Inclusion Criteria

DISEASE CHARACTERISTICS:

- Histologically confirmed de novo glioblastoma multiforme (primary)

- Unequivocal first progression after concurrent or adjuvant radiochemotherapy (at
least 3 months off the concurrent part of the radiochemotherapy)

- No more than 1 prior line of chemotherapy (concurrent and adjuvant
temozolomide-based chemotherapy, including in combination with another
investigational agent, is considered one line of chemotherapy)

- Prior surgery for recurrent disease allowed, provided the following criteria are met:

- surgery must have confirmed the recurrence

- Residual and measurable disease after surgery is not required

- Post-surgery MRI available within 48 hours following surgery

- Surgery must have been completed at least 2 weeks prior to randomization and
patients must have fully recovered

- Must meet the following criteria for recurrent disease for patients who have not
undergone surgery:

- At least 1 bidimensionally measurable contrast-enhancing lesion with clearly
defined margins by MRI scan, with minimal diameters of 10 mm, visible on 2 or
more axial slices 5 mm apart, based on MRI scan done within 2 weeks prior to
randomization

- Availability of biological material (tumor and blood)

- Craniotomy or intracranial biopsy site must be adequately healed, free of drainage or
cellulitis, and the underlying cranioplasty must appear intact at the time of
randomization

PATIENT CHARACTERISTICS:

- WHO performance status 0-2

- Platelet count ≥ 100 x 10^9/L

- Hemoglobin ≥ 9.9 g/dL

- Neutrophil count ≥ 1.5 x 10^9/L

- Bilirubin < 1.5 times upper limit of the normal (ULN)

- Alkaline phosphatase and transaminases < 2.5 times ULN

- INR < 1.5 times ULN

- Creatinine clearance > 30 mL/min OR protein < 2+ of by urine dipstick or ≤ 1 g by
24-hour urine collection

- Patients with a buffer range from the normal values of +/- 5% for hematology and +/-
10% for biochemistry are acceptable (a maximum of +/- 2 days for timelines may be
acceptable [1 day for postoperative MRI])

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 6 months after
completion of study therapy

- No other previous malignancies, except for malignancies that were treated with
curative intent more than 5 years prior to randomization, adequately controlled
limited basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of
the cervix

- No cardiovascular disorder including, but not limited to, any of the following:

- History of myocardial infarction or unstable angina within 6 months prior to
randomization

- NYHA class II-IV congestive heart failure or serious cardiac arrhythmia
requiring medication

- Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to randomization

- Prior history of hypertensive crisis or hypertensive encephalopathy

- Inadequately controlled hypertension (defined as systolic BP > 150 mm Hg and/or
diastolic BP > 100 mm Hg)

- No thrombotic or hemorrhagic event including, but not limited to, any of the
following:

- Evidence of recent hemorrhage on MRI of the brain

- Patients with clinically asymptomatic presence of hemosiderin, resolving
hemorrhagic changes related to surgery, or presence of punctate hemorrhage
in the tumor are permitted entry into the study

- History or evidence of inherited bleeding diathesis or coagulopathy with the
risk of bleeding

- Arterial or venous thrombosis ≤ 6 months prior to randomization

- History of stroke or transient ischemic attack within 6 months prior to
randomization

- History of pulmonary hemorrhage/hemoptysis ≥ grade 2 according to the NCI-CTCAE
version 4.0 criteria within 1 month prior to randomization

- 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
dipyridamole, ticlopidine, clopidogrel, or cilostazol

- INR/aPTT > 1.5 times ULN

- Use of full-dose anticoagulants is permitted as long as the INR or aPTT is
within therapeutic limits [according to the medical standard in the
institution] and the patient has been on a stable dose of anticoagulants
for at least 2 weeks before randomization

- No underlying or previous conditions that could interfere with treatment including,
but not limited to, any of the following:

- History of intracranial abscess within 6 months prior to randomization

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

- History of active gastroduodenal ulcer(s)

- History of abdominal fistula, non-gastrointestinal fistula, gastrointestinal
perforation, or intraabdominal abscess within 6 months prior to inclusion

- Evidence of active infection requiring hospitalization or antibiotics, within 2
weeks prior to randomization

- Other diseases interfering with follow up

- No known hypersensitivity to any part of the bevacizumab or lomustine formulations,
to Chinese hamster ovary cell products, or other recombinant human or humanized
antibody

- No psychological, familial, sociological, or geographical factors potentially
hampering compliance with the study protocol and follow-up schedule

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- No radiotherapy within 3 months prior to the diagnosis of progression

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

- At least 6 weeks since prior nitrosoureas

- At least 30 days since prior and no other concurrent anticancer agents or
investigational drugs

- At least 7 days since prior core biopsy or other minor surgical procedure

- Placement of a central vascular access device, if performed at least 2 days
prior to study treatment administration, is allowed

- At least 4 weeks since prior and no concurrent treatment with another investigational
drug

- At least 4 weeks since prior surgery (tumor-related or non-tumor-related) or other
invasive procedures (i.e., major surgical procedure, open biopsy, or significant
traumatic injury), or anticipation of the need for major surgery during the course of
the study treatment

- At least 4 weeks since prior temozolomide

- At least 2 weeks since prior and no concurrent enzyme-inducing antiepileptic drugs
(EIAED)

- Patients who require anti-convulsant therapy and who were previously on EIAED
must be switched to non-EIAED at least 2 weeks prior to randomization

- No prior bevacizumab or other VEGF inhibitors or VEGF-receptor signaling inhibitors

- No concurrent participation on another study

- Must be on a stable or decreasing dose of steroids for 7 days prior to the baseline
MRI scan