- - Histologically proven grade II or grade III astrocytoma, oligodendroglioma or
oligoastrocytoma according to the WHO 2007 at initial diagnosis.
- - Demonstrated absence of 1p/19q co-deletion according to local diagnosis.
- - Availability of biological material for central review processes and translational
research projects.
- - First recurrence after initial treatment with either radiotherapy and/or
chemotherapy.
- - Enhancing recurrence on MRI scan.
- - For non operated patients, recurrent disease must be at least one bi-dimensionally
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 two weeks prior to start of randomisation.
- - Stable or decreasing dosage of steroids for 7 days prior to the baseline MRI scan.
- - No more than one line of chemotherapy (concurrent and adjuvant temozolomide
chemotherapy is considered one line of chemotherapy)
- If given, chemotherapy must have consisted of either temozolomide or PCV, and
patients must be off chemotherapy treatment for more than 6 months without
progression.
- - No radiotherapy within the three 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.
- - No current or recent (within 4 weeks before randomization) treatment with another
investigational drug.
- - No prior treatment with Bevacizumab or other VEGF inhibitors or VEGF-Receptor
signaling inhibitors.
- - No invasive procedures (surgical resection, open biopsy, significant traumatic
injury or any other major surgery involving entry into a body cavity) within 4 weeks
prior to randomization, or 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 7 days prior to randomization.
Placement of a central vascular access device
(CVAD) if performed at least 2 days prior to bevacizumab administration is allowed.
- - Patient may have undergone surgery for recurrence.
If operated, 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 randomisation.
- - No previous other malignancies, except for any previous malignancy which was treated
with curative intent more than 5 years prior to randomisation, and except for
adequately controlled limited basal cell carcinoma of the skin, squamous carcinoma
of the skin or carcinoma in situ of the cervix.
- - Absence of any cardiovascular disorder, including but not limited to:
- No history of myocardial infarction, unstable angina within 6 months prior to
randomisation.
- - No "New York Heart Association" (NYHA) Grade II or greater congestive heart
failure, or serious cardiac arrhythmia requiring medication.
- - No significant vascular disease (e.g. aortic aneurysm requiring surgical repair
or recent peripheral arterial thrombosis) within 6 months prior to
randomisation.
- - No prior history of hypertensive crisis or hypertensive encephalopathy.
- - No inadequately controlled hypertension (defined as systolic blood pressure
>150 mmHg and/or diastolic blood pressure >100 m Hg)
- Absence of any thrombotic or hemorrhagic event, including but not limited to:
- No evidence of recent hemorrhage on MRI of the brain.
However, patients with
clinically asymptomatic presence of hemosiderin, resolving hemorrhagic changes
related to surgery, and presence of punctate hemorrhage in the tumor are
permitted entry into the study.
- - No history or evidence of inherited bleeding diathesis or coagulopathy with the
risk of bleeding.
- - No arterial or venous thrombosis ≤ 12 months prior to randomization.
- - No history of stroke or TIAs within 6 months prior to randomization.
- - No history of pulmonary haemorrhage/haemoptysis ≥ grade 2 according to the
NCI-CTCAE version 4.0 criteria within 1 month prior to randomization.
- - Absence of 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 or cilostaz.
- - International normalized ratio (INR) > 1.5 ULN and activated partial
thromboplastin time (aPTT) > 1.5 × the ULN.
Patients using full-dose
anticoagulants at baseline are excluded from the study; but prevention of
thrombosis with low-dose anticoagulant is allowed.
- - Absence of known hypersensitivity.
- - to any part of the Bevacizumab or Temozolomide formulations.
- - to Chinese hamster ovary cell products or other recombinant human or humanized
antibody.
- - No underlying or previous conditions that could interfere with treatment, including
but not limited to:
- No history of intracranial abscess within 6 months prior to randomisation.
- - No clinically serious (as judged by the investigator) non-healing wounds,
active skin ulcers or incompletely healed bone fracture.
- - No history of active gastroduodenal ulcer(s).
- - No history of abdominal fistula as well as non-GI fistula, gastrointestinal
perforation or intraabdominal abscess within 6 months prior to inclusion.
- - No evidence of active infection requiring hospitalization or antibiotics,
within 2 weeks prior to randomisation.
- - No other diseases, interfering with follow up.
- - Normal hematological functions: neutrophils ≥ 1.5 x 109 cells/l, platelets ≥100 x
109 cells/l and Hb ≥ 6.2 mmol/l (9.9 g/dl).
- - Normal liver function: bilirubin < 1.5 x upper limit of the normal range (ULN),
alkaline phosphatase and transaminases (ASAT) < 2.5 x ULN, INR < 1.5 ULN.
- - Normal renal function: calculated (Cockcroft-Gault) or measured creatinine clearance
> 30 mL/min; 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.
- - WHO Performance status 0 - 2.
- - Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study in such a manner that the risk
of pregnancy is minimized.
In general, the decision for appropriate methods to
prevent pregnancy should be determined by discussions between the investigator and
the study subject. WOCBP include any female who has experienced menarche and who has
not undergone successful surgical sterilization (hysterectomy, bilateral tubal
ligation, or bilateral oophorectomy) or is not postmenopausal.
- - Post menopause is defined as: amenorrhea ≥ 12 consecutive months without
another cause or for women with irregular menstrual periods and on hormone
replacement therapy (HRT), a documented serum follicle stimulating hormone
(FSH) level > 35 mIU/mL.
- - Women who are using oral contraceptives, other hormonal contraceptives (vaginal
products, skin patches, or implanted or injectable products), or mechanical
products such as an intrauterine device or barrier methods (diaphragm, condoms,
spermicides) to prevent pregnancy, or are practicing abstinence or where their
partner is sterile (eg, vasectomy) should be considered to be of childbearing
potential.
- - Women of child bearing potential must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours
prior to the start of investigational product.
- - 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 study treatment.
- - Female should not be breast feeding.
- - Absence of any psychological, familial, sociological or geographical factors
potentially hampering compliance with the study protocol and follow-up schedule;
such conditions should be assessed with the patient before randomization in the
trial.
- - Before patient randomization and study related procedures (that would not have been
performed as part as standard care), written informed consent must be given
according to ICH/GCP, and national/local regulations.
Informed consent should also
be given for biological material to be stored and used for future research on brain
tumors.
- - All indicated timelines and absolute values requested by the eligibility criteria
must be adhered to.
However, a maximum of +/- 10% of the reference value for
laboratory parameters and a maximum of +/- 2 days for timelines may be acceptable.
Discussion with Headquarters and study coordinator is encouraged.