TVB- 2640 in Combination With Bevacizumab in Patients With First Relapse of High Grade Astrocytoma

Eligible patients will be randomized into 2 separate arms:

• Arm number one will receive Bevacizumab every 2 weeks in combination with TVB-2640 from day 1 until day 28 of the first cycle.
• Arm number two will receive Bevacizumab alone every 2 weeks, from on days 1 and 15 of the first until day 28 of the first cycle.
• MR-Spectroscopy will be obtained on all patients (both arms) at day 28 of first cycle.
• Starting on cycle 2 day 1, all patients will converge to a single arm and will continue to receive bevacizumab every 2 weeks in combination with TVB-2640. Every cycle will last 28 days.

Inclusion criteria

• At least 18 years of age
• Ability to understand the purposes and risks of the study and has signed a written informed consent form approved by the investigator's IRB/Ethics Committee
• Histologically confirmed high-grade astrocytoma
• Progression following standard combined modality treatment with radiation and temozolomide chemotherapy
• Recovered from reversible toxicities of prior therapy to Grade 0 or Grade 1
• ECOG Performance Status of 0 to 2
• Life expectancy of at least 3 months
• Adequate renal and liver function: AST/ALT ≤ 3 x ULN, Bilirubin ≤ 1.5 times ULN, Creatinine ≤ ULN
• Adequate hematologic status (without hematologic support): Hemoglobin ≥ 9 g/dL, ANC ≥ 1500 cells/ml, Platelets ≥ 100,000 cells/ml
• All women of childbearing potential must have a negative serum pregnancy test and male and female subjects must agree to use effective means of contraception (for example, surgical sterilization or the use of barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an IUD) with their partner from entry into the study through six months after the last dose.

Exclusion criteria

• Receiving warfarin (or other coumarin derivatives) and is unable to switch to low molecular weight heparin (LMWH) before the first dose of study drug
• Evidence of acute intracranial or intratumoral hemorrhage either by MRI or CT scan. Subjects with resolving hemorrhage changes punctuate hemorrhage, or hemosiderin are eligible
• Unable to undergo MRI scan (e.g., pacemaker)
• Received enzyme-inducing anti-epileptic agents within 14 days of study drug (e.g., carbamazepine, phenytoin, phenobarbital, primidone)
• Not recovered to a NCI CTCAE v.4.03 Grade ≤ 1 from AEs (except alopecia and lymphopenia) due to surgery, antineoplastic agents, investigational drugs, or other medications that were administered prior to study drug
• Evidence of wound dehiscence
• Pregnant or breast-feeding
• Clinically significant Dry Eye or necessary contact lens use
• Serious intercurrent illness such as: Hypertension (two or more blood pressure readings performed at screening of > 150 mmHg systolic or > 100 mmHg diastolic) despite optimal treatment, Non-healing wound or ulcer, Uncontrolled life threatening cardiac arrhythmias, Untreated hypothyroidism, Uncontrolled active infection, Symptomatic congestive heart failure or unstable angina pectoris within 3 months prior to study drug, Gastrointestinal perforation, abdominal fistula, intra-abdominal abscess within 1 year
• Inherited bleeding diathesis or coagulopathy with the risk of bleeding
• HIV , Hepatitis B or C documented infections
• Received any of the following prior anticancer therapy: Non-standard radiation therapy such as brachytherapy, systemic radioisotope therapy (RIT), or intra-operative radiotherapy (IORT). Note: stereotactic radiosurgery (SRS) is allowed, Non-antiangiogenic therapy (including investigational agents and small molecular kinase inhibitors) within 7 days or 5 half-lives, whichever is shorter, prior to the first dose of study drug, Biologic agents (antibodies, immune modulators, vaccines, cytokines) within 21 days prior to first dose of study drug, Nitrosoureas or mitomycin C within 42 days or metronomic/protracted