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

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.

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 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:

- 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 Maximum Serum Creatinine (mg/dL) 6 to < 10 years 1(Male) 1(Female) 10 to < 13
years 1.2(Male) 1.2(Female) 13 to < 16 years 1.5(Male) 1.4(Female

≥ 16 years 1.7(Male) 1.4(Female)

- 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.