Ignite Creation Date:
2024-07-17 @ 12:06 PM
Last Modification Date:
2024-10-26 @ 3:32 PM
Study NCT ID:
NCT06471465
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-06-24
First Post:
2024-05-10
Brief Title:
Corticodependent or Corticoresistant Brain Radionecrosis After Radiotherapy for Brain Metastases
Sponsor:
Institut Cancerologie de lOuest
Organization:
Institut Cancerologie de lOuest
Study Overview
Official Title:
Corticodependent or Corticoresistant Brain Radionecrosis After Radiotherapy for Brain Metastases a Multicentre Randomized Controlled Double-blind Phase III Study Comparing Bevacizumab Versus Placebo
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
BRADI
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
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
Detailed Description:
Brain metastases BM are increasingly common in cancer patients between 10 and 50 1 will develop BM resulting in potentially disabling symptoms degrading quality of life and impacting overall survival The main local treatment options include surgery hypo-fractionated radiotherapy in stereotactic condition SRS and whole brain radiotherapy WBRT Over the past decade SRS has become the most frequently administered focal treatment2 SRS delivers a single or multi-fraction ablative dose as the sole treatment for BM with an overall survival OS benefit in patients with single BM HR 076 CI95 066 - 0883 or postoperatively decreasing the risk of recurrence HR 046 CI95 024 - 0884 SRS compared to neurosurgery has the ability to treat inoperable sites multiple lesions and has the advantage of being less invasive WBRT is now limited to certain patients with multiple BMs and not eligible for SRS SRS is often preferred to WBRT because of a lower rate of neurocognitive toxicities at 12 months difference -344 CI95 -744 to 55 P 04 for patients with 5 to 10 BMs Local control at 1 year is high in the order of 90 and SRS is generally considered a cost-effective treatment
However after SRS there can be late side effects that can start 3 months to several years after irradiation the most common is cerebral radio necrosis RN in 10 of treated patients The pathophysiology is poorly understood and includes vascular injury immune-mediated mechanisms and direct neuronal effects Vascular injury leads to increased permeability after radiotherapy resulting in vasogenic oedema and ischemia induce hypoxia and an increase in hypoxia inducible factor HIF-1α then upregulating vascular endothelial growth factor VEGF which exacerbates the oedema by increasing vascular permeability which creates a vicious cycle and RN hence the importance of inhibiting VEGF5
RN may remain as radiological changes CTCAE v5 grade I toxicity approximately 506 to be monitored or be symptomatic grade II-IV and requiring treatment Symptoms are usually manifested by focal neurological signs and symptoms related to cerebral oedema Corticosteroids are the only standard of care before surgery which is performed when possible The problem is that high-dose long-term corticosteroids have multiple side effects and some patients with RN may remain symptomatic despite corticosteroid administration cortico-resistance or relapse while decreasing the corticosteroid dose cortico-dependence and no standard treatment is available Only one small 14 patients randomized double-blind study compared bevacizumab 75 mgkg every 3 weeks versus placebo in RN after irradiation All 7 patients in the bevacizumab arm had a decrease in FLAIR oedema volume with clinical improvement in contrast to the placebo arm where everything worsened7
Thus the anti-VEGF bevacizumab is an option but needs to be validated in a phase 3 randomized trial
This randomized phase III trial aims to determine whether the impact of adding bevacizumab to standard corticosteroid therapy results in greater symptomatic improvement than corticosteroid therapy alone in patients with symptomatic RN RN will be defined by a multimodal imaging approach combining brain MRI and nuclear medicine imaging 18F-FDOPA PET or dual phase 18F-FDG PET on CT or MRI The primary objective of this study is to investigate whether the addition of bevacizumab to standard corticosteroid therapy compared to corticosteroid therapy plus placebo results in greater efficacy at 3 months on decrease in corticosteroids and in neurological symptoms associated with radionecrosis RN Secondary endpoints were toxicities quality of life PROs Patient Reported Outcomes and Clinician Reported Outcomes CRO imaging changes at 3 months total weaning of corticosteroids and response duration An ancillary study will evaluate the correlation between the initial nuclear medicine imaging parameters and the response to treatment as well as the evolution of biological parameters under bevacizumab
However after SRS there can be late side effects that can start 3 months to several years after irradiation the most common is cerebral radio necrosis RN in 10 of treated patients The pathophysiology is poorly understood and includes vascular injury immune-mediated mechanisms and direct neuronal effects Vascular injury leads to increased permeability after radiotherapy resulting in vasogenic oedema and ischemia induce hypoxia and an increase in hypoxia inducible factor HIF-1α then upregulating vascular endothelial growth factor VEGF which exacerbates the oedema by increasing vascular permeability which creates a vicious cycle and RN hence the importance of inhibiting VEGF5
RN may remain as radiological changes CTCAE v5 grade I toxicity approximately 506 to be monitored or be symptomatic grade II-IV and requiring treatment Symptoms are usually manifested by focal neurological signs and symptoms related to cerebral oedema Corticosteroids are the only standard of care before surgery which is performed when possible The problem is that high-dose long-term corticosteroids have multiple side effects and some patients with RN may remain symptomatic despite corticosteroid administration cortico-resistance or relapse while decreasing the corticosteroid dose cortico-dependence and no standard treatment is available Only one small 14 patients randomized double-blind study compared bevacizumab 75 mgkg every 3 weeks versus placebo in RN after irradiation All 7 patients in the bevacizumab arm had a decrease in FLAIR oedema volume with clinical improvement in contrast to the placebo arm where everything worsened7
Thus the anti-VEGF bevacizumab is an option but needs to be validated in a phase 3 randomized trial
This randomized phase III trial aims to determine whether the impact of adding bevacizumab to standard corticosteroid therapy results in greater symptomatic improvement than corticosteroid therapy alone in patients with symptomatic RN RN will be defined by a multimodal imaging approach combining brain MRI and nuclear medicine imaging 18F-FDOPA PET or dual phase 18F-FDG PET on CT or MRI The primary objective of this study is to investigate whether the addition of bevacizumab to standard corticosteroid therapy compared to corticosteroid therapy plus placebo results in greater efficacy at 3 months on decrease in corticosteroids and in neurological symptoms associated with radionecrosis RN Secondary endpoints were toxicities quality of life PROs Patient Reported Outcomes and Clinician Reported Outcomes CRO imaging changes at 3 months total weaning of corticosteroids and response duration An ancillary study will evaluate the correlation between the initial nuclear medicine imaging parameters and the response to treatment as well as the evolution of biological parameters under bevacizumab
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None