Clinical Trials

The James Cancer Center Columbus, OH

open for enrollment

Vismodegib and FAK Inhibitor GSK2256098 in Treating Patients with Progressive Meningiomas

Protocol: ALLIANCE-A071401

Full Title

Phase II Trial of SMO/AKT/NF2 Inhibitors in Progressive Meningiomas with SMO/AKT/NF2 Mutations

Purpose

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

Study Objective

PRIMARY OBJECTIVES:

I. To determine the activity of a smoothened, frizzled class receptor (SMO) 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 focal adhesion kinase (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.

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

ARM A (SMO 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 at 4 weeks, and then every 6 months for a maximum of 5 years from registration.

Are you eligible?

Inclusion Criteria:

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, 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 (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

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)