Pre-Registration Eligibility Criteria

• Central Pathology Review Submission: This review is mandatory prior to registration to confirm eligibility
• Must have local diagnosis of meningioma (any grade)
• Must have FFPE tumor block OR meningioma tissue slides available for submission to central pathology review and SMO and NF2 testing by a CLIA-certified lab

Registration Eligibility Criteria

• Documentation of Disease
  • Histologically proven intracranial meningioma as documented by central pathology review
  • Presence of SMO or NF2 mutation in tumor sample as documented by central laboratory (SMO W535L, SMO L412F or known missense COSMIC mutations, nonsense mutations, small indels or copy-number loss in NF2)
• Progressive OR residual disease
  • Residual measurable disease immediately after surgery without requirement for progression
  • For Grade I disease, progression pre-operatively needs to be documented, with an increase in size of the measurable primary lesion on imaging by 25% or more (bidirectional area)
    • The change must occur between MRI scans separated by no more than 12 months and will be defined by lesions with clearly defined margins  with a minimum diameter of 10mm in both dimensions
  • Patients with measurable and progressive meningioma who have received radiation are potentially eligible, but need to show evidence of progressive disease after completion of radiation. At least 24 weeks must have elapsed from completion of radiation to registration
  • Measurable disease is defined by a bidimensionally measurable main lesion on magnetic resonance imaging (MRI) or computed tomography (CT) images (MRI preferred) with clearly defined margins
  • Multifocal disease is allowed
• Prior Treatment
  • Prior therapy is allowed but not required
  • No limit on number of prior therapies
  • No chemotherapy, other investigational agents within 28 days of study treatment
  • No other concurrent investigational agents or other meningioma-directed therapy (chemotherapy, radiation) while on study
  • For patients treated with external beam radiation, interstitial brachytherapy or radiosurgery, an interval > 24 weeks must have elapsed from completion of radiation therapy (XRT) to registration
  • Steroid dosing must be stable for at least 4 days
  •  Must be recovered to Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or less toxicity from other agents with exception of alopecia and fatigue
  • No craniotomy within 28 days of registration
• Not pregnant and not nursing
  • A female of childbearing potential is a sexually mature female who
    • Has not undergone a hysterectomy or bilateral oophorectomy
    • Has not been naturally postmenopausal (has not had menses occur at any time) for at least 12 consecutive months
      • Pregnancy monitoring will occur during the duration of the trial
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
• Patients with history of neurofibromatosis (NF) may have other stable central nervous system (CNS) tumors (schwannoma, acoustic neuroma or ependymoma) if lesions have been stable for 6 months

Exclusion Criteria

• Metastatic meningiomas as defined by extracranial meningiomas
• History of allergic reactions attributed to compounds of similar or biologic composition to assigned study drug
• Known active hepatitis B or C
• Current Child Pugh Class B or C liver disease
• Uncontrolled gastric ulcer disease (Grade 3 gastric ulcer disease within 28 days of registration)
• Uncontrolled diabetes defined as a known diabetic with hemoglobin A1C (HBA1C) > 7.5 OR fasting glucose > 140
• Uncontrolled hypertension defined as blood pressure (BP) > 140/90
• Abdominal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within 28 days prior to registration
• Chronic concomitant treatment with strong CYP3A4 inhibitors
  • Patients with NF2 mutation enrolled to GSK2256098 must discontinue the drug for 14 days prior to study registration
• Chronic concomitant treatment with strong CYP3A4 inducers
  • Patients with NF2 mutation enrolled to GSK2256098 must discontinue the drug 14 days prior to the start of study treatment
• Required Initial Laboratory Values
  • Absolute Neutrophil Count (ANC) ≥ 1500/mm^3
  • Platelet Count ≥ 100,000/mm^3
  • Creatinine  ≤ 1.5 mg/dl x upper limit of normal (ULN)
  • Calc. Creatinine Clearance > 45 mL/min
  • Urine protein creatinine ratio (UPC) ≥ 45 mg/mmol,for patients with NF2 mutation
  • Total bilirubin ≤ 1.5 x ULN, Except in case of Gilbert's disease
  • AST/ALT ≤ 2.5 x ULN
  • Fasting triglyceride ≤ 200 mg/dL,for patients with NF2 mutation
  • Fasting cholesterol ≤ 240 mg/dL,for patients with NF2 mutation