Clinical Trials /

Vismodegib and FAK Inhibitor GSK2256098 in Treating Patients With Progressive Meningiomas

NCT02523014

Description:

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.

Related Conditions:
  • Meningioma
Recruiting Status:

Suspended

Phase:

Phase 2

Trial Eligibility

Document

A Study Looking at <span class="go-doc-concept go-doc-intervention">Targeted Therapy</span> According to Tumor Markers for People With Meningiomas

Title

  • Brief Title: A Study Looking at Targeted Therapy According to Tumor Markers for People With Meningiomas
  • Official Title: Phase II Trial of SMO/AKT/NF2 Inhibitors in Progressive Meningiomas With SMO/AKT/NF2 Mutations
  • Clinical Trial IDs

    NCT ID: NCT02523014

    ORG ID: A071401

    NCI ID: NCI-2015-00546

    Trial Conditions

    Intracranial Meningioma

    Recurrent Meningioma

    Trial Interventions

    Drug Synonyms Arms
    vismodegib Arm A - vismodegib
    GSK2256098 Arm B - GSK2256098

    Trial Purpose

    This phase II trial studies how well vismodegib and focal adhesion kinase (FAK) inhibitor
    GSK2256098 work in treating patients with meningiomas that may have gotten bigger or grew
    back after treatment. Vismodegib and FAK inhibitor GSK2256098 may stop the growth of tumor
    cells by blocking some of the enzymes needed for cell growth.

    Detailed Description

    Each arm is a prospective, one-stage phase 2 study evaluating the efficacy of smoothened
    receptor SMO or FAK inhibitors in patients with SMO-mutated or neurofibromin 2 (NF2)-mutated
    meningiomas, respectively. There will be a separate phase 2 arm for each of the two tumor
    mutation groups and each tumor grade cohort. Patients with recurrent or progressive Grade
    I-III meningiomas will be eligible for this trial. Samples will undergo central pathology
    review. Patient's tumor samples will be tested for the presence of SMO or NF2 mutations.
    Patients harboring SMO or NF2 mutations and who meet eligibility criteria will be enrolled.
    Within each arm, there will be two different patient cohorts based on histology: grade I
    versus II/III meningiomas.

    The primary and secondary objectives are described below.

    Primary objectives:

    1. To determine the activity of a SMO inhibitor in patients with meningiomas harboring SMO
    mutations as measured by 6-month progression free survival (PFS) and response rate.

    2. To determine the activity of a FAK inhibitor in patients with meningiomas harboring NF2
    mutations as measured by 6-month PFS and response rate.

    Secondary objectives:

    1. To determine overall survival and progression-free survival of SMO and FAK inhibitors
    in patients with meningioma.

    2. To determine adverse event rates of SMO and FAK inhibitors in patients with meningioma.

    NOTE: Afuresertib, the agent identified for patients with AKT1 mutation is not currently
    available. Testing for the AKT1 mutation will commence once afuresertib becomes available
    and sites are notified via a protocol amendment. Tumor samples will only be tested for SMO
    and NF2 mutations until further notice.

    Patients will be followed for 2 years after completion of treatment.

    Trial Arms

    Name Type Description Interventions
    Arm A - vismodegib Experimental In patients with SMO-mutated meningiomas, protocol therapy will consist of 150 mg vismodegib administered orally, daily. Each cycle will consist of 28 days. Treatment will be continued until progressive disease (PD) or study withdrawal due to toxicity or other rationale, at which time patients will be removed from the study. In patients who come off study for reasons other than progression, they will be followed for progression until progression is documented on imaging. All patients who are removed from the study treatment, regardless of rationale, will be followed for survival once off study. vismodegib
    Arm B - GSK2256098 Experimental In patients with NF2-mutated meningiomas, protocol therapy will consist of 750 mg GSK2256098 administered orally, twice daily. Each cycle will consist of 28 days. Treatment will be continued until progressive disease (PD) or study withdrawal due to toxicity or other rationale, at which time patients will be removed from the study. In patients who come off study for reasons other than progression, they will be followed for progression until progression is documented on imaging. All patients who are removed from the study treatment, regardless of rationale, will be followed for survival once off study. GSK2256098

    Eligibility Criteria

    Pre-Registration Eligibility Criteria

    1. Central Pathology Review Submission: This review is mandatory prior to registration to
    confirm eligibility.

    - Patients must have local diagnosis of meningioma (any grade) and

    - have FFPE tumor block OR meningioma tissue slides available for submission to central
    pathology review and SMO and NF2 testing by a CLIA-certified lab.

    Registration Eligibility Criteria

    1. 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:

    - 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. will be defined by bidimensionally measurable lesions
    with clearly defined margins by MRI scans, with a minimum diameter of 10mm
    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.

    2. Measurable disease: Measurable disease is defined by a bidimensionally measurable
    main lesion on magnetic resonance imaging (MRI) or computed tomography (CT) images
    (MRI preferred) with clearly defined margins. Multifocal disease is allowed.

    3. Prior Treatment

    - Prior 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.

    4. 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). Please note this information is
    strictly for eligibility purposes, please see the protocol (eg, study calendar)
    for details on pregnancy monitoring during the duration of the trial. Also
    please refer to the protocol section that discusses "On-Study Guidelines".

    5. Age 18 years

    6. Eastern Cooperative Oncology Group (ECOG) Performance Status 2

    7. 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.

    - Known active hepatitis B or C

    - Current Child Pugh Class B or C liver disease

    - Uncontrolled gastric ulcer disease (Grade 3 gastric ulcer disease within 28 days
    of registration)

    - Uncontrolled diabetes defined as a known diabetic with hemoglobin A1C (HBA1C) >
    7.5 OR fasting glucose > 140.

    - Uncontrolled hypertension defined as blood pressure (BP) > 140/90

    - Abdominal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess
    within 28 days prior to registration

    8. Concomitant Medications

    - Chronic concomitant treatment with strong inhibitors of CYP3A4 inhibitors must
    discontinue the drug for 14 days prior to registration on the study for patients
    with with NF2 mutation enrolled to GSK2256098. See the protocol for more
    information.

    - 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. See the protocol for more
    information.

    9. Required Initial Laboratory Values:

    - Absolute Neutrophil Count (ANC) 1500/mm^3

    - Platelet Count 100,000/mm^3

    - Creatinine OR 1.5 mg/dl x upper limit of normal (ULN) OR

    - Calc. Creatinine Clearance > 45 mL/min

    - Urine protein creatinine ratio (UPC) 45 mg/mmol*

    - Total bilirubin 1.5 x ULN **

    - AST/ALT*** 2.5 x ULN

    - Fasting triglyceride 200 mg/dL*

    - Fasting cholesterol 240 mg/dL*

    ONLY APPLICABLE for patients with NF2 mutation (GSK2256098)*

    Except in case of Gilbert's disease**

    Aspartate aminotransferase/alanine aminotransferase***

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Progression free survival rate at 6-months

    Response rate

    Secondary Outcome Measures

    Overall survival

    Adverse events will be summarized as the number and frequency of patients who experience any AE, AEs of grade 3+ and AEs of grade 4+.

    Trial Keywords