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A Study Looking at Targeted Therapy According to Tumor Markers for People With Meningiomas

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2017 by Alliance for Clinical Trials in Oncology
Sponsor:
Collaborators:
National Cancer Institute (NCI)
GlaxoSmithKline
Genentech, Inc.
Brain Science Foundation
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier:
NCT02523014
First received: August 11, 2015
Last updated: March 6, 2017
Last verified: March 2017
  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.

Condition Intervention Phase
Intracranial Meningioma
Recurrent Meningioma
Drug: vismodegib
Drug: GSK2256098
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Phase II Trial of SMO/AKT/NF2 Inhibitors in Progressive Meningiomas With SMO/AKT/NF2 Mutations

Resource links provided by NLM:


Further study details as provided by Alliance for Clinical Trials in Oncology:

Primary Outcome Measures:
  • Progression free survival rate at 6-months [ Time Frame: At 6 months ]
  • Response rate [ Time Frame: Up to 2 years post-treatment ]

Secondary Outcome Measures:
  • Overall survival [ Time Frame: Up to 2 years post-treatment ]
  • 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+. [ Time Frame: Up to 2 years post-treatment ]

Estimated Enrollment: 56
Study Start Date: August 2015
Estimated Primary Completion Date: August 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A - vismodegib
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.
Drug: vismodegib
oral
Experimental: Arm B - GSK2256098
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.
Drug: GSK2256098
oral

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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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***

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02523014

Contacts
Contact: Priscilla Brastianos, MD 617-643-1939

  Show 518 Study Locations
Sponsors and Collaborators
Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
GlaxoSmithKline
Genentech, Inc.
Brain Science Foundation
Investigators
Study Chair: Priscilla Brastianos, MD Massachusetts General Hospital
  More Information

Responsible Party: Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier: NCT02523014     History of Changes
Other Study ID Numbers: A071401
NCI-2015-00546 ( Registry Identifier: NCI Clinical Trials Reporting Program )
Study First Received: August 11, 2015
Last Updated: March 6, 2017

Additional relevant MeSH terms:
Meningioma
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Vascular Tissue
Meningeal Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Nervous System Diseases

ClinicalTrials.gov processed this record on March 24, 2017