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

This is an interventional treatment trial for Neurofibromatosis Type II focused on measuring Neurofibromatosis Type II, cranial nerve schwannomas, meningiomas, ependymomas Read More

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