| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018336 |
| E.1.2 | Term | Glioblastoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| progression-free (= no progression or death for any reason) survival for 6 months af-ter randomization. |
|
| E.2.2 | Secondary objectives of the trial |
• Overall survival
• Progression-free survival
• Acute toxicity according to CTCAE3.0
• Rate of permanent discontinuations of bevacizumab therapy
• Rate of permanent discontinuations of temozolomide therapy
• Response rate determined by Gd-MRI according to Macdonald et al. (1990)
• expoloratory determination of response on FLAIR imaging.
• Time to treatment failure
• Assessment of quality of life, determined by the EORTC QLQ questionnaires (C30 and B20), and neurocognitive functioning, determined by re-peated standardized measurements using MMSE.
• evaluation of all efficacy and safety criteria in patients treated with second-line study therapy BEV/IRI combination or BEV monotherapy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Female and male patients with at least 18 years of age.
2. Patient provided signed informed consent (informed consent document to be approved by the institution’s Independent Ethics Committee and consent obtained prior to any study-specific procedure). This includes: willingness to give written informed consent, written consent for data protection (legal requirement in Germany: „datenschutzrecht-liche Einwilligung“) and willingness to participate and to comply with the study.
3. Patients with newly diagnosed supratentorial Glioblastoma (GBM) confirmed histological (using WHO classification 2007) by complete resection, partial resection or open biopsy. This includes treatment-naïve-(chemotherapy and radiotherapy)-patients with prior diagnosis of a WHO grade II or III glioma that has progressed to a histological verified GBM.
4. Glioblastoma histology confirmed by reference neuropathology
5. Non-methylated MGMT promoter with cut off ratio < 0.6 in the tumor as determined by methylation-specific PCR (central MGMT assessment)
6. 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 randomization
7. Radiotherapy should be initiated ≥ 22 days and ≤ 35 days after surgery
8. Early postoperative (up to 72h) contrast-enhanced cranial MRI has been performed and is available for evaluation of resection status
9. Karnofsky score of 70% or higher
10. Stable or decreasing corticosteroids dose within 5 days prior to randomization
11. Adequate hematological function: white blood cell (WBC) count ≥ 3x109/L, absolute neutrophil count (ANC) >1,5x109/L, platelet count ≥ 100x109/L, hemoglobin ≥ 8 g/dl (may be obtained by the use of erythropoietin or transfusion for anemia)
12. Adequate liver function: Total bilirubin < 1.5 x upper limit of normal (ULN) AND
aspartate aminotransferase (AST), alanine aminotransferase (ALT)< 2.5 x ULN
13. Adequate renal function: Serum creatinine ≤ 1.5 x ULN AND patients with urine dip-stick for proteinuria < 2+. Patients with ≥ 2+ proteinuria on dipstick urinalysis at baseline should show urine protein creatinine ratio ≤ 1 or should undergo a 24 hour urine collection and must demonstrate ≤ 1 g of protein in 24 hours
14. International normalized ratio (INR) (in absence of anticoagulation treatment) ≤ 1.5 within 7 days prior to enrolment. Anticoagulation is allowed if target INR is < 3 and if the patient is on a stable dose of anticoagulant (coumarin type, low molecular weight heparin (LMWH) or bivalirudin or argatroban) for > 2 weeks at time of enrolment. Therefore, during the study, the preferred choice for anticoagulation treatment with therapeutic intent should be low molecular weight heparin as per ASCO guidelines.
15. Female patients should not be pregnant or breast-feeding. Women of child bearing potential (i.e., a woman who is biologically capable of becoming pregnant) must have a negative serum (β-HCG) pregnancy test within 7 days prior to the first dose of study medication and radiotherapy. If a serum pregnancy test is not performed within 7 days prior to the first dose of bevacizumab, irinotecan, temozolomide and radiotherapy, a confirmatory urine test (within 7 days prior to the first dose of study medication and radiotherapy) is required. Patients (men and women) must agree to use medically accepted contraceptive methods with their partners throughout the study and for 6 months after the last dose of study treatment (bevacizumab, temozolomide, irinotecan, radiotherapy, whichever is administered last). This includes: Women must be post-menopausal or women of childbearing potential must be surgically sterile or use a highly effective contraceptive method (allowed methods of birth control are methods with a failure rate of less than 1 % per year; these are implants, injectables, combined oral contraceptives, IUDs (only hormone spirals), sexual abstinence or vasectomized partners)
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| E.4 | Principal exclusion criteria |
1. Histological confirmation by stereotactic biopsy
2. Evidence of recent hemorrhage on postoperative Gd-MRI of the brain. 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
3. Subjects on any drug suspected to interfere with bevacizumab, irinotecan or temozolomide at randomization
4. Any prior chemotherapy for malignant glioblastomas and gliomas
5. Any prior radiotherapy to the brain or prior radiotherapy resulting in a potential over-lap in the radiation field
6. Significant cardiovascular disease defined as congestive heart failure (NYHA Class II, III, IV), unstable angina pectoris, or myocardial infarction within 6 months prior to enrolment
7. Inadequately controlled hypertension (defined as a blood pressure of >150 mmHg systolic and/or >100 mmHg diastolic on medication) or any prior history of hypertensive crisis or hypertensive encephalopathy
8. History of stroke or transient ischemic attack within 6 months prior to enrolment
9. Significant vascular disease (e.g. aortic aneurysm, aortic dissection or recent peripheral arterial thrombosis) within 6 months prior to enrolment
10. Evidence or history of recurrent thromboembolism (>1 episode of deep venous thrombosis/peripheral embolism) during the past 2 years
11. Evidence of bleeding diathesis of coagulopathy (in the absence of therapeutic anticoagulation)
12. Chronic daily intake of aspirin >325 mg/day or clopridogel >75 mg /day
13. History of intracranial abscess within 6 months prior to randomization
14. History of abdominal or tracheo-oesophageal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrolment
15. History of ≥ grade 2 hemoptysis according to NCI-CTC criteria within 1 month prior to randomization
16. Serious non-healing wound, ulcer or bone fracture
17. Major surgical procedure, open biopsy, intracranial biopsy, ventriculoperitoneal shunt or significant traumatic injury within 28 days prior to planned first dose of bevacizumab administration
18. Core biopsy (excluding intracranial biopsy) or other minor surgical procedure within 7 days prior to planned first dose of bevacizumab administration.
Placement of a central vascular access device (CVAD) if performed within 2 days prior to bevacizumab administration
19. Patients who participate currently in another clinical trial or patients who participated in another clinical trial during the 28 days (or five-half lives of the respective investigational product, whichever is longer) before enrolment
20. Patients who have participated in this trial before
21. Evidence for any active infection requiring hospitalization or i.v. antibiotics within 2 weeks prior to randomization
22. Patients who are underage or patients who are incapable to understand the aim, importance and consequences of the study and to give legal informed consent
23. Patients with a history of a psychological illness or condition such as to interfere with the patient’s ability to understand the requirements of the study. If there is any reasonable doubt that the patient may not be able to provide consent, an independent psychiatrist or neurologist has to be consulted. If the psychiatrist or neurologist will provide a written statement that confirms the patient’s ability to provide consent the patient can sign the consent form and participate
24. Patients who possibly are dependent on the sponsor or investigator
25. Concomitant treatment with preparations of St. John’s wort. Furthermore, the medications specified among section 4.4 can have interactive effects and may interfere with the patient’s ability to meet the study requirements. Precaution of use is according to the SmPC
26. Immunocompromised patients, including known seropositivity for HIV
27. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and fol-low-up schedule
28. History of chronic gastrointestinal disease with diarrhea; history of abdominal or pelvic radiotherapy
29. Morbus Meulengracht or known hypersensitivity to any component of the investigational drugs or excipients
30. Current active second malignancy other than non-melanoma skin cancers and post-treatment of localised prostate cancer. Patients are not considered to have a currently active malignancy if they are in complete remission for >3 years prior to study
31. Any other significant medical illness or medically significant laboratory finding that would make the patient inappropriate for this study, or would increase the risk associated with the patients participation in the study
32. Unable to undergo Gd-MRI
33. Prior treatment with bevacizumab for any indication
34. Prior systemic or local treatment with DNA-damaging agents, tyrosine kinase inhibitors or anti-angiogenic agents for any cancer
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| progression-free survival for 6 months (EFS6) after randomization |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 25 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
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