Sorafenib in Children and Young Adults With Recurrent or Progressive Low-Grade Astrocytomas

Novel therapies are urgently needed for children with relapsed LGA who are not surgical
candidates and/or have exhausted standard chemotherapy approaches. Although a vast number of
"molecular targeted" agents have been developed over the past decade for the treatment of
cancer, none have been evaluated for the treatment of LGAs. Recently, genetic alterations
resulting in oncogenic BRAF have been identified to be highly prevalent in LGAs, providing a
rational target for therapeutic intervention.

The aims of this clinical trial are to estimate the efficacy, as well as safety and
tolerability of sorafenib, a RAF and tyrosine kinase receptor inhibitor, in the treatment of
pediatric patients with recurrent LGA. Sorafenib targets several pathways that, based on
preliminary data from us and others, are likely contributing to the growth of LGAs:
oncogenic BRAF, which is present in the majority of grade I LGAs and VEGFR2 and PDGFR, which
are well-described mediators of tumor angiogenesis. Since sorafenib inhibits a number of
additional kinases whose role in LGA growth has not yet been explored, it is possible that
inhibition of pathways other than the primary targets may result in additional anti-tumor
effects of sorafenib in LGA. Although the investigators hypothesize that LGAs with oncogenic
BRAF should be most sensitive to sorafenib, the additional targets of sorafenib may also
result in significant anti-tumor effects in LGAs with wild-type BRAF. Therefore, the
investigators propose to evaluate the efficacy of sorafenib in children with LGAs in a
translational clinical trial, stratified by BRAF status and tumor grade.

The investigators expect to learn the following from this clinical translational trial:

- The anti-tumor activity of sorafenib in pediatric LGAs

- The safety and tolerability of sorafenib in pediatric patients with LGAs

- The association of molecular target expression, e.g. oncogenic BRAF, with response
rates

The investigators will use the results of the clinical translational trial to determine if
sorafenib warrants further clinical study in pediatric LGAs. If the investigators find
associations between molecular target expression and response, further studies may be
limited to or focus on patients whose tumors have specific molecular features, such as
oncogenic BRAF. Sorafenib has also shown promise in combination with classic chemotherapy
and can be given together with carboplatin, which is one of the most active agents in LGAs.
Therefore, possible synergy between sorafenib and traditional chemotherapy used in the
treatment of LGAs, such as carboplatin, could be explored in future clinical trials.

Inclusion Criteria:

- Age: greater than or equal to 2 years of age

- Patients with neurofibromatosis-1 (NF1) are eligible

- Recurrent/progressive optic pathway gliomas (OPG) by MRI criteria, after standard
therapy - histologic confirmation not required OR Histologically confirmed,
radiographically recurrent or progressive low-grade glioma (WHO grade I or II) by MRI
criteria, after standard therapy.

- Karnofsky performance status (PS) 60-100% (greater than or equal to 16 years of age)
OR Lansky PS 60-100% (< 16 years of age)

- Absolute neutrophil count ≥ 1,000/mm³ (unsupported)

- Platelet count ≥ 75,000/mm³ (unsupported)

- Normal PT, PTT, and INR (for patients on prophylactic anticoagulation only)

- Diastolic blood pressure (DBP) ≤ the 95th percentile for age and gender and not
currently receiving medication for the treatment of hypertension.

- Adequate pulmonary function, defined as: no evidence of dyspnea at rest, no exercise
intolerance, and pulse oximetry > 94% if termination is clinically indicated.

- Not received myelosuppressive chemotherapy or treatment with biologicals or
monoclonal antibodies within 4 weeks of enrollment onto this study (6 weeks if prior
nitrosurea)

- At least 7 days since the completion of therapy with a hematopoietic growth factor
and at least 14 days from the last administration of PEGylated GCSF (Neulasta®)

- If prior radiation therapy, ≥ 6 months must have elapsed since the last fraction for
craniospinal therapy and ≥ 3 months for focal radiotherapy including radiosurgery.

- If prior surgery, ≥ 8 weeks must have elapsed since (≥ 4 weeks for minor
surgery/procedures including central line placement)

- Steroids are allowed for progressive symptoms but patient must be on a stable or
decreasing dose for at least 1 week prior to study entry

- Any neurologic deficits must be stable for ≥ 1 week

Exclusion Criteria:

- Patients with serious concurrent infection or medical illness, including overt
hepatic or renal disease, which would jeopardize the ability of the patient to
receive the treatment outlined in this protocol with reasonable safety.

- Baseline hypertension greater than grade 1.

- Prior treatment with sorafenib

- Other concurrent investigational drugs

- Other concurrent anticancer agents or therapies, including chemotherapy,
radiotherapy, immunotherapy, or biologic therapy

- Concurrent therapeutic anticoagulation. Prophylactic anticoagulation (i.e. low dose
heparin) of venous or arterial access devices is allowed.

- Concurrent administration of any of cytochrome P450 enzyme-inducing agents, including
grapefruit juice and drugs listed under Section 9.7.

- Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.

- Uncontrolled hypertension Known human immunodeficiency virus (HIV) infection or
chronic Hepatitis B or C.

- Active clinically serious infection

- Thrombolic or embolic events such as a cerebrovascular accident including transient
ischemic attacks within the past 6 months.

- Pulmonary hemorrhage/bleeding event

- Any other hemorrhage/bleeding event

- Serious non-healing wound, ulcer, or bone fracture.

- Evidence or history of unresolved bleeding diathesis or coagulopathy.

- Major surgery, open biopsy or significant traumatic injury within 4 weeks of first
study drug.

- Known or suspected allergy to sorafenib.

- Any malabsorption problem.

- Patients with history of any prior CNS bleeding.

- Patients with any non-healed wounds.