Corticodependent or corticoresistant brain radionecrosis after radiotherapy for brain metastases: a multicentre randomized, controlled double-blind phase III study, comparing bevacizumab versus placebo (BRADI)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut De Cancerologie De L Ouest

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

29 Apr 2025 → ongoing

Decision date (initial)

2024-06-03

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

DGOS Inca PHRC K 2023 (PHRCK23-082)

External identifiers

EU CT number

2024-510893-25-00

ClinicalTrials.gov

NCT06471465

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

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 and in neurological symptoms associated with radionecrosis (RN) after radiotherapy for brain metastases

Secondary objectives 8

1. a) To compare safety in both arms
2. b) To compare quality of life in both arms
3. c) To compare success of treatment (decrease in corticosteroids, neurological symptoms and quality of life) in both arms;
4. d) To compare clinical changes under treatment in both arms, using Patient and Clinician Reported Outcomes;
5. e) To compare MRI modifications at 90 days with baseline in both arms;
6. f) To evaluate duration of response in both arms (from the time of stopping bevacizumab);
7. g) To compare the total weaning of corticosteroids at 3 months in both arms;
8. h) Correlative objectives: will be done as ancillary studies

Conditions and MedDRA coding

Brain metastases of cancer > brain radionecrosis

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 1. 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: o MRI evidence to support the diagnosis of RN (transient increase in irradiated lesion volume -FLAIR hypersignal and/or enhanced portion- without rCBV increase) o COMBINED with nuclear medicine imaging:  biphasic 18FDG-PET-TDM/MRI according to Horky or  18F-FDOPA PET TDM/MRI with stage 0-1 according to Lizarraga
2. 2. 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;
3. 3. Patients must have received the last cranial irradiation with photons or proton therapy for brain metastases ≥ 3 months with one or more sequences;
4. 4. Age ≥ 18-year-old;
5. 5. ECOG performance status score ≤ 2 or Karnofsky Performance Score (KPS) ≥ 50
6. 6. Life expectancy of at least 3 months assessed by graded prognostic score (DS-GPA) score 0.5 or greater;
7. 7. Patient who has never received Bevacizumab for the indication of radionecrosis.
8. 8. 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 ≥50 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
9. 9. Women of childbearing potential must use effective contraceptive measures during the treatment and for 6 months following its cessation
10. 10. Signed informed consent;
11. 11. Patient affiliated to a social security scheme.

Exclusion criteria 18

1. 1. 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
2. 10. History of severe allergic anaphylactic reactions to bevacizumab
3. 11. Patients with a known hypersensitivity to athe active substance or to any of the excipients of bevacizumab are not eligible for participation;
4. 12. Patients with a contraindication to the treatment with bevacizumab according to the European SmPC
5. 13. Patient pregnant and/or nursing;
6. 14. 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;
7. 15. Patient who has forfeited his/her freedom by administrative or legal award or who is under guardianship.
8. 2. Grade 4 venous thromboelism and peripheral arterial thrombus;
9. 3. Evidence of very high intracranial pressure that suggests brain hernia and needs emergency surgery;
10. 4. 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;
11. 5. 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;
12. 6. History of hypertensive crisis or hypertensive encephalopathy
13. 7. Patients scheduled to undergo head and neck, thoracic, or abdominal radiotherapy during the study treatment
14. 8. Prior bevacizumab ≤ 3 months before randomization;
15. 9. Progressive brain metastases;
16. 16. New cerebral metastasis detected during the inclusion imaging evaluation;
17. 17. Prior diagnosis of Posterior Reversible Encephalopathy Syndrome (PRES) with bevacizumab;
18. 18. Hypersensitivity known to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. - Corticosteroids dose at Cycle 1 Day 1 (C1D1) and at 3 months (90 days, End of treatment (EOT) visit) - NANO (Neurological Assessment in Neuro-Oncology) score (60) at C1D1 and at 3 months (90 days -EOT visit) The NANO scale evaluates 8 major domains of neurologic function that are most relevant to patients with supratentorial, infratentorial, and brainstem tumors

Secondary endpoints 8

1. a) Safety assessed using the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0 for up to 90 days following C1D1
2. b) Quality of life is measured with EORTC QLQ-C30 and BN20 (59) ; assessed at C1D1, C2D1, C3D1, C4D1 and EOT visit
3. c) Success assessed using: - Corticosteroid’s dose: at C1D1 and at 3 months (90 days) - NANO score: at C1D1, C2D1, C3D1, C4D1 and EOT visit - EORTC QLQC-30 and BN20 scores: at C1D1, C2D1, C3D1, C4D1 and EOT visit
4. d) Clinical changes assessed using: - Patient Global Impression of Change (PGIC) questionnaire (from 1 to 7) and Scale (from 0 to 10): at C4D1 and EOT visit - NANO score: at C1D1, C2D1, C3D1, C4D1 and EOT visit
5. e) volume on brain MRI T1 post-gadolinium and T2-weighted FLAIR: at EOT visit
6. f) Duration of response assessed using: - NANO scale: every 3 months until 2 years - dose of corticosteroids: every 3 months until 2 years
7. g) Corticosteroids dose at 3 months and vital status up to 3 months
8. h) Correlative biomarkers (ceramide, VEGF, angiopoietin, TGF-alpha) and nuclear medicine images

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut De Cancerologie De L Ouest

Sponsor organisation

Institut De Cancerologie De L Ouest

Address

Bd Du Professeur Jacques Monod

City

St Herblain

Postcode

44800

Country

France

Scientific contact point

Organisation

Institut De Cancerologie De L Ouest

Contact name

Luc OLLIVIER

Public contact point

Organisation

Institut De Cancerologie De L Ouest

Contact name

Marine TIGREAT

Locations

1 EU/EEA country · 22 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications