TH-302 in Combination With Bevacizumab for Glioblastoma

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:

• Bilirubin ≤ 1.5 times upper limit of normal
• 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):

• ANC ≥1500 cells/uL
• Platelet count ≥100,000/uL
• 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:

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

• Non-standard radiation therapy such as brachytherapy, systemic radioisotope therapy, or intra-operative radiotherapy (IORT). Note: stereotactic radiosurgery (SRS) is allowed
• 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
• 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
• Prior treatment with TH-302