Radiotherapy of Multiple Brain Metastases Using AGuIX®

Study Overview
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Brief Summary
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This is a Prospective Randomized Open Blinded Endpoint phase II clinical trial. The study will be adaptive: an interim analysis is planned after enrolment of 20 patients in each arm of treatment (WBRT and AGuIX® + WBRT), to select and continue the study with group(s) that present the best response rate to the experimental treatment (AGuIX® + WBRT). The main endpoint will be evaluated by a blinded endpoint committee.

Detailed Description
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The occurrence of brain metastases is a common event in the history of cancer and negatively affects the life expectancy of patients. Their incidence varies between 15 and 50% according to the histologic types. Surgery, stereotactic radiosurgery, radiotherapy and chemotherapy are the main treatments currently proposed. For patients with multiple brain metastases, whole brain radiation therapy (WBRT) remains the standard of care. However, the median overall survival is less than 6 months and new approaches need to be developed to improve treatment of these patients. In this context, the weak control of the disease comes from three main factors: the multiplicity of the brain lesions, the radioresistance of certain histologies and the poor distribution of cytotoxic agents in brain metastases. The use of radiosensitizing agents is here of great interest. The radiosensitizing agent chosen in this study is AGuIX®. It is a Gadolinium-chelated polysiloxane based nanoparticle developed by NH TherAguix company for its theranostic properties (radiosensitization and diagnosis by multimodal imaging). Preclinical studies have demonstrated the radiosensitizing effect of AGuIX® in vivo in 8 tumor models xenografted in rodents, and particularly in brain tumors.

Official Title
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Radiotherapy of Multiple Brain Metastases Using AGuIX® Gadolinium-chelated Polysiloxane Based Nanoparticles: a Prospective Randomized Phase II Clinical Trial.

Conditions
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Brain Metastases, Adult, Radiotherapy

Intervention / Treatment
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* Drug: AGuIX®
* Radiation: Whole Brain Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with brain metastases, from a histologically confirmed solid tumor, eligible for WBRT At least 18 years old Signed informed consent after informing the patient ECOG (Eastern Cooperative Oncology Group) performance status 0-2 Extracranial disease: Complete or partial response or stability under systemic treatment No extracranial disease Or first line of treatment Life expectancy greater than 6 weeks Effective contraceptive method for all patient of childbearing potential Affiliated to a social security regimen Exclusion Criteria: Leptomeningeal metastasis Evidence of metastasis with recent large hemorrhage Progressive and threatening extracranial disease under systemic treatment Previous cranial irradiation (except stereotactic irradiation) Known contra-indication, sensitivity or allergy to gadolinium Known contra-indication for Magnetic Resonance Imaging Renal insufficiency (glomerular filtration rate ≤ 50 mL/min/1.73m²) Pregnancy or breastfeeding Subject under administrative or judicial control

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective Randomized Open Blinded Endpoint phase II clinical trial.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AGuIX® + Whole Brain Radiation Therapy<br>Intervention: Drug: AGuIX® + WBRT Other Names: Gadolinium-chelated polysiloxane based nanoparticles 3 intravenous injections at 100mg/kg D0: AGuIX® injection followed by MRI (within 7 days before commencement of WBRT) Fr1: AGuIX® injection before the first radiation session Fr6: AGuIX® injection before the sixth radiation session 30 Gy in 10 fractions of 3 Gy over 2-3 weeks | Drug: AGuIX®<br>* 3 intravenous injection at 100mg/kg D0: AGuIX® injection followed by MRI (within 7 days before commencement of WBRT) Fr1: AGuIX® injection before the first radiation session Fr6: AGuIX® injection before the sixth radiation session<br>* Other names: Gadolinium-chelated polysiloxane based nanoparticles;Radiation: Whole Brain Radiation Therapy<br>* 30 Gy in 10 fractions of 3 Gy over 2-3 weeks<br>* Other names: WBRT;|
| Active Comparator: Whole Brain Radiation Therapy<br>Intervention: Radiation: Whole Brain Radiation Therapy ( WBRT) 30 Gy in 10 fractions of 3 Gy over 2-3 weeks | Radiation: Whole Brain Radiation Therapy<br>* 30 Gy in 10 fractions of 3 Gy over 2-3 weeks<br>* Other names: WBRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best objective intracranial response rate - intent-to-treat | Evaluation of brain metastases response, according to RECIST v1.1 criteria (or modified RECIST) by MRI, with MRI centralized reading | at 6 weeks | 
| Best objective intracranial response rate - intent-to-treat | Evaluation of brain metastases response, according to RECIST v1.1 criteria (or modified RECIST) by MRI, with MRI centralized reading | at 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of the quality of life | Quality of life test score EORTC QLQ C30 | at D0, 6 weeks, 3, 6, 9, 12 months | 
| Evaluation of the quality of life | Quality of life test score EORTC QLQ BN20 | at day 0, 6 weeks, 3, 6, 9, 12 months | 
| Neurocognitive evaluation | Neurocognitive test (MoCA) | at Day 0, 6 weeks, 3, 6, 9, 12 months | 
| Best objective intracranial response rate - per-protocol | Evaluation of brain metastases response on per-protocol population, according to RECIST v1.1 criteria (or modified RECIST), by MRI with centralized reading | at 6 weeks and 3 months | 
| Evaluation of the intracranial response rate | Evaluation of brain metastases response, according to RANO, to RECIST v1.1 criteria, and as the evolution of the sum of longest diameters (for all metastases with a sum of diameters > 1cm), by MRI, at 6 weeks and 3, 6, 9 and 12 months | for 12 months | 
| Evaluation of individual metastasis response | Evaluation of individual brain metastasis response, for all metastases with the sum of diameters > 1cm, by MRI rate | at 6 weeks and 3, 6, 9 and 12 months | 
| Intracranial progression-free survival | Evaluation of the time between the start of the treatment and the occurence of intracranial progression or neuriologic death | at 12 months | 
| Intracranial progression-free survival, brain survival | Death related to brain metastases progression | at 12 months | 
| Overall survival | Death | at 12 months | 
| Change in steroid dependence | Reporting of daily steroid dose | at 6 weeks and 3, 6, 9 and 12 months | 
| Incidence of adverse events | Reporting of adverse events by type, frequency and severity for both treatments (WBRT and AGuIX® + WBRT) | at 6 weeks and 3, 6, 9 and 12 months | 
| MRI study of the distribution of the product in brain metastases | MRI evaluation of contrast enhancement at D0 after AGuIX® injection | Day 0 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AGuIX, gadolinium nanoparticles