The goal of this clinical research study is to learn if the study drug AZD2014 can shrink growing or symptomatic meningiomas.

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

The goal of this clinical research study is to learn if the study drug AZD2014 can shrink growing or symptomatic meningiomas. Based on laboratory research, the cellular pathways which are blocked by AZD2014 are important for the growth and survival of meningiomas. Further treatment of meningioma cells in the laboratory setting has resulted in decreased survival of tumor cells. As such, the purpose of this research is to see whether treating your meningioma with AZD2014 will result in tumor shrinkage. The safety of AZD2014 will also be studied. Your physical state, your symptoms, changes in the size of the tumor, and laboratory findings obtained while on-study will help the research team decide if AZD2014 is safe and effective in patients with your condition.

AZD2014 is being studied in patients with various cancers as a single agent (a drug that is used alone to treat the cancer) or in combination with a number of anticancer therapies. Previous studies have also allowed investigators to determine the best dose and frequency of AZD2014 to achieve anti-tumor effects while reducing the likelihood of side effects.

The FDA (the U.S. Food and Drug Administration) has not approved AZD2014 as a treatment for any disease.

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) <1.5x institutional upper limit of normal

• The effects of AZD2014 on the developing human fetus are unknown. For this reason and because mTOR kinase inhibiting agents are known to be teratogenic, female patients must be willing to use 2 forms of highly effective contraception (per institution standards) from the time of screening until 4 weeks after discontinuing study, must not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child bearing potential or must have evidence of non-childbearing potential by fulfilling one of the following criteria at screening: (1) post-menopausal women, defined as either women aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments, or, (2) women under 50 years old who have been amenorrhoeic for at least 12 months following the cessation of exogenous hormonal treatments, and have serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels in the postmenopausal range for the institution. Alternatively, women must have documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.

• Male patients should either be surgically sterile or willing to use an effective barrier method of contraception during the study and for 16 weeks following the last dose of study treatment if sexually active with a female of childbearing potential. If not done previously, storage of sperm prior to receiving AZD2014 will be advised to male patients with a desire to have children.

• Ability to understand and the willingness to sign a written informed consent document prior to any study specific procedures, sampling, and analyses.

• Ability to swallow and retain oral medication

Exclusion Criteria:

• Prior chemotherapy, biological therapy, radiation therapy, androgens, thalidomide, immunotherapy, other anticancer agents within 21 days of starting study treatment (not including palliative radiotherapy at focal sites). Prior use of an investigational monoclonal antibody therapy within 3 months, or prior use of nitrosoureas or mitomycin C within 6 weeks. Patients must have recovered from acute toxicity due to radiotherapy.

• With the exception of alopecia, any unresolved toxicities from prior anti-tumor treatments (excluding corticosteroids) should be no greater than CTCAE (Version 4.0) Grade 1 at the time of study entry.

• Major surgery within 4 weeks prior to entry to the study (excluding placement of vascular access), or minor surgery (excluding tumor biopsies) within 14 days of first dose of study treatment

• Participation in another clinical study with an investigational product during the last 21 days.

• History of hypersensitivity to active or inactive excipients of AZD2014 or drugs with a similar chemical structure or class to AZD2014.

• Exposure to potent or moderate inhibitors or inducers of CYP3A4/5, Pgp (MDR1) and BCRP if taken within the stated washout periods before the first dose of study treatment (see Appendix B)

• Exposure to sensitive or narrow therapeutic range substrates of the drug metabolizing enzymes CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters Pgp (MDR1), BCRP, OATP1B1, OATP1B3, OCT1 and OCT2 within the appropriate wash-out period (a minimum of 5 x reported elimination half-life) before the first dose of study treatment (see Appendix B)

• Any haemopoietic growth factors (e.g., filgrastim [granulocyte colony-stimulating factor; G-CSF], sargramostim [granulocyte-macrophage colony-stimulating factor; GM-CSF]) within 14 days prior to receiving study treatment..

• Pre-treatment with other mTOR inhibitors may be allowed and should be discussed for each protocol and tumor type separately

• Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.

• Previous meningioma progression during treatment with other mTORC1/2 inhibitors (but not mTORC1 inhibitors such as everolimus or other rapalogues)

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, severe hepatic impairment, interstitial lung disease (bilateral, diffuse, parenchymal lung disease), uncontrolled chronic renal diseases (glomerulonephritis, nephrotic syndrome, Fanconi Syndrome or renal tubular acidosis), current unstable or uncompensated respiratory or cardiac conditions, uncontrolled hypertension, active bleeding diatheses, active hepatitis B or C infection, known active human immunodeficiency virus (HIV) infection, or psychiatric illness/social situations that would limit compliance with study requirements. Screening for chronic conditions is not required.

• History of other malignancies, except: Malignancy treated with curative intent and with no known active disease present for ≥5 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician, (2) adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease, (3) adequately treated carcinoma in situ without evidence of disease, or (4) Gleason 6 prostate cancer under observation.

• Patients who have experienced any of the following procedures or conditions currently or in the preceding 12 months:

  • coronary artery bypass graft
  • angioplasty
  • vascular stent
  • myocardial infarction
  • angina pectoris
  • congestive heart failure New York Heart Association Grade ≥2 ( ventricular arrhythmias requiring continuous therapy)
  • supraventricular arrhythmias including atrial fibrillation, which are uncontrolled
  • haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other central nervous system bleeding
  • History of drug abuse or alcohol abuse, as judged by the Investigator

• Abnormal echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) at baseline (left ventricular ejection fraction [LVEF] <55%. Appropriate correction to be used if a MUGA is performed.

• Pre-existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi Syndrome or renal tubular acidosis

• Mean resting corrected QT interval (QTc), calculated using Fridericia's formula, > 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 with AZD2014.

• HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD2014. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy.

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca, CRO staff, and/or staff at the CPU)

24 months