E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Newly diagnosed glioblastoma multiforme with unmethylated MGMT gene promoter status |
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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 | 10018337 |
E.1.2 | Term | Glioblastoma multiforme |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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E.2.2 | Secondary objectives of the trial |
• Progression free survival time. • Safety and tolerability of the combination of cilengitide with standard RTX and TMZ . • PK profile of cilengitide when given daily (5 out of 7 days) at 2000 mg in combination with RTX and TMZ on days of RTX. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent obtained before undergoing any study-related activities. 2. Newly diagnosed histologically proven supratentorial GBM (World Health Organization [WHO] Grade IV, including GBM subtypes, e.g. gliosarcoma). The histological diagnosis must be obtained from a neurosurgical resection of the tumor or by an open biopsy (stereotactic biopsy not allowed). 3. Tumor tissue specimens from the GBM surgery or open biopsy (formalin-fixed paraffin-embedded [FFPE] block) must be available for MGMT gene promoter status analysis and central pathology review. 4. Proven unmethylated MGMT gene promoter status (i.e. cut-off ratio <1 by means of applied test to determine MGMT gene promoter status) 5. Males or females ≥18 years of age. 6. Interval of ≥2 weeks but ≤7 weeks after surgery or biopsy before first administration of study treatment. 7. Available post-operative Gd-MRI performed within <48 hours after surgery (in case that it was not possible to obtain a Gd-MRI within <48 hours post surgery, a Gd-MRI is to be performed prior to randomization). 8. Stable or decreasing dose of steroids for ‡5 days prior to randomization. 9. ECOG PS of 0-1. 10. Meets 1 of the following RPA classifications: • Class III (Age <50 years and ECOG PS 0). • Class IV (meeting one of the following criteria: a) Age <50 years and ECOG PS 1 or b) Age ≥50 years, underwent prior partial or total tumor resection, Mini Mental State Examination [MMSE] ≥27). • Class V (meeting one of the following criteria: a) Age ≥50 years and underwent prior partial or total tumor resection, MMSE <27 or b) Age ≥50 years and underwent prior tumor biopsy only). 11. Laboratory values (within 2 week prior to randomization): • Absolute neutrophil count ‡1500/mm3. • Platelets ‡100,000/mm3. • Creatinine £1.5 x upper limit of normal (ULN) or creatinine clearance rate ‡60 mL/min. • Prothrombin time (PT) international normalized ratio (INR) within normal limits and partial thromboplastin time (PTT) below upper limit of normal. • Hemoglobin ‡10 g/dL. • Total bilirubin £1.5 x the ULN. • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) £2.5 x ULN (except when attributable to anticonvulsants). • Alkaline phosphatase £2.5 x ULN. |
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E.4 | Principal exclusion criteria |
1. Prior chemotherapy within the last 5 years. 2. Prior RTX of the head (except for low dose radiotherapy for Tinea capitis). 3. Receiving concurrent investigational agents or has received an investigational agent within the past 30 days prior to the first dose of cilengitide. 4. Prior systemic antiangiogenic therapy. 5. Placement of Gliadel® wafer at surgery. 6. Planned major surgery for other diseases (e.g. dental extraction). 7. History of recent peptic ulcer disease (endoscopically proven gastric ulcer, duodenal ulcer, or esophageal ulcer) within 6 months of enrollment. 8. History of malignancy. Subjects with curatively treated cervical carcinoma in situ or basal cell carcinoma of the skin, or subjects who have been free of other malignancies for ‡5 years are eligible for this study. 9. History of coagulation disorder associated with bleeding or recurrent thrombotic events. 10. Clinically manifest myocardial insufficiency (New York Heart Association [NYHA] III, IV) or history of myocardial infarction during the past 6 months; or uncontrolled arterial hypertension. 11. Inability to undergo Gd-MRI. 12. Concurrent illness, including severe infection, which may jeopardize the ability of the subject to receive the procedures outlined in this protocol with reasonable safety. 13. Subject is pregnant (positive serum beta human chorionic gonadotropin [b-HCG] test at screening) or is currently breast-feeding, or has the potential and anticipates becoming pregnant/ impregnating their partner during the study or within 6 months after study participation, or subject does not agree to follow acceptable methods of birth control, such as hormonal contraception, intra-uterine pessar, condoms or sterilization, to avoid conception during the study and for at least 6 months after receiving the last dose of study treatment. 14. Current alcohol dependence or drug abuse. 15. Known hypersensitivity to the study treatment. 16. Legal incapacity or limited legal capacity. 17. Presence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. |
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E.5 End points |
E.5.1 | Primary end point(s) |
To investigate the overall survival (OS) time in subjects receiving 2 different regimens of 2000 mg cilengitide in combination with RTX and TMZ standard therapy. |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | 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 | Yes |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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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• The last subject received the last dose of study medication (including a safety follow-up of 28 days). • The study objectives could be answered, i.e. the final analysis on survival has been performed. |
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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |