Bevacizumab for Symptomatic Vestibular Schwannoma in Neurofibromatosis Type 2 (NF2)
Condition: Vestibular Schwannoma; Neurofibromatosis Type 2
MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurilemmoma; Neuroma, Acoustic; Neurofibromatosis 2
Intervention: bevacizumab; laboratory biomarker analysis; quality-of-life assessment
Intervention description: Given IV; Correlative studies; Ancillary studies
Intervention MeSH terms: Bevacizumab; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 14.0
Sex: All
Minimum age: 12 Years
Healthy volunteers: No

Summary:

      People who have neurofibromatosis type 2 (NF2) can have tumors that grow on the auditory
      nerves and cause hearing loss. These tumors are called vestibular schwannomas (VSs), or
      acoustic neuromas. People with NF2 can also get schwannomas in other parts of their body, as
      well as tumors called meningiomas and ependymomas. Because VSs can cause hearing loss, many
      people with NF2 will have treatment to preserve their hearing. This treatment usually
      involves surgery. Because surgery has risks and is not able to help everyone with VSs, other
      methods of treatment are being explored. One area of exploration is looking to see if there
      is a drug that can be taken that might prevent the VSs from growing larger and causing
      hearing loss or brainstem compression. This study is exploring whether a drug that is
      approved by the FDA and is currently used to treat other tumors might also work to treat VSs.
      Based on people who have taken this drug to treat VSs already, there is some reason to think
      that it might be helpful to certain people with NF2. People enrolled in this study will
      receive the drug one time every three weeks for one year by infusion. This study will follow
      subjects over the course of the year that the person is taking the drug and for six months
      after the drug is stopped. This study is recruiting people who have NF2 and are currently
      having symptoms of tinnitus, dizziness, and/or hearing loss from their VSs. If you have NF2
      and are currently having symptoms caused by your VSs, you may be eligible to participate.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have a confirmed diagnosis of neurofibromatosis 2 by fulfilling National
             Institute of Health (NIH) criteria or Manchester criteria, or by detection of a
             causative mutation in the NF2 gene

               -  The NIH criteria (82) includes presence of:

                    -  Bilateral vestibular schwannomas, OR

                    -  First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR
                       two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile
                       posterior subcapsular lenticular opacity

               -  The Manchester criteria (101) includes presence of:

                    -  Bilateral vestibular schwannomas, OR

                    -  First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR
                       two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile
                       posterior subcapsular lenticular opacity, OR

                    -  Unilateral vestibular schwannoma AND any two of: neurofibroma, meningioma,
                       glioma, schwannoma, juvenile posterior subcapsular lenticular opacity, OR

                    -  Multiple meningiomas (two or more) AND unilateral vestibular schwannoma OR
                       any two of: schwannoma, glioma, neurofibroma, cataract

          -  Patients must have measurable disease, defined as at least one VS >= 1.5 cm (on
             longest diameter) as measured by contrast-enhanced cranial MRI scan with fine cuts
             through the internal auditory canal (3 mm slices, no skip)

          -  Life expectancy of greater than 6 months

          -  ECOG performance status (Karnofsky >= 60% or Lansky Score >= 60)

          -  Patients must have normal organ and marrow function as defined below:

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,500/mcL

          -  Platelets >= 150,000/mcL or lower limit of institutional normal

          -  Total bilirubin =< 2 X institutional upper limit of normal

          -  AST(SGOT)/ALT(SGPT) =< 2.5 X institutional upper limit of normal

          -  Patients must have recovered from acute toxicity of prior treatment to grade 1 or less
             unless otherwise specified

          -  Patients must have a creatinine clearance or radioisotope GFR >= 60ml/min/1.73 m^2 or
             a normal serum creatinine based on age described in the table below:

               -  Age(years) =< 5: 0.8 mg/dL

               -  5 < age (years) =< 10: 1.0 mg/dL

               -  10 < age (years) =< 15: 1.2 mg/dL

               -  Age (years) > 15: 1.5 mg/dL

          -  Subjects must have a VS not amenable to surgery or have refused surgery due to high
             risk for permanent complications related to surgery (e.g. damage to lower cranial
             nerve function, facial palsy, risk for cerebrospinal fluid leak, etc.) as determined
             by a surgeon with experience in management of NF2 associated VS

          -  Subjects must have had a discussion of all available treatment options and their risks
             and benefits of these options including surgery, radiation therapy, observation, other
             clinical trials and expressed their preference for participation in this trial in the
             informed consent process

          -  The effects of bevacizumab on the developing human fetus at the recommended
             therapeutic dose are unknown; for this reason and because anti-angiogenic agents are
             known to be teratogenic, women of child-bearing potential and men must agree to use
             adequate contraception (hormonal or barrier method of birth control; abstinence) prior
             to study entry and for the duration of study participation; should a woman become
             pregnant or suspect she is pregnant while participating in this study, she should
             inform her treating physician immediately

          -  Ability to understand and the willingness give written informed consent or assent

          -  Evidence of active disease, defined as progressive hearing loss (with decrease in word
             recognition score) related to VS (i.e., not due to prior interventions such as surgery
             or radiation) documented in the preceding 24 months with a word recognition score of <
             90% in the target ear

          -  Proteinuria (including albuminuria) should be screened for by either urine analysis
             for urine protein creatinine (UPC) ratio or by urine dipstick; if the UPC ratio is
             greater than or equal to 0.5 or if urine dipstick shows 2+ proteinuria, 24-hour urine
             protein should be obtained and the level should be < 1000 mg for patient enrollment

        Exclusion Criteria:

          -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study or those who have not
             recovered from adverse events due to agents administered more than 4 weeks earlier

          -  Patients may not be receiving any other investigational agents

          -  Patients with nervous system tumors associated with NF2 (e.g., schwannomas,
             meningiomas, ependymomas, or gliomas) will not be excluded from this clinical trial as
             long as these tumors do not require treatment with radiation, surgery, or medical
             treatment at the time of enrollment on trial

          -  Patients with known hypersensitivity of Chinese hamster ovary cell products, other
             recombinant human antibodies, or compounds of similar chemical or biologic composition
             to bevacizumab

          -  Inability to tolerate periodic MRI scans or gadolinium contrast without general
             anesthesia

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Clinically significant cardiovascular disease, such as:

               -  Inadequately controlled HTN (adult subjects: SBP > 160 mmHg and/or DBP > 90 mmHg
                  despite antihypertensive medication, pediatric subjects: Requirement for
                  antihypertensive treatment prior to enrollment, or diastolic blood pressure >
                  95th percentile for age)

               -  History of CVA within 12 months

               -  Myocardial infarction or unstable angina within 12 months

               -  New York heart association grade II or greater congestive heart failure

               -  Serious and inadequately controlled cardiac arrhythmia

               -  Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection)

               -  Clinically significant peripheral vascular disease

          -  Pregnant women (positive pregnancy test) are excluded from this study because
             bevacizumab is an anti-angiogenic agent with the potential for teratogenic or
             abortifacient effects; because there is an unknown but potential risk for adverse
             events in nursing infants secondary to treatment of the mother with bevacizumab,
             breastfeeding should be discontinued if the mother is treated with bevacizumab; both
             fertile men and women must agree to use adequate contraceptive measures during study
             therapy and for at least 6 months after the completion of bevacizumab therapy;
             abstinence is considered an adequate contraceptive measure

               -  In the event that a minor (age 12-17) who undergoes a pregnancy test as part of
                  the screening process receives a positive result, they will be excluded from the
                  study and their parent(s) of record will be notified of this result

          -  HIV-positive patients or cancer survivors are eligible for this study if they fulfill
             all other eligibility criteria

          -  Inability to perform volumetric measurement of target VS (e.g., due to the MRI
             artifact from auditory brainstem implant or due to presence of collision tumor (two or
             more tumors abutting each other) in the cerebellopontine angle); Note: questions about
             the ability to perform volumetric analysis on a baseline MRI scan should be directed
             to the study radiologist, Dr. Gregory Sorensen

          -  Concurrent use of anti-coagulant drugs (not including prophylactic doses), history of
             coagulopathy, or evidence of bleeding diathesis or coagulopathy

          -  Imaging (CT or MRI) evidence of newly identified hemorrhage (new within the last in
             the 6 months prior to enrollment), any history of symptomatic intracranial hemorrhage,
             or any history of spontaneous intracranial hemorrhage

          -  Serious or non-healing wound, ulcer or bone fracture

          -  History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
             within 6 months prior to day 1

          -  Invasive procedures defined as follows:

               -  Major surgical procedure, open biopsy or significant traumatic injury within 28
                  days prior to Day 1 therapy

               -  Brain biopsy within 28 days prior to day 1 of therapy (wounds must be fully
                  healed from brain biopsies performed more than 28 days prior to day 1 of therapy)

               -  Anticipation of need for major surgical procedures during the course of the study

               -  Core biopsy within 7 days prior to D1 therapy

          -  Prior treatment with bevacizumab or other VEGF targeting therapies

          -  Personal history of autoimmune coagulopathy, including idiopathic thrombocytopenia
             purpura (ITP)