| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018336 |
| E.1.2 | Term | Glioblastoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
| The principal research question is to assess the number of patients alive in the re-irradiation arm at 9 months post-start of treatment. Overall survival will be defined as the time from randomisation to the date of death from any cause. OS rates in the chemotherapy arm will also be assessed for calibration purposes only and not for direct statistical comparison. |
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| E.2.2 | Secondary objectives of the trial |
Secondary endpoints will assess Health Related Quality of Life (HRQOL), using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QLQ-C30) and Brain Cancer module (BN20) questionnaires, which will be completed by participants. Additionally, HRQOL will be also assessed by a one-off semi-structured interview in a participant/caregiver subset of 15 participants or until data saturation.
Other secondary endpoints include Dexamethasone use, anti-epileptic drug use, radiological response rate, acute and late toxicities, overall survival (OS) and progression free survival (PFS).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Histologically proven diagnosis of GBM with consistent molecular pathology, based on original pathology.
• First recurrence of GBM, with contrast enhancing disease, following primary treatment (or following surgery alone for first recurrence of GBM; i.e. no previous systemic therapy or re-irradiation for recurrence permitted).
• The MRI scan that reveals recurrence must be reviewed by the local multi-disciplinary meeting, including agreement of a Consultant Neuro-Radiologist that imaging changes are in keeping with recurrence and not pseudo-progression.
• Randomisation must be performed within 21 days of the MRI that confirms recurrence. Outside of 21 days, an updated MRI is required to confirm eligibility and serve as a contemporaneous baseline scan to assess response to further treatment. Please see section 9 Assessments for further details for achieving this.
• ≥6 months since completion of primary radiotherapy (where the interval since radiotherapy completion is 5 months and 2 weeks or greater, this may be rounded up to 6 months and the patient included in the trial).
• Prior history of standard dose, conventionally fractionated CNS radiotherapy (i.e. 54-60Gy in 28-33 fractions).
• As a minimum patients will have completed at least two weeks of temozolomide, concurrent with their original radiotherapy.
• Up to and including three enhancing lesions:
- In cases of a single recurrent enhancing lesion:
-predicted re-irradiation GTV<75cm3 (based on diagnostic MR imaging and on maximum diameters of enhancing disease in all 3 planes, calculated from 4/3π x ½ x diameter 1 x ½ x diameter 2 x ½ x diameter 3, and
-maximum diameter of enhancing disease must be ≤6cm. In cases where there is circumferential enhancement around a cavity, such that the cavity and enhancing disease will be included in the GTV, then the maximum diameter of enhancing disease and cavity must be ≤6cm.
-In cases of multiple (i.e. two or three) discrete recurrent enhancing lesions:
-the total (i.e. combined) predicted re-irradiation GTV must be <50cm3 and lesions must be clustered in a similar brain region such that PTVs are anticipated to be adjacent or overlapping, and
-maximum diameter of combined enhancing disease, across all enhancing lesions (including any gaps between), must be ≤6cm.
• Karnofsky Performance Status 70+
• Adequate hematologic, renal, and hepatic function (absolute neutrophil count, ≥1.5 x 109/L; platelet count, ≥100 x 109/L; White cell count ≥3.0 x 109/L; haemoglobin ≥10g/L (may be corrected by transfusion); serum creatinine clearance (measured or estimated) ≥30ml/min; total serum bilirubin level <1.5 times ULN; and ALT <5 times ULN) within 14 days prior to randomisation. (Dose modifications may still be required based on these parameters). Lymphopaenia is not a contra-indication to trial entry.
• Patients who have had surgery for first recurrence may also be included provided there is residual enhancing disease on the immediate post-operative MRI or if enhancing disease develops on subsequent follow-up imaging, provided no prior systemic therapy or re-irradiation for recurrence has been given. As above, this MRI must be reviewed within the local multi-disciplinary meeting, with agreement of a Consultant Neuro-Radiologist that the imaging changes are in keeping with residual or new enhancing disease. Randomisation must be performed within 21 days of the MRI that confirms recurrence. Outside of 21 days, an updated MRI is required to confirm eligibility and serve as a contemporaneous baseline scan to assess response to further treatment.
Patients must have recovered from the prior effects of therapy:
- There must be a gap of at least 28 days since completion of adjuvant temozolomide or any other systemic anti-cancer therapy and commencement of re-irradiation or nitrosourea-based chemotherapy (note randomisation may occur prior to this provided all other eligibility criteria are met and the gap is at least 28 days when the trial treatment commences).
- Patients who receive resection for recurrence must have adequate wound healing and resolution of any significant meningocoele or any other cause of swelling in close proximity to the wound.
• Medical history and physical examination, including CNS examination, must be performed within 14 days prior to randomisation.
• Female participants of child-bearing potential must agree to be pregnancy screened prior to entering BRIOChe and before signing the main informed consent form.Male participants must agree to practice methods of contraception that are considered medically acceptable for the duration of the trial treatment and, if randomised to chemotherapy, for 6 months post-end of treatment if sexually active with a female of child-bearing potential.
•Patients must be able to provide study-specific informed consent.
•Age 18 or over
See protocol for full criteria |
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| E.4 | Principal exclusion criteria |
• Pregnant (positive pregnancy test) or lactating.
• Critical normal brain structures treated above usual tolerance during initial radiotherapy (i.e. based on 30 fractions initial treatment, >55Gy delivered to 1% or 0.1cm3 of optic nerve or chiasm or >55Gy delivered to >1cm3 of brainstem or >57Gy delivered to >0.1cm3 of brainstem or >50Gy to 1% or 0.1cm3 of globes).
• Recurrence with leptomeningeal disease or only leptomeningeal disease.
• Recurrence defined by non-enhancing disease only.
• More than three enhancing lesions present on MRI or multi-focal recurrence.
• IDH1/2 mutant tumours on original pathology (to avoid unbalance between arms).
• GBM with known features of PXA, BRAF mutations or 1p19q co-deletion (on original pathology or updated pathology if available)
• Prior invasive malignancy (except non-melanomatous skin cancer), unless disease free for a minimum of one year.
• Severe active co-morbidity making patient unsuitable for chemotherapy or re-irradiation (e.g. uncontrolled diabetes, uncontrolled hypertension).
• Prior allergic reaction to nitrosoureas.
• Coeliac disease.
• Any recognised genetic syndrome causing sensitivity to radiotherapy.
• Patient unwilling/ unable to attend for follow up in the radiotherapy centre.
• Contraindication to MRI or gadolinium.
• Previous radiotherapy dose distribution unavailable.
• Previous systemic therapy or re-irradiation for recurrent GBM.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome measure is overall survival rate at 9 months. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The assessment of the primary endpoint is based on the 9-month overall survival rates i.e. the number and proportion of patients alive in the re-irradiation arm at 9 months post-start of treatment. Overall survival is defined from randomisation to the date of death from any cause and survival data will be collected at all standard follow-up visits. |
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| E.5.2 | Secondary end point(s) |
Health Related Quality of Life (HRQOL)
Questionnaires to be completed by participants include the European Organisation for Research and Treatment of Cancer (EORTC) Quality of life questionnaire core 30 (QLQ-C30) and Brain Cancer module (BN20). These will be completed independently by participants at clinic visits at baseline and at 6 weekly intervals post start of treatment up to 48 weeks post-start of treatment.
In addition HRQOL will be evaluated through one-off semi-structured qualitative interviews in patient/carer subset (n~15 or until data saturation). This will include HRQOL before/ during treatment, experience of treatment and what matters most to patients/carers.
Dexamethasone use
Dexamethasone use will be defined by the dose and frequency of dexamethasone received. Data on dexamethasone use, including dose, any change in dose including the date of change will be collected at baseline and then on a 6 weekly basis post start of treatment.
Anti-epileptic drug use
Anti-epileptic drug use will be defined by the type, dose and frequency of anti-epileptic received. Data on anti- epileptic use including name of anti-epileptic drug(s), dose, any change in dose including the date of change will be collected at baseline and then on a 6 weekly basis post start of treatment.
Radiological response rate
Participants will be assessed for response to treatment at 12 weeks post start of treatment and then at 12 weekly intervals up to 48 weeks post start of treatment or until progression. Radiological response to treatment will be assessed via MRI imaging in accordance with Response Assessment in Neuro-Oncology (RANO) criteria.
Acute and late toxicities
Assessment of toxicities will take place at 6 weekly intervals post start of treatment up to 48 weeks or until progression. They will be evaluated according to the current NCI-CTCAE criteria and include all AEs. Acute toxicities will be defined as those occurring up to 12 weeks post end of treatment. Late toxicities will be defined as those occurring after 12 weeks post end of treatment. The end of treatment will be the date of the last radiotherapy dose or the final chemotherapy cycle. The period of collection of acute toxicity data will differ between arms due to different treatment lengths, but the overall period of data collection for toxicities will be the same for both treatment arms.
Participant reported toxicities will be captured via the EORTC QLQ-C30 and QLQ-BN20 at baseline and every 6 weeks from the start of treatment up to 48 weeks or until progression.
Progression free survival (PFS)
Progression-free survival is defined as the time from randomisation to the first documented evidence of disease progression or death (from any cause). PFS includes radiological progression assessed in accordance with RANO criteria and non RANO evaluable progression where RANO assessment is not possible (e.g. clinical progression in a patient who is too unwell for further imaging).
Overall survival (OS)
Overall survival is calculated as the time from randomisation to date of death from any cause, or date last known to be alive. Patients not known to have died at the time of analysis will be censored at the date last known to be alive. Date of death or date last known to be alive will be collected throughout the trial, and from sites at the end of the trial for all participants not known to have died prior to the end of follow up.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Health Related Quality of Life HRQOL
Evaluated at each follow up time point
Dexamethasone use
Evaluated at 6, 12 and 18 weeks post start of treatment and overall at the end of follow up. Evaluated over treatment period for the re-irradiation arm.
Anti-epileptic use
Evaluated at 6, 12 and 18 weeks post start of treatment and overall at end of follow up.
Radiological response rate
Evaluated at baseline, 12, 24, 36 and 48 weeks post start of treatment
Acute and late toxicities
Acute toxicities evaluated within 12 weeks of treatment, late toxicities >12 weeks following treatment and overall
PFS
Evaluated 48 weeks post start of treatment, presented for 6, 9 and 12 months post start of treatment and overall
OS
Evaluated at end of trial |
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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 | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | 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) | 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.8.2.4 | 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 | 16 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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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| The end of the trial is defined as the date of the collection of the last participant’s data item. All evaluable trial participants will be followed up until this point. Follow-up data will be collected from sites until 48 weeks post start of treatment. A final data sweep to gather up to date survival data and information regarding additional treatments will be sent by email after the last patient has reached one year after randomisation to 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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