Evaluation of Bevacizumab Versus Dexamethasone for Symptomatic Cerebral Radiation Necrosis in High-Grade Glioma and Brain Metastases Patients

Trial ID: 2024-512466-34-00
Sponsor: Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Stichting

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Diseases & Conditions

Glioma

Objectives

The primary objective of this study is to compare the **clinical efficacy** of first-line **bevacizumab** versus **dexamethasone** for the treatment of symptomatic cerebral radiation necrosis (sCRN) in patients with high-grade glioma (HGG) and brain metastases (BM). This comparison is clinically relevant as it aims to determine the most effective treatment option for managing sCRN, a significant complication following radiation therapy in these patient populations.

Secondary objectives include:

Comparing health-related quality of life (QoL) between bevacizumab and dexamethasone treatments.
Evaluating the clinical efficacy of bevacizumab over 2 cycles (6 weeks) versus 4 cycles (12 weeks).
Assessing radiologic response to the treatments.
Comparing cognitive functioning in patients treated with bevacizumab versus dexamethasone.
Evaluating epileptic seizure control between the two treatments.
Assessing treatment toxicity of bevacizumab and dexamethasone.
Comparing recurrence rates of sCRN between the treatments.
Evaluating time to next sCRN treatment.
Comparing tumor progression-free survival (PFS) and overall survival (OS) between the treatments.
Validating a prognostic tool from the retrospective BRAINS study for clinical favorable response.
Assessing the cost-effectiveness of bevacizumab versus dexamethasone.

Participants

The clinical trial involves participants diagnosed with **brain metastases** or **high-grade glioma**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have experienced their first episode of symptomatic cerebral radiation necrosis (sCRN) at least three months following focal (re-)irradiation, with a clear diagnosis of cerebral radiation necrosis without evidence of mixed tumor progression. The trial does not include a vulnerable population. Participants must have a Karnofsky Performance Status (KPS) score of 90 or less and a minimum loss of two points in at least one domain of the NANO scale due to sCRN. The maximum daily dexamethasone use should be 1 mg/day for the eight weeks preceding randomization, with allowances for higher doses specifically for sCRN treatment in the week before randomization. Participants must be able to comprehend patient information, online tests, and questionnaires, and provide written informed consent. The sponsor has not provided information regarding the total number of participants in the trial.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy and safety of **bevacizumab** as a first-line treatment for symptomatic cerebral radiation necrosis in comparison to the standard treatment, **dexamethasone**. This is a multicenter, open-label, randomized clinical trial. Participants will be randomly assigned to receive either bevacizumab or dexamethasone. The trial is expected to start recruitment on January 1, 2025, and conclude by April 1, 2028. The study will involve adult patients aged 18 years or older who have experienced their first episode of symptomatic cerebral radiation necrosis at least three months after completing focal irradiation for high-grade glioma or brain metastases.

The trial will consist of several study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, diagnosis, and performance status. Following randomization, participants will undergo regular follow-up visits to monitor treatment response and safety. These visits will include assessments of clinical response, cognitive function, and imaging studies to evaluate changes in cerebral edema and lesion size. The primary endpoint will be assessed 12 weeks after treatment initiation, focusing on clinical response and performance status. Secondary endpoints include improvements in quality of life, cognitive function, and survival rates, as well as the cost-effectiveness of the treatments.

Participants are expected to be involved in the study for a maximum of 12 months, with the possibility of early termination if they experience significant adverse events, disease progression, or withdrawal of consent. The trial aims to provide evidence to potentially expand the approved indications of bevacizumab for use as a first-line treatment for symptomatic cerebral radiation necrosis. The study will adhere to ethical guidelines, and informed consent will be obtained from all participants prior to enrollment.

Treatment

The clinical trial involves the administration of two primary treatments: **bevacizumab** and **dexamethasone**. **Bevacizumab** is an experimental medication used as the test treatment in this study. It is a protein-based therapeutic agent, specifically classified under the ATC code L01FG01. The pharmaceutical form of bevacizumab is denoted as PHF00230MIG, and it is administered via intravenous infusion. The maximum daily dose of bevacizumab is 28.57 mg, with a total maximum dose of 2400 mg over a treatment period of up to 12 months. The administration schedule is designed to ensure optimal therapeutic efficacy while monitoring participant compliance through regular assessments.

**Dexamethasone**, used as the comparator treatment, is a corticosteroid with the active substance **betamethasone sodium phosphate**. It is classified under the ATC code H02AB02. The pharmaceutical form of dexamethasone is indicated as PHF00169MIG, and it is administered orally. The maximum daily dose for dexamethasone is 16 mg, with a total maximum dose of 1344 mg over a treatment period of up to 12 months. As a standard-of-care therapy, dexamethasone serves as a benchmark to evaluate the efficacy of bevacizumab in treating symptomatic cerebral radiation necrosis. Participant compliance is monitored through scheduled follow-ups and dosage adjustments as necessary to maintain safety and efficacy standards.

Efficacy

The clinical trial aims to assess the efficacy of bevacizumab compared to dexamethasone as a first-line treatment for **symptomatic cerebral radiation necrosis** (sCRN) in patients with high-grade glioma and brain metastases. The primary endpoint for evaluating efficacy is a favorable clinical response, defined as the utilization of 1.5 mg/day or less of dexamethasone and meeting one of the following criteria: an improvement of at least 10 points in the Karnofsky Performance Status (KPS) with at least stable Neurologic Assessment in Neuro-Oncology (NANO) or an improvement of at least 2 points in NANO with at least stable KPS. This assessment will be conducted 12 weeks after the initiation of treatment.

Secondary endpoints include improvement of at least 10 points on the EORTC QLQ C30 physical functioning scale, reduction of cerebral edema on T2/Fluid Attenuated Inversion Recovery (FLAIR) and contrast-enhancing lesions on T1 MRI, change in cognitive functioning measured by the Amsterdam Cognition Scan (ACS), experienced epileptic seizure frequency and antiseizure medication use, and the number of treatment-related adverse events until 21 days post end of treatment. Additional secondary endpoints are 2-year sCRN recurrence-free survival, time to next anti-CRN treatment, 2-year progression-free survival, 2-year overall survival, cost-effectiveness of both treatments, and the number of patients who reached the main endpoint between 2 and 4 cycles of bevacizumab. These secondary endpoints will be evaluated at 12 weeks and other specified time points as applicable.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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

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Exclusion Criteria

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: 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