A Single Arm Phase II Study Of The Dual mTORC1/mTORC2 Inhibitor Vistusertib (AZD2014) Provided On An Intermittent Schedule For Sporadic Patients With Grade II-III Meningiomas That Recur Or Progress After Surgery And Radiation

• Participants must have histologically confirmed intracranial meningioma, grade II-III,that has recurred or progressed at previous treatment.

• Participants must be willing and able to undergo regular MRI scans of the brain.

• Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension as ≥10 mm with MRI, performed within 30 days prior to study registration.

• Patients must have received prior surgical resection and radiation therapy for the progressive meningioma.

• Patients must have received less than three prior chemotherapy regimens for progressive meningioma.

• 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%, see Appendix A) with no deterioration over the previous 2 weeks.

• Life expectancy of greater than three 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 four 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 amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments, or (2) women under 50 years old who have been amenorrheic 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 sterilization 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.