A Phase 2, Investigator Initiated Study to Determine the Safety, Efficacy and CNS Penetration of TH-302 in Recurrent High Grade Astrocytoma Following Bevacizumab

Inclusion Criteria:

1. At least 18 years of age

2. 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

3. Histologically confirmed high grade astrocytoma

4. Progression following both standard combined modality treatment with radiation and
temozolomide chemotherapy, as well as anti-angiogenic therapy (ie, bevacizumab)

5. Recovered from toxicities of prior therapy to grade 0 or 1

6. ECOG performance status of 0 or 1

7. Life expectancy of at least 3 months

8. Acceptable liver function

9. Acceptable renal function

10. Acceptable hematologic status

11. 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:

1. 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.

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

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

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

5. The subject has not recovered to National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE) v4.0 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.

6. The subject has evidence of wound dehiscence

7. 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

8. The subject is pregnant or breast-feeding.

9. The subject has serious intercurrent illness

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

11. The subject has 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

- Antiangiogenic agents whose primary mode of action is through the VEGF signaling
within 28 days prior to first dose of study drug

- Non-antiangiogenic 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

- 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 low-dose
chemotherapy within 14 days, or other cytotoxic chemotherapy within 28 days,
prior to first dose of study drug

- Prior treatment with carmustine wafers