Phase 1/2 CTO + Bevacizumab for Recurrent Glioma Post-Bevacizumab Failure

Inclusion Criteria:

* Phase 1 portion: Patients must have recurrent histologically confirmed diagnosis of World Health Organization (WHO) grade III or IV malignant glioma with no more than 3 prior progressions
* Phase 2 portion: Patients must have recurrent histologically confirmed diagnosis of WHO grade IV malignant glioma (glioblastoma or gliosarcoma) with no more than 3 prior progressions.
* Must have had a least 1 prior progression on a bevacizumab-containing regimen
* Age greater than or equal to 18 years
* Karnofsky ≥ 70%
* Bi-dimensionally measurable disease, as assessed by magnetic resonance imaging based on The Revised Assessment in Neuro-Oncology (RANO) criteria
* Absolute neutrophil count (ANC) ≥1000 cells/µl, Platelets ≥ 100,000 cells/µl (without transfusion within 14 days before enrollment)
* Adequate renal function as indicated by the following: Serum creatinine \< 1.25 times upper limit of normal (ULN) or calculated creatinine clearance ≥ 50 ml/min; Urine dipstick for proteinuria \< 2+ unless a 24-hour urine protein \<1 g of protein is demonstrated
* Prothrombin time (PT) ≤ 1.5 x ULN and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN within 14 days prior to first study treatment for patients not receiving anti-coagulation. The use of full-dose oral or parenteral anticoagulants is permitted as long as the PT or aPTT is within therapeutic limits (according to the medical standard of the enrolling institution) and the patient has been on a stable dose of anticoagulants for at least two weeks prior to the first study treatment.
* For patients on corticosteroids, they must be on a stable dose for 7 days prior to anticipated start of study drug, and the dose should not be escalated over entry dose level, if clinically possible
* Signed informed consent approved by the Institutional Review Board
* No evidence of \> grade 1 active central nervous system (CNS) hemorrhage on the baseline magnetic resonance imaging (MRI) or computed tomography (CT) scan
* Female patients must not be pregnant or breast-feeding. Female patients of childbearing potential (defined as \< 2 years after last menstruation or not surgically sterile) must use a highly effective contraceptive method (allowed methods of birth control, \[i.e. with a failure rate of \< 1% per year\] are implants, injectables, combined oral contraceptives, intra-uterine device (IUD) (only hormonal), sexual abstinence or vasectomized partner) during the trial and for a period of \> 6 months following the last administration of trial drug(s). Female patients with an intact uterus (unless amenorrhea for the last 24 months) must have a negative serum pregnancy test within 48 hours prior to first study treatment.
* Fertile male patients must agree to use a highly effective contraceptive method (allowed methods of birth control \[i.e. with a failure rate of \< 1% per year\] include a female partner using implants, injectables, combined oral contraceptives, IUDs \[only hormonal\], sexual abstinence or prior vasectomy) during the trial and for a period of \> 6 months following the last administration of trial drugs.

Exclusion Criteria:

* Pregnancy or breast-feeding
* Co-medication that may interfere with study results, for example, immuno-suppressive agents other than corticosteroids
* Active infection requiring intravenous (IV) antibiotics within 7 days before enrollment
* Prior, unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin
* Taking cytochrome P450 3A4 (CYP3A4) inducers and moderate or strong inhibitors (Note: Corticosteroids are allowed, as long as patients have been on a stable dose for 7 days prior to anticipated start of study drug, and the dose should not be escalated over entry dose level, if clinically possible)
* Less than 12 weeks from radiation therapy, unless progressive disease outside of the radiation field or progression on 2 consecutive scans or histopathologic confirmation
* Treated with immunotherapeutic agents or vaccines within 4 weeks before enrollment, unless the patient has recovered from the expected toxic effects of such therapy
* Treated with alkylating agents within 4 weeks before enrollment or treated with daily or metronomic chemotherapy within 1 week before enrollment, unless the patient has recovered from the expected toxic effects of such therapy
* Prior chemotherapy (non-alkylating agents) within 2 weeks before enrollment, unless the patient has recovered from the expected toxic effects of such therapy
* Current, recent (within 4 weeks of the first infusion of this study) use of an experimental drug, unless the patient has recovered from the expected toxic effects of study therapy

Vascular endothelial growth factor (VEGF) Inhibitor-Specific Exclusion Criteria are:

* Inadequately controlled hypertension (defined as systolic blood pressure \> 150 mmHg and/or diastolic blood pressure \> 100 mmHg) within 28 days of first study treatment
* Prior history of hypertensive crisis, hypertensive encephalopathy, reverse posterior leukoencephalopathy syndrome (RPLS)
* Prior history of gastrointestinal perforation or abscess
* Clinically significant (active) cardiovascular disease, for example cerebrovascular accidents ≤ 6 months prior to study enrollment, myocardial infarction ≤ 6 months prior to study enrollment, unstable angina, New York Heart Association (NYHA) Grade 2 or greater congestive heart failure (CHF), or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with protocol treatment
* History or evidence upon physical/neurological examination of central nervous system disease (for example, seizures) unrelated to cancer unless adequately controlled by medication or potentially interfering with protocol treatment
* Significant vascular disease (for example, aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to start of study treatment
* History of pulmonary hemorrhage/hemoptysis ≥ grade 2 (defined as ≥ 2.5 mL bright red blood per episode) within 1 month of first study treatment
* History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (in the absence of therapeutic anticoagulation)
* Current or recent (within 10 days of study enrollment) use of aspirin (\> 325 mg/day), clopidogrel (\> 75 mg/day) or equivalent. Prophylactic or therapeutic low molecular weight heparin (LMWH) is allowed.
* Surgical procedure (including open biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to first study treatment, or anticipation of need for major surgical procedure during the course of the study
* Minor surgical procedure, for example, stereotactic biopsy, within 7 days of first study treatment; placement of a vascular access device, within 2 days of first study treatment
* History of intracranial abscess within 6 months prior to first study treatment
* History of active gastrointestinal bleeding within 6 months prior to first study treatment
* Serious, non-healing wound, active ulcer, or untreated bone fracture
* Known hypersensitivity to any component of bevacizumab or CTO