A Study in Subjects With Recurrent Malignant Glioma

Inclusion Criteria

1. Histologically confirmed diagnosis of Grade 3 or 4 malignant glioma.
2. All subjects who have a first or second recurrence following primary management with surgical resection or biopsy, radiotherapy and up to 2 prior systemic treatments with addition of:

   * No prior bevacizumab treatment is allowed for Cohort 1 and Cohort 2.
   * Subjects must have disease progression following prior bevacizumab treatment for Cohort 3.
   * For all cohorts, no prior anti-vascular endothelial growth factor (VEGF/VEGFR) therapy except for bevacizumab as specified above.
3. Karnofsky score of 70% or greater.
4. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP less than 150/90 mmHg at screening and no change in antihypertensive medications within 1 week prior to the Screening Visit.
5. Adequate renal function, adequate bone marrow function, adequate blood coagulation function and adequate liver function, as defined in protocol.
6. No evidence of hemorrhage on the baseline magnetic resonance imaging (MRI) scan other than in those subjects who are stable grade 1.

Exclusion criteria:

1. Females who are pregnant or breastfeeding.
2. Subjects who received enzyme-inducing anti-epileptic agents within 14 days before the first dose of study drug (eg, carbamazepine, phenytoin, phenobarbital, primidone, or oxcarbazepine).
3. Active infection requiring intravenous antibiotics.
4. Therapeutic anti-coagulation with warfarin, aspirin, nonsteroidal anti-inflammatory drugs or clopidogrel (low molecular weight heparin is acceptable).
5. Subjects with 24-hour urine protein greater than or equal to 1 gm.
6. Prior surgical resection within 4 weeks, or prior stereotactic biopsy within 2 weeks, of Screening Visit.
7. Prior radiotherapy within 12 weeks unless there is a new area of enhancement consistent with recurrent tumor outside of the radiation field, or there is biopsy-proven unequivocal viable tumor on histopathologic sampling.
8. Prior chemotherapy (6 weeks for nitrosoureas), or any investigational agent within 4 weeks unless the subject has recovered from all anticipated toxicities associated with that therapy; prior bevacizumab therapy (Cohorts 1 and 2); for Cohort 3, prior bevacizumab therapy within 3 weeks.
9. Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II ; unstable angina; myocardial infarction or stroke within 6 months of the first dose of study drug; or cardiac arrhythmia requiring medical treatment.
10. Prolongation of QTc interval to greater than 480 msec.
11. Active hemoptysis (bright red blood of at least 1/2 teaspoon) within 3 weeks prior to the first dose of study drug.