Brain Metastases
Conditions
Keywords
AGuIX, polysiloxane gadolinium-chelates based nanoparticles
Brief summary
RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. AGuIX particles may increase the effectiveness of radiation therapy by making tumor cells more sensitive to radiation. PURPOSE: This first-in-man Phase I trial will study the side effects and best dose of AGuIX when injected together with whole brain radiation therapy in treating patients with multiple brain metastases. The effectiveness of the combination of AGuIX and radiation therapy will be also assessed.
Detailed description
The present study will investigate the safety, tolerability and spectrum of side effects of AGuIX in combination with whole brain radiation therapy. As such, this study will characterize the dose limiting toxicities (DLT) and maximum tolerated dose (MTD) of in combination with whole brain radiation therapy in patients with multiple brain metastases. On day 1, patients will receive a single intravenous injection of AGuIX. An MRI scan will be performed 2 hours after injection to visualize the distribution of AGuIX in brain metastases and surrounding healthy tissue, and to evaluate the contrast enhancement in brain metastases. Then patients will undergo a whole brain radiation therapy, starting 4 hours after AGuIX injection, up to completion of 2 weeks, 5 days a week of treatment (30Gy, 3Gy/fraction). During the first 24h after injection, several blood draws will be also performed in order to assess the pharmacokinetic of AGuIX. After completion of study treatment, patients will be followed periodically. Patients will be enrolled in cohorts and will be treated at sequentially rising dose levels of AGuIX combined with whole brain radiation therapy. Three subjects will initially enter at each dose. If none of the three experiences a dose-limiting toxicity we will proceed to the next dose. If one of the three experiences that level of toxicity, we will accrue 3 more subjects at that dose. If at any time there are two or more dose-limiting toxicities (in the 3-6 subjects) on a given dose, we will drop down to a lower dose. Dose escalation will continue until the MTD of AGuIX and whole brain radiation therapy is established. The MTD will then be one dose below the DLT occurring in at least 1 out of 3 subjects (2 out of 6 patients).
Interventions
DRUGAGuIX
A single intravenous injection on day 1. Dose level 1: 15mg/kg; Dose level 2: 30mg/kg, Dose level 3: 50mg/kg; Dose level 4: 75mg/kg; Dose level 5: 100mg/kg
RADIATIONwhole brain radiation therapy
30Gy in 10 sessions of 3Gy (5 days a week in weeks 1-2); first session 4 hours after AGuIX injection.
Sponsors
NH TherAguix SAS
University Hospital, Grenoble
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with brain metastasis ineligible for local treatment by surgery or stereotactic radiation * At least 18 years old * Secondary brain metastases from a histologically confirmed solid tumor * Patient competent to give informed consent (ou Signed informed consent after informing the patient) * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3 * No prior brain irradiation * No renal insufficiency (glomerular filtration rate \> 60 mL/min/1.73m²) * Normal liver function (bilirubin \< 30 µmol/L; Alkaline phosphatase \< 400 UI/L; Aspartate aminotransferase (AST) \< 75 UI/L; Alanine aminotransferase (ALT) \< 175 UI/L) * For both male and female patients, effective methods of contraception must be used throughout the study. Acceptable methods of contraception are oral or implantable contraceptives, intrauterine device, condoms, spermicidal gels, or surgical sterilization. * Affiliated to a social security scheme or assimilated
Exclusion criteria
* Meningeal carcinomatosis * Progressive and threatening extracranial disease * Previous cranial irradiation (whether whole or partial brain radiation therapy, except stereotactic irradiation) or total body irradiation * Known contra-indication, sensitivity or allergy to gadolinium * Patients unable to undergo or tolerate Magnetic Resonance Imaging * Patients participating in another clinical investigation at the time * Protected persons under articles L1121-5 to L1121-8, Code of Public Health
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum-tolerated dose (MTD) of polysiloxane gadolinium-chelates based nanoparticles (AGuIX) given concurrently to the whole brain radiation therapy for the treatment of multiple brain metastases | 18 months | To determine Maximum-tolerated dose (MTD) of polysiloxane gadolinium-chelates based nanoparticles (AGuIX) given concurrently to the whole brain radiation therapy, according to incidence of dose limiting toxicity (DLT) graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic characteristics of AGuIX particles after intravenous injection | 18 months | Cmax |
| Distribution of AGuIX particles in brain metastases and surrounding healthy tissue evaluated by MRI | 30 months | Measure of the T1 contrast enhancement in brain metastases and surrounding healthy tissue after intravenous administration of AGuIX particles |
| Intracranial progression-free survival | 12 months after radiation | The intracranial progression-free survival will be assessed by MRI (1,3, 6, 9 and 12 months from the date of discovery of the metastases) |
| Overall survival | 30 months | The overall survival will be assessed starting from the date of discovery of the metastases |
Countries
France
Outcome results
None listed