Bevacizumab versus bevacizumab plus lomustine versus lomustine in recurrent glioblastoma.

1. Age ≥ 18 years;

2. WHO Performance status 0 - 2;

3. Histologically or biopsy proven glioblastoma multiforme including patients with anaplastic oligoastrocytomas with necrosis (which meets WHO 2007 criteria for glioblastoma;

4. First relapse after prior treatment with combined chemo-irradiation with temozolomide;

5. Patient may have undergone surgery for the recurrence. If operated, residual and measurable disease after surgery is not required but surgery must have confirmed the recurrence. In case of operation, post-operative MRI must be made within 48 hours following surgery. Minimum interval of at least 4 weeks between surgery and the start of Bevacizumab treatment, and patients should have fully recovered from the surgery;

6. For non operated patients, recurrent disease must be at least one bidimensionally measurable target lesion (contrast enhancing lesion) with one diameter of at least 2cm, based on MRI scan done within two weeks prior to start of treatment;

7. Stable or decreasing dosage of steroids for 7 days prior to the baseline MRI scan;

8. No prior treatment with Lomustine or other nitrosourea’s;

9. No prior treatment with Bevacizumab or other VEGF-R signalling inhibitors;

10. No radiotherapy within the three months prior to the diagnosis of progression;

11. No chemotherapy in the past four weeks;

12. No radiotherapy with a dose over 65 Gy, stereotactic radiosurgery or brachytherapy unless the recurrence is histologically proven;

13. Normal hematological functions: neutrophils ≥ 1.5 x 109 cells/l, platelets ≥100 x 109 cells/l, Hb ≥ 6.2 mmol/l;

14. Normal liver function: bilirubin < 1.5 x upper limit of the normal range (ULN), alkaline phosphatase and transaminases (ASAT/ALAT) < 2.5 x ULN, INR < 1.5;

15. Normal renal function:

A. Calculated (Cockcroft-Gault) or measured creatinine clearance > 30 mL/min;

B. Urine dipstick for proteinuria < 2+. Patients with >2+ proteinuria on dipstick urinalysis at baseline should undergo 24 hours urine collection and must demonstrate ≤1 g of protein/24 hr.

16. Women of reproductive potential, female patients within one year of entering the menopause as well as males must agree to use an effective non-hormonal method of contraception during the treatment period and for at least 6 months after the last dose of Bevacizumab;

17. No other diseases, interfering with follow up;

18. No geographical, psychological or other non-medical conditions interfering with follow-up;

19. Written informed consent.

1. History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding;

2. Arterial or venous thrombosis ≤ 12 months prior to registration;

3. History of myocardial infarction (≤ 6 months prior to inclusion), unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication;

4. Uncontrolled hypertension defined by a systolic pressure > 150 mm Hg and/or diastolic pressure > 100 mm Hg, with or without anti-hypertensive medication. Patients with initial blood pressure elevation are eligible if initiation or adjustment of anti-hypertensive medication lowers pressure to meet the entry criteria;

5. Current or recent (within 10 days of first dose of Bevacizumab) use of aspirin (> 325 mg/day) or other NSAID with anti-platelet activity or treatment with dipyramidole, ticlopidine, clopidogrel and cilostaz;

6. Use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic (as opposed to prophylactic) purposes;

7. Clinically serious (as judged by the investigator) non-healing wounds, active skin ulcers or incompletely healed bone fracture;

8. History of active gastroduodenal ulcer(s);

9. History of abdominal fistula as well as non-GI fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to inclusion;

10. Evidence of any active infection requiring hospitalization or antibiotics, within 2 weeks prior to day 1 of cycle 1;

11. Invasive procedures (major surgical procedure, open biopsy or significant traumatic injury) within 4 weeks prior to randomization, or anticipation of the need for major surgery during the course of the study treatment. Placement of a vascular access device is not considered as a major surgical procedure if performed more than 24 hours prior to Bevacizumab administration;

12. Current or recent (within 4 weeks of enrollment) treatment with another investigational drug or participation in another investigational study;

13. Known hypersensitivity to any part of the Bevacizumab formulation;

14. Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibody;

15. Pregnant or lactating females. Serum pregnancy test to be assessed within 7 days prior to randomization;

16. Previous or concurrent malignancies at other sites with the exception of surgically cured carcinoma in situ of the cervix and non-melanoma skin cancer.