaneous neurofibromas; to determine whether everolimus modify the signaling
      pathways in cutaneous neurofibromas.

      Eligibility:

      - Adults with neurofibromatosis type 1 with at least one internal plexiform neurofibroma,
      life-threatening or causing significant morbidity through compression of organs. This or
      these internal plexiform neurofibroma(s) should be intractable by surgery.

      Design:

      An open-label, single arm, non-randomized, single stage phase IIa study. Baseline phase:
      Baseline evaluations will be performed within 2 weeks, and up to a maximum of 4 weeks for
      specific exams, before the first dose of study drug.

      Treatment phase/duration of treatment: All patients will be treated with RAD001 10 mg p.o
      daily dose for one year except in case of unacceptable toxicity, death, or discontinuation
      from the study for any other reason.

      Follow-up phase: All patients will have two follow-up visits scheduled at 18 and 24 months
      after the first dose of the study drug to follow for adverse events (AEs) and serious adverse
      events (SAEs) that may have occurred after discontinuation from the study and for internal
      plexiform neurofibromas assessment.

      Radiological review: All Magnetic Resonance Imaging (MRIs) obtained at baseline, during the
      treatment period and the follow-up period will be reviewed by the Neuroradiologist of the
      study.
    

Detailed description: 
      Neurofibromatosis 1 (NF1) is an autosomal dominant disease affecting 1 in 3000 to 1 in 4000
      people. NF1 is characterized by multiple dermal neurofibromas, plexiform neurofibromas,
      malignant peripheral nerve sheath tumors (MPNST), and optic pathway gliomas, as well as by
      café-au-lait spots and abnormalities of the skeletal, cardiovascular and central nervous
      systems. The NF1 gene is located on chromosome 17q11.2, and its protein, neurofibromin,
      functions as a tumor suppressor.

      People with NF1 have a decrease in life expectancy of 15 years, with MPNST as a leading cause
      of death in young adults. A specific phenotype at risk of mortality has been identified,
      patients with subcutaneous neurofibromas. Individuals with subcutaneous neurofibromas are
      more than 3 times as likely to have internal plexiform neurofibromas as others. Individuals
      with internal plexiform neurofibromas are 18 times more likely to develop MPNST than patients
      without internal plexiform neurofibromas. Beside MPNST, internal plexiform neurofibromas can
      be life-threatening or cause of significant morbidity through compression of organs mainly
      spine or nerve roots.

      The conventional treatment of these internal plexiform neurofibromas is surgery. This surgery
      can be possible on a single and limited tumor. On the other hand these tumors are often
      surgically intractable due to their multiplicity and their infiltrating characteristics. In
      this context a medical treatment decreasing the size of these tumors would have its place
      with as short term aim to lower the consequence of compression and long-term aim to reduce
      the risk of malignant transformation.

      NF1 is a consequence of the loss-of-function mutations in the NF1 tumor suppressor gene. The
      NF1-encoded protein, neurofibromin, functions as a Ras-GTPase activating protein (RasGAP).
      Accordingly, deregulation of Ras is thought to contribute to NF1 development. The mTOR
      pathway is tightly regulated by neurofibromin. mTOR is constitutively activated in both
      NF1-deficient primary cells and human tumors in the absence of growth factors. This aberrant
      activation depends on Ras and PI3 kinase, and is mediated by the phosphorylation and
      inactivation of the TSC2-encoded protein tuberin by AKT. Importantly, tumor cell lines
      derived from NF1 patients, and a genetically engineered cell system that requires
      Nf1-deficiency for transformation, are highly sensitive to the mTOR inhibitor rapamycin.
      Furthermore, the activation of endogenous Ras leads to constitutive mTOR signaling in this
      disease state, and in normal cells Ras is differentially required for mTOR signaling in
      response to various growth factors. Thus, the NF1 tumor suppressor is an indispensable
      regulator of TSC2 and mTOR. Ras plays a critical role in the activation of mTOR in both
      normal and tumorigenic settings.

      mTOR inhibitor rapamycin potently suppresses the growth of aggressive NF1-associated
      malignancies in a genetically engineered murine model. In these tumors rapamycin does not
      function via mechanisms generally assumed to mediate tumor suppression, including inhibition
      of HIF-1 alpha and indirect suppression of AKT, but does suppress the mTOR target Cyclin D1.
      The mammalian target of rapamycin complex 1 inhibitor RAD001 (Everolimus) decreased growth
      19% to 60% after 4 days of treatment in NF1 MPNST cell lines.

      Finally, these data suggest that rapamycin, or its derivatives such as everolimus may
      represent a viable therapy for NF1. This proof of concept has been done in tuberous sclerosis
      where rapamycin was efficient to treat angiomyolipomas11.

      The management of neurofibromatoses in France is coordinated by Pr. Pierre WOLKENSTEIN
      through the French National Referral Centre for Neurofibromatoses and a network, NF-France.
      The cohort followed up by the centre and its network is constituted of about 3000 patients
      and among them between 80 and 100 have life-threatening internal plexiform neurofibromas.

      Therefore the investigators propose a trial to evaluate the efficacy of everolimus in
      surgically intractable and life-threatening internal neurofibromas in neurofibromatosis 1
      based on the data of the literature and on our cohort.
    

Intervention name(s): RAD001: Everolimus
Intervention type(s): Drug
Intervention description(s): 10 mg of RAD001 will be self-administered orally once daily continuously for one year or until unacceptable toxicity or discontinuation from the study from any other reason.
Intervention MeSH terms: Everolimus
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Neurofibromatosis type 1; Everolimus; Plexiform neurofibromas; Rapamycin