Study of Axitinib in Patients With Neurofibromatosis Type 2 and Progressive Vestibular Schwannomas

NF2 is a condition that mainly affects the skin and nervous system. It causes non-cancerous
tumors to grow on the nerves around a person's body. Some signs of NF2 include a gradual loss
of hearing and tumors growing on the skin, the brain and the spinal cord, which can lead to
complications.

AXITINIB is an oral drug (taken by mouth) that is approved by the United States Food and Drug
Administration (FDA) for the treatment of other types of tumors. However, in this research
study, AXITINIB is considered investigational because it is not approved by the FDA for
treatment of NF2. Much is known regarding how well it is tolerated (handled), but
investigators do not know if it is effective in treating NF2.

This research study will test whether AXITINIB may shrink tumors commonly found in patients
with NF2 or stop them from growing. This will help to decide if AXITINIB should be used to
treat NF2 patients in the future. AXITINIB is a drug that has been used to treat various
forms of cancer. It has not been studied for the treatment of tumors in NF2 patients.
Investigators have selected AXITINIB for this clinical trial in patients with NF2 and
NF2-related tumors because a very similar drug, bevacizumab, can shrink Vestibular
Schwannomas (VS) in some NF2 patients.

Pfizer, Inc., the manufacturer of the study drug, AXITINIB, will provide the AXITINIB being
used in this study.

Primary Objective: To estimate the objective volumetric response rates to axitinib in adult
NF2 patients with VS.

Secondary Objectives: To assess the toxicity of axitinib given daily in patients with NF2 and
to examine the association of objective measures of response on MRI, i.e. volumetric tumor
analysis with clinical measures of response, i.e. (audiogram), as well as quality of life
assessments (NFTI-QOL). In addition, response in non-VS tumors, such as other schwannomas and
meningiomas, may be explored.

Inclusion criteria

- Age ≥18 years

- Meets clinical diagnostic criteria for NF2

- At least one volumetrically measurable and ≥1 cc NF2-related VS (histological
confirmation not required)

- MRI evidence of progression (either as >2 mm increase in maximum linear diameter on
conventional MRI, or a >20%volume increase by 3D volumetrics) over the past ≤18
months, OR progressive hearing loss, defined as a decline in word recognition score
below the 95% critical difference interval from baseline score related to VS (i.e.,
not due to prior interventions such as surgery or radiation)

- Karnofsky performance status (PS) 60-100%. Note: Patients who are unable to walk
because of paralysis, but who are up in a wheelchair, will be considered ambulatory
for the purpose of assessing the performance score.

- Adequate bone marrow function as shown by: absolute neutrophil count ≥1.5 x 10^9/L,
Platelets ≥100 x 10^9/L, Hb >9 g/dL

- Adequate liver function as shown by:

- serum bilirubin ≤1.5 x upper limit of normal (ULN)

- ALT and AST ≤2.5x ULN

- INR ≤1.5. (anticoagulation with low molecular weight heparin is allowed if on a stable
dose for >2 weeks at time of enrollment.)

- Adequate renal function: serum creatinine ≤1.5 x ULN

- Fully recovered from acute toxic effects of any prior chemotherapy, biological
modifiers or radiotherapy

- Any neurologic deficits must be stable for ≥1 week

- Able to provide signed informed consent Exclusion criteria

- Patients currently receiving medical anticancer therapies or who have received medical
anticancer therapies within 4 weeks of the start of study drug (including
chemotherapy, antibody based therapy, etc.)

- Radiation therapy to a study target tumor within 1 year prior to enrollment, or any
radiation therapy within 4 weeks prior to enrollment.

- Patients who have had a major surgery or significant traumatic injury within 4 weeks
of start of study drug, patients who have not recovered from the side effects of any
major surgery (defined as requiring general anesthesia) or patients that may require
major surgery during the course of the study

- Prior treatment with bevacizumab or other agents targeting vascular endothelial growth
factor (VEGF) or VEGF receptor

- Prior treatment with any investigational drug within the preceding 4 weeks

- Unstable or rapidly progressive disease, including patients who require
glucocorticoids for symptomatic control of brain or spinal tumors

- Treatment with strong CYP3A4 enzyme inhibitors or inducers, including but not limited
to ketoconazole, itraconazole, ritonavir, phenytoin, carbamazepine, rifampin,
rifabutin, phenobarbital and St. John's wort

- Requirement of therapeutic anticoagulant therapy with oral vitamin K antagonists;
low-dose anticoagulants for maintenance of patency of central venous access devise or
prevention of deep venous thrombosis is allowed; therapeutic use of low molecular
weight heparin (or similar parenteral drug) for venous-thromboembolic disease is
allowed.

- Other malignancies within the past 3 years except for adequately treated carcinoma of
the cervix or basal or squamous cell carcinomas of the skin.

- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as:

- Symptomatic congestive heart failure of New York heart Association Class III or IV

- unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction
within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any
other clinically significant cardiac disease

- severely impaired lung function as defined as spirometry and diffusion capacity of
lung for carbon monoxide (DLCO) that is 50% of the normal predicted value and/or O2
saturation that is 90% or less at rest on room air

- active (acute or chronic) or uncontrolled severe infections

- liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C).

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of axitinib (e.g., ulcerative disease, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)

- Patients with an active bleeding diathesis

- Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods. Adequate contraception
must be used throughout the trial and for 8 weeks after the last dose of study drug,
by both sexes. (Females of childbearing potential must have a negative serum pregnancy
test within 7 days prior to administration of axitinib)

- Male patient whose sexual partner(s) are women of child bearing potential, who are not
willing to use adequate contraception, during the study and for 8 weeks after the end
of treatment

- History of noncompliance to medical regimens

- Patients unwilling to or unable to comply with the protocol