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

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 Neurofibromatosis 2 (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 6 years or greater (no upper limit) on day 1 of treatment. Given the potential risk of long-term bevacizumab use, children under age 6 are not eligible for treatment. No upper limit for adults.
• Life expectancy of greater than 1 year.
• Karnofsky performance status ≥ 70.
• Participants must have normal organ and marrow function as defined below with definitions micro liter (mcL), Aspartate aminotransferase (AST), Serum glutamic oxaloacetic transaminase (SGOT), Alanine aminotransferase (ALT), Serum glutamic pyruvic transaminase (SGPT):
• Leukocytes > 3,000/mcL
• Absolute neutrophil count > 1,500/mcL
• Platelets > 100,000/mcL
• Total bilirubin within normal institutional limits
• AST (SGOT)/ALT (SGPT) 3 cm in longest diameter, or multilobulated tumor appearance on MRI scan).
• Associated with a word recognition score of 160 mmHg and/or Diastolic Blood Pressure (DBP) > 90 mmHg despite antihypertensive medication; for children: please refer to Appendix D for age-appropriate values indicating ≥ Grade 2)
• History of cerebrovascular accident (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 central nervous system (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.