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

• Register: EUCTR
• Last refreshed on: 16 November 2015
• Main ID: EUCTR2008-006146-26-GR
• Date of registration: 20/10/2009
• Prospective Registration: Yes
• Primary sponsor: F. Hoffmann-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
• 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
• Date of first enrolment: 20/04/2010
• 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: 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 greater than or equal to 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-naïve -(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 = 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 randomization
8. Adequate hematological function:
• Absolute neutrophil count (ANC) = 1.5 x 1'000'000'000/L
• Platelet count = 100 x 1'000'000'000/L
• Haemoglobin = 10 g/dL (may be transfused to maintain or exceed this level)
9. Adequate liver function
• Total bilirubin = 1.5 x ULN
• AST and ALT = 2.5 x ULN
10. Adequate renal function
•Creatinine = 1.25 x ULN
• Urine dipstick for proteinuria < 2+. Patients discovered to have = 2+ proteinuria
on dipstick urinalysis at baseline should undergo a 24 hour urine collection and
must demonstrate = 1.0 g of protein in 24 hours
OR
• Urine protein/creatinine ratio (UPC) = 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 randomization. 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 tumor 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
(see Appendix 6)
8. History of myocardial infarction or unstable angina within 6 months prior to
randomization
9. History of stroke or TIAs within 6 months prior to randomization
10.Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to randomization
11.History of = grade 2 haemoptysis according to the NCI-CTC criteria within 1
month prior to randomization
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 randomization
14.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 within 2 days prior to bevacizumab/placebo
administration
15.History of abdominal fistula or gastrointestinal perforation within 6 months prior
to randomization
16.History of intracranial abscess within 6 months prior to randomization
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
and 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 randomization, 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 randomization
22.Patients who have any other disease, either metabolic or psychological, or who
have any evidence on clinical examination or special investigations (in

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

Health Condition(s) or Problem(s) studied

Glioblastoma
MedDRA version: 9.1 Level: LLT Classification code 10018336 Term: Glioblastoma

Intervention(s)

Trade Name: Avastin
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Bevacizumab
CAS Number: 216974-75-3
Current Sponsor code: RO4876646
Other descriptive name: rhuMAb VEGF, anti-VEGF
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Concentrate for solution for infusion
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

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

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 the 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

Primary end point(s): • OS, defined as the time between randomization and death due to any cause. Patients without an event will be censored the last time they were known to be alive.
• PFS, defined as the time between randomization and disease progression (using adapted MacDonald Response Criteria) or death due to any cause. Patients without an event will be censored at the date of last follow up for progression. Patients with no post baseline follow up for progression will be censored at the day of randomization. For submission purposes in the United States, patients who receive non protocol specified anti-cancer therapy (NPT) will be censored at the last tumour assessment prior to receiving NPT. Also, only deaths occurring within 112 days (two tumour assessments) of the last tumour assessment will be counted as events

Secondary ID(s)

2008-006146-26-FR

BO21990