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Central Nervous System TumorsPhase 2TAVARECNCT01164189

Bevacizumab in Recurrent Grade II and III Glioma

A Phase 2 study testing Bevacizumab and Temozolomide in people with Central Nervous System Tumors, run by European Organisation for Research and Treatment of Cancer - EORTC at 39 sites in 8 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

RATIONALE: Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Central Nervous System Tumors
What is being tested?
Bevacizumab and Temozolomide
Could I receive a placebo?
No, everyone receives an active treatment
How many people
155 participants
Where
39 sitesin 8 countries
Study dates
Feb 2011to 24 Sep 2017
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult
  • 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.
  • Age ≥ 18 years
  • 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.

Trial locations and contacts

39 sites in 8 countries.

39 sites in 8 countries

United Kingdom12 sites

  • University Hospitals Bristol NHS Foundation Trust - Bristol Haematology And Oncology Centre

    Bristol

  • University Of Dundee - Ninewells Hospital

    Dundee

  • NHS Lothian - Western General Hospital

    Edinburgh

  • NHS Greater Glasgow and Clyde - Beatson West of Scotland Cancer Centre - Gartnavel General Hospital

    Glasgow

  • Leeds Teaching Hospitals NHS Trust - St. James's University Hospital

    Leeds

  • Imperial College Healthcare NHS Trust - Charing Cross Hospital

    London

  • University College Hospital

    London

  • The Christie NHS Foundation Trust

    Manchester

  • Freeman Hospital, Northern Centre For Cancer Care

    Newcastle upon Tyne

  • Nottingham University Hospitals NHS Trust - City Hospital

    Nottingham

  • Sheffield Teaching Hospitals NHS Foundation Trust - Weston Park Hospital

    Sheffield

  • Royal Marsden Hospital - Sutton, Surrey

    Sutton

Other trials in United Kingdom

France9 sites

  • CHRU de Lille

    Lille

  • CHU de Lyon - CHU Lyon - Hopital neurologique Pierre Wertheimer

    Lyon

  • Assistance Publique - Hôpitaux de Marseille - Hôpital de La Timone

    Marseille

  • CHU de Nice - Hopital Pasteur

    Nice

  • CHU Pitie-Salpetriere

    Paris

  • Institut Gustave Roussy

    Paris

  • Centre Eugene Marquis

    Rennes

  • Institut de Cancerologie de l'Ouest (ICO) - Centre Rene Gauducheau

    Saint-Herblain

  • Centre Paul Strauss

    Strasbourg

Other trials in France

Netherlands6 sites

  • University Medical Center Groningen

    Groningen

  • Academisch Ziekenhuis Maastricht

    Maastricht

  • Radboud University Nijmegen Medical Centre

    Nijmegen

  • Daniel Den Hoed Cancer Center at Erasmus Medical Center

    Rotterdam

  • Medisch Centrum Haaglanden - Westeinde

    The Hague

  • Universitair Medisch Centrum - Academisch Ziekenhuis

    Utrecht

Other trials in Netherlands

Germany5 sites

  • Universitaetsklinikum Bonn

    Bonn

  • Universitaetsklinikum - Essen

    Essen

  • Klinikum Der J.W. Goethe Universitaet

    Frankfurt am Main

  • Universitaetsklinikum Heidelberg - UniversitaetsKlinikum Heidelberg - Head Hospital

    Heidelberg

  • Universitaetskliniken Regensburg

    Regensburg

Other trials in Germany

Austria2 sites

  • Landesnervenklinik Wagner Jauregg

    Linz

  • Medical University Vienna - General Hospital AKH

    Vienna

Other trials in Austria

Belgium2 sites

  • Universitair Ziekenhuis Brussel

    Brussels

  • U.Z. Leuven - Campus Gasthuisberg

    Leuven

Other trials in Belgium

Switzerland2 sites

  • Centre Hospitalier Universitaire Vaudois

    Lausanne

  • UniversitaetsSpital Zurich - Division of Oncology

    Zurich

Other trials in Switzerland

Italy1 site

  • Ospedale Bellaria

    Bologna

Other trials in Italy

About this study

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

RATIONALE: Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether temozolomide is more effective when given with or without bevacizumab in treating patients with recurrent glioma.

PURPOSE: This randomized clinical trial is studying how well temozolomide works with or without bevacizumab in treating patients with recurrent glioma.

Read the detailed description

OBJECTIVES:

Primary

  • 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.

Secondary

  • 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 toxicity.
  • 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.

Keywords
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
Medical subject headings
Central Nervous System Neoplasms, Astrocytoma, Oligodendroglioma, Brain Neoplasms, Glioblastoma, Gliosarcoma, Glioma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BevacizumabBiological

    Also called Avastin

    Bevacizumab (vial of 400mg/16mL) at a dose of 10 mg/kg bodyweight i.v. in 90 min on day 1 and day 14 of 4 week cycles

  • TemozolomideDrug

    Also called Temodar, Temodal, Temcad

    Temozolomide (250, 100, 20 and 5 mg caps) will be administered orally on day 1-5, 150-200 mg/m², and will be repeated every 4 weeks. This will be repeated for up to 12 cycles.

Study groups in NCT01164189
Study groupRoleWhat they receive
TemozolomideOtherAdministered orally on day 1-5, 150-200 mg/m(2), repeated every 4 weeks, up to 12 cycles
Receives: Drug: Temozolomide
Temozolomide + BevacizumabExperimentalTMZ: Administered orally on day 1-5, 150-200 mg/m(2), repeated every 4 weeks, up to 12 cycles Beva: 10 mg/kg bw IV in 90 minutes on day 1 and 14, 4 week cycles.
Receives: Biological: Bevacizumab; Drug: Temozolomide

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Probability of survival at 1 year

    Patients alive at 12 months

    Measured: From the date of randomization up to the date of death, assessed up to 12 months

Secondary outcomes (8)

  1. Objective response rate and duration of response

    Objective response includes best overall responses complete response and partial response

    Measured: From the date of randomization until disease progression

  2. Progression-free survival

    Measured: From the date of randomization until the date of objective progression or the date of patient's death whichever occurs first

  3. Overall survival and survival at 24 months

    Measured: From the date of randomization up to the date of death

  4. Safety

    Measured: After the first ten patients in each arm have completed the first two cycles or have stopped treatment, an interim safety review of those patients will be conducted.

  5. Clinical/neurological deterioration-free survival

    Measured: From the date of randomization until the date of neurological deterioration

  6. Steroid use

    Measured: At baseline and every 3 months untill lost to follow-up

  7. Quality of life of patients and caregivers/relatives

    Measured: At baseline and every 3 months untill lost to follow-up

  8. Cognitive deterioration

    Measured: At baseline and every 3 months untill lost to follow-up

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Jul 2010 (estimated)
  2. Study startFeb 2011
  3. Primary completion19 Jan 2017
  4. Study completion24 Sep 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
155 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01164189
Sponsor's protocol ID
EORTC-26091
Other IDs
2009-017422-39, 2009
Acronym
TAVAREC
Status last verified
Feb 2019
First submitted
15 Jul 2010
Last updated
28 Feb 2019
Results posted
No
Data monitoring committee
Yes

Publications

  • Draaisma K, Tesileanu CMS, de Heer I, Klein M, Smits M, Reijneveld JC, Clement PM, de Vos FYF, Wick A, Mulholland PJ, Taphoorn MJB, Weller M, Chinot OL, Kros JM, Verschuere T, Coens C, Golfinopoulos V, Gorlia T, Idbaih A, Robe PA, van den Bent MJ, French PJ. Prognostic Significance of DNA Methylation Profiles at MRI Enhancing Tumor Recurrence: a Report from the EORTC 26091 TAVAREC Trial. Clin Cancer Res. 2022 Jun 1;28(11):2440-2448. doi: 10.1158/1078-0432.CCR-21-3725.

    PubMed 35294545

  • van den Bent MJ, Klein M, Smits M, Reijneveld JC, French PJ, Clement P, de Vos FYF, Wick A, Mulholland PJ, Taphoorn MJB, Lewis J, Weller M, Chinot OL, Kros JM, de Heer I, Verschuere T, Coens C, Golfinopoulos V, Gorlia T, Idbaih A. Bevacizumab and temozolomide in patients with first recurrence of WHO grade II and III glioma, without 1p/19q co-deletion (TAVAREC): a randomised controlled phase 2 EORTC trial. Lancet Oncol. 2018 Sep;19(9):1170-1179. doi: 10.1016/S1470-2045(18)30362-0. Epub 2018 Aug 13.

    PubMed 30115593

  • Ediebah DE, Reijneveld JC, Taphoorn MJ, Coens C, Zikos E, Aaronson NK, Heimans JJ, Bottomley A, Klein M; EORTC Quality of Life Department and Patient Reported Outcome and Behavioral Evidence (PROBE). Impact of neurocognitive deficits on patient-proxy agreement regarding health-related quality of life in low-grade glioma patients. Qual Life Res. 2017 Apr;26(4):869-880. doi: 10.1007/s11136-016-1426-z. Epub 2016 Oct 15.

    PubMed 27744512

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Bevacizumab and Temozolomide in people with Central Nervous System Tumors, run by European Organisation for Research and Treatment of Cancer - EORTC at 39 sites in 8 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Feb 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 39 sites in United Kingdom, France, Netherlands, Germany, Austria and 3 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Probability of survival at 1 year (time frame: From the date of randomization up to the date of death, assessed up to 12 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01164189, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Feb 2019.

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