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Phase II Study of Everolimus (RAD001) in Children and Adults With Neurofibromatosis Type 2

Phase 2
3 Years
Open (Enrolling)
Neurofibromatosis Type II

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Trial Information

Phase II Study of Everolimus (RAD001) in Children and Adults With Neurofibromatosis Type 2

Everolimus (RAD001) has been in clinical development since 1996 as an immunosuppressant in
solid organ transplantation and has obtained marketing authorization (Certican®) for
prophylaxis of rejection in renal and cardiac transplantation in a number of countries,
including the majority of the European Union. Everolimus has been in development for
patients with various malignancies since 2002. Everolimus 2.5mg, 5mg and 10mg tablets were
approved under the trade name Afinitor® for patients with advanced renal cell carcinoma
(RCC) after failure of treatment with Sutent® (sunitinib) or Nexavar® (sorafenib) in the US,
EU and several other countries and is undergoing registration in other regions worldwide.
Afinitor® was also recently approved for the treatment of patients with subependymal giant
cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) who require therapeutic
intervention but are not candidates for curative surgical resection. Everolimus is being
investigated as an anticancer agent based on its potential to act: 1. Directly on the tumor
cells by inhibiting tumor cell growth and proliferation; and 2. Indirectly by inhibiting
angiogenesis leading to reduced tumor vascularity.

For pediatric cancer patients, safety of RAD001 has been established in a phase 1 trial and
the recommended phase II dose is 5 mg/m2 once daily. This existing pediatric data allows for
inclusion of children in this phase 2 trial, which is an important consideration since some
NF2 patients with the most aggressive clinical course present at school age.

RAD001 was recently approved by the Food and Drug Administration (FDA) for the treatment of
children and adults with subependymal giant cell astrocytoma (SEGA), a benign brain tumor
associated with tuberous sclerosis (TS). Although surgical resection is effective at tumor
reduction, serious complications may follow a radical resection, such as permanent deafness
and facial nerve damage. Most importantly, the tumors often recur after surgery. Radiation
therapy (RT) has been proposed as an alternative. However, its safety and efficacy in the
NF2 population has not been established. A medical therapy option is desperately needed.
This study is a single-center, 2-stage, phase II open-label study. All subjects will get
RAD001 taken continuously until disease progression or unacceptable toxicity. The primary
objective of this study is to look at the objective response rate to RAD001 in patients with
NF2-related tumors including cranial nerve schwannomas, meningiomas and ependymomas.
Participation will consist of screening/baseline visit(s), Day 1, Weeks 1, 2, and 4; and up
to 12 cycles and will include standard of care procedures such as medical history, vital
signs, physical examinations, ECGs, MRIs, audiograms, and laboratory tests. Novartis will
provide the RAD001 free of charge to eligible study subjects. The primary efficacy response
for study purposes will be a greater than or equal to 15% reduction in tumor volume in any
of the target tumors (partial response). Complete disappearance of any of the target tumors
will constitute a complete response (CR).

Inclusion Criteria:

- Age ≥ 3 years and body surface area ≥ 0.5 m2

- Meets diagnostic criteria for NF2

- At least one volumetrically measurable and ≥ 0.5 cc NF2-related brain or spinal tumor
(schwannoma, ependymoma, meningioma - histological confirmation not required) with
radiographic evidence of progression (either as unequivocal progression on
conventional MRI, or a >10% volume increase by 3D volumetrics) over the past ≤12
months, designated as the primary target tumor OR Volumetrically measurable and ≥ 0.5
cc VS with ipsilateral progressive hearing loss over the past ≤12 months, designated
as the primary target tumor

- Progressive Hearing Loss Criteria for Enrollment: Audiogram showing drop in pure tone
average (PTA) of 10dB HL at ≥ 2 nonconsecutive or consecutive frequencies or drop in
speech discrimination score (SDS) below the 95% critical difference threshold,
compared to previous audiogram ≤ 1 year prior.

- Karnofsky/Lansky performance status (PS) 50-100%. Note: Patients who are unable to
walk because of paralysis, but who are up in a wheelchair, will be considered
ambulatory for the purpose of assessing the performance score.

- Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x
109/L, Hb > 9 g/dL

- Adequate liver function as shown by:

1. serum bilirubin ≤ 1.5 x ULN

2. ALT and AST ≤ 2.5x ULN

- INR ≤ 1.5. (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of
warfarin or on a stable dose of LMW heparin for >2 weeks at time of enrollment.)

- Adequate renal function: serum creatinine ≤ 1.5 x ULN

- Fasting serum cholesterol ≤300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5
x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can
only be included after initiation of appropriate lipid lowering medication.

- Fully recovered from acute toxic effects of any prior chemotherapy, biological
modifiers or radiotherapy

- Any neurologic deficits must be stable for ≥ 1 week

- Able to provide signed informed consent (or consent by parent/legal guardian for

Exclusion Criteria:

- Patients currently receiving medical anticancer therapies or who have received
medical anticancer therapies within 4 weeks of the start of study drug (including
chemotherapy, antibody based therapy, etc.)

- Radiation therapy to a study target tumor within 1 year prior to enrollment, or any
radiation therapy within 4 weeks prior to enrollment.

- Patients who have had a major surgery or significant traumatic injury within 4 weeks
of start of study drug, patients who have not recovered from the side effects of any
major surgery (defined as requiring general anesthesia) or patients that may require
major surgery during the course of the study

- Prior treatment with any investigational drug within the preceding 4 weeks

- Patients receiving chronic, systemic treatment with corticosteroids or another
immunosuppressive agent. Topical or inhaled corticosteroids are allowed.

- Patients should not receive immunization with attenuated live vaccines within one
week of study entry or during study period. Close contact with those who have
received attenuated live vaccines should be avoided during treatment with everolimus.
Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral
polio, BCG, yellow fever, varicella and TY21a typhoid vaccines.

- Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases

- Other malignancies within the past 3 years except for adequately treated carcinoma of
the cervix or basal or squamous cell carcinomas of the skin.

- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as:

1. Symptomatic congestive heart failure of New York heart Association Class III or

2. unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction within 6 months of start of study drug, serious uncontrolled cardiac
arrhythmia or any other clinically significant cardiac disease

3. severely impaired lung function as defined as spirometry and DLCO that is 50% of
the normal predicted value and/or 02 saturation that is 88% or less at rest on
room air

4. uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN (Note:
Optimal glycemic control should be achieved before starting trial therapy.)

5. active (acute or chronic) or uncontrolled severe infections

6. liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class

Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done
at screening for all patients. HBV DNA and HCV RNA PCR testing are required at screening
for all patients with a positive medical history based on risk factors and/or confirmation
of prior HBV/HCV infection.

- A known history of HIV seropositivity

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of everolimus (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel

- Patients with an active, bleeding diathesis

- Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods. Adequate contraception
must be used throughout the trial and for 8 weeks after the last dose of study drug,
by both sexes. (Females of childbearing potential must have a negative urine or serum
pregnancy test within 7 days prior to administration of everolimus)

- Male patient whose sexual partner(s) are WOCBP who are not willing to use adequate
contraception, during the study and for 8 weeks after the end of treatment

- Patients who have received prior treatment with an mTOR inhibitor (e.g., sirolimus,
temsirolimus, everolimus).

- Patients with a known hypersensitivity to everolimus or other rapamycins (e.g.,
sirolimus, temsirolimus) or to its excipients

- History of noncompliance to medical regimens

- Patients unwilling to or unable to comply with the protocol

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Radiographic Response

Outcome Description:

To estimate the objective response rates to RAD001 in patients with NF2-related tumors including cranial nerve schwannomas, meningiomas and ependymomas. Radiographic response for study purposes = greater than or equal to 15% reduction in tumor volume in any of the target tumors (partial response). Complete disappearance of any of the target tumors = complete response. MRI of the brain and spine will be performed every 3 months. If an objective response (15% reduction in tumor volume compared to baseline) is observed in any target tumor or stable disease, drug will be continued.

Outcome Time Frame:

Any point within 12 months from beginning of therapy

Safety Issue:


Principal Investigator

Matthias A Karajannis, MD, MS

Investigator Role:

Principal Investigator

Investigator Affiliation:

New York University


United States: Institutional Review Board

Study ID:

RAD001 NF2 (11-00587)



Start Date:

October 2011

Completion Date:

October 2013

Related Keywords:

  • Neurofibromatosis Type II
  • Neurofibromatosis Type II
  • cranial nerve schwannomas
  • meningiomas
  • ependymomas
  • Neurofibromatoses
  • Neurofibromatosis 1
  • Osteitis Fibrosa Cystica
  • Neurofibromatosis 2



New York University Medical Center New York, New York  10016