E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Histologically proven low-grade glioma ♦ Astrocytoma WHO grade II (gemistocytic, fibrillary and protoplasmatic) ♦ Oligoastrocytoma WHO grade II ♦ Oligodendroglioma WHO grade II |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 7.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025783 |
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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 |
To demonstrate a difference in progression-free survival for primary treatment with temozolomide versus primary irradiation. |
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E.2.2 | Secondary objectives of the trial |
to assess: • whether OS can be prolonged by primary chemotherapy with temozolomide • whether the incidence of late toxicity can be decreased by using primary chemotherapy • the toxicity profile of the two treatments and the quality of life of the patients
Cytogenetic objective
The impact of 1p deletions in low-grade gliomas: prognostic effect of cytogenetic deletions detected in tumors on PFS overall and by treatment group. Benefit for patients with LGGs and deletions treated with TMZ compared to radiotherapy alone with respect to survival. Interaction between treatment and cytogenetic features.
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
At the time of registration •Histologically proven low-grade glioma •Astrocytoma WHO grade II (gemistocytic, fibrillary and protoplasmatic) •Oligoastrocytoma WHO grade II •Oligodendroglioma WHO grade II •Supratentorial tumor location only •WHO performance status <=2 •Age ≥ 18 years
•No previous chemotherapy or radiotherapy for brain tumor •Absence of known HIV infection, chronic hepatitis B or hepatitis C infection •Absence of any medical condition, which could interfere with oral medication intake (e.g., frequent vomiting, partial bowel obstruction) •Availability of histopathologic slides for central pathology review (see chapter 6.1.1, “criteria of evaluation”; and chapter 13 “pathology”) •Availability of tumor material (paraffin-embedded) and blood for molecular testing* •Before patient registration, written informed consent for the randomization and for the collection, transfer and analysis of the pathological material, molecular biology testing (1p testing) must be given according ICH GCP, and any applicable local regulations •For those participating to the translational research, before patient registration, written informed consent for the collection, transfer and analysis of the material for translational research must be given according ICH GCP, and any applicable local regulations
* Patients having had previous 1p testing in a different laboratory than the one specified for this study, will need repeated testing in the central reference laboratory.
At the time of randomization •Histologically proven low-grade glioma ** ** (based on the latest performed histology, if no repeat biopsy has been performed, based on initial histology) •Astrocytoma WHO grade II (gemistocytic, fibrillary and protoplasmatic) •Oligoastrocytoma WHO grade II •Oligodendroglioma WHO grade II; •Supratentorial tumor location only •Not candidate for treatment exclusively by surgery •Requiring treatment as demonstrated by at least one of the following criteria: •Age ≥ 40 years •Radiologically proven progressive lesion •New or worsening neurological symptoms other than seizures only (focal deficits, signs of raised intracranial pressure, mental deficits) •Intractable seizures defined as: Suffering from persistent seizures, defined as having both: • persistent seizures interfering with every day life activities other than driving a car AND •failed three lines of anti-epileptic drug regimen, including at least one combination regimen •WHO performance status <=2 •RTOG Neurological Function 0-3 •1p testing performed (for stratification: 1p deleted versus 1p normal versus undeterminable) •No previous irradiation to the brain •No prior chemotherapy •Patients must have recovered from prior surgery, if applicable •Adequate hematological, renal and hepatic function according to all of the following laboratory values (to be performed within 14 days, inclusive, prior to randomization): •Absolute neutrophil count >= 1.5 x109/l •Platelets >=100x109/l •Serum creatinine ≤1.5 times upper limit of laboratory normal •Total serum bilirubin ≤ 1.5 times upper limit of laboratory normal •ASAT(AST) or ALAT(ALT) ≤ 2.5 times upper limit of laboratory normal •Alkaline phosphatase of ≤ 2.5 times upper limit of laboratory normal •Absence of known HIV infection, chronic hepatitis B or hepatitis C infection •Absence of any other serious medical condition according to the medical judgment of the physician prior to randomization •Absence of any medical condition, which could interfere with oral medication intake (e.g., frequent vomiting, partial bowel obstruction) •Absence of previous or concurrent malignancies at other sites with the exception of surgically cured carcinoma in-situ of the cervix and non-melanoma skin cancer •All patients of reproductive potential (male and female) must use effective contraception for the whole duration of the treatment and until 6 months thereafter. Females must not be pregnant or lactating •Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule as discussed with the patient before randomization •Completion of baseline quality of life questionnaires (QLQ-C30 + BN20) must be obtained before randomization (see Appendix D, Appendix H and Appendix I) •Completion of baseline neuropsychological testing must be obtained before randomization (see Appendix M) for specified centers
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E.4 | Principal exclusion criteria |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival |
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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 | 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 | No |
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 | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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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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End of study occurs when all of the following criteria have been satisfied: 1. Thirty days after all patients have stopped protocol treatment 2. The trial is mature for the analysis of the primary endpoint as defined in the protocol 3. The database has been fully cleaned and frozen for this analysis
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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 | 7 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 6 |