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

Phase 2

• Conditions: Malignant neoplasm of brain; Brain cancer, recurrent glioblastoma; Cancer

• Registration Number: ISRCTN16052954
• Lead Sponsor: niversity of Leeds

Brief Summary

2024 Protocol article in https://pubmed.ncbi.nlm.nih.gov/38458809/ (added 11/03/2024)

Detailed Description

Not available

Study Timeline

• Study Start: 2021-02-25
• Last Update Posted: 9 September 2024
• Study Completion: 2026-05-30

Recruitment & Eligibility

• Status: Ongoing
• Sex: All
• Target Recruitment: 70

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 4/3p 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,

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

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
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. Overall survival rates in the chemotherapy arm will also be assessed for calibration purposes only and not for direct statistical comparison.