First-line bevacizumab versus dexamethasone for symptomatic cerebral radiation necrosis after radiation for high-grade glioma or brain metastases.

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

This trial will test whether first-line bevacizumab or dexamethasone works better at reducing symptoms in adults with symptomatic cerebral radiation necrosis after radiation for high-grade glioma or brain metastases.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 408 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: The Netherlands Cancer Institute (Academic / other)
• Drugs / interventions: bevacizumab, radiation
• Locations: 5 sites (Amsterdam and 4 other locations)
• Trial ID: NCT06888817 on ClinicalTrials.gov

What this trial studies

This randomized Phase 3 trial enrolls adults with symptomatic cerebral radiation necrosis after focal (re-)irradiation for high-grade glioma or brain metastases and assigns participants 1:1 to intravenous bevacizumab (600 mg every three weeks for four doses) or protocolized oral dexamethasone with a 12-week taper. The primary comparison is clinical efficacy at 12 weeks, with planned MRI assessments, cognitive testing, quality-of-life, seizure, productivity and health-economic questionnaires, and optional blood draws for translational research. Patients in the bevacizumab arm may receive dexamethasone concurrently if clinically needed, and standard laboratory monitoring is performed according to the assigned therapy. Follow-up continues for two years to monitor durability of response and longer-term outcomes.

Who should consider this trial

Good fit: Adults (≥18 years) with a first episode of symptomatic cerebral radiation necrosis at least 3 months after focal radiotherapy for high-grade glioma or brain metastases, with measurable neurologic decline and limited recent dexamethasone use, are the intended participants.

Not a fit: Patients whose neurologic worsening is due to tumor progression rather than radiation necrosis, those less than 3 months from radiation, or those with contraindications to bevacizumab or corticosteroids are unlikely to benefit from this comparison.

Why it matters

Potential benefit: If successful, first-line bevacizumab could better control brain edema and symptoms while reducing steroid exposure and its side effects, improving quality of life and facilitating ongoing cancer treatment.

How similar studies have performed: Small randomized and several non-randomized studies have shown that bevacizumab can rapidly reduce cerebral edema on MRI and improve symptoms in refractory radiation necrosis, but randomized first-line Phase 3 data have been lacking until now.

Eligibility criteria

Inclusion Criteria:

Inclusion all patients (both HGG and BM):

1. Age ≥ 18 years old
2. 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
3. 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
4. Maximum daily dexamethasone use of 1 mg/day for the 8 weeks preceding randomization

   1. Dexamethasone may have been prescribed for various indications, except for managing (ongoing) cerebral edema
   2. Higher doses of dexamethasone are permitted during the week 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

Inclusion BM:

1\. BM of solid tumour, including all primary tumour types

Inclusion HGG:

1\. 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:

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:

   1. Intolerance for murine proteins
   2. Hypersensitivity or allergy to the active substance or to any of the excipients of bevacizumab or dexamethasone
   3. 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.
   4. 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
   5. History of gastro-intestinal fistula, perforation or abscess \< 6 months
   6. 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
   7. Excess risk of bleeding

      * History or evidence of inherited bleeding diathesis or significant coagulopathy with the risk of bleeding
      * Decreased platelet count \< 75x109/L
   8. 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
   9. Patients with ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo 24 hours urine collection and must demonstrate ≤ 1 g of protein/24 hr.
   10. Previous, current or planned high dose radiotherapy in the abdomen
   11. 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
   12. 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
   13. 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.

Where this trial is running

Amsterdam and 4 other locations

• Netherlands Cancer Institute - Antoni van Leeuwenhoek — Amsterdam, Netherlands (Recruiting)
• Amsterdam University Medical Centers, location VUmc and AMC — Amsterdam, Netherlands (Recruiting)
• Leiden University Medical Center — Leiden, Netherlands (Recruiting)
• Haaglanden Medical Center — The Hague, Netherlands (Recruiting)
• University Medical Center Utrecht — Utrecht, Netherlands (Recruiting)

Study contacts

• Principal investigator: Dieta Brandsma, MD, PhD — Netherlands Cancer Institute - Antoni van Leeuwenhoek
• Study coordinator: Danique Laan, MSc

Conditions Radiation Necrosis; High Grade Glioma; Brain Metastasases; Radiation Toxicity; Radiation Effect; Radiation Injury; Radiation Injuries; Cerebral radiation necrosis