Brain Metastases, Adult, Radiotherapy
Conditions
Keywords
gadolinium nanoparticles, AGuIX
Brief summary
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
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.
Interventions
DRUGAGuIX®
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
RADIATIONWhole Brain Radiation Therapy
30 Gy in 10 fractions of 3 Gy over 2-3 weeks
Sponsors
NH TherAguix SAS
University Hospital, Grenoble
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
The main endpoint will be evaluated by a blinded endpoint committee.
Intervention model description
Prospective Randomized Open Blinded Endpoint phase II clinical trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best objective intracranial response rate - intent-to-treat | at 6 weeks | Evaluation of brain metastases response, according to RECIST v1.1 criteria (or modified RECIST) by MRI, with MRI centralized reading |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of the quality of life | at D0, 6 weeks, 3, 6, 9, 12 months | Quality of life test score EORTC QLQ C30 |
| Best objective intracranial response rate - per-protocol | at 6 weeks and 3 months | Evaluation of brain metastases response on per-protocol population, according to RECIST v1.1 criteria (or modified RECIST), by MRI with centralized reading |
| Evaluation of the intracranial response rate | for 12 months | 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 |
| Evaluation of individual metastasis response | at 6 weeks and 3, 6, 9 and 12 months | Evaluation of individual brain metastasis response, for all metastases with the sum of diameters \> 1cm, by MRI rate |
| Intracranial progression-free survival | at 12 months | Evaluation of the time between the start of the treatment and the occurence of intracranial progression or neuriologic death |
| Neurocognitive evaluation | at Day 0, 6 weeks, 3, 6, 9, 12 months | Neurocognitive test (MoCA) |
| Overall survival | at 12 months | Death |
| Change in steroid dependence | at 6 weeks and 3, 6, 9 and 12 months | Reporting of daily steroid dose |
| Incidence of adverse events | at 6 weeks and 3, 6, 9 and 12 months | Reporting of adverse events by type, frequency and severity for both treatments (WBRT and AGuIX® + WBRT) |
| MRI study of the distribution of the product in brain metastases | Day 0 | MRI evaluation of contrast enhancement at D0 after AGuIX® injection |
| Intracranial progression-free survival, brain survival | at 12 months | Death related to brain metastases progression |
Countries
France
Outcome results
None listed