Radiosensitization of Multiple Brain Metastases Using AGuIX Gadolinium Based Nanoparticles (NANO-RAD)

Etude Clinique de Phase I de Radiosensibilisation de métastases cérébrales Par Nanoparticules de Gadolinium

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.

Study Overview

• Status: Completed
• Conditions: Brain Metastases
• Intervention / Treatment: Drug: AGuIX; Radiation: whole brain radiation therapy

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).

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Grenoble, France, 38100
    • University Hospital Grenoble

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: AGuIX and radiotherapy; Patients receive a single intravenous injection of AGuIX on day 1. Then patients undergo a whole brain radiation therapy, 5 days a week in weeks 1-2. The first radiotherapy session will be performed 4 hours after AGuIX injection. Five dose escalation cohorts : 15 mg/kg, 30mg/kg, 50mg/kg, 75mg/kg and 100 mg/kg	Drug: AGuIX; 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; Other Names: Nano-sized gadolinium particles; Radiation: whole brain radiation therapy; 30Gy in 10 sessions of 3Gy (5 days a week in weeks 1-2); first session 4 hours after AGuIX injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic characteristics of AGuIX particles after intravenous injection	Cmax	18 months
Pharmacokinetic characteristics of AGuIX particles after intravenous injection	AUC	18 months
Pharmacokinetic characteristics of AGuIX particles after intravenous injection	T1/2	18 months
Distribution of AGuIX particles in brain metastases and surrounding healthy tissue evaluated by MRI	Measure of the T1 contrast enhancement in brain metastases and surrounding healthy tissue after intravenous administration of AGuIX particles	30 months
Intracranial progression-free survival	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)	12 months after radiation
Overall survival	The overall survival will be assessed starting from the date of discovery of the metastases	30 months

Collaborators and Investigators

• Sponsor: University Hospital, Grenoble
• Collaborators: NH TherAguix SAS

Publications and helpful links

General Publications

• Verry C, Sancey L, Dufort S, Le Duc G, Mendoza C, Lux F, Grand S, Arnaud J, Quesada JL, Villa J, Tillement O, Balosso J. Treatment of multiple brain metastases using gadolinium nanoparticles and radiotherapy: NANO-RAD, a phase I study protocol. BMJ Open. 2019 Feb 11;9(2):e023591. doi: 10.1136/bmjopen-2018-023591.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 1, 2016
• Primary Completion (ACTUAL): February 1, 2019
• Study Completion (ACTUAL): February 1, 2019

Study Registration Dates

• First Submitted: June 2, 2016
• First Submitted That Met QC Criteria: June 28, 2016
• First Posted (ESTIMATE): July 1, 2016

Study Record Updates

• Last Update Posted (ACTUAL): June 7, 2019
• Last Update Submitted That Met QC Criteria: June 5, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: AGuIX; polysiloxane gadolinium-chelates based nanoparticles
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Neoplasms by Site; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasm Metastasis; Brain Neoplasms
• Other Study ID Numbers: 38RC15.278; 2015-004259-30 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No