A Phase 3, Pivotal Trial of VB-111 Plus Bevacizumab vs. Bevacizumab in Patients With Recurrent Glioblastoma (GLOBE)

Inclusion criteria

• First or second progression of Glioblastoma;
• Measurable disease by RANO criteria at progression;
• Patients ≥18 years of age;
• Patient may have been operated for recurrence. If operated: residual and measurable disease after surgery is required;
• Surgery completed at least 28 days before randomization;
• An interval of at least 12 weeks between prior radiotherapy or at least 23 days from prior chemotherapy, 42 days from nitrosoureas and enrollment in this study;
• Adequate performance, i.e."Karnofsky Performance Score" of at least 70%;
• Adequate renal, liver, and bone marrow function according to the following criteria:

• Absolute neutrophil count ≥1500 cells/ml,
• Platelets ≥ 100,000 cells/ml,
• Total bilirubin within upper limit of normal (ULN),
• Aspartate aminotransferase (AST) ≤ 2.0 X ULN,
• Serum creatinine level ≤ ULN or creatinine clearance ≥ 50 ml/min for patients with creatinine levels above normal limits (creatinine clearance calculated by the Cockcroft-Gault formula, see Appendix II),
• PT, PTT (in seconds) not to be prolonged beyond >20% of the upper limits of normal.

Exclusion criteria

• Prior anti-angiogenic therapy including VEGF sequestering agents (i.e. bevacizumab, aflibercept, etc.) or VEGFR inhibitors (cedirinib, pazopanib, sunitinib, sorafenib, etc.);
• Prior stereotactic radiotherapy;
• Pregnant or breastfeeding patients;
• Concomitant medication that may interfere with study results; e.g. immunosuppressive agents other than corticosteroids;
• Active infection;
• Evidence of significant CNS haemorrhage i.e. CTCAE grade 2 or above;
• Expected to have surgery during study period;
• Patients with active vascular disease, either myocardial or peripheral (i.e. acute coronary syndrome, cerebral stroke, transient ischemic attack or arterial thrombosis or symptomatic peripheral vascular disease within the past 3 months);
• Patients with known proliferative and/or vascular retinopathy;
• Patients with known liver disease (alcoholic, drug/toxin induced, genetic, or autoimmune);
• Patients with known active second malignancy other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer, and ductal or lobular carcinoma in situ of the breast. Patients are not considered to have a currently active malignancy if they have completed anticancer therapy and have been disease free for greater than 2 years prior to screening;
• Patients testing positive to one of the following viruses: HIV, HBV and HCV within the last 6 months;
• Patients that have undergone major surgery within the last 4 weeks before enrollment;
• Patients who have received treatment with any other investigational agent within 4 weeks before enrollment.