Dose-Escalation Study of TPI 287 + Avastin Followed by Randomized Study of the Same Versus Avastin for Glioblastoma

Inclusion Criteria

• Histologically proven GBM
• Disease progression following radiation and TMZ
• Up to 2 prior relapses allowed
• Baseline MRI within 17 days of Day 1 & on steroid dosage that has been stable or decreasing for at least 5 days
• Recent resection of recurrent or progressive tumor allowed as long as at least 4 weeks have elapsed from date of surgery and the subject has recovered from surgery
• Life expectancy >12 weeks
• Eighteen years old or older
• KPS equal to or greater than 70
• Recovered from toxic effects of prior therapy to < Grade 2 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) prior to Day
• Minimum duration required between prior therapy and Day 1 is:
• At least 12 weeks from completion of radiation therapy except if there is unequivocal evidence for tumor recurrence in which case at least 4 weeks
• 4 weeks from prior cytotoxic therapy
• 4 weeks from prior experimental drug
• 6 weeks from nitrosoureas
• 3 weeks from procarbazine
• 1 week for non-cytotoxic agents, such as interferon, tamoxifen, & cis-retinoic acid
• Adequate bone marrow function (absolute neutrophil count > 1,500/mm3 and platelet count of > 100,000/mm3), adequate liver function [ALT and AST <3 x upper limit normal (ULN), alkaline phosphatase <2 x ULN, and total bilirubin <1.5 mg/dL], & adequate renal function (BUN and creatinine <1.5 x ULN)
• Minimum hemoglobin of 9 g/dL
• Males & women of childbearing potential must agree to abstain from sex or use an adequate method of contraception for the duration of study, & for 6 months after last dose of study drug
• Signed & dated informed consent prior to Screening evaluations

Exclusion Criteria

• Radiographic evidence of contrast-enhancing tumor crossing midline, leptomeningeal dissemination, gliomatosis cerebri or infratentorial tumor
• Evidence or suspicion of disease metastatic to sites remote from the supratentorial brain
• Prior treatment with bevacizumab or other anti-vascular endothelial growth factor (VEGF) drugs
• Prior treatment with tyrosine-kinase inhibitors targeting VEGF, platelet-derived growth factor, fibroblast growth factor, tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 2 (TIE-2), or angiopoietin (or their receptors)
• Prior treatment with histone deacetylase inhibitors or mammalian target of rapamycin (mTOR) inhibitors
• Prior treatment with TPI 287
• Treatment with Enzyme-Inducing Anti-Epileptic Drugs within 2 weeks prior to Day 1
• Treatment with drugs or herbal supplements known to be strong inhibitors/inducers of cytochrome P450 3A4 or cytochrome P450 2C8 within 2 weeks prior to Day 1
• Received more than one course of radiation therapy or more than a total dose of 65 Gy. May have received radiosurgery as part of initial therapy; however, the dose counts against the total dose limit.
• Prior taxane, vincristine, or other microtubule inhibitor chemotherapies for treatment of GBM or other malignancy
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study
• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1
• Any condition, including the presence of clinically significant laboratory abnormalities, which places subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study, including:
• Active infection including known AIDS or Hepatitis C or with a fever ≥38.5°C within 3 days prior to enrollment
• Diseases or conditions that obscure toxicity or dangerously alter drug metabolism
• Serious intercurrent medical illness (e.g., symptomatic congestive heart failure)
• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from providing informed consent
• Inadequately controlled hypertension (defined as systolic blood pressure >140 mmHg and/or diastolic blood pressure > 90 mmHg)
• Prior history of hypertensive crisis or hypertensive encephalopathy
• New York Heart Association Grade II or greater congestive heart failure
• History of myocardial infarction or unstable angina within 6 months prior to Day 1
• History of stroke or transient ischemic attack within 6 months prior to Day1
• Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1
• History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1
• Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
• Grade 2 or higher peripheral neuropathy per NCI CTCAE
• History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1
• Serious, non-healing wound, active ulcer, or untreated bone fracture
• Proteinuria at Screening. Subjects with a urine dipstick protein ≥2+ at Screening should undergo a 24-hour urine collection and must demonstrate ≤1g of protein in 24 hours to be eligible
• Known hypersensitivity to inactive ingredient of bevacizumab
• Known hypersensitivity to inactive ingredient of TPI 287
• Pregnancy or lactation
• Inability to comply with protocol