Clinical Trials /

Phase 2 Study of Bevacizumab in Children and Young Adults With NF 2 and Progressive Vestibular Schwannomas

NCT01767792

Description:

To determine the hearing response rate at 24 weeks after treatment with bevacizumab for symptomatic vestibular schwannomas (VS) in children and young adults with NF2.

Related Conditions:
  • Schwannoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Phase 2 Study of <span class="go-doc-concept go-doc-intervention">Bevacizumab</span> in Children and Young Adults With NF 2 and Progressive Vestibular Schwannomas

Title

  • Brief Title: Phase 2 Study of Bevacizumab in Children and Young Adults With NF 2 and Progressive Vestibular Schwannomas
  • Official Title: Open-label, Phase 2 Study of Bevacizumab in Children and Young Adults With Neurofibromatosis 2 and Progressive Vestibular Schwannomas That Are Poor Candidates for Standard Treatment With Surgery or Radiation
  • Clinical Trial IDs

    NCT ID: NCT01767792

    ORG ID: AVF4807

    NCI ID: W81XWH-12-1-0155

    Trial Conditions

    Neurofibromatosis Type 2

    Progressive Vestibular Schwannomas

    Trial Interventions

    Drug Synonyms Arms
    Bevacizumab rhuMAb, VEGF, Avastin Bevacizumab

    Trial Purpose

    To determine the hearing response rate at 24 weeks after treatment with bevacizumab for
    symptomatic vestibular schwannomas (VS) in children and young adults with NF2.

    Detailed Description

    Subjects will be treated with open-label bevacizumab 10 mg/kg every 2 weeks for 24 weeks
    (induction therapy). Clinical response will be assessed by audiology and MRI at weeks 12 and
    24. Subjects with hearing decline at weeks 12 or 24 will be taken off of protocol. At week
    24, patients with a clinical response or stable disease (together comprising "clinical
    benefit") will transition to maintenance therapy with bevacizumab. During the maintenance
    phase, subjects will be treated with open-label bevacizumab 5 mg/kg every 3 weeks for up to
    72 weeks. Subjects will be followed with audiology and MRI scans every 12 weeks. The total
    time of the study will be 96 weeks (24 weeks induction + 72 weeks maintenance).

    Subjects will be allowed to increase their bevacizumab dose to 10 mg/kg every 2 weeks during
    maintenance therapy if they experience hearing decline during maintenance therapy (defined
    as decrease in word recognition score below the 95% critical difference compared with the
    word recognition score at baseline, Appendix A). Subjects will be taken off of study if
    their word recognition score does not remain within the 95% critical difference after
    receiving bevacizumab 10 mg/kg every 2 weeks.

    Trial Arms

    Name Type Description Interventions
    Bevacizumab Experimental Follow participant for 2 years and assess hearing response rates Bevacizumab

    Eligibility Criteria

    Inclusion Criteria - Participants must meet the following criteria on screening
    examination to be eligible to participate in the study:

    - 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.

    - Patients must have measurable disease, defined as at least one VS > 1.0 ml (on
    volumetric analysis) that can be accurately measured by contrast-enhanced cranial MRI
    scan with fine cuts through the internal auditory canal (3 mm slices, no skip).

    - Age 12 to 40 years on day 1 of treatment. Given the potential risk of long-term
    bevacizumab use, children under age 12 are not eligible for treatment. Adults older
    than 30 are not eligible as these patients may be eligible for other
    bevacizumab-based protocols.

    - Life expectancy of greater than 1 year.

    - Karnofsky performance status 70.

    - Participants must have normal organ and marrow function as defined below:

    - Leukocytes > 3,000/mcL

    - Absolute neutrophil count > 1,500/mcL

    - Platelets > 100,000/mcL

    - Total bilirubin within normal institutional limits

    - AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal

    - Patients must have a creatinine clearance or radioisotope GFR 60ml/min/1.73 m2 or a
    normal serum creatinine based on age described in the table below:

    - Age (years) Maximum Serum Creatinine (mg/dL) 12<age15 1.2 >15 1.5

    - Subjects must have a target VS with the following qualities:

    - Not amenable to surgery due to patient refusal, high risk for surgical complications
    (e.g., damage to lower cranial nerve function, tumor size > 3 cm in longest diameter,
    or multilobulated tumor appearance on MRI scan).

    - Associated with a word recognition score of < 85%

    - Documented clinical progression defined as EITHER:

    - Progressive hearing loss (defined as a decline in word recognition score below the
    95% critical difference interval from baseline score [Appendix A] related to VS
    (i.e., not due to prior interventions such as surgery or radiation)

    OR

    - Progressive tumor growth in the preceding 18 months, defined as 20% increase in
    volume

    - The effects of bevacizumab on the developing human fetus are unknown. For this reason
    and because bevacizumab 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 to sign written informed consent and assent
    documents.

    - Must have established relationship with primary care physician and provide contact
    information

    Exclusion Criteria:

    - Participants who exhibit any of the following conditions at screening will not be
    eligible for admission into the study.

    - Patients who have had chemotherapy 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. Prior radiation
    treatment to the target vestibular schwannoma is allowed if provided 3 years prior to
    participation in the clinical trial. Prior radiation treatment to non-target tumors
    is allowed.

    - Participants may not be receiving any other study agents.

    - Patients with nervous system tumors associated with NF2 (e.g., schwannomas,
    meningiomas, ependymomas, or gliomas) will not be excluded from this clinical trial
    unless (in the opinion of the investigator) these tumors are growing and are likely
    to require treatment during the clinical trial.

    - History of allergic reactions attributed to compounds of similar chemical or biologic
    composition to bevacizumab.

    - 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.

    - Uncontrolled intercurrent illness including, but not limited to ongoing or active
    infection, unstable angina pectoris, or psychiatric illness/social situations that
    would limit compliance with study requirements.

    - History of arterial/myocardial disease.

    - Clinically significant cardiovascular disease, such as:

    - Inadequately controlled HTN (for adults: SBP > 160 mmHg and/or DBP > 90 mmHg despite
    antihypertensive medication; for children: please refer to Appendix D for
    age-appropriate values indicating Grade 2)

    - 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 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 of adverse events in nursing infants secondary to
    treatment of the mother with bevacizumab, breastfeeding should be discontinued if the
    mother is treated with bevacizumab. These potential risks may also apply to other
    agents used in this study.

    - HIV-positive patients or cancer survivors are eligible for this study if they fulfill
    all other eligibility criteria.

    - 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 hemorrhage deemed significant by the treating
    physician (> grade 1). Subjects with history of CNS hemorrhage are not eligible.

    - Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC)
    ratio. For UPC ratio > 0.5, 24-hour urine protein should be obtained and the level
    should be <1000 mg for patient enrollment.

    - 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.

    Minimum Eligible Age: 12 Years

    Maximum Eligible Age: 40 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Hearing Response Rates

    Secondary Outcome Measures

    safety

    tolerability

    durability

    Radiographic Response

    Changes in function of auditory system

    Changes in Tinnitus during treatment

    Trial Keywords

    Neurofibromatosis Type 2

    Progressive Vestibular Schwannomas