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

Phase 2
18 Years
Open (Enrolling)
Brain and Central Nervous System Tumors

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Trial Information

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



- To document the activity of both combination temozolomide plus bevacizumab and
temozolomide alone in patients with recurrent grade II or grade III glioma without
1p/19q co-deletion.


- To characterize the safety of treatment in these patients.

- To document the quality of life and cognitive functioning, as a measure of clinical
benefit, of these patients.

- To explore qualification or occurrence of prognostic and/or predictive biomarkers of
activity or efficacy in these patients. (exploratory)

- To document the discordances between RANO and Macdonald's criteria for the evaluation
of response and progression. (exploratory)

OUTLINE: This is a multicenter study. Patients are stratified according to institution,
initial histology (grade II vs grade III), WHO performance status (0-1 vs 2), and prior
treatment (radiotherapy [RT] alone, temozolomide [TMZ] or procarbazine, lomustine and
vincristine [PCV] alone vs TMZ/RT). Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive oral temozolomide once daily on days 1-5. Treatment repeats
every 28 days for 12 courses in the absence of disease progression or unacceptable

- Arm II: Patients receive oral temozolomide as in arm I and bevacizumab IV over 90
minutes on days 1 and 15. Treatment repeats every 28 days for 12 courses in the absence
of disease progression or unacceptable toxicity.

Patients complete neurocognitive questionnaires (i.e., the Hopkins Verbal Learning test, the
Controlled Oral Word Association test, and the Trail Making tests A and B). Quality-of-life
assessment questionnaires, including EORTC QLQ-C30 and EORTC-BN20, are completed by both
patients and caregivers/relatives at baseline and then periodically.

Frozen tumor biopsies or paraffin blocks and blood specimens are collected for bio-banking
and translational research.

After completion of study therapy, patients are followed up every 3 months.

Inclusion Criteria


- 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

- 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


- 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

- 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

- Other diseases interfering with follow up

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


- 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

- 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

Type of Study:


Study Design:

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Probability of survival at 1 year

Safety Issue:


Principal Investigator

Martin J. van Den Bent, MD

Investigator Affiliation:

Daniel Den Hoed Cancer Center at Erasmus Medical Center



Study ID:




Start Date:

February 2011

Completion Date:

Related Keywords:

  • Brain and Central Nervous System Tumors
  • adult anaplastic astrocytoma
  • adult diffuse astrocytoma
  • adult pilocytic astrocytoma
  • adult pineal gland astrocytoma
  • adult subependymal giant cell astrocytoma
  • adult oligodendroglioma
  • adult anaplastic oligodendroglioma
  • recurrent adult brain tumor
  • adult giant cell glioblastoma
  • adult glioblastoma
  • adult gliosarcoma
  • adult mixed glioma
  • Glioma
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms