E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Recurrent grade II and grade III gliomas |
|
E.1.1.1 | Medical condition in easily understood language |
Recurrent grade II and grade III gliomas |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027744 |
E.1.2 | Term | Mixed astrocytoma-oligodendroglioma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10060971 |
E.1.2 | Term | Astrocytoma malignant |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10026659 |
E.1.2 | Term | Malignant oligodendroglioma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 is to compare the activity of both the combination Temozolomide (TMZ) plus bevacizumab and TMZ alone in recurrent grade II or grade III glioma
patients without 1p/19q co-deletion. |
|
E.2.2 | Secondary objectives of the trial |
Secondary objectives: Safety, patient-oriented assessment of clinical benefit.
Exploratory objectives: qualification or discovery of prognostic and/or predictive biomarkers of activity or efficacy. Discordances between RANO and Macdonald's criteria. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Histologically proven grade II or grade III astrocytoma, oligodendroglioma or oligoastrocytoma.
- Demonstrated absence of 1p/19q co-deletion.
- Availability of tumor material for central review processes and translational research projects
- First recurrence after initial treatment with either radiotherapy and/or
chemotherapy.
- Enhancing recurrence on MRI scan.
- Absence of any cardiovascular disorder.
- Absence of any thrombotic or hemorrhagic issue.
- Absence of known hypersensitivity.
- No underlying or previous conditions that could interfere with treatment.
- Normal hematological functions.
- Normal liver function.
- Normal renal function.
- Age ≥ 18 years.
- WHO Performance status 0 - 2.
- Women of childbearing potential (WOCBP) must be using an adequate method of contraception
- Before patient randomization, written informed consent must be given according to ICH/GCP, and national/local regulations. Informed consent should also be given for biological material to be stored and used for future research on brain tumors.
|
|
E.4 | Principal exclusion criteria |
- More than one line of chemotherapy.
- Radiotherapy within the three months prior to the diagnosis of progression.
- Radiotherapy with a dose over 65 Gy, stereotactic radiosurgery or brachytherapy unless the recurrence is histologically proven.
- Prior treatment with Bevacizumab or other VEGF inhibitors or VEGF-Receptor signaling inhibitors
- Invasive procedures within 4 weeks prior to randomization.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint will be probability of survival at 1 year (i.e. patients alive at 12 months, OS12). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Secondary endpoints will be:
- response (distribution, objective response rate, duration of response, according to RANO criteria)
- Progression Free Survival distribution according to RANO criteria (PFS: distribution, PFS 6 and PFS 12),
- Overall survival: distribution and OS 24 complete safety profile,
- Patient-oriented criteria: clinical/neurological deterioration free survival, steroid use, quality of life (by patients and caregivers/relatives) and development of cognitive deterioration. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
After 6, 12 and 24 months.
Clinical/neurological deterioration free survival, steroid use, quality of life (by patients and caregivers/relatives) and development of cognitive deterioration until progression disease. |
|
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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Quality of life, Neurocognitive testing |
|
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 | 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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 27 |
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 | No |
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
|
Consider protocol (chapter 8.4).
End of study occurs when all of the following criteria have been
satisfied:
1.The trial is mature for the analysis of the primary endpoint (ie at
least 1 year follow-up for each of the first 144 eligible patients).
2.The database has been fully cleaned and frozen for this analysis
3.Thirty days after last treatment administration to the last patient on
protocol |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
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 | 6 |
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 |