The purpose of this study is to determine the highest safe dose of XL184 administered orally in combination with temozolomide (TMZ, Temodar®) and radiation therapy (RT). XL184 is a new chemical entity that inhibits VEGFR2, MET, and RET, kinases implicated in tumor formation, growth and migration. Temozolomide (TMZ, Temodar®) is an orally administered alkylating agent. It is approved by the Food and Drug Administration (FDA) for the treatment of newly diagnosed glioblastoma (GB) patients when given in combination with radiation therapy (RT) followed by maintenance treatment. First-line treatment for patients with GB consists of a concurrent phase (6-7 weeks in duration) during which TMZ is given with RT, followed by a rest phase (4 weeks in duration; to allow for recovery from delayed toxicity, if present), and a maintenance phase, during which patients receive TMZ for approximately twelve 28-day cycles. To determine the highest safe dose, subjects will receive different amounts of XL184 at different times according to the phase of TMZ and radiation therapy. The first group of subjects will receive the lowest dose of XL184. As long as no medically unacceptable side effects are noted, the dose will be increased for the next group. If the dose is not well-tolerated by the first group of subjects, the dose will be lowered for the next group.

Inclusion Criteria:

• Histologically confirmed diagnosis of Grade 4 astrocytic tumor, which includes glioblastoma, giant cell glioblastoma, gliosarcoma, and glioblastoma with oligodendroglial components.
• Must have had a partial or complete surgical resection of the Grade 4 astrocytic tumor.
• Subjects in Arm 1 must have had no previous treatment except surgery (ie, no previous RT, local chemotherapy, or systemic therapy). Subjects must meet certain other eligibility requirements.
• Subjects in Arm 2 must have completed a standard first line regimen of concurrent TMZ and RT for newly diagnosed GB, followed by a rest phase, and has not had any other previous treatment except surgery (including any other regimens of RT and local or systemic chemotherapy). Subjects must meet certain other eligibility requirements.
• Subjects must be able to undergo serial MRIs (computerized tomography [CT] may not substitute for magnetic resonance imaging [MRI]).
• Must be ≥ 18 years old.
• Must have a Karnofsky performance status of ≥ 70% and the ability to swallow whole capsules
• Must have no other diagnosis of malignancy (except surgically excised non-melanoma skin cancer or carcinoma in situ of the cervix, treated early stage prostate cancer, or a malignancy diagnosed ≥ 2 years previously with no current evidence of disease and no therapy within two years prior to enrollment on this study).
• Must be capable of understanding and complying with the protocol requirements and has signed the informed consent document.
• Sexually active fertile subjects (male and female) must agree to use accepted methods of contraception during the course of the study and for 3 months after the last dose of study drug(s).
• Female subjects of childbearing potential must have a negative pregnancy test at screening.

Exclusion Criteria:

• Subject has received prior systemic chemotherapy or RT (Arm 1) or prior systemic chemotherapy other than TMZ (Arm 2), biologic agents, or any other type of investigational agent for the treatment of brain tumors. Subjects who have progressed on TMZ are not eligible.
• Subject has evidence of acute intracranial or intratumoral hemorrhage > Grade 1 either by MRI or CT scan. Subjects with resolving hemorrhage changes, punctate hemorrhage, or hemosiderin may enter the study.
• Subject has serious intercurrent illness such as: hypertension despite optimal treatment, or significant cardiac arrhythmias; or a recent history of serious disease such as symptomatic congestive heart failure, or abdominal fistula or gastrointestinal (GI) perforation within 6 months, prior to starting study treatment.
• Subject has had major surgery within 28 days prior to starting study treatment, or had non water-tight dural closure during previous surgery, or has unhealed wounds from previous surgery.
• Subject has inherited bleeding diathesis or coagulopathy with the risk of bleeding.
• Subject is pregnant or breastfeeding.
• Subject is known to be positive for the human immunodeficiency virus (HIV) (a test for HIV at screening is not required).
• Subject has a previously-identified allergy or hypersensitivity to components of either the XL184 or TMZ formulations.
• Subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.