E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10018336 |
E.1.2 | Term | Glioblastoma |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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 |
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E.2.2 | Secondary 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
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full 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.
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E.3 | Principal 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
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E.4 | Principal 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
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E.5 End points |
E.5.1 | 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
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Biomarker discovery, Quality of life |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 91 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial 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
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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).
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 1 |