Vismodegib, FAK Inhibitor GSK2256098, and Capivasertib in Treating Patients with Progressive Meningiomas

This phase II trial studies how well vismodegib, focal adhesion kinase (FAK) inhibitor GSK2256098, and capivasertib work in treating patients with meningioma that is growing, spreading, or getting worse. Vismodegib, FAK inhibitor GSK2256098, and capivasertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Inclusion Criteria

• Documentation of disease: * Histologic documentation: histologically proven intracranial meningioma as documented by central pathology review * Molecular documentation: presence of SMO, PTCH1 or 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 14 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 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; 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; 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 of study treatment * 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 > 2 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 AZD5363 * For patients going on to receive AZD5363 (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 injection 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 AZD5363 *** History of hypersensitivity to active or inactive excipients of AZD5363 or drugs with a similar chemical structure or class to AZD5363 *** Current disease or condition known to interfere with absorption, distribution, metabolism, or excretion of drugs *** Past medical history of interstitial lung disease, drug-induced insterstitial 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 AZD5363 * For NF2 patients going on to receive GSK2256098 and for patients with AKT1/PIK3CA/PTEN mutations enrolled to AZD5363: concomitant treatment with strong CYP3A4 inducers or CYP2D6 substrates is not allowed; patients must discontinue the drug 14 days prior to registration
• 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; except in case of Gilbert’s disease
• 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, magnesium, 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 single EKG)

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.

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.

CORRELATIVE SCIENCE OBJECTIVES:

I. To evaluate genetic and histological biomarkers in meningioma that are associated with treatment response, toxicity, and/or clinical variables, as well circulating/cell-free biomarkers.

II. To evaluate dynamic contrast enhanced magnetic resonance imaging (MRI) during treatment with SMO, FAK, AKT and CDK inhibitors for meningioma.

III. To evaluate volumetric response by central radiology review.

OUTLINE: Patients are assigned to 1 of 3 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.

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.

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

Lead Organization
Alliance for Clinical Trials in Oncology

Principal Investigator
Priscilla Kaliopi Brastianos