Safety & Efficacy Study of TPI 287 + Avastin in Adults With Glioblastoma That Progressed Following Prior Avastin Therapy

Inclusion Criteria:

1. Histologically proven GBM
2. Disease progression following radiation \& TMZ
3. 1st progression of GBM on bevacizumab-containing regimen or within 8 weeks of discontinuing bevacizumab. In either case, must have received a minimum of 8 weeks (4 infusions) of bevacizumab.
4. Baseline MRI must be performed after subject signs informed consent form (ICF), within 17 days of Day 1, \& on steroid dosage that has been stable or decreasing for at least 5 days
5. Recent resection of recurrent or progressive tumor allowed as long as at least 4 weeks have elapsed from date of surgery \& subject has recovered from surgery
6. Life expectancy \>12 weeks
7. Eighteen years old or older
8. KPS equal to or greater than 70
9. Recovered from toxic effects of prior therapy to \< Grade 2 toxicity per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) prior to Day 1. Minimum duration required between prior therapy \& Day 1 is:

   1. 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
   2. 4 weeks from prior cytotoxic therapy
   3. 4 weeks from prior experimental drug
   4. 6 weeks from nitrosoureas
   5. 3 weeks from procarbazine
   6. 1 week for non-cytotoxic agents (e.g., interferon, tamoxifen, \& cis-retinoic acid)
   7. 14 days from last dose of bevacizumab
10. Adequate bone marrow function \[absolute neutrophil count (ANC) \> 1,500/mm3 \& platelet count of \> 100,000/mm3\], adequate liver function \[alanine aminotransferase (ALT) \& aspartate aminotransferase (AST) \<3 x upper limit normal (ULN), alkaline phosphatase \<2 x ULN, \& total bilirubin \<1.5 mg/dL\], \& adequate renal function (BUN \& creatinine \<1.5 x ULN)
11. Minimum hemoglobin of 9 g/dL
12. Males \& women of childbearing potential must agree to abstain from sex or use an adequate method of contraception for duration of study \& for 6 months after last dose of study drug
13. Signed \& dated ICF prior to Screening evaluations

Exclusion Criteria:

1. Radiographic evidence of contrast-enhancing tumor crossing midline, leptomeningeal dissemination, gliomatosis cerebri or infratentorial tumor
2. Evidence or suspicion of disease metastatic to sites remote from supratentorial brain
3. Prior treatment with anti-vascular endothelial growth factor (VEGF) drugs other than bevacizumab
4. 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)
5. Prior treatment with histone deacetylase inhibitors or mammalian target of rapamycin (mTOR) inhibitors
6. Prior treatment with TPI 287
7. Treatment with Enzyme-Inducing Anti-Epileptic Drugs within 2 weeks prior to Day 1
8. Treatment with drugs or herbal supplements known to be strong inhibitors/inducers of cytochrome P450 3A4 or 2C8 within 2 weeks prior to Day 1
9. 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, dose counts against total dose limit.
10. Prior taxane, vincristine, or other microtubule inhibitor chemotherapies for treatment of GBM or other malignancy
11. 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 course of study
12. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1
13. Any condition, including the presence of clinically significant laboratory abnormalities, which places subject at unacceptable risk if he/she were to participate in study or confounds the ability to interpret data from study, including:

    1. Active infection including known AIDS or Hepatitis C or with a fever ≥38.5°C within 3 days prior to study enrollment
    2. Diseases or conditions that obscure toxicity or dangerously alter drug metabolism
    3. Serious intercurrent medical illness (e.g., symptomatic congestive heart failure)
14. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent subject from providing informed consent
15. Inadequately controlled hypertension (defined as systolic blood pressure \>140 mmHg and/or diastolic blood pressure \> 90 mmHg)
16. Prior history of hypertensive crisis or hypertensive encephalopathy
17. New York Heart Association Grade II or greater congestive heart failure
18. History of myocardial infarction or unstable angina within 6 months prior to Day 1
19. History of stroke or transient ischemic attack within 6 months prior to Day 1
20. Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1
21. History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1
22. Evidence of bleeding diathesis or significant coagulopathy (in absence of therapeutic anticoagulation)
23. Grade 2 or higher peripheral neuropathy per NCI CTCAE
24. History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1
25. Serious, non-healing wound, active ulcer, or untreated bone fracture
26. Proteinuria at Screening. Subjects with a urine dipstick protein ≥ 2+ at Screening will undergo a 24-hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible.
27. Known hypersensitivity to any inactive ingredient of bevacizumab
28. Known hypersensitivity to any inactive ingredient of TPI 287
29. Pregnancy (positive pregnancy test) or lactation
30. Inability to comply with protocol or study procedures
31. Previously or currently enrolled in Protocol No. TPI-287-17