|Inclusion Criteria:||1) The subject has a histologically confirmed diagnosis of AG (including AA, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma) or Grade 4 astrocytic tumor which includes glioblastoma, giant cell glioblastoma, gliosarcoma, and glioblastoma with oligodendroglial components.|
2) For subjects in Arm 1 and MTD expansion cohort: 1) The subject has had no previous treatment except surgery (ie, no previous RT, local chemotherapy, or systemic therapy). 2) The subject must be able to initiate RT within 49 days but no sooner than 28 days after surgery with adequate wound healing prior to starting study treatment.
3) (2. continued) 3) For subjects in Arm 1c documentation of non-methylated MGMT promoter status by means of a quantitative methylation-specific polymerase chain reaction (MS-PCR) test applied to tumor samples. 4) For subjects in MTD cohort documentation of MGMT promoter status by means of a quantitative methylation-specific polymerase chain reaction (MS-PCR) test applied to tumor samples.
4) For subjects in Arm 2: 1) The subject has completed a standard first line regimen of concurrent TMZ and RT for newly diagnosed GB or AG followed by a rest phase(28 days in duration after chemoradiation ), and has not had any other previous treatment except surgery (including any other regimens of RT and local or systemic chemotherapy. Note: stereotactic radiosurgery is allowed). 2) For subjects in Arm 2a/c/d, the subject has been on a TMZ dose of 200 mg/m2/day administered on Days 1-5 of 28-day cycles for a minimum of 1 cycle without unacceptable toxicity
5) (4. continued) (ie, requiring a dose interruption or reduction) and without progression of their disease. 3) For subjects in Arm 2b/e, the subject has been on a TMZ dose of 100 mg/m2/day administered on Days 1-21 of 28-day cycles for a minimum of 1 cycle without unacceptable toxicity (ie, requiring a dose interruption or reduction) and without progression of their disease. 4) The subject is expected to receive at least 2 more cycles of TMZ treatment to be given in combination with XL184
6) Subjects must be able to undergo serial MRIs (CT may not substitute for MRI)
7) A brain MRI must be performed within 14 days prior to first dose of study treatment. Subjects requiring glucocorticoids must be on a dose that has been stable or decreasing for at least 5 days prior to the scan.
8) The subject is >/= 18 years old.
9) A sample of the subject's tumor (archival or fresh tumor tissue) should be identified and designated for laboratory analysis. At least 10 unstained slides (>/= 10 sections, preferably 10 microns thick, without cover slips), or a block (with >/= 0.5 cm3 tissue composed primarily of tumor), should be submitted. The eligibility of subjects with < 10 unstained slides of available tissue must be discussed with the sponsor.
10) The subject has a Karnofsky performance status of >/= 70% and has the ability to swallow whole capsules.
11) The subject has organ and marrow function as follows: 1) ANC >/= 1500/mm^3. 2) Platelets >/= 100,000/mm^3. 3) Hemoglobin >/= 10 g/dL (may be transfused to maintain or exceed this level). 4) Bilirubin </= 1.5 × the upper limit of normal (ULN). 4) Serum creatinine </= 1.5 × the ULN or calculated creatinine clearance >/= 60 mL/min and urine dipstick for proteinuria < 2+ or urine protein/creatinine ratio < 1. Subjects with >/= 2+ proteinuria by urine dipstick at baseline should have </= 1 g of protein in 24 hours. 5) ALT and AST </= 2.5 × the ULN.
12) (11. continued) 6) International Normalized Ratio (INR) < 1.5 or prothrombin time/partial thromboplastin time (PT/PTT) within 1.5 × ULN. Subjects receiving Coumadin must be converted to low-molecular-weight heparin (LMWH) such as enoxaparin 1 mg/kg q12h and INR should be < 1.5 prior to initiation of XL184. Subjects on a stable dose of unfractionated heparin or LMWH therapy are eligible provided INR < 1.5 and PTT within 1.5-2.5 × control prior to initiation of XL184.
13) The subject has had 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.
14) The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document.
15) 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).
16) Female subjects of childbearing potential must have a negative pregnancy test at screening. Females of childbearing potential are defined as premenopausal females capable of becoming pregnant, ie, females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression, or any reason other than menopause.