Treatment of multiple brain metastases using gadolinium nanoparticles and radiotherapy: NANO-RAD, a phase I study protocol

Camille Verry, Lucie Sancey, Sandrine Dufort, Geraldine Le Duc, Christophe Mendoza, François Lux, Sylvie Grand, Josiane Arnaud, Jean Louis Quesada, Julie Villa, Olivier Tillement, Jacques Balosso, Camille Verry, Lucie Sancey, Sandrine Dufort, Geraldine Le Duc, Christophe Mendoza, François Lux, Sylvie Grand, Josiane Arnaud, Jean Louis Quesada, Julie Villa, Olivier Tillement, Jacques Balosso

Abstract

Introduction: Occurrence of multiple brain metastases is a critical evolution of many cancers with significant neurological and overall survival consequences, despite new targeted therapy and standard whole brain radiotherapy (WBRT). A gadolinium-based nanoparticle, AGuIX, has recently demonstrated its effectiveness as theranostic and radiosensitiser agent in preclinical studies. The favourable toxicity profile in animals and its administration as a simple intravenous injection has motivated its use in patients with this first in human study.

Methods and analysis: The NANO-RAD study is a phase I, first in human injection, monocentric, open-label, dose-escalation study to investigate the safety, the tolerability and the spectrum of side effects of AGuIX in combination with WBRT (30 Gy, 10 fractions of 3 Gy) for patients with multiple brain metastases. Five dose escalation cohorts are planned: 15, 30, 50, 75 and 100 mg/kg. A total of 15-18 patients will be recruited into this trial. The primary objective is to determine the maximum-tolerated dose of AGuIX nanoparticles combined with WBRT for the treatment of multiple brain metastases. Toxicity will be assessed using the National Cancer Institute Common Toxicity Criteria V.4.03. Secondary objectives are pharmacokinetic profile, distribution of AGuIX in metastases and surrounding healthy tissue visualised by MRI, intracranial progression-free survival and overall survival. Intracranial response will be determined according to Response Evaluation Criteria in Solid Tumour Criteria V.1.1 comparing MRI performed prior to treatment and at each follow-up visits.

Ethics and dissemination: Approval was obtained from the ethics committee Sud Est V, France (Reference number 15-CHUG-48). The study was approved by the French National Agency for the Safety of Medicines and Health Products (ANSM) (Reference number 151519A-12). The results will be published in peer-reviewed journals or disseminated through national and international conferences.

Trial registration number: NCT02820454; Pre-results.

Keywords: adult radiotherapy; brain metastases; gadolinium nanoparticle; theranostic.

Conflict of interest statement

Competing interests: FL and OT have to disclose the patent WO2011/135101. GLD and OT have to disclose the patent WO2009/053644. These patents protect the AGuIX® nanoparticles described in this publication. SD and GLD are employees from NH TherAguix that is developing the AGuIX® nanoparticles. The trial medication (AGuIX®) and a financial grant for study organization are supplied by NH TherAguix, Villeurbanne, France.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Schematic representation of AGuIX. Gadolinium ions are chelated by 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid derivatives. Polysiloxane core (Si, metallic grey; O, red; H, white; C, grey; N, blue) is surrounded by covalently grafted chelates of gadolinium (Gd, metallic green).
Figure 2
Figure 2
Illustration of multiple brain metastases on T1-injected MRI. The images correspond to inclusion criteria of NANO-RAD trial.

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