Everolimus in Treating Vestibular Schwannoma in Patients with Neurofibromatosis Type 2

Inclusion Criteria

• Diagnosis of NF2 by National Institutes of Health (NIH) criteria (1988) with evidence of either: * Bilateral vestibular schwannomas, or * First-degree family relative with NF2 and either unilateral vestibular schwannomas (VS) or any 2 of: meningioma, schwannoma, glioma, neurofibroma, or juvenile posterior subcapsular lens opacity
• Patients must have at least one unresected VS
• Evidence of disease progression defined by progressive VS growth during the previous 12 months (> 20% increase in volume, as clinically determined) in all patients; usually patients with disease progression proceed to microsurgical resection, however for those patients who are at increased risk for surgical complications (e.g., deafness, lower cranial nerve injury, facial weakness) or who refuse surgery, enrollment in the study may be the best clinical option
• In the judgment of the investigator, participation in the protocol offers acceptable risk/benefit ratio when considering current NF2 disease status, medical condition, and the potential benefits of and risks of surgery or irradiation
• World Health Organization (WHO) performance status =< 2
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
• Platelets >= 100 x 10^9/L
• Hemoglobin (Hb) > 9 g/dL
• Serum bilirubin =< 1.5 x upper limit of normal (ULN)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN (=< 5 x ULN in patients with liver metastases)
• International normalized ratio (INR) =< 1.5; (anticoagulation is allowed if target INR =< 1.5 on a stable dose of warfarin or on a stable dose of low molecular weight [LMW] heparin for > 2 weeks at time of randomization)
• Serum creatinine =< 1.5 x ULN
• Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND * NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication
• 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
• Signed informed consent
• Willingness and ability to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions

Exclusion Criteria

• Inability to tolerate periodic magnetic resonance imaging (MRI) scans or gadolinium contrast
• Inability to tolerate periodic audiologic testing or to understand a language with established scoring for word recognition testing
• Inability to adequately perform volumetric measurement of at least 1 target lesion (e.g., due to the presence of artifacts from cochlear or auditory brainstem implants, ill-defined tumor margins resulting from the juxtaposition of tumors abutting each other, or sequela from prior irradiation to the target lesion); Note: patients with cochlear or auditory brainstem implants may participate if a target lesion can be accurately assessed
• Radiation therapy for the target lesion in the 60 months preceding inclusion in the study
• Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of study drug (including chemotherapy, antibody based therapy, e.g. lapatinib, bevacizumab, erlotinib, imatinib, that are sometimes offered on a compassionate-use basis to NF2 patients)
• Prior treatment with any investigational drug within the preceding 4 weeks
• 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
• Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent; topical or inhaled corticosteroids are allowed
• 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, Bacillus Calmette-Guerin (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
• Presence of a fungal infection requiring systemic antifungal treatment at enrollment
• 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: * Symptomatic congestive heart failure of New York Heart Association class III or IV * 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 * Severely impaired lung function as defined as spirometry and DLCO (diffusing capacity of the lung for carbon monoxide) that is 50% of the normal predicted value and/or oxygen (O2) saturation that is 88% or less at rest on room air * Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN (Note: optimal glycemic control should be achieved before starting trial therapy) * Active (acute or chronic) or uncontrolled severe infections * Liver disease such as hepatitis B/C, cirrhosis or severe hepatic impairment (Child-Pugh class C) * Blood test indicates hepatitis B/C (Hep B/C) positive or human immunodeficiency virus (HIV) positive * 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 2 effective and reliable birth control methods; adequate protection must be used throughout the trial and for 8 weeks after the last dose of study drug, by both sexes; (women 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 women of child-bearing potential 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 a mammalian target of rapamycin (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