Bevacizumab in Recurrent Grade II and III Glioma

NCT ID: NCT01164189

Last Updated: 2019-02-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 155 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-02-28
• Study Completion Date: 2017-09-24

Brief 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. 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.

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.

Conditions

Central Nervous System Tumors

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Temozolomide

Administered orally on day 1-5, 150-200 mg/m(2), repeated every 4 weeks, up to 12 cycles

Group Type: OTHER

Temozolomide

Intervention Type: DRUG

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.

Temozolomide + Bevacizumab

TMZ: 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.

Group Type: EXPERIMENTAL

Bevacizumab

Intervention Type: BIOLOGICAL

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

Temozolomide

Intervention Type: DRUG

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.

Interventions

Bevacizumab

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

Intervention Type: BIOLOGICAL

Temozolomide

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.

Intervention Type: DRUG

Other Intervention Names

Avastin; Temodar; Temodal; Temcad

Eligibility Criteria

Exclusion Criteria

• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: collaborator

European Organisation for Research and Treatment of Cancer - EORTC

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Martin J. van Den Bent, MD

Role: STUDY_CHAIR

Daniel Den Hoed Cancer Center at Erasmus Medical Center

Ahmed Idbaih

Role: STUDY_CHAIR

CHU Pitie-Salpetriere

Locations

Landesnervenklinik Wagner Jauregg

Linz, , Austria

Medical University Vienna - General Hospital AKH

Vienna, , Austria

Universitair Ziekenhuis Brussel

Brussels, , Belgium

U.Z. Leuven - Campus Gasthuisberg

Leuven, , Belgium

CHRU de Lille

Lille, , France

CHU de Lyon - CHU Lyon - Hopital neurologique Pierre Wertheimer

Lyon, , France

Assistance Publique - Hôpitaux de Marseille - Hôpital de La Timone

Marseille, , France

CHU de Nice - Hopital Pasteur

Nice, , France

CHU Pitie-Salpetriere

Paris, , France

Institut Gustave Roussy

Paris, , France

Centre Eugene Marquis

Rennes, , France

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

Saint-Herblain, , France

Centre Paul Strauss

Strasbourg, , France

Universitaetsklinikum Bonn

Bonn, , Germany

Universitaetsklinikum - Essen

Essen, , Germany

Klinikum Der J.W. Goethe Universitaet

Frankfurt am Main, , Germany

Universitaetsklinikum Heidelberg - UniversitaetsKlinikum Heidelberg - Head Hospital

Heidelberg, , Germany

Universitaetskliniken Regensburg

Regensburg, , Germany

Ospedale Bellaria

Bologna, , Italy

University Medical Center Groningen

Groningen, , Netherlands

Academisch Ziekenhuis Maastricht

Maastricht, , Netherlands

Radboud University Nijmegen Medical Centre

Nijmegen, , Netherlands

Daniel Den Hoed Cancer Center at Erasmus Medical Center

Rotterdam, , Netherlands

Medisch Centrum Haaglanden - Westeinde

The Hague, , Netherlands

Universitair Medisch Centrum - Academisch Ziekenhuis

Utrecht, , Netherlands

Centre Hospitalier Universitaire Vaudois

Lausanne, , Switzerland

UniversitaetsSpital Zurich - Division of Oncology

Zurich, , Switzerland

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

Bristol, , United Kingdom

University Of Dundee - Ninewells Hospital

Dundee, , United Kingdom

NHS Lothian - Western General Hospital

Edinburgh, , United Kingdom

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

Glasgow, , United Kingdom

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

Leeds, , United Kingdom

Imperial College Healthcare NHS Trust - Charing Cross Hospital

London, , United Kingdom

University College Hospital

London, , United Kingdom

The Christie NHS Foundation Trust

Manchester, , United Kingdom

Freeman Hospital, Northern Centre For Cancer Care

Newcastle upon Tyne, , United Kingdom

Nottingham University Hospitals NHS Trust - City Hospital

Nottingham, , United Kingdom

Sheffield Teaching Hospitals NHS Foundation Trust - Weston Park Hospital

Sheffield, , United Kingdom

Royal Marsden Hospital - Sutton, Surrey

Sutton, , United Kingdom

Countries

Austria; Belgium; France; Germany; Italy; Netherlands; Switzerland; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 35294545 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30115593 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27744512 (View on PubMed)

Other Identifiers

2009-017422-39

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

EORTC-26091

Identifier Type: -

Identifier Source: org_study_id