Vistusertib (AZD2014) For Recurrent Grade II-III 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 FDA (the U.S. Food and Drug Administration) has not approved AZD2014 as a treatment for
any disease.

The goal of this clinical research study is to learn if the study drug AZD2014 can shrink or
slow the growth of meningioma. 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 has resulted in decreased survival of tumor
cells. As such, the purpose of this research is to see whether treating recurrent grade 2-3
meningioma with AZD2014 will result in tumor size stabilization or shrinkage. The safety of
AZD2014 will also be studied. The physical state, the 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 participants with this 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 well known 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.

Inclusion Criteria:

- 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.

Exclusion Criteria:

- Participants with a clinical diagnosis of NF2 (either by NIH or Manchester criteria)
or with a molecular diagnosis of NF2

- Participants who received biopsy only or have received more than 2 prior courses of
radiation for meningioma

- Participants who have had chemotherapy, radiotherapy, biological therapy,
immunotherapy or other anticancer agents within 14 days (six weeks for nitrosoureas or
mitomycin C) prior to entering the study.

- 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 four 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 strong 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 specific substrates of the drug transporters OATP1B1, OATP1B3, MATE1 and
MATE2K 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 hematopoietic 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 with
the medical monitor.

- 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 rapalogs).

- 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

- hemorrhagic or thrombotic stroke, including transient ischemic 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 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,
hypokalemia, congenital long QT syndrome, family history of long QT syndrome or
unexplained sudden death under 40 years-of-age). See appendix B for a list of
medications.

- Vaccinated with live, attenuated vaccines within four 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.

- 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. Appropriate studies will be undertaken in participants
receiving combination antiretroviral therapy when indicated.

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