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    Summary
    EudraCT Number:2008-006146-26
    Sponsor's Protocol Code Number:BO21990
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-03-24
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2008-006146-26
    A.3Full title of the trial
    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
    A.4.1Sponsor's protocol code numberBO21990
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorF. Hoffmann-La Roche Ltd
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Avastin
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBevacizumab
    D.3.9.1CAS number 216974-75-3
    D.3.9.2Current sponsor codeRO4876646
    D.3.9.3Other descriptive namerhuMAb VEGF, anti-VEGF
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeRecombinant humanized monoclonal antibody
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Glioblastoma
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10018336
    E.1.2Term Glioblastoma
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • 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
    E.2.2Secondary objectives of the trial
    • 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
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Title : Roche Clinical Repository (RCR) project for exploratory biomarker research, included in the main protocol (full title : see section A3)

    objectives : Genetic and non-genetic samples will be collected and will be used for research purposes to identify dynamic biomarkers that are predictive of treatment response (including therapeutic response or resistance, dose, safety and
    tolerability) and will help to better understand the pathogenesis, course and outcome of glioblastoma and related diseases. The collected samples might allow the generation of statistically meaningful biomarker data.
    E.3Principal 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
    E.4Principal 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 (including a
    laboratory finding) which gives reasonable suspicion of a disease or condition
    that contraindicates the use of the investigational drug, or that may affect the
    patient’s compliance with study requirements, or would place the patient at
    higher risk of potential treatment complications
    23.Current or recent (within 30 days of enrollment) treatment with another
    investigational drug or participation in another investigational study
    24. Known hypersensitivity to any excipients of bevacizumab formulation or to the
    chemotherapy regimen (temozolomide)
    25.Any contraindication to temozolomide listed in the local label
    26.Hypersensitivity to Chinese hamster ovary cell products or other recombinant
    human or humanized antibody
    27.Unable to comply with the administration of the study treatment
    E.5 End points
    E.5.1Primary 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
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Biomarker discovery, Quality of life
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA91
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    This is an event driven trial. The end of the trial will be when the last data of the last patient required for the overall survival analysis has been received. Based on the statistical assumptions (see Section 8 of the Protocol) and anticipating a recruitment period of approximately 42 months, the end of the study is estimated to occur when the last randomized patient has been followed for 17 months (at the time of the final OS analysis).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state70
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 728
    F.4.2.2In the whole clinical trial 920
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The treatment allocation of all patients will be unblinded at the end of the study. Patients who have not yet progressed at this time and are still receiving bevacizumab monotherapy will have the opportunity to continue to receive treatment with bevacizumab upon enrollment into an extension study.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2009-04-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-05-11
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-09-09
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