The survival benefits of re-irradiation and chemotherapy for patients with relapsed glioblastoma

Trial ID: ISRCTN16052954

Other - Phase 2 - No longer available

Background and study aims Glioblastoma (GBM) is the most common adult malignant brain tumour, with an incidence of 5 per 100,000 per year in England. The condition is incurable and, despite aggressive treatment at first presentation (surgery, radiotherapy and chemotherapy), after an average of 7 months, almost all tumours recur within the brain. At the time of recurrence, prognosis is measured in months, with median survival around 6.5 months. The aim of further treatment at the time of recurrence is to prolong survival and maintain health-related quality of life (HRQOL), which is of paramount importance to patients and carers, given the limited life expectancy. Chemotherapy is typically employed in the setting of recurrent GBM, often using nitrosourea-based regimens. Effectiveness is limited, with a median survival of around 5-9 months. Chemotherapy is delivered over a protracted period, lasting up to 6.5 months. There is growing evidence that re-irradiation is an alternative treatment for recurrent GBM, which is less commonly used in the UK. Evidence suggests that a 10-day outpatient course of external beam re-irradiation results in survival outcomes that are at least similar to patients treated with nitrosourea-based chemotherapy. The aim of this study is to assess the survival benefits of re-irradiation and chemotherapy and provide clinically meaningful HRQOL data for both treatments. Who can participate? Patients aged 18 and over with relapsed GBM who have previously completed their first round of chemoradiotherapy treatment more than 6 months ago What does the study involve? Patients will receive either radiotherapy (re-irradiation) treatment in 10 daily fractions over 2 weeks, or chemotherapy regimens delivered in six 6-week cycles. All patients will be followed up until 48 weeks after the start of treatment. Clinical visits and health-related quality of life will be performed every 6 weeks and MRI imaging will be performed every 3 months for up to 1 year. Interviews will take place in a small number of patients and carers, which will allow for a greater understanding of HRQOL. What are the possible benefits and risks of participating? By taking part in this study, the researchers hope to understand better how both chemotherapy and re-irradiation work in patients with GBM, what side effects these treatments cause and how they impact a patients quality of life. This will help hospitals in choosing the best treatment for future patients when their GBM recurs. Participants have a risk of side effects in both the chemotherapy and radiotherapy groups. Possible side effects of chemotherapy are tiredness, nausea, vomiting, taste changes, sore mouth or mouth ulcer, infections, bruising and bleeding, poor appetite, diarrhoea, constipation, abdominal pain, anaemia, skin changes and allergic reactions. Possible side effects from re-irradiation could include; tiredness, patchy hair loss, headaches, dizziness, swelling in the brain, nausea, vomiting, skin redness or irritation on the scalp, weakness, seizures and dry mouth or taste changes. Where is the study run from? University of Leeds (UK) When is the study starting and how long is it expected to run for? May 2019 to September 2026 Who is funding the study? The Jon Moulton Charity Trust (Guernsey) Who is the main contact? Dr Samantha Noutch BRIOCHE@leeds.ac.uk https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-giving-radiotherapy-again-for-glioblastoma-brioche

Conditions

• Brain cancer, recurrent glioblastoma
• Cancer
• Malignant neoplasm of brain

Interventions

• Lomustine, procarbazine, vincristine

Eligibility

Inclusion criteria

• 1. Histologically proven diagnosis of GBM with consistent molecular pathology, based on original pathology (repeat biopsy at recurrence is NOT required). 2. 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). 3. 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 pseudoprogression. 4. 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 4.1 Inclusion Criteria for further details for achieving this. 5. ≥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). 6. Prior history of standard dose, conventionally fractionated CNS radiotherapy (i.e. 54-60Gy in 28-33 fractions). 7. As a minimum patients will have completed at least two weeks of temozolomide, concurrent with their original radiotherapy. 8. Up to and including three enhancing lesions: 8.1. In cases of a single recurrent enhancing lesion: 8.1.1. 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 8.1.1. 1 x ½ x diameter 2 x ½ x diameter 3: see Appendix D – Calculation of volume and explanation for volume limitations for study eligibility for explanation) and 8.1.2. Maximum diameter of enhancing disease must be ≤6 cm. 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 ≤6 cm. 8.2. In cases of multiple (i.e. two or three) discrete recurrent enhancing lesions: 8.2.1. The total (i.e. combined) predicted reirradiation 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 8.2.2. Maximum diameter of the combined enhancing disease, across all enhancing lesions (including any gaps between), must be ≤6 cm 9. Karnofsky Performance Status 70+ 10. 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 ≥10 g/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. See section 9.1 Chemotherapy Arm for further details). Lymphopaenia is not a contra-indication to trial entry. 11. 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 reirradiation for recurrence has been given. As above, this MRI must be reviewed within the local multi-disciplinary meeting, with agreement of a Consultant NeuroRadiologist 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. Please see section 4.1 Eligibility for further details for achieving this. 12. Patients must have recovered from the prior effects of therapy: 12.1. 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). 12.2. 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. 13. Medical history and physical examination, including CNS examination, must be performed within 14 days prior to randomisation. 14. Female participants of childbearing potential must agree to be pregnancy screened prior to entering the BRIOChe trial and before signing the main informed consent form. They should provide informed consent on the eligibility pregnancy screening PISICF to allow pregnancy screening. They should provide a negative pregnancy result and agree to continue 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. They must have a negative pregnancy test within 7 days prior to randomisation. 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. See section 4.3 Birth control: contraception and pregnancy testing for further details. 15. Patients must be able to provide study-specific informed consent 16. Aged 18 years or over 17. Should be able to start treatment within 21 days of randomisation and must start within 28 days of randomisation 18. Patients must be able to swallow oral medication

Exclusion criteria

• 1. Pregnant (positive pregnancy test) or lactating 2. Critical normal brain structures treated above usual tolerance during initial radiotherapy (i.e. based on 30 fractions initial treatment, >55 Gy delivered to 1% or 0.1 cm³ of optic nerve or chiasm or >55 Gy delivered to >1 cm³ of brainstem or >57 Gy delivered to >0.1 cm³ of brainstem or >50 Gy to 1% or 0.1 cm³ of globes) 3. Recurrence with leptomeningeal disease or only leptomeningeal disease 4. Recurrence defined by non-enhancing disease only 5. More than three enhancing lesions present on MRI or multi-focal recurrence 6. IDH1/2 mutant tumours on original pathology (to avoid unbalance between arms) 7. GBM with known features of PXA, BRAF mutations or 1p19q co-deletion (on original pathology or updated pathology if available) 8. Prior invasive malignancy (except non-melanomatous skin cancer), unless disease-free for a minimum of 1 year 9. Severe active co-morbidity making patient unsuitable for chemotherapy or re-irradiation (e.g. uncontrolled diabetes, uncontrolled hypertension) 10. Prior allergic reaction to nitrosoureas 11. Coeliac disease 12. Any recognised genetic syndrome causing sensitivity to radiotherapy 13. Patient unwilling/unable to attend for follow up in the radiotherapy centre 14. Contraindication to MRI or gadolinium 15. Previous radiotherapy dose distribution unavailable 16. Previous systemic therapy or re-irradiation for recurrent GBM

Sponsor

University of Leeds

Source: https://www.isrctn.com/

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