Corticodependent or Corticoresistant Brain Radionecrosis After Radiotherapy for Brain Metastases

NCT06471465 | Recruiting Phase 3

• 1 other identifier: ICO-2023-15
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 10

Brief Summary

Brain metastases (BM) afflict a significant portion of cancer patients, ranging from 10% to 50%, leading to debilitating symptoms and diminished quality of life, thereby impacting overall survival. Treatment options typically include surgery, stereotactic radiosurgery (SRS), and whole brain radiotherapy (WBRT). SRS has emerged as the preferred focal treatment due to its efficacy, delivering ablative doses with notable overall survival benefits, especially for single BM or postoperative cases, while being less invasive than neurosurgery and capable of addressing inoperable sites and multiple lesions. Contrastingly, WBRT is now reserved for select cases with multiple BMs ineligible for SRS, owing to its lower rate of neurocognitive toxicities and high local control rates at one year. Despite its advantages, SRS can engender late side effects, with cerebral radio necrosis (RN) being the most common, occurring in approximately 10% of patients treated. The exact pathophysiology of RN remains unclear but is thought to involve vascular injury, immune-mediated mechanisms, and direct neuronal effects, culminating in radiological changes or symptomatic manifestations necessitating treatment. Corticosteroids are the mainstay therapy, albeit with associated side effects and instances of cortico-resistance or cortico-dependence. Bevacizumab, an anti-VEGF agent, has shown promise in small studies but awaits validation in larger trials. Consequently, a randomized phase III trial seeks to evaluate the efficacy of adding bevacizumab to standard corticosteroid therapy in patients with symptomatic RN. The trial aims to determine if this combination therapy yields superior symptomatic improvement compared to corticosteroids alone. RN will be diagnosed using multimodal imaging, and the primary objective is to assess the efficacy of bevacizumab in reducing corticosteroid usage and neurological symptoms associated with RN at three months. Secondary endpoints include toxicities, quality of life, imaging changes, and response duration. Additionally, an ancillary study will explore correlations between initial imaging parameters and treatment response, as well as changes in biological parameters with bevacizumab therapy.

Conditions

Radionecrosis of Brain; Brain Metastases

Keywords

radionecrosis of brain; brain metastasis; quality of life; bevacizumab

Outcome Measures

Primary Outcomes (1)

• Efficacy at 90 days on decrease in corticosteroids

  To investigate whether the addition of bevacizumab to standard corticosteroid therapy, compared to corticosteroid therapy plus placebo, results in greater efficacy at 3 months (90 days) on decrease in corticosteroids with radionecrosis (RN) after radiotherapy for brain. metastases. Will be assessed corticosteroids dose at Cycle 1 Day 1 and at 3 months (90 days after Cycle 1 Day 1, End of treatment visit)

  90 days after start of treatment

Secondary Outcomes (2)

• Patient-reported outcome symptoms of radionecrosis

  90 days after start of treatment

• Toxicity (CTCAE Version 4.0)

  up to 90 days after end of treatment

Study Arms (2)

Experimental arm

EXPERIMENTAL

Experimental: bevacizumab + prednisolone The patient will receive bevacizumab 7.5 mg/kg IV given on Q3W for4 cycles or until progression of radionecrosis or unacceptable adverse event. Once the patient has started the study treatment, the dose of prednisolone will be tapered every 7 days beginning at C2D1 (at least 10 mg prednisolone or equivalent), depending on tolerance. If the patient weighs more than 100 kg, the tapering can be increased by 10 to 20 mg per week for the first 3 months. Interventions: Drug: bevacizumab Drug : prednisolone

Drug: Bevacizumab; Drug: Prednisolone

Placebo arm

PLACEBO COMPARATOR

Placebo arm: placebo + prednisolone The patient will receive placebo 0.9% NaCl volume equal to bevacizumab volume added to 100 mL bag of 0.9% NaCl delivered IV given on on Q3W for4 cycles or until progression of radionecrosis or unacceptable adverse event. Once the patient has started the study treatment, the dose of prednisolone will be tapered every 7 days beginning at C2D1 (at least 10 mg prednisolone or equivalent), depending on tolerance. If the patient weighs more than 100 kg, the tapering can be increased by 10 to 20 mg per week for the first 3 months. Interventions: Drug: placebo Drug : prednisolone

Drug: Placebo; Drug: Prednisolone

Interventions

Bevacizumab DRUG

Drug: bevacizumab IV

Also known as: Avastin

Experimental arm

Placebo DRUG

Drug: placebo IV

Also known as: NaCl

Placebo arm

Prednisolone DRUG

Drug: corticosteroids IV

Also known as: Corticosteroids

Experimental arm; Placebo arm

Eligibility Criteria

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

You may qualify if:

• Patient with a diagnosis of radionecrosis based on a clinical onset of symptoms and radiological findings of RN following radiotherapy, with or without pathological confirmation:
• MRI evidence to support the diagnosis of RN (transient increase in irradiated lesion volume -FLAIR hypersignal and/or enhanced portion- without rCBV increase) COMBINED with nuclear medicine imaging:
• biphasic 18FDG-PET-TDM/MRI according to Horky or 18F-FDOPA with stage 0-1 according to Lizarraga;
• 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 ≤ 3
• 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+

You may not qualify if:

• 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;
• 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;
• History of severe allergic anaphylactic reactions to bevacizumab
• Patients with a known hypersensitivity to the 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;

Sponsors & Collaborators

• Institut Cancerologie de l'Ouest: lead

Study Sites (10)

CHRU de Brest

Brest, 29609, France

RECRUITING

Centre Francois Baclesse

Caen, 14000, France

RECRUITING

Centre D'Oncologie Et de Radiotherapie 37

Chambray-lès-Tours, 37170, France

RECRUITING

Centre Georges François Leclerc

Dijon, 21079, France

NOT YET RECRUITING

Centre Guillaume le Conquérant

Le Havre, 76600, France

RECRUITING

Centre Léon Bérard

Lyon, 69373, France

RECRUITING

Centre Eugène marquis

Rennes, 35042, France

RECRUITING

Institut de Cancérologie de l'Ouest

Saint-Herblain, 44805, France

RECRUITING

Centre Paul Strauss

Strasbourg, 67000, France

RECRUITING

Centre Saint Yves

Vannes, 56000, France

RECRUITING

MeSH Terms

Conditions

Brain Neoplasms

Interventions

Bevacizumab; Prednisolone; Adrenal Cortex Hormones

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; 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; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Luc Ollivier, MD

  Institut de Cancérologie de l'Ouest

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Luc Ollivier, MD

CONTACT

02 40 67 99 00; luc.ollivier@ico.unicancer.fr

Marine Tigreat

CONTACT

02 40 67 98 78; marine.tigreat@ico.unicancer.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 10, 2024
• First Posted: June 24, 2024
• Study Start: April 29, 2025
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 1, 2030
• Last Updated: August 17, 2025

Record last verified: 2025-07

Locations

FR (10)