Treatment of brain metastases using gadolinium nanoparticles: NANORAD first in man study

Abstract : The occurrence of multiple brain metastases is a critical evolution of many cancers with a major impact on overall survival. A new gadolinium-based nanoparticle, AGuIX®, has recently demonstrated its efficacy as a radiosensitizer and MRI contrast agent in several preclinical studies. The objective of this research is to establish a proof of concept on an animal model and then to perform the first intravenous administration of this new drug in humans in a phase 1 trial. The first part of this work consisted of a 6 MeV irradiation after AGuIX® injection of a Fisher rat model carrying 9L cerebral gliomas assessed by MRI. A favorable distribution of nanoparticles was observed by EPR effect (Enhanced Permeability and Retention) with a concentration of gadolinium into the tumor 20 times higher than in healthy brain. The radiosensitizing effect was demonstrated with a significant decrease in tumor size (p=0.02) for the irradiated group with AGuIX® injection. These results, combined with the favorable safety profile in animal models, motivated the transfer of this new drug to humans in a Phase 1 study named NANO-RAD (EudraCT2015-004259-30; NCT02820454). This is a monocentric, open-label study evaluating the feasibility and safety of intra venous AGuIX® combined with whole brain radiation therapy (30 Gy, 10 Fr of 3 Gy) for patients with multiple brain metastases. The main objective is to determine the maximum tolerated dose of nanoparticles with a dose escalation scheme by steps of 3 patients at 15, 30, 50, 75 and 100 mg/kg. Secondary objectives are the pharmacokinetics, distribution of AGuIX® by MRI, intracranial progression-free survival and overall survival. The first human administration was performed at Grenoble University Hospital on 18 July 2016 and the last patient (n=15) was included on 06 February 2018. All metastases, whatever the histological type (lung, melanoma, breast) had a uptake of AGuIX® whose concentration in the tumor was proportional to the injected dose. The average blood half-life is 1h09 (± 26 min). Tolerance to the treatment was good with a dose escalation up to 100 mg/kg, which became the dose selected for further clinical trials. Of the 14 evaluable patients, 12 had a clinical benefit of treatment with a decrease in tumor volume. These preliminary results are promising in terms of safety, distribution and efficacy and should be confirmed by the randomized multicenter Phase 2 study started in March 2019.
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Submitted on : Friday, November 8, 2019 - 11:31:33 AM
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  • HAL Id : hal-02355431, version 1



Camille Verry. Treatment of brain metastases using gadolinium nanoparticles: NANORAD first in man study. ICRR 2019, Aug 2019, Manchester, United Kingdom. ⟨hal-02355431⟩



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