Conditions

• Intracranial Meningioma
• Recurrent Meningioma
• NF2 Gene Mutation

Eligibility

Eligible Ages

Over 18 Years

Eligible Genders

All

Accepts Healthy Volunteers

No

Criteria

- Documentation of disease:

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

- Molecular documentation: Presence of SMO, PTCH1, NF2, CDKN2A, AKT1, PIK3CA,
PTEN mutations, CDKN2A copy number loss, CDK4, CDK6, CCND1, CCND2, CCND3, or
CCNE1 copy number gain in tumor sample as documented specifically by the
central laboratory, regardless of whether prior genotype testing outside of the
central laboratory was performed

- 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 25 months; for patients with SMO/PTCH1 mutations enrolling to
receive vismodegib, the change can occur between scans separated by up to
25 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 25
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; if
the progressive meningioma lesion has been radiated, at least 24 weeks
must have elapsed from completion of radiation to registration; if the
progressive lesion is outside of the radiation field, then an interval of
at least 2 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 and a minimum diameter of 10 mm in both dimensions; multifocal
disease is allowed

- Prior treatment

- Prior medical therapy is allowed but not required

- No limit on number of prior therapies

- No chemotherapy, or other investigational agents within 28 days prior to
registration

- No other concurrent investigational agents or other meningioma-directed therapy
(chemotherapy, radiation) while on study; additionally, no cases of nitrosourea
or mitomycin C within 6 weeks prior to registration

- For patients treated with external beam radiation, interstitial brachytherapy
or radiosurgery, an interval > 4 weeks must have elapsed from completion of
radiation therapy to registration; if the progressive lesion is outside of the
radiation field, then an interval of at least 2 weeks must have elapsed from
completion of radiation 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 28 days prior to and after 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)

- For patients with NF2/CDKN2A/AKT1/PIK3CA/PTEN mutation, CKDN2A copy number loss, or
CDK4/CDK6/CCND1/CCND2/CCND3/CCNE1 copy number gain: Age >= 18 years

- For patients with SMO/PTCH1 mutation: Age >= 30 years

- 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 outside of
CNS) allowed; spinal meningiomas are 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 hypertension defined as blood pressure (BP) > 140/90

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

- No major surgery within 28 days prior to registration for any patients with
AKT1/PIK3CA/PTEN mutations receiving capivasertib

- For patients going on to receive capivasertib (i.e. enrolled after Update #08)

- Patients should not have any of the following cardiac criteria:

- Any clinically important abnormalities in rhythm, conduction, or
morphology of resting electrocardiogram (EKG) (e.g., complete left
bundle branch block, third degree heart block)

- Any factors that increase the risk of corrected QT (QTc) prolongation
or risk of arrhythmic events such as heart failure, hypokalemia,
potential for Torsade de Pointes, congenital long QT syndrome, family
history of long QT syndrome, or unexplained sudden death under 40
years of age, or any concomitant medication known to prolong the QT
interval

- Experience any of the following procedures or conditions in the
preceding 6 months: coronary artery bypass graft, angioplasty,
vascular stent, myocardial infarction, angina pectoris, congestive
heart failure New York Heart Association (NYHA) class >= II

- Uncontrolled hypertension (systolic blood pressure [SBP] < 90 mmHg
and/or diastolic blood pressure [DBP] < 50 mmHg)

- Cardiac ejection fraction outside institutional range of normal or <
50% (whichever is higher) as measured by echocardiogram (or
multigated acquisition [MUGA] scan if an echocardiogram can't be
performed or is inconclusive); left ventricular ejection fraction
(LVEF) below lower limit of normal for site

- Patients should not have any of the following criteria:

- With the exception of alopecia, any unresolved toxicities from prior
therapy greater than Common Terminology Criteria for Adverse Events
(CTCAE) grade 1 at the time of registration

- Hemoglobin < 9 g/dL (< 5.59 mmol/L); note: any blood transfusion must
be >= 14 days prior to the determination of a hemoglobin >= 9 g/dL
(>= 5.59 mmol/L)

- Proteinuria 3+ on dipstick analysis or > 500 mg/24 hours

- Refractory nausea and vomiting, chronic gastrointestinal diseases,
inability to swallow the formulated product or previous significant
bowel resection that would preclude adequate absorption of
capivasertib

- History of hypersensitivity to active or inactive excipients of
capivasertib or drugs with a similar chemical structure or class to
capivasertib

- Current disease or condition known to interfere with absorption,
distribution, metabolism, or excretion of drugs

- Past medical history of interstitial lung disease, drug-induced
interstitial lung disease, radiation pneumonitis which required
steroid treatment, or any evidence of clinically active interstitial
lung disease

- Previous allogeneic bone marrow transplant

- Known immunodeficiency syndrome

- Concomitant medications (only regarding
NF2/CDKN2A/CDK4/CDK6/CCND1/CCND2/CCND3/CCNE1/AKT1/PIK3CA/PTEN genetic alterations):

- 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, as well as for patients with AKT1/PIK3CA/PTEN mutations
enrolled to capivasertib

- For NF2 patients going on to receive GSK2256098 and for patients with
AKT1/PIK3CA/PTEN mutations enrolled to capivasertib: concomitant treatment with
strong CYP3A4 inducers or CYP2D6 substrates is not allowed; patients must
discontinue the drug 14 days prior to registration

- For NF2 patients going on to receive abemaciclib: avoid concomitant use of
CYP3A inducers and strong CYP3A inhibitors; use caution with coadministered
moderate or weak CYP3A inhibitors

- Diabetic status:

- For patients with NF2 or SMO/PTCH1 mutations: No uncontrolled diabetes defined
as a known diabetic with HBA1C > 7.5 OR fasting glucose > 140 mg/dL.

- For patients with AKT1/PIK3CA/PTEN mutations:

- Glycosylated hemoglobin (HbA1C) < 8.0% (63.9 mmol/mol)

- No type 1 diabetes mellitus

- No requirement for insulin for routine diabetic management and control

- No requirement for more than two oral hypoglycemic medications for routine
diabetic management and control

- Patients with a pre-existing diagnosis of type 2 diabetes mellitus must
have fasting glucose < 9.3 mmol/L (167mg/dL); fasting is defined as no
caloric intake for at least 8 hours

- Patients without a pre-existing diagnosis of type 2 diabetes mellitus must have
fasting glucose =< 7.0 mmol/L (126 mg/dL); fasting is defined as no caloric
intake for at least 8 hours

- 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 > 50 mL/min

- Urine protein:creatinine ratio (UPC) =< 45 mg/mmol

- 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 ULN

- Sodium, potassium, total calcium (corrected for serum albumin) & phosphorus within
normal limits per institutional guidelines

- QTcF < 450 msec (QT calculated using Fridericia formula)

- Mean resting heart rate (determined from EKG) 50-100 beats per minute (BMP) (must be
obtained from 12-lead EKG defined by a triplicate EKG for patients assigned to the
capivasertib arm; patients assigned to all other arms will require a single EKG

- No uncontrolled medical comorbidities per investigator discretion (e.g. interstitial
lung disease, severe dyspnea at rest or requiring oxygen therapy, history of major
surgical resection involving the stomach or small bowel, or pre-existing Crohn's
disease or ulcerative colitis or a preexisting chronic condition resulting in
baseline Grade 2 or higher diarrhea)

- ADDITIONAL REGISTRATION ELIGIBILITY CRITERIA FOR ABEMACICLIB ARM: Hemoglobin >= 8
g/dL

* Patients may receive erythrocyte transfusions to achieve this hemoglobin level at
the discretion of the investigator; initial treatment must not begin earlier than
the day after the erythrocyte transfusion

- ADDITIONAL REGISTRATION ELIGIBILITY CRITERIA FOR ABEMACICLIB ARM: Prior Treatment

- Patients who received chemotherapy must have recovered (Common Terminology
Criteria for Adverse Events [CTCAE] grade =< 1) from the acute effects of
chemotherapy except for residual alopecia or grade 2 peripheral neuropathy
prior to registration; a washout period of at least 28 days is required between
last chemotherapy dose and registration (provided the patient did not receive
radiotherapy)

- Patients who received adjuvant radiotherapy must have completed and fully
recovered from the acute effects of radiotherapy; a washout period of at least
28 days is required between end of radiotherapy and registration

- ADDITIONAL REGISTRATION ELIGIBILITY CRITERIA FOR ABEMACICLIB ARM: No active
bacterial infection (requiring intravenous [IV] antibiotics at time of initiating
study treatment), fungal infection, or detectable viral infection (such as known
human immunodeficiency virus positivity or with known active hepatitis B or C [for
example, hepatitis B surface antigen positive]); screening is not required for
enrollment in the absence of symptoms

- ADDITIONAL REGISTRATION ELIGIBILITY CRITERIA FOR ABEMACICLIB ARM: No personal
history of any of the following conditions: syncope of cardiovascular etiology,
ventricular arrhythmia of pathological origin (including, but not limited to,
ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest

Recruiting Locations

Study Contact

Detailed Description

PRIMARY OBJECTIVES: I. To determine the activity of a SMO inhibitor in patients with meningiomas harboring SMO and PTCH1 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 NF2 mutations as measured by 6-month PFS and response rate. III. To determine the activity of an AKT inhibitor in patients with meningiomas harboring AKT1/PIK3CA/PTEN mutations as measured by 6-month PFS and response rate. IV. To determine the activity of a CDK inhibitor in patients with meningiomas harboring alterations in the CDK pathway or NF2 alterations as measured by 6-month PFS and response rate. SECONDARY OBJECTIVES: I. To determine overall survival and progression-free survival of SMO, FAK, AKT and CDK inhibitors in patients with meningioma. II. To determine adverse event rates of SMO, FAK, AKT and CDK inhibitors in patients with meningioma. III. To determine the activity of SMO, FAK, AKT and CDK inhibitors as measured by response rate by central radiology review. OUTLINE: Patients are assigned to 1 of 4 treatment arms based on their mutation status. ARM A (SMO/PTCH1 mutation): Patients receive vismodegib orally (PO) once daily (QD). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. (CLOSED TO ACCRUAL FEBRUARY 2018) ARM B (NF2 mutation): Patients receive FAK inhibitor GSK2256098 PO twice daily (BID). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. (CLOSED TO ACCRUAL JULY 2017) ARM C (AKT1, PIK3CA, or PTEN mutation): Patients receive capivasertib PO BID on days 1-4. Treatment repeats every 7 days for up to 1 cycle (28 days) in the absence of disease progression or unacceptable toxicity. ARM D (CDK4, CDK6, CDKN2A, CCND1, CCND2, CCND3, CCNE1 alterations): Patients receive abemaciclib PO every 12 hours (Q12H). Cycles 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.