Lake Regional Health System | Lake Regional Hospital - Cancer Center
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About
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 (progressive). Vismodegib, FAK inhibitor GSK2256098, capivasertib, and abemaciclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Full 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.
Enrollment
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Inclusion and exclusion 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:
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
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:
Patients should not have any of the following criteria:
Concomitant medications (only regarding NF2/CDKN2A/CDK4/CDK6/CCND1/CCND2/CCND3/CCNE1/AKT1/PIK3CA/PTEN genetic alterations):
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:
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
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
Primary purpose
Allocation
Interventional model
Masking
124 participants in 4 patient groups
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Central trial contact
Priscilla Brastianos, MD
Data sourced from clinicaltrials.gov
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