AZD2014 In NF2 Patients With Progressive or Symptomatic Meningiomas
Condition: Neurofibromatosis 2; Meningioma
MeSH terms: Meningioma; Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurofibromatosis 2
Intervention: AZD2014
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Neurofibromatosis 2

Summary:

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

Eligibility criteria:

        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)