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

NCT06888817 | Recruiting Phase 3

• 1 other identifier: M23BNS
• Study Type: interventional
• Target: 408
• Locations: 1 country
• Sites: 5

Brief Summary

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.

Conditions

Radiation Necrosis; High Grade Glioma (III or IV); Brain Metastasases; Radiation Toxicity; Radiation Effect; Radiation Injury; Radiation Injuries

Keywords

Cerebral radiation necrosis; High Grade Glioma; Brain Metastases; Bevacizumab; Dexamethasone; Randomized Clinical Trial; First-line treatment; Anti-VEGF monocolonal antibody; Corticosteroids; Radiation induced necrosis; Radiation effects; Radiation injury; Radiation toxicity

Outcome Measures

Primary Outcomes (1)

• Clinical efficacy, defined as ≤ 1.5mg dexamethasone/day with one of the following 1) an improved KPS (of ≥ 10 points ) + at least stable NANO or 2) improved NANO (of ≥ 2 points) + at least stable KPS

  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. 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.

  12 weeks

Secondary Outcomes (17)

• Health-related quality of life using the EORTC-QLQ-C30

  up to 2 years

• Health-related quality of life using EORTC-QLQ-BN20

  up to 2 years

• Health-related quality of life using the QLQ-IADL-BN32

  up to 2 years

• Clinical efficacy using the KPS

  up to 2 years

• Clinical efficacy using the NANO scale

  up to 2 years

Other Outcomes (3)

• Immuno-oncology protein biomarkers using Olink Target 96 Immuno-oncology panel

  12 weeks

• Tumour educated platelets

  up to 2 years

• Pharmacokinetics bevacizumab and dexamethasone

  12 weeks

Study Arms (2)

Bevacizumab

EXPERIMENTAL

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

Drug: Bevacizumab; Drug: Dexamethasone

Dexamethasone

ACTIVE COMPARATOR

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

Drug: Dexamethasone

Interventions

Bevacizumab DRUG

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

Also known as: Avastin, Anti-VEGF monoclonal antibody

Bevacizumab

Dexamethasone DRUG

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

Also known as: Corticosteroids

Bevacizumab; Dexamethasone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 a minimum loss of two points in at least one domain of the NANO scale as compared to the maximum score of at that domain due to sCRN
• 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 during the week immediately preceding randomization if used specifically for the treatment of sCRN
• Able to understand the patient information, online tests and questionnaires
• Written informed consent
• \. BM of solid tumour, including all primary tumour types
• \. 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

You may not qualify if:

• 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

Sponsors & Collaborators

• UMC Utrecht: collaborator
• Amsterdam UMC: collaborator
• Medical Center Haaglanden: collaborator
• Leiden University Medical Center: collaborator
• The Netherlands Cancer Institute: lead

Study Sites (5)

Netherlands Cancer Institute - Antoni van Leeuwenhoek

Amsterdam, 1066 CX Amsterdam, Netherlands

RECRUITING

Amsterdam University Medical Centers, location VUmc and AMC

Amsterdam, Netherlands

RECRUITING

Leiden University Medical Center

Leiden, 2333 ZA Leiden, Netherlands

RECRUITING

Haaglanden Medical Center

The Hague, 2262 BA Leidschendam, Netherlands

RECRUITING

University Medical Center Utrecht

Utrecht, 3584 CX Utrecht, Netherlands

RECRUITING

MeSH Terms

Conditions

Glioma; Radiation Injuries; Brain Neoplasms

Interventions

Bevacizumab; Dexamethasone; Adrenal Cortex Hormones

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Wounds and Injuries; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Dieta Brandsma, MD, PhD

  Netherlands Cancer Institute - Antoni van Leeuwenhoek

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Danique Laan, MSc

CONTACT

+31 20 512 9111; brains@nki.nl

Dieta Brandsma, MD, PhD

CONTACT

+31 20 512 9111; brains@nki.nl

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 26, 2025
• First Posted: March 21, 2025
• Study Start: June 19, 2025
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 1, 2030
• Last Updated: February 25, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

NL (5)