Randomized Trial Assessing the Significance of Bevacizumab in Recurrent Grade II and Grade III Gliomas - The TAVAREC Trial

Inclusion Criteria

DISEASE CHARACTERISTICS:

- Histologically confirmed diagnosis of the following:

- Grade II or grade III astrocytoma, oligodendroglioma, or oligoastrocytoma
according to the WHO 2007

- Absence of 1p/19q co-deletion

- Tumor recurrence by MRI scan following initial therapy with radiotherapy or
chemotherapy

- Recurrent disease of non-operated patients must be ≥ 1 bidimensionally
measurable contrast-enhancing lesion with clearly defined margins by MRI scan
(minimal diameters of 10 mm, visible on 2 or more axial slices 5 mm apart) done
within the past two weeks

- Must have stable or decreasing dosage of steroids for 7 days prior to the
baseline MRI scan

- Tissue samples available

PATIENT CHARACTERISTICS:

- WHO performance status 0-2

- ANC ≥ 1.5 x 10^9 cells/L

- Platelet count ≥ 100 x 10^9 cells/L

- Hemoglobin ≥ 9.9 g/dL

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

- Alkaline phosphatase < 2.5 times ULN

- AST and ALT < 2.5 times ULN

- INR < 1.5 times ULN

- aPTT ≤ 1.5 times ULN

- Calculated or measured creatinine clearance > 30 mL/min

- Urine protein < 2+ by urine dipstick OR 24-hour urine protein < 1,000 mg

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective (non-hormonal) contraception during study and for
≥ 6 months after completion of study treatment

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

- No significant traumatic injury in the past 4 weeks

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

- History of myocardial infarction or unstable angina within the past 6 months

- NYHA class II-IV congestive heart failure

- Serious cardiac arrhythmia requiring medication

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

- History of hypertensive crisis or hypertensive encephalopathy

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

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

- Recent hemorrhage on MRI of the brain (patients with clinically asymptomatic
presence of hemosiderin, resolving hemorrhagic changes related to surgery, and
presence of punctate hemorrhage in the tumor are allowed)

- Inherited bleeding diathesis or coagulopathy with the risk of bleeding

- Arterial or venous thrombosis within the past 12 months

- Stroke or transient ischemic attack within the past 6 months

- Pulmonary hemorrhage/hemoptysis ≥ grade 2 (NCI-CTCAE version 4.0) within the
past 4 weeks

- No known hypersensitivity to any of the following:

- Bevacizumab or temozolomide formulations

- Chinese hamster ovary cell products or other recombinant human or humanized
antibody

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

- History of intracranial abscess within the past 6 months

- 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 intra-abdominal abscess within the past 6 months

- Active infection requiring hospitalization or antibiotics within the past 2
weeks

- Other diseases interfering with follow up

- 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 prior treatment with bevacizumab or other VEGF inhibitors or VEGF-receptor
signaling inhibitors

- No more than 1 line of chemotherapy (concurrent and adjuvant temozolomide, or
procarbazine, lomustine, or vincristine chemotherapy is considered 1 line of
chemotherapy) for more than 6 months without progression

- At least 4 weeks since prior and no other concurrent investigational drugs or
anticancer agents

- At least 3 months since radiotherapy prior to the diagnosis of progression

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

- No invasive procedures (e.g., surgical resection, open biopsy, or any other major
surgery involving entry into a body cavity) within the past 4 weeks

- May have undergone surgery for recurrence (residual and measurable disease after
surgery is not required but histology must have confirmed the recurrence)

- 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

- No anticipation of the need for major surgery during the course of the study
treatment

- No core biopsy (excluding intracranial biopsy) or other minor surgical procedure
within the past 7 days

- Placement of a central vascular access device performed ≥ 2 days prior to
bevacizumab administration is allowed

- At least 10 days since prior aspirin (> 325 mg/day) or other NSAID with anti-platelet
activity, or treatment with dipyramidole, ticlopidine, clopidogrel, or cilostaz

- No full-dose anticoagulants at baseline, but prevention of thrombosis with low-dose
anticoagulant allowed

- No concurrent prophylactic use of growth factors, but red cell transfusions or
erythropoietin allowed