Phase III Multicenter Randomized Controlled Double-Blind Study of Bevacizumab Versus Placebo in Corticodependent or Corticoresistant Brain Radionecrosis Post-Radiotherapy for Brain Metastases
- Trial ID
- 2024-510893-25-00
- Protocol
- BRADI ICO-2023-15
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the efficacy of **bevacizumab** in combination with standard corticosteroid therapy compared to corticosteroid therapy plus placebo in patients with corticodependent or corticoresistant brain radionecrosis following radiotherapy for brain metastases. The primary endpoint is the reduction in corticosteroid use and improvement in neurological symptoms at 3 months (90 days). This is clinically relevant as it addresses the management of brain radionecrosis, a significant complication of radiotherapy, potentially improving patient outcomes and quality of life.
Secondary objectives include:
- Comparing safety profiles between the two treatment arms.
- Assessing quality of life differences between the treatment groups.
- Evaluating treatment success, defined by reductions in corticosteroid use, neurological symptoms, and quality of life improvements.
- Analyzing clinical changes using Patient and Clinician Reported Outcomes.
- Comparing MRI modifications at 90 days relative to baseline.
- Evaluating the duration of response from the cessation of bevacizumab.
- Assessing the total weaning off corticosteroids at 3 months.
- Conducting correlative objectives as ancillary studies.
Participants
The clinical trial involves participants diagnosed with **radionecrosis** following radiotherapy for brain metastases. The study population includes both male and female subjects aged 18 years and older. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less, or a Karnofsky Performance Score (KPS) of 50 or greater, indicating a relatively stable general health status. The trial does not involve a vulnerable population. Participants must have a life expectancy of at least three months and must not have previously received Bevacizumab for radionecrosis. Adequate organ function is a prerequisite, with specific criteria for bone marrow, coagulation, renal, and hepatic functions. Women of childbearing potential are required to use effective contraceptive measures during the treatment and for six months following its cessation. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the efficacy of **bevacizumab** in combination with standard corticosteroid therapy compared to corticosteroid therapy plus placebo in patients with brain radionecrosis following radiotherapy for brain metastases. The trial is a phase III study, with an estimated recruitment start date of October 1, 2024, and an estimated end date of April 30, 2030. The primary objective is to assess the reduction in corticosteroid dosage and improvement in neurological symptoms at three months (90 days) post-treatment initiation.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of radionecrosis, persistent symptoms despite corticosteroid use, and adequate organ function. The trial will include multiple follow-up visits at specified intervals, including Cycle 1 Day 1 (C1D1), Cycle 2 Day 1 (C2D1), Cycle 3 Day 1 (C3D1), Cycle 4 Day 1 (C4D1), and an end-of-treatment (EOT) evaluation visit at 90 days. During these visits, assessments will include corticosteroid dosage, the NANO score for neurological function, and quality of life measures using EORTC QLQ-C30 and BN20 questionnaires.
The expected length of participant involvement is up to 12 months, with the possibility of early termination if adverse events occur or if the participant withdraws consent. Safety will be monitored using the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0. Secondary endpoints include safety, quality of life, clinical changes, and duration of response, with assessments continuing every three months until two years post-treatment initiation. The trial will also explore correlative biomarkers and imaging changes on brain MRI.
Treatment
The clinical trial involves the administration of **bevacizumab**, marketed as Avastin, which is a **concentrate for solution for infusion**. This experimental medication is administered intravenously. The dosage is calculated based on body weight, with a maximum daily dose of 7.5 mg/kg and a maximum total dose of 30 mg/kg over the treatment period. The treatment duration is set for a maximum of 12 months. Bevacizumab is a targeted therapy, and its active substance is derived from a protein of non-human origin. The product is manufactured by Roche Registration GmbH.
In addition to the experimental treatment, the study utilizes **Sodium Chloride Fresenius Kabi Italia 0.9% Solution for infusion** as a placebo. This solution is also administered intravenously. The maximum daily dose is 0.9% (V/V), with a total maximum dose of 3.6% (V/V) over the course of the study. The treatment period is consistent with the experimental medication, lasting up to 12 months. Sodium chloride serves as an electrolyte solution and is produced by Fresenius Kabi Italia S.R.L.
Furthermore, **Prednisolone 10mg Tablets** are used as a standard-of-care therapy in the trial. Prednisolone is administered orally, with a maximum daily dose of 4 mg/kg and a total maximum dose of 360 mg/kg. The treatment period is also up to 12 months. Prednisolone is a glucocorticoid, and its active substance is of chemical origin. The tablets are manufactured by Accord-UK Limited.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the measurement of corticosteroid dose and the **NANO (Neurological Assessment in Neuro-Oncology)** score. These parameters will be evaluated at Cycle 1 Day 1 (C1D1) and at 3 months (90 days), which corresponds to the end-of-treatment (EOT) visit. The NANO scale is a validated tool that assesses nine major domains of neurological function relevant to patients with brain tumors.
Secondary endpoints include safety assessments using the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0, and quality of life measurements using the EORTC QLQ-C30 and BN20 questionnaires. These assessments will occur at C1D1, C2D1, C3D1, C4D1, and the EOT evaluation visit. Additional secondary endpoints involve clinical changes evaluated through the Patient Global Impression of Change (PGIC) questionnaire and scale, as well as MRI assessments of brain volume at the EOT visit. The duration of response will be monitored using the NANO scale and corticosteroid dose every 3 months until 2 years post-treatment.
Correlative biomarkers, including ceramide, VEGF, angiopoietin, and TGF-alpha, along with nuclear medicine images, will also be analyzed to provide further insights into the treatment's efficacy. These comprehensive assessments will ensure a robust evaluation of the treatment's impact on patients with corticodependent or corticoresistant brain radionecrosis following radiotherapy for brain metastases.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient with a clinical presentation compatible with corticosteroid‑dependent or corticoresistant radionecrosis, supported by imaging findings on at least one of the following modalities: FDG or DOPA PET imaging, and/or MRI including perfusion sequences, demonstrating features in favour of radionecrosis
- Symptoms are persistent or worsening despite administration of corticosteroids: at least 1 mg/kg/d of prednisolone or equivalent: - Corticoresistant: neurological symptoms despite administration of at least 2 weeks of 1 mg/kg/d prednisolone or equivalent; - Corticodependant: worsening of neurological signs or symptoms after an initial improvement when weaning off steroids at a dose < 0.5 mg/kg/d prednisolone or equivalent;
- Patients must have received the last cranial irradiation with photons or proton therapy for brain metastases ≥ 3 months with one or more sequences;
- Age ≥ 18-year-old;
- ECOG performance status score ≤ 2 or Karnofsky Performance Score (KPS) ≥ 50
- Life expectancy of at least 3 months assessed by graded prognostic score (DS-GPA) score 0.5 or greater;
- Patient who has never received Bevacizumab for the indication of radionecrosis.
- Adequate organ function: Bone marrow function • Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 Platelet Count ≥ 100,000/mm3, Haemoglobin ≥ 10 g/dL (allowing transfusion or other intervention to achieve this minimum haemoglobin) Coagulation • International normalized ratio (INR) or prothrombin time < 1.5 × ULN Renal function • No proteinuria with urine dipstick for proteinuria > 2+ • Serum creatinine ≤1.5 x ULN or creatinine clearance ≥30 mL/min (measured or calculated using the CDK-EPI formula) Hepatic Function • Total bilirubin ≤1.5 x the upper limit of normal (ULN) • Alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤3 x ULN
- Women of childbearing potential must use effective contraceptive measures during the treatment and for 6 months following its cessation
- Signed informed consent;
- Patient affiliated to a social security scheme.
Exclusion Criteria
- Evidence of active bleeding or a pathological condition at high risk of bleeding: CNS hemorrhage, bleeding diathesis or coagulopathy, hemoptysis (>2.5ml of bright red blood per episode), evidence of history of bowel obstruction, abdominal fistula, or gastrointestinal tract perforation or gastro intestinal abscess occurring less than 28 days prior study entry
- History of severe allergic anaphylactic reactions to bevacizumab
- Patients with a known hypersensitivity to athe active substance or to any of the excipients of bevacizumab are not eligible for participation;
- Patients with a contraindication to the treatment with bevacizumab according to the European SmPC
- Patient pregnant and/or nursing;
- Mental impairment (psychiatric illness/social situations) that may compromise the ability of the patient to give informed consent and comply with the requirements of the study;
- Patient who has forfeited his/her freedom by administrative or legal award or who is under guardianship.
- Grade 4 venous thromboelism and peripheral arterial thrombus;
- Evidence of very high intracranial pressure that suggests brain hernia and needs emergency surgery;
- Major surgical procedure or significant traumatic injury less than 28 days prior study entry; minor surgery within 3 days prior to initiation of study treatment;
- Clinically significant cardiovascular disease such as uncontrolled arterial hypertension (BP ≥160 mm Hg or diastolic BP ≥100 mm Hg despite maximal medical therapy), cerebrovascular event, myocardial infarction, cardiac arrhythmias, unstable angina, or congestive heart failure within the last 6 months;
- History of hypertensive crisis or hypertensive encephalopathy
- Patients scheduled to undergo head and neck, thoracic, or abdominal radiotherapy during the study treatment
- Prior bevacizumab ≤ 3 months before randomization;
- Progressive brain metastases;
- New cerebral metastasis detected during the inclusion imaging evaluation;
- Prior diagnosis of Posterior Reversible Encephalopathy Syndrome (PRES) with bevacizumab;
- Hypersensitivity known to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 29 Apr 2025 | 84 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Avastin 25 mg/ml concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 7.5 | 12 | PRD2153901 |
Sodium Chloride Fresenius Kabi Italia 0.9 % Solution for infusion | Placebo | SOLUTION FOR INFUSION | INTRAVENOUS | 0.9 | 12 | PRD10411934 |
Prednisolone 10mg Tablets | Other | TABLETS | ORAL | 4 | 12 | PRD4940399 |