Know Cancer

forgot password

A Single Arm, Multicenter Phase II a Trial of RAD001 as Monotherapy in the Treatment of Neurofibromatosis 1 Related Internal Plexiform Neurofibromas That Cannot be Removed by Surgery

Phase 2
18 Years
60 Years
Open (Enrolling)
Neurofibromatosis Type 1, Plexiform Neurofibroma, Neurofibromatoses

Thank you

Trial Information

A Single Arm, Multicenter Phase II a Trial of RAD001 as Monotherapy in the Treatment of Neurofibromatosis 1 Related Internal Plexiform Neurofibromas That Cannot be Removed by Surgery

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.

Inclusion Criteria:

- Clinical diagnosis of NF1, according to NIH criteria, with internal plexiform
neurofibroma (PN) and at least 1 of criteria for NF1:

6 or more café-au-lait spots Freckling in the axilla or groin Optic glioma 2 or more
Lisch nodules Distinctive bony lesion

1-degree relative with NF1

- At least 1 inoperable PN(s) that has/have the potential to cause significant
morbidity: Paravertebral lesions that could compromise the spinal cord Head and neck
lesions that could compromise the airway or great vessels Brachial or lumbar plexus
lesions that could cause nerve compression and loss of function Lesions that could
result in major deformity (e.g., orbital lesions) or significant cosmetic problems
Lesions of the extremity that cause limb hypertrophy or loss of function Painful

- Complete resection of a PN with acceptable morbidity is not feasible OR patient
refuses surgery OR the number of PNs leads to not feasible surgery according to the
steering committee's site

- Measurable PN amenable to volumetric MRI analysis using fusion of images

- Measurable lesion (at least 3 cm in one dimension)

- Karnofsky >70%

- 18≤ Age ≤60

- absolute neutrophil count (ANC) ≥1.5x109/L, Platelets ≥100x109/L, Hb >9g/dL

- bilirubin: ≤1.5xULN, ALT and AST ≤2.5xULN unless evident Gilbert disease (amendment
n°2). For patients with known liver metastases: AST and ALT ≤ 5xULN

- Creatinine ≤ 1.5xULN

- Life expectancy ≥ 2 years

- Cholesterol ≤300 mg/dL or ≤7.75 mmol/L and triglycerides ≤ 2.5x ULN

- Women of childbearing potential must have had a negative serum pregnancy test within
7 days and a negative urine pregnancy test within 72 hours prior to the
administration of RAD001 start and must use an effective birth control method.

- Men should use condoms and their partner(s) use an effective birth control method

- A written informed consent obtained

Exclusion Criteria:

Patients who/with:

- have previously received mTOR inhibitors

- a known hypersensitivity to RAD001 or other rapamycin or to its excipients

- receiving chronic systemic treatment with corticosteroids or another
immunosuppressive agent. (Dose equivalent to 10 mg/day of methylprednisone), topical
steroids or organotherapy for bilateral adrenalectomy are acceptable

- a known history of HIV seropositivity

- acute viral hepatitis

- autoimmune hepatitis

- with an active, bleeding diathesis. Patients may use coumadin or heparin preparations

- have any severe and/or uncontrolled medical conditions or other conditions that could
affect their participation

- have a history of another primary malignancy ≤3 years, with the exception of
non-melanoma skin cancer and carcinoma in situ of the uterine cervix

- Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods. If barrier
contraceptives are being used, these must be continued throughout the trial by both
sexes. Oral contraceptives are not acceptable alone

- a contraindication to MRI

- are using other investigational agents or who had received investigational drugs ≤ 4
weeks prior to study treatment start

- unwilling or unable to comply with the protocol

- not affiliated to health system

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Radiographic response assessed by MRI analysis

Outcome Time Frame:

after 1 year of treatment

Safety Issue:


Principal Investigator

Pierre Wolkenstein, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Assistance Publique - Hôpitaux de Paris


France: Ministry of Health

Study ID:




Start Date:

April 2011

Completion Date:

January 2015

Related Keywords:

  • Neurofibromatosis Type 1
  • Plexiform Neurofibroma
  • Neurofibromatoses
  • Neurofibromatosis type 1
  • Everolimus
  • Plexiform neurofibromas
  • Rapamycin
  • Neurofibroma
  • Neurofibromatoses
  • Neurofibromatosis 1
  • Osteitis Fibrosa Cystica
  • Neurofibroma, Plexiform