Clinical Trial: Cancer, Brain Tumor

A071401: Phase II Trial of SMO/AKT/NF2 Inhibitors in Progressive Meningiomas with SMO/AKT/NF2 Mutations

Full Name

Description

Experimental: Arm A - vismodegib

Patients receive vismodegib PO QD. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Intervention: Drug: vismodegib

Experimental: Arm B - GSK2256098

Patients receive FAK inhibitor GSK2256098 PO BID. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Intervention: Drug: GSK2256098

Eligibility

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 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)