E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
progressive glioblastoma multiforme (GBM) following failure of front-line therapy defined to include surgery, radiotherapy and exposure to temozolomide chemotherapy regimen. |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Information not present in EudraCT |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the clinical efficacy of the combined treatment of imatinib plus HU based on the objective overall response (OR) rate. The objective overall response rate is calculated as the rate of best overall response of complete response plus partial response (CR+PR) to treatment. |
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E.2.2 | Secondary objectives of the trial |
To assess the duration of objective overall response of the treatment in patients with GBM refractory to TMZ (temozolomide). To assess the clinical benefit of the treatment. (Based on the objective overall response plus stable disease (SD) for more than six months (OR + (SD>6 months)). To assess the progression free survival (PFS) rate at 6 & 12 months, and the median PFS of the treatment in patients with GBM refractory to TMZ (Temozolomide). To assess survival rates at 12 & 24 months. To assess the safety profile of 500mg b.i.d. imatinib administered with 500mg b.i.d. HU. To compare the PK profiles of imatinib with that of imatinib with HU and to evaluate the PK profile of HU in combination with imatinib. To evaluate the metabolic activity, extent and change of GBM tumors induced by the treatment using PET scanning To evaluate the molecular characteristics of progressive GBM tumors in individual patients and offer a mechanistic understanding of clinical responses to treatment. |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
Patients must have histologically confirmed diagnosis of progressive primary GBM based on original diagnosis. Original histology slides must be available for central diagnostic review. Patients with prior low-grade glioma are eligible if histological re-assessment demonstrates transformation to GBM. The most recent histology slides or biopsy sample must be available for central diagnostic review.
Patients must have no more than one prior episode of progressive disease following previously received surgery and/or radiation and only one prior chemotherapy exposure of either Temozolomide or nitrosourea. The chemotherapy could have been administered either in an adjuvant or later setting. The application of Gliadel wafers will be considered a regimen of nitrosourea chemotherapy.
Patients must have measurable disease on gadolinium enhanced MRI
Patients who are currently taking EIACDs (such as carbamazepine, phenobarbital, phenytoin, phosphenytoin, oxcarbamazepine, primadone).
Patients taking steroids: must have been on stable dose for >/= 7 days
ECOG performance score </= 2
Hemoglobin >/= 10g/dL (or Hematocrit > 29%), ANC > 1,500 cells/l, platelets > 100,000 cells/l.
Serum creatinine < 1.5 mg/dl, BUN < 25 mg/dl, serum SGOT and bilirubin < 1.5 times upper limit of normal.
Male and female patients with age equal or greater than 18 years.
Male and female patients who are sexually active must use double-barrier contraception, oral contraceptive plus barrier contraceptive, or must have undergone clinically documented total hysterectomy and/or ovariectomy or tubal ligation.
Female patients of child bearing potential must have had a negative pregnancy test within 48 hours prior to visit (start of study drug).
Patients with a life expectancy of at least 8 weeks.
Signed informed consent by the patient prior to patient entry and any study procedure. |
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E.4 | Principal exclusion criteria |
Patients who have received previous imatinib or hydroxyurea prior to study entry
Patients with >/= grade 2 peripheral edema, or pulmonary or pericardial effusions or ascites of any grade.
Patients who have had prior stereotactic radiosurgery or radioimmunotherapy unless there was obvious radiographic disease progression outside the radiation field or biopsy proven recurrent tumor within the field.
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 1) or intraocular bleed.
Patients who have any uncontrolled systemic infection.
Patients with evidence of intra-tumor hemorrhage on pretreatment diagnostic imaging, except for stable post-operative grade 1 hemorrhage.
Patients who have had major surgery within 4 weeks prior to study entry, or who have not recovered from prior major surgery.
Patients within three months following second surgery for progressing GBM, unless an immediate postoperative scan is made demonstrating measurable disease that is now progressing.
Patients who received chemotherapy within 4 weeks prior to study start (6 weeks for nitrosourea) or other investigational agents (biological, immunotherapeutic or cytostatic agents) prior to study start, or who have not recovered from the toxic effects of such therapy. Other investigational agents or targeted agents may be employed with the chemotherapy mentioned above, but the use of such agents separately will be considered a second regimen and render the patient ineligible for this protocol.
Patients with an impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of imatinib
Patients who are taking Coumadin (warfarin sodium).
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.).
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.
Patients with a known history of Human Immunodeficiency Virus (HIV) seropositivity; testing for HIV is not required at study entry.
Patients who are considered by the investigator as unlikely to be able to be compliant with the study, take the study medications, travel for the necessary assessment visits, or have other medical conditions likely to interfere with the study assessments should not be entered onto the trial.
Patients who are not able to provide reliable informed consent and who do not have a legal representative for healthcare decisions on their behalf should not be entered onto the protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Objective overall response rate of combined treatement of imatinib plus HU. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Information not present in EudraCT |
E.6.2 | Prophylaxis | Information not present in EudraCT |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Information not present in EudraCT |
E.6.8 | Bioequivalence | Information not present in EudraCT |
E.6.9 | Dose response | Information not present in EudraCT |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
E.6.13 | Others | Information not present in EudraCT |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
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 | 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 | 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 | 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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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |