AZD2014 In NF2 Patients With Progressive or Symptomatic Meningiomas

Inclusion Criteria

• Patients must have a confirmed diagnosis of neurofibromatosis 2 by fulfilling National Institute of Health (NIH) criteria or Manchester criteria, or by detection of a causative mutation in the NF2 gene.
• Participants must have progressive or symptomatic meningioma. NOTE 1: Histologic confirmation of meningioma is not required in the setting of compatible radiographic appearance, NOTE2: progression is defined as an increase in target meningioma volume ≥ 20% OR ≥ 3 mm during the past 2 years.

-- Subjects must have a target meningioma that is not amenable to surgery due to patient preference or high risk for surgical complications

• Participants must be willing and able to undergo regular MRI scans of the brain
• Patients must have measurable disease, defined as at least one meningioma ≥ 1.0 ml that can be accurately measured by contrast-enhanced cranial MRI scan, performed within 28 days of study registration.
• Prior surgical resection and radiation therapy for the progressive meningioma are not required for study enrollment.
• Patients must have received less than 3 prior chemotherapy regimens for progressive meningioma.
• Patients receiving dexamethasone must be able to be treated with alternative corticosteroids such as prednisone, prednisolone, or methylprednisolone in the opinion of the treating physician.
• Patients must have available an archival paraffin tumor block sufficient to generate at least 20 unstained slides; or, if a paraffin tumor block is unavailable, at least 20 unstained slides.
• Age ≥ 18 years at the time of study enrollment.
• ECOG performance status ≤2 (Karnofsky ≥60%) with no deterioration over the previous 2 weeks
• Life expectancy of greater than 3 months
• Within 14 days of study registration, participants must have normal organ and marrow function as defined below:
• leukocytes ≥3,000/mcL
• absolute neutrophil count ≥1,500/mcL
• hemoglobin ≥90 g/L
• platelets ≥100,000/mcL
• total bilirubin ≤1.5 x institutional upper limit of normal
• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal
• Serum creatinine ≤1.5 x institutional upper limit of normal concurrent with creatinine clearance ≥50 mL/min (measured or calculated by Cockcroft and Gault equation), confirmation of creatinine clearance is only required when creatinine is >1.5xULN
• Urine protein ≤1+ on urine dipstick (if 2+ seen on first test, re-test at least 24 hours later)
• PT/INR/PTT (aPTT) 470 msec obtained from 3 electrocardiograms (ECGs), family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes within 12 months of the patient entering in the study
• Patients with Diabetes Type I or uncontrolled Type II (HbA1c >8% assessed locally) as judged by the Investigator or Abnormal fasting glucose value defined as >126 mg/dL (>7 mmol/L).
• Concomitant medications known to prolong QT interval, or with factors that increase the risk of QTc prolongation or risk of arrhythmic events (such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age).
• Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug.
• Judgment by the Investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements. Note: patients who are likely to require surgery or radiation for NF2-related tumors during the first year of treatment in the investigator's opinion should not be enrolled on this clinical trial.
• Pregnant women are excluded from this study because AZD2014 is an mTORC1/2 inhibiting agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD2014, breastfeeding should be discontinued if the mother is treated