| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with Glioblastoma Multiforme |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10018337 |
| E.1.2 | Term | Glioblastoma multiforme |
|
| 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 |
| To determine if dose-intensifying (increase the 'dose-density') the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy as measured by overall survival |
|
| E.2.2 | Secondary objectives of the trial |
To determine if dose-intensifying the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy as measured by progression-free survival.
To determine in patients with unmethylated MGMT if dose-intensifying the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy (overall and progression-free survival) compared with patients receiving conventional temozolomide dosing.
To determine in patients with methylated MGMT if dose-intensifying the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy (overall and progression-free survival) compared with patients receiving conventional temozolomide dosing.
To determine if there is an association between tumor MGMT gene methylation status and treatment response.
To compare and record the toxicities of the conventional and dose-intense chemotherapy regimens |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Histopathologically proven diagnosis of glioblastoma multiforme.
Patients must have at least 1 block of tissue available for analysis of MGMT status; fresh frozen tumor tissue acquisition is encouraged.
Diagnosis must be made by surgical biopsy or excision.
The tumor must have supratentorial component.
Patients must have recovered from the effects of surgery, post-operative infection, and other complications before study registration.
A diagnostic contrast-enhanced MRI or CT scan (if MRI is not available) of the brain must be performed preoperatively and postoperatively prior to the initiation of radiotherapy, within 28 days prior to study registration. Preoperative and postoperative scans must be the same type. If CT scans were performed perioperatively, a CT and an MRI should be performed before randomization.
Patients diagnosed only by stereotactic biopsy do not require the postoperative scan. However, these patients will only be eligible once review of the tissue block determines that an adequate sample is available for molecular analysis.
Patients unable to undergo MR imaging because of non-compatible devices can be enrolled, provided pre- and post-operative contrast-enhanced CT scans are obtained and are of sufficient quality.
Therapy must begin ≤ 5 weeks after surgery.
History/physical examination within 14 days prior to study registration.
Neurologic examination within 14 days prior to study registration.
Documentation of steroid doses within 14 days prior to study registration and stable or decreasing steroid dose within 5 days prior to registration.
Karnofsky performance status of ≥ 60.
Age ≥ 18 years.
CBC/differential obtained within 14 days prior to study registration, with adequate bone marrow function as defined below:
Absolute neutrophil count (ANC) ≥ 1500 cells/mm3.
Platelets ≥ 100,000 cells/mm3.
Hemoglobin ≥ 10 g/dl. (Note: The use of transfusion or other intervention to achieve Hgb ≥ 10 g/dl is acceptable.)
Adequate renal function, as defined below:
BUN ≤ 25 mg/dl within 14 days prior to study registration
Creatinine ≤ 1.7 mg/dl within 14 days prior to study registration
Adequate hepatic function, as defined below:
Bilirubin ≤ 2.0 mg/dl within 14 days prior to study registration
ALT ≤ 3 x normal range within 14 days prior to study registration
AST ≤ 3 x normal range within 14 days prior to study registration
Patients must sign a study-specific informed consent prior to study registration. If the patient’s mental status precludes his/her giving informed consent, written informed consent may be given by the responsible family member.Patients are informed on the use of their coded data. If the patient refuses to have his data used, he/she cannot sign the informed consent and cannot be included in the study.
For females of child-bearing potential, negative serum pregnancy test within 72 hours prior to starting temozolomide.
Women of childbearing potential and male participants must practice adequate contraception.
There is no reason to believe that the representation of males and females would differ in the studied population, therefore no specific stratification is perfomed to ensure gender distribution. |
|
| E.4 | Principal exclusion criteria |
Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease free for ≥ 3 years. (For example, carcinoma in situ of the breast, oral cavity, and cervix are all permissible).
Recurrent or multifocal malignant gliomas
Metastases detected below the tentorium or beyond the cranial vault.
Prior chemotherapy or radiosensitizers (including Gliadel wafers) for cancers of the head and neck region; note that prior chemotherapy for a different cancer is allowable.
Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields.
Severe, active co-morbidity, defined as follows:
Unstable angina and/or congestive heart failure requiring hospitalization
Transmural myocardial infarction within the last 6 months
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol.
Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive.
Major medical illnesses or psychiatric impairments that in the investigator's opinion will prevent administration or completion of protocol therapy.
Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity.
Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.
Pregnant or lactating women, due to possible adverse effects on the developing fetus or infant due to study drug;
Prior allergic reaction to temozolomide.
Patients treated on any other therapeutic clinical protocols within 30 days prior to study entry or during participation in the study.
No tissue provided for histopathologic central review and MGMT status.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
To determine if dose-intensifying (increase the 'dose-density') the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy as measured by overall survival.
To determine if dose-intensifying the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy as measured by progression-free survival.
To determine in patients with unmethylated MGMT if dose-intensifying the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy (overall and progression-free survival) compared with patients receiving conventional temozolomide dosing.
To determine in patients with methylated MGMT if dose-intensifying the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy (overall and progression-free survival) compared with patients receiving conventional temozolomide dosing.
To determine if there is an association between tumor MGMT gene methylation status and treatment response.
To compare and record the toxicities of the conventional and dose-intense chemotherapy regimens
|
|
| 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 | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Information not present in EudraCT |
| 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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| temozolomide (with different regimen) |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
|
| 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
|
| The end of trial will occur when the last patient (the 834th) will have his last visit. on the basis of estimations, the study should meet its targeted sample size in 48 months. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| 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 |
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