Vismodegib and FAK Inhibitor GSK2256098 in Treating Patients With Progressive Meningiomas

PRIMARY OBJECTIVES:

I. To determine the activity of a smoothened, frizzled class receptor (SMO) and PTCH1
inhibitor in patients with meningiomas harboring SMO mutations as measured by 6-month
progression free survival (PFS) and response rate.

II. To determine the activity of a FAK inhibitor in patients with meningiomas harboring
neurofibromin 2 (NF2) mutations as measured by 6-month PFS and response rate.

SECONDARY OBJECTIVES:

I. To determine overall survival and progression-free survival of SMO and FAK inhibitors in
patients with meningioma.

II. To determine adverse event rates of SMO and FAK inhibitors in patients with meningioma.

III. To determine the activity of SMO and FAK inhibitor as measured by response rate by
central radiology review.

TERTIARY OBJECTIVES:

I. To evaluate genetic biomarkers in meningioma. II. To evaluate dynamic contrast enhanced
magnetic resonance imaging (MRI) during treatment with SMO and FAK inhibitors for meningioma.

III. To evaluate volumetric response by central radiology review.

OUTLINE: Patients are assigned to 1 of 2 treatment arms based on their mutation status.

ARM A (SMO/PTCH1 mutation): Patients receive vismodegib orally (PO) once daily (QD). Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B (NF2 mutation): Patients receive FAK inhibitor GSK2256098 PO twice daily (BID). Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for a maximum of
5 years from registration.

- Documentation of disease:

- Histologic documentation: histologically proven intracranial meningioma as
documented by central pathology review

- Molecular documentation: presence of SMO, PTCH1 or NF2 mutation in tumor sample
as documented by central laboratory

- Progressive OR residual disease, as defined by the following:

- 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; residual measurable disease will be defined by bidimensionally
measurable lesions with clearly defined margins by MRI scans, with a minimum
diameter of 10 mm 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
months

- 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 registration

- Measurable disease: measurable disease is defined by a bidimensionally measurable main
lesion on MRI or computed tomography (CT) images (MRI preferred) with clearly defined
margins; multifocal disease is allowed

- Prior treatment

- Prior medical 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 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

- 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)

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- 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

- No known active hepatitis B or C

- No current Child Pugh class B or C liver disease

- No uncontrolled gastric ulcer disease (grade 3 gastric ulcer disease within 28
days of registration)

- No uncontrolled diabetes defined as a known diabetic with hemoglobin A1C (HBA1C)
> 7.5 OR fasting glucose > 140

- No uncontrolled hypertension defined as blood pressure (BP) > 140/90

- No abdominal fistula, gastrointestinal (GI) perforation, or intra-abdominal
abscess within 28 days prior to registration

- Concomitant medications:

- Chronic concomitant treatment with strong inhibitors of cytochrome P450, family
3, subfamily A, polypeptide 4 (CYP3A4) inhibitors must discontinue the drug for
14 days prior to registration on the study for patients with NF2 mutation
enrolled to GSK2256098

- 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

- Absolute neutrophil count (ANC) >= 1,500/mm^3

- Platelet count >= 100,000/mm^3

- Creatinine OR =< 1.5 mg/dl x upper limit of normal (ULN) OR calculated (calc.)
creatinine clearance > 45 mL/min

- Urine protein:creatinine ratio (UPC) =< 45 mg/mmol; ONLY APPLICABLE for patients with
NF2 mutation (GSK2256098)

- Total bilirubin =< 1.5 x upper limit of normal (ULN); except in case of Gilbert's
disease

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit
of normal (ULN)

- Fasting triglyceride =< 200 mg/dL; ONLY APPLICABLE for patients with NF2 mutation
(GSK2256098)

- Fasting cholesterol =< 240 mg/dL; ONLY APPLICABLE for patients with NF2 mutation
(GSK2256098)

- Corrected QC interval calculated using Fridericia's formula (QTcF) =< 500 msec; ONLY
APPLICABLE for patients with NF2 mutation (GSK2256098)