A randomized, double blind, placebo controlled, multicenter Phase III trial of bevacizumab, temozolomide and radiotherapy, followed by bevacizumab and temozolomide versus placebo, temozolomide and radiotherapy followed by placebo and temozolomide in patients with newly diagnosed glioblastoma. - ND

• Register: EUCTR
• Last refreshed on: 11 April 2016
• Main ID: EUCTR2008-006146-26-IT
• Date of registration: 31/07/2009
• Prospective Registration: Yes
• Primary sponsor: F.Hoffman-La Roche Ltd
• Public title: A randomized, double blind, placebo controlled, multicenter Phase III trial of bevacizumab, temozolomide and radiotherapy, followed by bevacizumab and temozolomide versus placebo, temozolomide and radiotherapy followed by placebo and temozolomide in patients with newly diagnosed glioblastoma. - ND
• Scientific title: A randomized, double blind, placebo controlled, multicenter Phase III trial of bevacizumab, temozolomide and radiotherapy, followed by bevacizumab and temozolomide versus placebo, temozolomide and radiotherapy followed by placebo and temozolomide in patients with newly diagnosed glioblastoma. - ND
• Date of first enrolment: 11/09/2009
• Target sample size: 920
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-006146-26
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Belgium, Denmark, France, Germany, Greece, Hungary, Italy, Netherlands, Portugal, Spain, Sweden, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
1.Signed informed consent 2.Age &#8805; 18 years 3.Present with newly diagnosed supratentorial Glioblastoma (GBM) with a tissue diagnosis that has been established following either a surgical resection or biopsy. This includes treatment-na?ve -(chemotherapy and radiotherapy)- patients with prior diagnosis of a lower grade astrocytoma that has been upgraded to a histologically verified GBM 4.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. Study treatment should be initiated > 28 days and < 49 days following the last surgical procedure (including biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) 5. WHO performance status &#8804; 2. 6. Patient must have at least 1 formalin fixed paraffin embedded tumour tissue block representative of glioblastoma available for pathology central review and analysis of MGMT status. If tumour block is not available or not of adequate quality, sufficient pathology material, representative of glioblastoma, must be available for central review. 7.Stable or decreasing corticosteroids dose within 5 days prior to randomisation 8.Adequate haematological function: Absolute neutrophil count (ANC) &#8805; 1.5 x 109/L; Platelet count &#8805; 100 x 109/L; Haemoglobin &#8805; 10 g/dL (may be transfused to maintain or exceed this level) 9. Adequate liver function:Total bilirubin &#8804; 1.5 x ULN; AST and ALT &#8804; 2.5 x ULN 10.Adequate renal function:Creatinine &#8804; 1.25xULN; Urine dipstick for proteinuria < 2+. Patients discovered to have &#8805; 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate &#8804; 1.0 g of protein in 24 hours OR Urine protein/creatinine ratio (UPC) &#8804; 1.0 11.International normalized ratio (INR) or PT (secs) and activated partial thromboplastin time (aPTT): 1.5 x ULN (except for subjects receiving anticoagulation therapy) in the absence of therapeutic intent to anticoagulate the subject; within therapeutic limits (according to the medical standard in the institution) in the presence of therapeutic intent to anticoagulate the subject NOTE: Use of full-dose anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose of anticoagulants for at least two weeks before randomisation. As per ASCO guidelines, LMWH should be the preferred approach 12.Willing and able to comply with the protocol as judged by the investigator.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Disease and Treatment History: 1.Evidence of recent hemorrhage on postoperative 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 tumour are permitted entry into the study 2.Previous centralized screening for MGMT status for enrolment into a clinical trial 3.Any prior chemotherapy (including carmustine-containing wafers (Gliadel) or immunotherapy (including vaccine therapy) for glioblastomas and low grade astrocytomas NOTE: 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) administered prior to surgery to aid in optimal surgical resection is not considered a chemotherapy agent 4. Any prior radiotherapy to the brain or prior radiotherapy resulting in a potential overlap in the radiation field. Bevacizumab related Exclusion Criteria: 5.Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 m Hg) 6.Prior history of hypertensive crisis or hypertensive encephalopathy 7.New York Heart Association (NYHA) Grade II or greater congestive heart failure 8.History of myocardial infarction or unstable angina within 6 months prior to randomisation 9.History of stroke or TIAs within 6 months prior to randomisation 10.Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to randomisation 11.History of &#8805; grade 2 haemoptysis according to the NCI-CTC criteria within 1 month prior to randomisation 12.Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation) 13.Major surgical procedure, open biopsy, intracranial biopsy, ventriculoperitoneal shunt or significant traumatic injury within 28 days prior to randomisation 14.Core biopsy (excluding intracranial biopsy) or other minor surgical procedure within 7 days prior to randomisation. Placement of a central vascular access device (CVAD) if performed within 2 days prior to bevacizumab/placebo administration 15.History of abdominal fistula or gastrointestinal perforation within 6 months prior to randomisation 16.History of intracranial abscess within 6 months prior to randomisation 17.Serious non-healing wound, active ulcer or untreated bone fracture 18.Pregnant or lactating females NOTE: Serum pregnancy test to be assessed within 7 days prior to study treatment start 19.Fertile women < 2 years after last menstruation and men (surgically sterilized or of childbearing potential) unwilling or unable to use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly) General Exclusion Criteria 20.Any previous malignancy which was treated with curative intent within 5 years prior to randomisation, except for adequately controlled limited basal cell carcinoma of the skin, squamous carcinoma of the skin or carcinoma in situ of the cervix 21.Evidence of any active infection requiring hospitalization or IV antibiotics within 2 weeks prior to randomisation. Etc...


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Patients with newly diagnosed glioblastoma.
MedDRA version: 12.0 Level: LLT Classification code 10018336 Term: Glioblastoma

Intervention(s)

Trade Name: Avastin
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Bevacizumab
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 400-
Pharmaceutical form of the placebo: Concentrate for solution for infusion
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Secondary Objective: To compare 1-year and 2-year survival rates between treatment arms To evaluate the safety profile between treatment arms To compare health-related quality of life (EORTC QLQ-C30, BN20) between treatment arms.- Exploratory Objectives- To compare the objective response rate (ORR) based on adapted MacDonald criteria, and the duration of objective response, between treatment arms To assess and compare OS and PFS between and within arms in relation to MGMT status To compare neurocognitive function (NCF) using MMSE? between treatment arms To explore and compare the use of corticosteroids between treatment arms Roche Clinical Repository (RCR) samples will be collected to enable exploratory correlative analysis of biomarkers with the overall survival, progression-free survival, and objective response rate RCR samples will also be collected to explore and compare changes in biomarkers

Main Objective: To demonstrate the superiority in overall survival (OS) when bevacizumab is added to temozolomide with radiotherapy followed by temozolomide for the treatment of patients with newly diagnosed glioblastoma To demonstrate the superiority in progression-free survival (PFS) (using adapted MacDonald criteria) when bevacizumab is added to temozolomide with radiotherapy followed by temozolomide for the treatment of patients with newly diagnosed glioblastoma.

Primary end point(s): The study will have 2 co-primary endpoints: Overall survival and
Progression free survival (using adapted MacDonald Response
Criteria).

Secondary ID(s)

BO21990

2008-006146-26-FR