| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Glioblastoma multiforme/astrocytoma WHO grade IV, with progression on temozolomide containing regimen |
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| MedDRA Classification |
| 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 |
| The main objective of the study is to show that the combination of imatinib mesylate (GLIVEC) and hydroxyurea is superior to hydroxyurea alone in prolonging progression free survival (PFS) of patients with GBM according to Macdonald-criteria. |
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| E.2.2 | Secondary objectives of the trial |
•Assessment of overall survival during the study.
•Assessment of duration of response, whereby response is defined as at least according to the Macdonald-criteria or partial response (PR) according to the Macdonald-criteria.
•Assessment of response status (overall response) with a combination of imatinib mesylate and hydroxyurea or hydroxyurea alone, i.e. relative number of patients with at least according to Macdonald-criteria or with at least PR or CR according to the Macdonald-criteria.
•To assess the clinical benefit of the combined treatment of imatinib mesylate with HU, or of HU alone. The clinical benefit will be assessed based on the overall response (OR) plus stable disease (SD) lasting more than six months (OR + (SD>6 months)).
|
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Signed informed consent prior to initiation of any study procedure.
2. Patients > 18 years of age.
3. Histological confirmed diagnosis of glioblastoma multiforme / astrocytoma WHO grade IV by a reference pathologist.
4. ECOG Performance Status of 0, 1 or 2.
5. Adequate hepatic, renal and bone marrow function as defined by the following:
total bilirubin < 1.5 x ULN, SGOT and SGPT < 2.5 x ULN, creatinine < 1.5 x ULN, ANC > 1.5 x 109/L, platelets > 100 x 109/L and Hgb >10g/dL.
6. Female patients of childbearing potential with a negative pregnancy test within 7 days of initiation of study drug dosing. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients of reproductive potential who agree to employ an effective barrier method of birth control throughout the study, and for up to 3 months following discontinuation of study drug.
7. Life expectancy of >3 months.
8. MRI available every 6 weeks for disease management.
9. No intracerebral inflammation.
10. Deleted
11. Patients must have previously received surgery and/or radiation therapy and only one prior chemotherapy exposure of either Temozolomide or nitrosourea. The chemotherapy could have been administered in either an adjuvant or later setting. The application of Gliadel wafers will be considered a regimen of nitrosourea chemotherapy.
12. Patients must have measurable disease on enhanced MRI.
13. Patients taking steroids must have been on stable dose for ≥ 5 days
14. Ensured compliance
15. Patients who had a second or third resection after disease progression can not be included earlier than 2 weeks following the resection. MRI should be performed not later than 72 h post operation. If patients are to be included later than 4 weeks after the resection, a new baseline MRT must be performed. |
|
| E.4 | Principal exclusion criteria |
1. Female patients who are pregnant or breast-feeding.
2. Patients who have been treated with any investigational agent(s) within 28 days of the first day of administration of study drug.
3. Patients with uncontrolled medical disease such as diabetes mellitus, thyroid dysfunction, neuropsychiatric disorders, infection, angina or Grade 3 or 4 cardiac problems as defined by the New York Heart Association Criteria.
4. Patients with another primary malignancy treated within the prior three years except excised squamous cell carcinomas of the skin and carcinoma in situ lesions of other organs which have been treated for cure.
5. Patient with acute or known chronic liver disease (i.e., chronic active hepatitis, cirrhosis).
6. Patients who are known to be HIV positive (no specific tests are required for confirmation of eligibility).
7. Expected incompliance according to treatment, treatment diary and examination schedule.
8. Not confirmed histological diagnosis glioblastoma multiforme/astrocytoma WHO grade IV.
9. Other drugs with potential cytostatic main or side effect.
10. No chemotherapy or irradiation therapy.
11. Patients without hematological recovery after previous chemotherapy who have been treated with Chemotherapy within 28 days (6 weeks for nitrosourea) of the first day of administration of study drug.
12. Patients who have received Glivec® for any duration prior to study entry.
13. Patients with ≥ grade 2 peripheral edema, or pulmonary or pericardial effusions and ascites of any grade.
14. Patients who have had prior stereotactic radiosurgery or radioimmunotherapy unless there was obvious radiographic disease progression or biopsy proven recurrent tumor.
15. Patients who have an excessive risk of an intracranial hemorrhagic event (defined by stroke within the prior 6 months, history of CNS (excluding post-operative grade one) or intraocular bleed).
16. Patients with evidence of intra-tumor hemorrhage on pretreatment diagnostic imaging, except for stable post-operative grade 1 hemorrhage.
17. Patients who have had major surgery within 4 weeks prior to study entry, or who have not recovered from prior major surgery.
18. Patients with an impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of Glivec®.
19. Patients who are taking Coumadin (warfarin sodium).
20. For the purposes of MRI Imaging patients with a pacemaker; ferromagnetic metal implants other than those approved as safe for use in MR scanners (e.g. some types of aneurysm clips, shrapnel); patients suffering from uncontrollable claustrophobia or physically unable to fit into the machine (e.g. obesity etc)
21. Patients with a mental impairment limiting their ability to comply with the study requirements (= inclusion criteria 14).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Rate of patients with progression free survival (PFS) during entire study. |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | 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 | 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 | Yes |
| 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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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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| Follow up every three months for the first year and following years every 6 months |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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