Theranostic AGuIX nanoparticles as radiosensitizer: A phase I, dose-escalation study in patients with multiple brain metastases (NANO-RAD trial).

Camille Verry, Sandrine Dufort, Julie Villa, Marylaure Gavard, Carole Iriart, Sylvie Grand, Julie Charles, Benoit Chovelon, Jean-Luc Cracowski, Jean-Louis Quesada, Christophe Mendoza, Lucie Sancey, Audrey Lehmann, Florence Jover, Jean-Yves Giraud, François Lux, Yannick Crémillieux, Stephen McMahon, Petrus J Pauwels, Daniel Cagney, Ross Berbeco, Ayal Aizer, Eric Deutsch, Markus Loeffler, Géraldine Le Duc, Olivier Tillement, Jacques Balosso

Journal: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 2021;160():159-165

PMID: 33961915

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Abstract

BACKGROUND AND PURPOSE

Brain metastasis impacts greatly on patients' quality of life and survival. The phase I NANO-RAD trial assessed the safety and maximum tolerated dose of systemic administration of a novel gadolinium-based nanoparticle, AGuIX, in combination with whole brain radiotherapy in patients with multiple brain metastases not suitable for stereotactic radiotherapy.

MATERIALS AND METHODS

Patients with measurable brain metastases received escalating doses of AGuIX nanoparticles (15, 30, 50, 75, or 100 mg/kg intravenously) on the day of initiation of WBRT (30 Gy in 10 fractions) in 5 cohorts of 3 patients each. Toxicity was assessed using NCI Common Terminology Criteria for Adverse Events v4.03.

RESULTS

Fifteen patients with 354 metastases were included. No dose-limiting toxic effects were observed up to AGuIX 100 mg/kg. Plasma elimination half-life of AGuIX was similar for all groups (mean 1.3 h; range 0.8-3 h). Efficient targeting of metastases (T MRI enhancement, tumor selectivity) and persistence of AGuIX contrast enhancement were observed in metastases from patients with primary melanoma, lung, breast, and colon cancers. The concentration of AGuIX in metastases after administration was proportional to the injected dose. Thirteen of 14 evaluable patients had a clinical benefit, with either stabilization or reduction of tumor volume. MRI analysis showed significant correlation between contrast enhancement and tumor response, thus supporting a radiosensitizing effect.

CONCLUSION

Combining AGuIX with radiotherapy for patients with brain metastases is safe and feasible. AGuIX specifically targets brain metastases and is retained within tumors for up to 1 week; ongoing phase II studies will more definitively assess efficacy.

Address: Radiotherapy Department, Grenoble Alps University Hospital, Grenoble, France; INSERM UA7, University of Grenoble Alps, Synchrotron Radiation for Biomedical Research (ESRF), Grenoble, France. Electronic address: [email protected].; NH TherAguix SA, Meylan, France.; Radiotherapy Department, Grenoble Alps University Hospital, Grenoble, France.; Clinical Research Vigilance, Grenoble Alps University Hospital, Grenoble, France.; Neuroradiology Department, Grenoble Alps University Hospital, Grenoble, France.; Dermatology Department, Grenoble Alps University Hospital, Grenoble, France.; Unit of Hormonal and Nutritional Biochemistry, Institute of Biology and Pathology, Grenoble Alps University Hospital, Grenoble, France.; Clinical Investigation Center, Grenoble Alps University Hospital, Grenoble, France.; Institute Light and Matter, UMR5306, Lyon1 University-CNRS, Lyon University, Villeurbanne, France.; Pharmacy Department, Grenoble Alps University Hospital, Grenoble, France.; NH TherAguix SA, Meylan, France; Institut des Sciences Moléculaires, UMR5255, Université de Bordeaux, France.; Center for Cancer Research and Cell Biology, Queen's University Belfast, United Kingdom.; Dap-Santé Consulting, Dolomieu, France.; Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA.; Radiation Oncology Department, INSERM1030 Molecular Radiotherapy and Therapeutic Innovations, Paris-Saclay University, Gustave Roussy, Villejuif, France.

DOI: 10.1016/j.radonc.2021.04.021