BEVACIZUMAB for High-grade glioma|Brain metastases

Inclusion criteria

• {"criterion_text":"- Age ≥ 18 years old"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- 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"}
• {"criterion_text":"- Able to understand the patient information, online tests and questionnaires"}
• {"criterion_text":"- Written informed consent"}
• {"criterion_text":"- Only for BM patients: BM of solid tumor, including all primary tumor types"}
• {"criterion_text":"- 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

• {"criterion_text":"- Prior treatment with bevacizumab <6 months before diagnosis of sCRN"}
• {"criterion_text":"- Life expectancy <3 months"}
• {"criterion_text":"- Impending radiological or clinical signs of brain herniation necessitating immediate decompressive surgery"}
• {"criterion_text":"- 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 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"}

Primary endpoints

• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Favourable clinical response defined by steroid use ≤1.5 mg/day dexamethasone plus meeting one of the specified KPS/NANO improvement combinations; assessment at 12 weeks after treatment initiation."}

Secondary endpoints

• {"endpoint_text":"- 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","definition_or_measurement_approach":"Measured using EORTC QLQ-C30 physical functioning and other relevant scales; assessed at 12 weeks; thresholds: ≥10 points for BM, ≥5 points for glioma."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Radiologic assessment on MRI (T2/FLAIR and contrast-enhancing T1) at 12 weeks."}
• {"endpoint_text":"- change in cognitive functioning measured by the Amsterdam Cognition Scan (ACS) at 12 weeks","definition_or_measurement_approach":"Cognitive functioning measured using the Amsterdam Cognition Scan (ACS); assessed at 12 weeks."}
• {"endpoint_text":"- experienced epileptic seizure frequency and antiseizure medication use at 12 weeks","definition_or_measurement_approach":"Patient-reported/clinical assessment of seizure frequency and antiseizure medication usage; assessed at 12 weeks."}
• {"endpoint_text":"- number of treatment related adverse events until 21 days post end of treatment","definition_or_measurement_approach":"Safety endpoint counting treatment-related adverse events up to 21 days after end of treatment."}
• {"endpoint_text":"- 2-year sCRN recurrence free survival","definition_or_measurement_approach":"Recurrence-free survival for symptomatic cerebral radiation necrosis assessed over 2 years."}
• {"endpoint_text":"- time to next anti-CRN treatment","definition_or_measurement_approach":"Time from randomization or treatment start to initiation of next anti-CRN treatment."}
• {"endpoint_text":"- 2-year progression free survival","definition_or_measurement_approach":"Progression-free survival assessed over 2 years."}
• {"endpoint_text":"- 2-year overall survival","definition_or_measurement_approach":"Overall survival assessed at 2 years."}
• {"endpoint_text":"- the cost-effectiveness of both treatments","definition_or_measurement_approach":"Health economic evaluation comparing cost-effectiveness of first-line bevacizumab versus dexamethasone."}
• {"endpoint_text":"- the number of patients who reached the main endpoint between 2 and 4 cycles of bevacizumab","definition_or_measurement_approach":"Count of patients achieving the primary endpoint within the comparison of 2 versus 4 cycles of bevacizumab."}

Netherlands

Earliest CTIS Part Ii Submission Date

03-02-2025

Latest Decision Or Authorization Date

13-03-2026

Processing Time Days

403

Number Of Sites

6

Number Of Participants

408

Primary sponsor

Full Name

Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Netherlands