Dual center, single arm, two-stage, non-blinded, prospective study of combination therapy bevacizumab at 10mg/kg and TH-302 at 670mg/m2 every 2 weeks (6 week cycle) until disease progression.

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 glioblastoma

• Progression following both standard combined modality treatment with radiation and temozolomide chemotherapy, as well as bevacizumab

• Recovered from toxicities of prior therapy to grade 0 or 1

• ECOG performance status ≤ 2

• Life expectancy of at least 3 months

• Acceptable liver function:

  1. Bilirubin ≤ 1.5 times upper limit of normal
  2. AST (SGOT) and ALT (SGPT) ≤ 3.0 times upper limit of normal (ULN);

• Acceptable renal function:

  a. Serum creatinine ≤ULN

• Acceptable hematologic status (without hematologic support):

  1. ANC ≥1500 cells/uL
  2. Platelet count ≥100,000/uL
  3. Hemoglobin ≥9.0 g/dL

• 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 (surgical sterilization or the use or 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 6 months after the last dose

Exclusion Criteria:

• The subject is receiving warfarin (or other coumarin derivatives) and is unable to switch to low molecular weight heparin (LMWH) before the first dose of study drug.

• The subject has evidence of acute intracranial or intratumoral hemorrhage either by MRI or computerized tomography (CT) scan. Subjects with resolving hemorrhage, punctate hemorrhage, or hemosiderin are eligible.

• The subject is unable to undergo MRI scan (eg, has pacemaker).

• The subject has received enzyme-inducing anti-epileptic agents within 14 days of study drug (eg, carbamazepine, phenytoin, phenobarbital, primidone).

• The subject has not recovered to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 Grade ≤ 1 from AEs (except alopecia, anemia and lymphopenia) due to surgery, antineoplastic agents, investigational drugs, or other medications that were administered prior to study drug.

• The subject has evidence of wound dehiscence

• Severe chronic obstructive or other pulmonary disease with hypoxemia (requires supplementary oxygen, symptoms due to hypoxemia or oxygen saturation <90% by pulse oximetry after a 2 minute walk) or in the opinion of the investigator any physiological state likely to cause normal tissue hypoxia

• The subject is pregnant or breast-feeding.

• The subject has serious intercurrent illness, such as:

  1. hypertension (two or more blood pressure [BP] readings performed at screening of > 150 mmHg systolic or > 100 mmHg diastolic) despite optimal treatment
  2. non-healing wound, ulcer, or bone fracture
  3. significant cardiac arrhythmias
  4. untreated hypothyroidism
  5. uncontrolled active infection
  6. symptomatic congestive heart failure or unstable angina pectoris within 3 months prior study drug
  7. myocardial infarction, stroke, transient ischemic attack within 6 months
  8. gastrointestinal perforation, abdominal fistula, intra- abdominal abscess within 1 year
  9. history or clinical evidence of pancreatitis within 2 years

• The subject has inherited bleeding diathesis or coagulopathy with the risk of bleeding.

• The subject has received any of the following prior anticancer therapy:

  1. Non-standard radiation therapy such as brachytherapy, systemic radioisotope therapy, or intra-operative radiotherapy (IORT). Note: stereotactic radiosurgery (SRS) is allowed
  2. Non-bevacizumab systemic therapy (including investigational agents and small-molecule kinase inhibitors) or non-cytotoxic hormonal therapy (eg, tamoxifen) within 7 days or 5 half-lives, whichever is shorter, prior first dose of study drug
  3. Biologic agents (antibodies, immune modulators, vaccines, cytokines) within 21 days prior to first dose of study drug
  4. Nitrosoureas or mitomycin C within 42 days, or metronomic/protracted low-dose chemotherapy within 14 days, or other cytotoxic chemotherapy within 28 days, prior to first dose of study drug
  5. Prior treatment with carmustine wafers
  6. Prior treatment with TH-302

Adverse events are collected from start of drug administration until 30 days after study drug is discontinued, giving a total of 5 months potential evaluation period.