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NCT Number: NCT06888817

Bevacizumab Versus Corticosteroids as First-line Treatment in Patients With Symptomatic Cerebral Radiation Necrosis After Radiation for High-grade Glioma or Brain Metastases

Cerebral radiation necrosis (CRN) is a severe complication of high-dose radiation for brain metastases (BM) or glioma, which can potentially cause significant neurologic symptoms leading to serious morbidity and impaired quality of life (QoL). The first-line therapy for symptomatic CRN (sCRN) is corticosteroids, primarily dexamethasone, which often leads to complications, refractory symptoms, and interference with anti-cancer treatment. Since 2017, bevacizumab, an antibody against Vascular Endothelial Growth Factor (VEGF), has been used in a second-line treatment setting for refractory sCRN. A small randomized clinical trial (RCT) has shown that bevacizumab significantly diminishes cerebral edema on MRI and decreases clinical symptoms of sCRN in irradiated glioma patients. Several non-randomized clinical studies demonstrated a beneficial radiological and clinical effect of bevacizumab in patients with sCRN after irradiation for BM. The optimal first-line treatment for sCRN is currently unknown. Effective and safe first-line treatment of sCRN will optimize the patient's well-being and health-related QoL. Furthermore, minimizing corticosteroid use will benefit the clinical treatment options and outcomes of concomitant or future anti-cancer treatment. This phase III multicenter, open-label, randomized clinical trial compares the clinical efficacy of first-line bevacizumab versus standard-of-care dexamethasone for sCRN in patients with high-grade glioma (HGG) or BM.

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Key information

Conditions

Radiation Necrosis Brain Diseases Brain Metastasases Brain Neoplasms Central Nervous System Diseases Central Nervous System Neoplasms Glioma High Grade Glioma (III or IV) Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Germ Cell and Embryonal Neoplasms, Glandular and Epithelial Neoplasms, Nerve Tissue Neoplasms, Neuroepithelial Nervous System Diseases Nervous System Neoplasms Neuroectodermal Tumors Radiation Effect Radiation Injuries Radiation Injury Radiation Toxicity Wounds and Injuries

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Amsterdam University Medical Centers, location VUmc and AMC, Amsterdam, Netherlands

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About this study

The primary objective of this trial is to compare the clinical efficacy of first-line bevacizumab versus dexamethasone for sCRN in HGG and BM patients at 12 weeks.

Both patients with HGG and patients with BM will be randomly assigned in a 1:1 ratio to one of two following treatment arms.

ARM 1 Intervention arm: intravenous bevacizumab at a 600 mg flat dose every three weeks for four courses over 12 weeks at hospital daycare.

ARM 2 Control arm: daily oral dexamethasone followed by a protocol-based tapering dose over 12 weeks.

Patients in the intervention (bevacizumab) arm may use dexamethasone concurrently with bevacizumab if clinically indicated.

The study treatment will be administered over 12 weeks, with a follow-up period of 2 years. Patients in both arms will have regular inpatient hospital visits and MRI brain scans, complete the Amsterdam Cognition scan twice during treatment, complete QoL, epilepsy, productivity, and medical costs questionnaires during treatment and follow up, and undergo optional blood withdrawal for translational research purposes. Standard of care laboratory blood tests during treatment depend on the treatment arm.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

Inclusion all patients (both HGG and BM):

  • Age ≥ 18 years old
  • First episode of sCRN ≥ 3 months after completion of focal (re-)irradiation, as determined by the local Multidisciplinary Neuro-Oncology Board. A clear working diagnosis of CRN without evidence of a combination with tumour progression is required
  • 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
  • Maximum daily dexamethasone use of 1 mg/day for the 8 weeks preceding randomization
  • Dexamethasone may have been prescribed for various indications, except for managing (ongoing) cerebral edema
  • Higher doses of dexamethasone are permitted 3 weeks immediately preceding randomization if used specifically for the treatment of sCRN
  • Able to understand the patient information, online tests and questionnaires
  • Written informed consent

Inclusion BM:

  • BM of solid tumour, including all primary tumour types

Inclusion HGG:

  • 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

A potential subject who meets any of the following criteria will be excluded from participation in this study, both for the BM and HGG group:

  • Prior treatment with bevacizumab <6 months before diagnosis of sCRN
  • Life expectancy <3 months
  • Impending radiological or clinical signs of brain herniation necessitating immediate decompressive surgery
  • Any comorbidity or condition that prevents safe administration of the studied medication, determined by the treating physician, including but not limited to:
  • Intolerance for murine proteins
  • Hypersensitivity or allergy to the active substance or to any of the excipients of bevacizumab or dexamethasone
  • Nephrotic syndrome or abnormal renal function

o Calculated (Cockcroft-Gault) or measured creatinine clearance <30 mL/min; urine dipstick for proteinuria ≥ 2+. Patients with ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo 24 hours urine collection and must demonstrate ≤ 1 g of protein/24 hr.

  • Clinical significant cardiovascular disease
  • Uncontrolled hypertension (systolic BP >150mmHg and/or diastolic >100mmHg) despite the use of ≥ 3 antihypertensive drugs
  • Previous hypertensive crisis, hypertensive encephalopathy or previous reversible posterior leukoencephalopathy syndrome (RPLS)
  • 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
  • History of aortic aneurysm or dissection
  • Congestive heart failure NYHA II-IV
  • History of gastro-intestinal fistula, perforation or abscess < 6 months
  • History of bleeding
  • 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
  • Active gastrointestinal bleeding < 6 months
  • Evidence of recent intracranial hemorrhage on MRI brain <3 months. Asymptomatic presence of hemosiderin depositions or punctate hemorrhage in the tumour do not serve as a ground for exclusion
  • Excess risk of bleeding
  • History or evidence of inherited bleeding diathesis or significant coagulopathy with the risk of bleeding
  • Decreased platelet count < 75x109/L
  • Risk of wound healing complications
  • Significant non-healing wound, (peptic) ulcer or bone fracture
  • 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
  • Minor surgical procedure, stereotactic/core biopsy, fine needle aspiration within 7 days prior to first study treatment
  • 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
  • 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
  • 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
  • Current or recent (within 30 days of first study treatment) treatment with another investigational drug or participation in another interventional study In case of uncertainty, consult the principal investigator of the study site.

Treatment and study plan

Bevacizumab

Drug

Intravenous bevacizumab at a 600 mg flat dose every three weeks for four courses over 12 weeks

Other names: Avastin, Anti-VEGF monoclonal antibody

Dexamethasone

Drug

Daily oral dexamethasone followed by a protocol-based tapering dose over 12 weeks

Other names: Corticosteroids

Primary outcomes

  1. Clinical efficacy: dexamethasone ≤ 1.5 mg/day plus KPS increased ≥10 with stable NANO (1)

    Time frame: 12 weeks

    The Karnofsky Performance Score (KPS) assesses a patient's overall functional status on a 0-100 scale, with higher scores indicating better physical ability and lower scores indicating greater disability or dependence on others for care.

    The Neurologic Assessment in Neuro-Oncology (NANO) scale evaluates nine neurologic domains (gait, strength, ataxia, sensation, visual fields, facial strength, language, consciousness, and behavio) each scored from normal (0) to most impaired (2-3), with a maximum total score of 23.

  2. Clinical efficacy: dexamethasone ≤ 1.5 mg/day plus NANO increased ≥ 2 with stable KPS (2)

    Time frame: 12 weeks

    The Karnofsky Performance Score (KPS) assesses a patient's overall functional status on a 0-100 scale, with higher scores indicating better physical ability and lower scores indicating greater disability or dependence on others for care.

    The Neurologic Assessment in Neuro-Oncology (NANO) scale evaluates nine neurologic domains (gait, strength, ataxia, sensation, visual fields, facial strength, language, consciousness, and behavio) each scored from normal (0) to most impaired (2-3), with a maximum total score of 23.

  3. Clinical efficacy: dexamethasone ≤ 1.5 mg/day plus KPS and NANO both improved (3)

    Time frame: 12 weeks

    The Karnofsky Performance Score (KPS) assesses a patient's overall functional status on a 0-100 scale, with higher scores indicating better physical ability and lower scores indicating greater disability or dependence on others for care.

    The Neurologic Assessment in Neuro-Oncology (NANO) scale evaluates nine neurologic domains (gait, strength, ataxia, sensation, visual fields, facial strength, language, consciousness, and behavio) each scored from normal (0) to most impaired (2-3), with a maximum total score of 23.

  4. Clinical efficacy: dexamethasone ≤ 1.5 mg/day plus stable KPS/NANO with headache improved (NRS ≥2, remaining <5) (4)

    Time frame: 12 weeks

    The Karnofsky Performance Score (KPS) assesses a patient's overall functional status on a 0-100 scale, with higher scores indicating better physical ability and lower scores indicating greater disability or dependence on others for care.

    The Neurologic Assessment in Neuro-Oncology (NANO) scale evaluates nine neurologic domains (gait, strength, ataxia, sensation, visual fields, facial strength, language, consciousness, and behavio) each scored from normal (0) to most impaired (2-3), with a maximum total score of 23.

    The headache intensity is measured using the 0-10 Numeric Rating Scale (NRS), where 0 indicates no pain and 10 the worst imaginable pain.

Secondary outcomes

  1. Health-related quality of life using the EORTC-QLQ-C30

    Time frame: up to 2 years

    The EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30) is a validated tool designed to assess the overall health-related quality of life in cancer patients. It consists of 30 items measuring five functional scales (physical, role, emotional, cognitive, and social functioning), three symptom scales (fatigue, pain, and nausea/vomiting), a global health status/quality of life scale, and five single items evaluating additional symptoms (dyspnea, insomnia, appetite loss, constipation, and diarrhea) as well as perceived financial impact.

    Each item is scored on a 4-point Likert scale (1 = "Not at all" to 4 = "Very much"), except for the global quality of life domain, which is rated on a 7-point Likert scale. For functional and global quality of life scales, higher scores indicate better functioning and quality of life. For symptom scales and single items, higher scores reflect greater symptom burden and worse quality of life.

  2. Health-related quality of life using EORTC-QLQ-BN20

    Time frame: up to 2 years

    The EORTC QLQ-BN20 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Brain Neoplasm 20) is a brain cancer-specific module designed to assess the quality of life in brain cancer patients. It consists of 20 items, including seven symptom items (headaches, seizures, drowsiness, hair loss, itchy skin, leg weakness, and bladder control) and four multi-item scales (future uncertainty, visual disorder, motor dysfunction, and communication deficit). Each item is scored on a 4-point Likert scale (ranging from 1 = "Not at all" to 4 = "Very much"). The total score is converted to a 0-100 scale, with higher scores indicating a worse quality of life due to greater symptom burden.

  3. Health-related quality of life using the QLQ-IADL-BN32

    Time frame: up to 2 years

    The EORTC QLQ-IADL-BN32 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Instrumental Activities of Daily Living in Brain Neoplasms 32) is a validated questionnaire designed to assess the quality of life of brain tumor patients in relation to their ability to perform instrumental activities of daily living (IADL). It consists of five multi-item scales and two single-item scales, with each item scored on a 4-point Likert scale (ranging from 1 = "Not at all" to 4 = "Very much"). The total score is converted to a 0-100 scale, where higher scores indicate a greater impairment in IADL and worse quality of life.

  4. Clinical efficacy using the KPS

    Time frame: up to 2 years

    The Karnofsky Performance Score (KPS) is a standard tool used to assess a patients' overall functional status and ability to carry out daily activities. The KPS is scored on a scale of 0 to 100, with higher scores indicating better physical function and lower scores indicating greater disability or dependence on others for care.

  5. Clinical efficacy using the NANO scale

    Time frame: up to 2 years

    The Neurologic Assessment in Neuro-Oncology (NANO) scale consists of 9 relevant neurologic domains (gait, strengths, ataxia, sensation, visual fields, facial strengths, language, level of consciousness, and behavior), which can be quantified based on direct observation and testing during routine clinical visits. Each domain is subdivided into 3 or 4 levels of function with a score of 0 indicating normal function, and a score of 2 or 3 indicating the most severe level of deficit for that domain. The maximum possible score on the NANO scale is 23, reflecting the highest level of impairment.

  6. Clinical efficacy using the headache intensity NRS

    Time frame: up to 2 years

    Absolute headache intensity will be assessed using the 11-point Numeric Rating Scale (NRS), ranging from 0 (no headache) to 10 (worst imaginable headache).

  7. Dexamethasone use

    Time frame: up to 2 years

    Dexamethasone tapering in mg/day

  8. Clinical efficacy of 2 vs 4 bevacizumab cycles: dexamethasone ≤ 1.5 mg/day plus KPS ≥10 with stable NANO (1)

    Time frame: 12 weeks

    The Karnofsky Performance Score (KPS) assesses a patient's overall functional status on a 0-100 scale, with higher scores indicating better physical ability and lower scores indicating greater disability or dependence on others for care.

    The Neurologic Assessment in Neuro-Oncology (NANO) scale consists of 9 relevant neurologic domains (gait, strengths, ataxia, sensation, visual fields, facial strengths, language, level of consciousness, and behavior), which can be quantified based on direct observation and testing during routine clinical visits. Each domain is subdivided into 3 or 4 levels of function with a score of 0 indicating normal function, and a score of 2 or 3 indicating the most severe level of deficit for that domain. The maximum possible score on the NANO scale is 23, reflecting the highest level of impairment.

  9. Clinical efficacy of 2 vs 4 bevacizumab cycles: dexamethasone ≤ 1.5 mg/day plus NANO ≥ 2 with stable KPS (2)

    Time frame: 12 weeks

    The Karnofsky Performance Score (KPS) assesses a patient's overall functional status on a 0-100 scale, with higher scores indicating better physical ability and lower scores indicating greater disability or dependence on others for care.

    The Neurologic Assessment in Neuro-Oncology (NANO) scale consists of 9 relevant neurologic domains (gait, strengths, ataxia, sensation, visual fields, facial strengths, language, level of consciousness, and behavior), which can be quantified based on direct observation and testing during routine clinical visits. Each domain is subdivided into 3 or 4 levels of function with a score of 0 indicating normal function, and a score of 2 or 3 indicating the most severe level of deficit for that domain. The maximum possible score on the NANO scale is 23, reflecting the highest level of impairment.

  10. Clinical efficacy of 2 vs 4 bevacizumab cycles: dexamethasone ≤ 1.5 mg/day plus KPS and NANO both improved (3)

    Time frame: 12 weeks

    The Karnofsky Performance Score (KPS) assesses a patient's overall functional status on a 0-100 scale, with higher scores indicating better physical ability and lower scores indicating greater disability or dependence on others for care.

    The Neurologic Assessment in Neuro-Oncology (NANO) scale consists of 9 relevant neurologic domains (gait, strengths, ataxia, sensation, visual fields, facial strengths, language, level of consciousness, and behavior), which can be quantified based on direct observation and testing during routine clinical visits. Each domain is subdivided into 3 or 4 levels of function with a score of 0 indicating normal function, and a score of 2 or 3 indicating the most severe level of deficit for that domain. The maximum possible score on the NANO scale is 23, reflecting the highest level of impairment.

  11. Clinical efficacy of 2 vs 4 bevacizumab cycles: dexamethasone ≤ 1.5 mg/day plus stable KPS/NANO with headache improved (NRS ≥ 2, <5) (4)

    Time frame: 12 weeks

    The Karnofsky Performance Score (KPS) assesses a patient's overall functional status on a 0-100 scale, with higher scores indicating better physical ability and lower scores indicating greater disability or dependence on others for care.

    The Neurologic Assessment in Neuro-Oncology (NANO) scale consists of 9 relevant neurologic domains (gait, strengths, ataxia, sensation, visual fields, facial strengths, language, level of consciousness, and behavior), which can be quantified based on direct observation and testing during routine clinical visits. Each domain is subdivided into 3 or 4 levels of function with a score of 0 indicating normal function, and a score of 2 or 3 indicating the most severe level of deficit for that domain. The maximum possible score on the NANO scale is 23, reflecting the highest level of impairment.

    The headache intensity is measured using the 0-10 Numeric Rating Scale (NRS), where 0 indicates no pain and 10 the worst imaginable pain.

  12. Cognitive functioning measured by the online cognitive test battery the Amsterdam Cognition Scan

    Time frame: 12 weeks

    Neurocognitive functioning will be assessed using the ACS (Amsterdam Cognition Scan) test battery at baseline and after 12 weeks. The ACS consists of seven online neuropsychological tests. Participants can complete the ACS remotely on their own computer at home, eliminating the need for an additional hospital visit. Each test within the ACS produces a standardized score, typically ranging from a minimum of 0 (indicating the lowest level of performance) to a maximum of 100 (indicating the highest level of performance). Higher scores reflect better cognitive functioning, while lower scores indicate greater cognitive impairment.

  13. Radiologic response according to the RANO criteria

    Time frame: 12 weeks

    The Response Assessment in Neuro-Oncology 2.0 (RANO 2.0) criteria are an updated standardized framework for evaluating treatment response in patients with glioma. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria are used to evaluate treatment response in patients with brain metastases. A scoring system is not explicitly defined, but assessments are based on changes in contrast-enhancing and non-enhancing tumor components, as well as neurological status and corticosteroid dependency. Higher classifications indicating PD represent a worse outcome, signifying tumor growth or worsening symptoms.

    Lower classifications indicating CR or PR represent a better outcome, suggesting tumor reduction or stability.

  14. Epileptic seizure control using the Seizure Control Composite Score Index

    Time frame: up to 2 years

    The Seizure Control Composite Score Index (SCCSI) is a standardized metric designed to assess seizure control by integrating both epileptic seizure frequency and antiseizure medication use. It provides a comprehensive evaluation of treatment effectiveness in reducing seizures while considering medication burden.

  15. Treatment toxicity (CTCAE v5.0)

    Time frame: 15 weeks

    Incidence and severity of treatment toxicity of bevacizumab and dexamethasone according to CTCAE v5.0, reported for period of study treatment plus 21 days after. The percentage of patients reporting a grade 3 or higher, 4 or higher, or 5 at least possibly related to treatment will be reported.

  16. Recurrence of symptomatic cerebral radiation necrosis

    Time frame: up to 2 years

    Recurrence of sCRN is defined as increase in edema volume on T2-weighted FLAIR images over that of the last MRI taken after treatment and necessity for treatment for recurrent sCRN (dexamethasone, bevacizumab, or surgery) due to neurological decline that is not attributable to tumour progression

  17. Time to next symptomatic cerebral radiation necrosis treatment

    Time frame: up to 2 years

    Time to next sCRN treatment is defined as the time from completion of first-line dexamethasone/bevacizumab treatment for sCRN to initiating second-line treatment or reintroduction of treatment for sCRN

  18. Tumour progression free survival

    Time frame: up to 2 years. After 2 years, yearly tumour progression (intra vs extra cranial) follow up will take place.

    Tumour progression free survival (PFS) is defined as the time from randomization to the first documented tumour progression as per RANO criteria for BM or HGG

  19. Overall survival

    Time frame: up to 2 years. After 2 years, yearly survival follow up will take place.

    Overall survival (OS) is defined as time from randomization to death due to any cause

  20. External validation prognostic tool

    Time frame: 1 year

    Validation of prognostic tool from retrospective BRAINS study for favourable clinical response (defined as in retrospective study: improvement of KPS by ≥ 10 points and dexamethasone tapering to ≤ 1.5 mg/day within 12 weeks following initiation of bevacizumab treatment) of second-line bevacizumab in first-line bevacizumab groups of the HGG and BM patient groups

  21. Cost-effectiveness

    Time frame: 2 years

    Economic evaluation performing a cost-utility analysis (costs in relation to QALYs) from a societal perspective with a time horizon of two years for both HGG and BM patient groups

Other outcomes

  1. Immuno-oncology protein biomarkers using Olink Target 96 Immuno-oncology panel

    Time frame: 12 weeks

    Immuno-oncology proteins as blood-based biomarkers for (early) treatment response in both treatment arms using Olink Target 96 Immuno-oncology panel

  2. Tumour educated platelets

    Time frame: up to 2 years

    Platelet RNA profiles as blood-based biomarkers for (early) treatment response in both treatment arms

  3. Pharmacokinetics bevacizumab and dexamethasone

    Time frame: 12 weeks

    Bevacizumab and dexamethasone serum and plasma concentrations pre- and post-dose

Study contacts

Contact information is provided by the study sponsor or research team.

Danique Laan, MSc

CONTACT

[email protected]

+31 20 512 9111

Dieta Brandsma, MD, PhD

CONTACT

[email protected]

+31 20 512 9111

Sponsors and collaborators

Lead sponsor

The Netherlands Cancer Institute

Other

Collaborators

  • Amsterdam UMC
  • Leiden University Medical Center
  • Maastricht University Medical Center
  • Medical Center Haaglanden
  • UMC Utrecht

Registry information

Official study title

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

Acronym: BRAINS

Important dates

Study start
2025
Primary completion
2028
Study completion
2030
First posted
Mar 21, 2025
Registry last updated
Jul 13, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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