Bevacizumab for the treatment of cerebral RAdiation Induced NecrosiS (BRAINS) study: A multicenter, open-label, randomized clinical trial to assess the clinical efficacy and cost-effectiveness of bevacizumab versus corticosteroids as first-line treatment in patients with symptomatic cerebral radiation necrosis after radiation for high grade glioma or brain metastases

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Nervous System Diseases [C10], Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutics [E02]

Trial duration

10 Jul 2025 → ongoing

Decision date (initial)

2025-02-18

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To compare the clinical efficacy of first-line bevacizumab vs dexamethasone for cerabral radiation necrosis (sCRN) in high grade glioma (HGG) and brain metastases (BM) patients

Secondary objectives 12

1. To compare health-related quality of life (QoL) of first-line bevacizumab vs dexamethasone for sCRN in HGG and BM patients
2. To compare clinical efficacy of first-line bevacizumab between 2 cycles (6 weeks) and 4 cycles (12 weeks) for sCRN in HGG and BM patients
3. To compare radiologic response of first-line bevacizumab vs dexamethasone for sCRN in HGG and BM patients
4. To compare cognitive functioning in patients treated with first-line bevacizumab vs dexamethasone in HGG and BM patients
5. To compare epileptic seizure outcomes of first-line bevacizumab vs dexamethasone in BM and HGG patients
6. To evaluate treatment toxicity of bevacizumab and dexamethasone in BM and HGG patients
7. To compare time to recurrence of sCRN in first-line bevacizumab vs dexamethasone in BM and HGG patients
8. To compare time to next sCRN treatment in firstline bevacizumab vs dexamethasone in BM and HGG patients
9. To compare tumor progression free survival (PFS) in first-line bevacizumab vs dexamethasone in BM and HGG patients
10. To compare overall survival (OS) in first-line bevacizumab vs dexamethasone in BM and HGG patients
11. To validate prognostic tool from retrospective BRAINS study for clinical favourable response for patients with HGG and BM
12. To assess cost-effectiveness of first-line bevacizumab vs dexamethasone for patients with HGG and BM

Conditions and MedDRA coding

High grade glioma (HGG)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Age ≥ 18 years old
2. First episode of sCRN ≥ 3 months after completion of focal (re-)irradiation, as determined by the local Multidisciplinary Brain Tumour Board. A clear working diagnosis of CRN without evidence of mixed tumour progression is required
3. KPS score ≤ 90 and either (a) a minimum loss of two points in at least one domain of the Neurologic Assessment in Neuro-Oncology (NANO) scale as compared to the maximum score of that domain due to sCRN, or (b) a headache attributable to sCRN with an average intensity ≥5/10 on the NRS, persisting for ≥10 consecutive days, with inadequate relief despite an adequate trial of paracetamol and/or an NSAID unless these medications are contra-indicated or not tolerated
4. Maximum daily dexamethasone use of 1 mg/day for the 8 weeks preceding randomization a. Dexamethasone may have been prescribed for various indications, except for managing (ongoing) cerebral edema b. Higher doses of dexamethasone are permitted 3 weeks immediately preceding randomization if used specifically for the treatment of sCRN
5. Able to understand the patient information, online tests and questionnaires
6. Written informed consent
7. Only for BM patients: BM of solid tumor, including all primary tumor types
8. Only for HGG patients: A confirmed histological diagnosis of high-grade diffuse glioma according to WHO 2021 criteria, including: astrocytoma, IDH-mutant, grade 3-4; astrocytoma, IDH-wildtype (sybtype molecular glioblastoma); oligodendroglioma, 1p/19q codeleted, grade 3; diffuse glioma, NEC, grade 3-4; or glioblastoma, IDH-wildtype, grade 4

Exclusion criteria 4

1. Prior treatment with bevacizumab <6 months before diagnosis of sCRN
2. Life expectancy <3 months
3. Impending radiological or clinical signs of brain herniation necessitating immediate decompressive surgery
4. Any comorbidity or condition that prevents safe administration of the studied medication, determined by the treating physician, including but not limited to: a. Intolerance for murine proteins b. Hypersensitivity or allergy to the active substance or to any of the excipients of bevacizumab or dexamethasone c. Nephrotic syndrome or abnormal renal function - Calculated (Cockcroft-Gault) or measured creatinine clearance < urine dipstick for proteinuria ≥ 2+. Patients with ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo 24 hours urine c30 mL/min;ollection and must demonstrate ≤ 1 g of protein/24 hr. d. Clinical significant cardiovascular disease o Uncontrolled hypertension (systolic BP >150mmHg and/or diastolic >100mmHg) despite the use of ≥ 3 antihypertensive drugs o Previous hypertensive crisis, hypertensive encephalopathy or previous reversible posterior leukoencephalopathy syndrome (RPLS) o Non tumour related vascular event (e.g. cerebral or cardiac ischemia/bleeding (including transient ischemic attack, cerebral ischemia, unstable angina or angina requiring intervention, myocardial infarction), peripheral arterial thrombus, peripheral artery disease, deep venous thrombosis, lung embolism) < 6 months o History of aortic aneurysm or dissection o Congestive heart failure NYHA II-IV e. History of gastro-intestinal fistula, perforation or abscess < 6 months f. History of bleeding o Relevant pulmonary hemorrhage/ hemoptysis < 1 month or the presence of a pulmonary lesion with a high risk of bleeding (= central lung tumour and/or untreated squamous cell carcinoma) according to the treating physician o Active gastrointestinal bleeding < 6 months o Evidence of recent intracranial hemorrhage on MRI brain <3 months. Asymptomatic presence of hemosiderin depositions or punctate hemorrhage in the tumor do not serve as a ground for exclusion g. Excess risk of bleeding o History or evidence of inherited bleeding diathesis or significant coagulopathy with the risk of bleeding o Decreased platelet count < 75x109/L h. Risk of wound healing complications o Significant non-healing wound, (peptic) ulcer or bone fracture o Major surgical procedure (including open biopsy) or significant traumatic injury within 28 days prior to first study treatment or planned surgical procedure within the following next 28 days after planned study inclusion o Minor surgical procedure, stereotactic/core biopsy, fine needle aspiration within 7 days prior to first study treatment i. Patients with ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo 24 hours urine collection and must demonstrate ≤ 1 g of protein/24 hr. j. i. High-dose radiotherapy to the mediastinum, abdomen, or lower pelvis; administration of bevacizumab should only be considered after prior consultation with a pulmonologist or oncologist k. Pregnancy or lactation. Women of child bearing potential (WOCBP) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 days prior to randomization. WOCBP and female partners of male patients must comply with adequate contraception methods as requested by the study protocol (Paragraph 8.2.1 Pregnancy, contraception and breastfeeding) l. Evidence of any other medical conditions (such as psychiatric illness, physical examination or laboratory findings) that may interfere with the study treatment, affect patient compliance or place the patient at high risk for treatment-related complications according to the treating physician m. Current or recent (within 30 days of first study treatment) treatment with another investigational drug or participation in another interventional study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. a favourable clinical response, which is defined as (a) utilization of 1.5mg/day or less dexamethasone and (b) meeting one of the following two criteria: 1) improved Karnofsky Performance Status (KPS) (≥ 10 points ) + at least stable Neurologic Assessment in Neuro-Oncology (NANO) or 2) improved NANO (≥ 2 points) + at least stable KPS, assessed 12 weeks after initiation of treatment or 3) an improved KPS (of ≥ 10 points ) + improved NANO (of ≥ 2 points)

Secondary endpoints 11

1. improvement of ≥10 points for BM and ≥5 points (based on anchor based minimally important differences) for glioma on the EORTC QLQ C30 physical functioning (and other clinically relevant functioning and symptom scales) at 12 weeks
2. reduction of cerebral edema on T2/Fluid Attenuated Inversion Recovery (FLAIR) and contrast-enhancing lesion on Based on CCMO protocol template CTR Version 3.0, May 2023 14 of 103 T1 MRI at 12 weeks
3. change in cognitive functioning measured by the Amsterdam Cognition Scan (ACS) at 12 weeks
4. experienced epileptic seizure frequency and antiseizure medication use at 12 weeks
5. number of treatment related adverse events until 21 days post end of treatment
6. 2-year sCRN recurrence free survival
7. time to next anti-CRN treatment
8. 2-year progression free survival
9. 2-year overall survival
10. the cost-effectiveness of both treatments
11. the number of patients who reached the main endpoint between 2 and 4 cycles of bevacizumab

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Sponsor organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Address

Plesmanlaan 121

City

Amsterdam

Postcode

1066 CX

Country

Netherlands

Scientific contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

Dr. D. Brandsma

Public contact point

Organisation

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Contact name

Dr. D. Brandsma

Locations

1 EU/EEA country · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 20 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications