Protective VEGF Inhibition for Isotoxic Dose Escalation in Glioblastoma (PRIDE)

Inclusion Criteria: IDH wild-type, MGMT unmethylated glioblastoma patients Informed consent Age ≥18 and ≤ 70 years, smoking or non-smoking, of any ethnic origin ECOG 0-2 Neutrophil counts > 1500/μl; Platelet counts > 100.000/μl; Hemoglobin > 8 g/dl; Serum creatinine < 1.5-fold upper limit of normal (ULN); Bilirubin, AST or ALT < 2.5-fold ULN unless attributed to anticonvulsants; Alkaline phosphatase < 2.5-fold ULN Adequate contraception Serum creatinine ≤ 1.5 x ULN AND patients with urine dipstick for proteinuria < 2+. Patients with ≥ 2+ proteinuria on dipstick urinalysis at baseline should show urine protein to creatinine ratio ≤ 1 Exclusion Criteria: Evidence of recent hemorrhage on postoperative MRI of the brain Subjects on any drug suspected to interfere with bevacizumab at the time of study inclusion Immuno-compromised patients, including known seropositivity for human immunodeficiency virus (HIV) Known hypersensitivity to any component of the investigational drugs or excipients (allergy to or other intolerability of bevacizumab or excipients) Any other significant medical illness or medically significant laboratory finding that would, in the investigator's judgement, make the patient inappropriate for this study, or would increase the risk associated with the patients' participation in the study Incapability to undergo MRI Prior treatment with bevacizumab for any indication Significant cardiovascular disease defined as congestive heart failure (NYHA Class II, III, IV), unstable angina pectoris, or myocardial infarction within 6 months prior to enrolment Inadequately controlled hypertension (de-fined as a blood pressure of > 150 mmHg systolic and/or >100 mmHg diastolic on medication), or any prior history of hypertensive crisis or hypertensive encephalopathy History of stroke or transient ischemic attack within 6 months prior to enrolment Significant vascular disease (e.g. aortic aneurysm, aortic dissection or recent peripheral arterial thrombosis) within 6 months prior to enrolment Evidence or history of recurrent thromboembolism (> 1 episode of deep venous thrombosis / peripheral embolism) during the past 2 years Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation) Chronic daily intake of aspirin > 325 mg/day or clopidogrel > 75 mg /day History of intracranial abscess within 6 months prior to inclusion History of abdominal or tracheo-oesophageal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrolment History of ≥ grade 2 hemoptysis according to NCI-CTC criteria within 1 month prior to inclusion Serious non-healing wound, ulcer or bone fracture