Phase II Study of Everolimus (RAD001) in Children and Adults With Neurofibromatosis Type 2
Condition: Neurofibromatosis Type II
MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurofibromatosis 2
Intervention: Everolimus (RAD001) , Afinitor®
Intervention description: Everolimus will be provided by Novartis. Everolimus is formulated as tablets for oral administration of 2.5 mg, 5 mg, 10 mg strength. Everolimus will be self-administered (by the patients themselves) or administered by the patient's parent or guardian (for minors). The investigator will instruct the patient to take the study drug exactly as specified in the protocol. Depending the age-based dosing schedule, everolimus should be administered orally once (or twice) daily, preferably in the morning (and evening), at the same time every day with our without food. Everolimus tablets should be swallowed whole with a glass of water. The tablets must not be chewed or crushed. In cases where tablets can not be swallowed, the tablets should be disintegrated in water just prior to being taken. Everolimus will be administered orally as per the age-based dosing schedule continuously from study day 1 until progression of disease or unacceptable toxicity.
Intervention MeSH terms: Everolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 3 Years
Healthy volunteers: No
Keywords: Neurofibromatosis Type II; cranial nerve schwannomas; meningiomas; ependymomas

Summary:

      This trial studies whether Everolimus is efficacious in treating neurofibromatosis 2.
    

Eligibility criteria:

        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
             minors)

        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
                  IV

               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
                  C).

        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
             resection)

          -  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