Each arm is a prospective, one-stage phase 2 study evaluating the efficacy of smoothened
receptor SMO or FAK inhibitors in patients with SMO-mutated or neurofibromin 2 (NF2)-mutated
meningiomas, respectively. There will be a separate phase 2 arm for each of the two tumor
mutation groups and each tumor grade cohort. Patients with recurrent or progressive Grade
I-III meningiomas will be eligible for this trial. Samples will undergo central pathology
review. Patient's tumor samples will be tested for the presence of SMO or NF2 mutations.
Patients harboring SMO or NF2 mutations and who meet eligibility criteria will be enrolled.
Within each arm, there will be two different patient cohorts based on histology: grade I
versus II/III meningiomas.
The primary and secondary objectives are described below.
1. To determine the activity of a SMO inhibitor in patients with meningiomas harboring SMO
mutations as measured by 6-month progression free survival (PFS) and response rate.
2. To determine the activity of a FAK inhibitor in patients with meningiomas harboring NF2
mutations as measured by 6-month PFS and response rate.
1. To determine overall survival and progression-free survival of SMO and FAK inhibitors
in patients with meningioma.
2. To determine adverse event rates of SMO and FAK inhibitors in patients with meningioma.
NOTE: Afuresertib, the agent identified for patients with AKT1 mutation is not currently
available. Testing for the AKT1 mutation will commence once afuresertib becomes available
and sites are notified via a protocol amendment. Tumor samples will only be tested for SMO
and NF2 mutations until further notice.
Patients will be followed for 2 years after completion of treatment.
Pre-Registration Eligibility Criteria
1. Central Pathology Review Submission: This review is mandatory prior to registration to
- Patients must have local diagnosis of meningioma (any grade) and
- 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
1. Documentation of Disease:
- Histologic Documentation: Histologically proven intracranial meningioma as
documented by central pathology review.
- Molecular Documentation: 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: 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 scans separated by no
more than 12 months. will be defined by bidimensionally measurable lesions
with clearly defined margins by MRI scans, with a minimum diameter of 10mm
in both dimensions.
- Progressive measurable disease: Progression defined as an increase in size
of the measurable primary lesion on imaging by 25% or more (bidirectional
area). The change must occur between scans separated by no more than 12
- Post radiation patients: 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
2. Measurable disease: 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.
3. 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 stable for at least 4 days.
- 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.
4. Not pregnant and not nursing:
- A female of childbearing potential is a sexually mature female who: 1) has not
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally
postmenopausal for at least 12 consecutive months (i.e., has had menses at any
time in the preceding 12 consecutive months). Please note this information is
strictly for eligibility purposes, please see the protocol (eg, study calendar)
for details on pregnancy monitoring during the duration of the trial. Also
please refer to the protocol section that discusses "On-Study Guidelines".
5. Age 18 years
6. Eastern Cooperative Oncology Group (ECOG) Performance Status 2
7. Patient history:
- 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.
- No metastatic meningiomas (as defined by extracranial meningiomas) allowed.
- No 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
- 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
8. Concomitant Medications
- Chronic concomitant treatment with strong inhibitors of CYP3A4 inhibitors must
discontinue the drug for 14 days prior to registration on the study for patients
with with NF2 mutation enrolled to GSK2256098. See the protocol for more
- Chronic concomitant treatment with strong CYP3A4 inducers is not allowed.
Patients must discontinue the drug 14 days prior to the start of study treatment
for patients with NF2 mutation enrolled to GSK2256098. See the protocol for more
9. Required Initial Laboratory Values:
- Absolute Neutrophil Count (ANC) 1500/mm^3
- Platelet Count 100,000/mm^3
- Creatinine OR 1.5 mg/dl x upper limit of normal (ULN) OR
- Calc. Creatinine Clearance > 45 mL/min
- Urine protein creatinine ratio (UPC) 45 mg/mmol*
- Total bilirubin 1.5 x ULN **
- AST/ALT*** 2.5 x ULN
- Fasting triglyceride 200 mg/dL*
- Fasting cholesterol 240 mg/dL*
ONLY APPLICABLE for patients with NF2 mutation (GSK2256098)*
Except in case of Gilbert's disease**
Aspartate aminotransferase/alanine aminotransferase***
Minimum Eligible Age: 18 Years
Maximum Eligible Age: N/A
Eligible Gender: Both