Phase I/II study testing the combination of AGuIX nanoparticles with radiochemotherapy and concomitant temozolomide in patients with newly diagnosed glioblastoma (NANO-GBM trial protocol)

Emilie Thivat, Mélanie Casile, Juliette Moreau, Ioana Molnar, Sandrine Dufort, Khalide Seddik, Géraldine Le Duc, Olivier De Beaumont, Markus Loeffler, Xavier Durando, Julian Biau, Emilie Thivat, Mélanie Casile, Juliette Moreau, Ioana Molnar, Sandrine Dufort, Khalide Seddik, Géraldine Le Duc, Olivier De Beaumont, Markus Loeffler, Xavier Durando, Julian Biau

Abstract

Background: Despite standard treatments including chemoradiotherapy with temozolomide (TMZ) (STUPP protocol), the prognosis of glioblastoma patients remains poor. AGuIX nanoparticles have a high radiosensitizing potential, a selective and long-lasting accumulation in tumors and a rapid renal elimination. Their therapeutic effect has been proven in vivo on several tumor models, including glioblastoma with a potential synergetic effect when combined with TMZ based chemoradiotherapy, and they are currently evaluated in 4 ongoing Phase Ib and II clinical trials in 4 indications (brain metastases, lung, pancreatic and cervix cancers) (> 100 patients received AGuIX). Thus, they could offer new perspectives for patients with newly diagnosed glioblastoma. The aim of this study is to determine the recommended dose of AGuIX as a radiosensitizer in combination with radiotherapy and TMZ during the concurrent radio-chemotherapy period for phase II (RP2D) and to estimate the efficacy of the combination.

Methods: NANO-GBM is a multicenter, phase I/II, randomized, open-label, non-comparative, therapeutic trial. According to a dose escalation scheme driven by a TITE-CRM design, 3 dose levels of AGuIX (50, 75 and 100 mg/kg) will be tested in phase I added to standard concomitant radio-chemotherapy. Patients with grade IV glioblastoma, not operated or partially operated, with a KPS ≥ 70% will be eligible for the study. The primary endpoints are i) for phase I, the RP2D of AGuIX, with DLT defined as any grade 3-4 NCI-CTCAE toxicity and ii) for phase II, the 6-month progression-free survival rate. The pharmacokinetics, distribution of nanoparticles, tolerance of the combination, neurological status, overall survival (median, 6-month and 12-month rates), response to treatment, and progression-free survival (median and 12-month rates) will be assessed as secondary objectives. Maximum sixty-six patients are expected to be recruited in the study from 6 sites.

Discussion: The use of AGuIX nanoparticles could allow to overpass the radioresistance to the reference treatment of newly diagnosed glioblastomas that have the poorest prognosis (incomplete resection or biopsy only).

Trial registration: Clinicaltrials.gov: NCT04881032 , registered on April 30, 2021. Identifier with the French National Agency for the Safety of Medicines and Health Products (ANSM): N°Eudra CT 2020-004552-15.

Protocol: version 3, 23 May 2022.

Keywords: AGuIX; Glioblastoma; Nanomedicine; Nanoparticles; Radiosensitization; Radiotherapy.

Conflict of interest statement

GLD discloses patent No. WO2009/053644 which protects the AGuIX nanoparticles described in this publication. SD, KS, ML, ODB and GLD are employees of NH TherAguix (Meylan, France), which is developing the AGuIX nanoparticles. SD, ML and GLD own shares in this company. The other authors declare that they have no competing interests.

© 2023. The Author(s).

Figures

Fig. 1
Fig. 1
Overview of the treatment period of the NANO-GBM study

References

    1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96. doi: 10.1056/NEJMoa043330.
    1. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJB, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459–466. doi: 10.1016/S1470-2045(09)70025-7.
    1. Minniti G, Amelio D, Amichetti M, Salvati M, Muni R, Bozzao A, et al. Patterns of failure and comparison of different target volume delineations in patients with glioblastoma treated with conformal radiotherapy plus concomitant and adjuvant temozolomide. Radiother Oncol J Eur Soc Ther Radiol Oncol. 2010;97(3):377–81. doi: 10.1016/j.radonc.2010.08.020.
    1. Kotb S, Detappe A, Lux F, Appaix F, Barbier EL, Tran VL, et al. Gadolinium-based nanoparticles and radiation therapy for multiple brain melanoma metastases: proof of concept before phase I trial. Theranostics. 2016;6(3):418–427. doi: 10.7150/thno.14018.
    1. Dufort S, Le Duc G, Salomé M, Bentivegna V, Sancey L, Bräuer-Krisch E, et al. The high radiosensitizing efficiency of a trace of gadolinium-based nanoparticles in tumors. Sci Rep. 2016;6:29678. doi: 10.1038/srep29678.
    1. Bianchi A, Moncelet D, Lux F, Plissonneau M, Rizzitelli S, Ribot EJ, et al. Orotracheal administration of contrast agents: a new protocol for brain tumor targeting. NMR Biomed. 2015;28(6):738–746. doi: 10.1002/nbm.3295.
    1. Dufort S, Bianchi A, Henry M, Lux F, Le Duc G, Josserand V, et al. Nebulized gadolinium-based nanoparticles: a theranostic approach for lung tumor imaging and radiosensitization. Small Weinh Bergstr Ger. 2015;11(2):215–21. doi: 10.1002/smll.201401284.
    1. Verry C, Dufort S, Barbier EL, Montigon O, Peoc’h M, Chartier P, et al. MRI-guided clinical 6-MV radiosensitization of glioma using a unique gadolinium-based nanoparticles injection. Nanomed. 2016;11(18):2405–17. doi: 10.2217/nnm-2016-0203.
    1. Le Duc G, Miladi I, Alric C, Mowat P, Bräuer-Krisch E, Bouchet A, et al. Toward an image-guided microbeam radiation therapy using gadolinium-based nanoparticles. ACS Nano. 2011;5(12):9566–74. doi: 10.1021/nn202797h.
    1. Miladi I, Aloy MT, Armandy E, Mowat P, Kryza D, Magné N, et al. Combining ultrasmall gadolinium-based nanoparticles with photon irradiation overcomes radioresistance of head and neck squamous cell carcinoma. Nanomedicine Nanotechnol Biol Med. 2015;11(1):247–257. doi: 10.1016/j.nano.2014.06.013.
    1. Detappe A, Kunjachan S, Sancey L, Motto-Ros V, Biancur D, Drane P, et al. Advanced multimodal nanoparticles delay tumor progression with clinical radiation therapy. J Control Release Off J Control Release Soc. 2016;238:103–13. doi: 10.1016/j.jconrel.2016.07.021.
    1. Sancey L, Lux F, Kotb S, Roux S, Dufort S, Bianchi A, et al. The use of theranostic gadolinium-based nanoprobes to improve radiotherapy efficacy. Br J Radiol. 2014;87(1041):20140134. doi: 10.1259/bjr.20140134.
    1. Dufort S, Appelboom G, Verry C, Barbier EL, Lux F, Bräuer-Krisch E, et al. Ultrasmall theranostic gadolinium-based nanoparticles improve high-grade rat glioma survival. J Clin Neurosci. 2019;67:215–9. doi: 10.1016/j.jocn.2019.05.065.
    1. Verry C, Dufort S, Villa J, Gavard M, Iriart C, Grand S, et al. Theranostic AGuIX nanoparticles as radiosensitizer: a phase I, dose-escalation study in patients with multiple brain metastases (NANO-RAD trial) Radiother Oncol J Eur Soc Ther Radiol Oncol. 2021;160:159–65. doi: 10.1016/j.radonc.2021.04.021.
    1. Verry C, Dufort S, Lemasson B, Grand S, Pietras J, Troprès I, et al. Targeting brain metastases with ultrasmall theranostic nanoparticles, a first-in-human trial from an MRI perspective. Sci Adv. 2020;6(29):eaay5279. doi: 10.1126/sciadv.aay5279.
    1. Cheung YK, Chappell R. Sequential designs for phase i clinical trials with late-onset toxicities. Biometrics. 2000;56(4):1177–1182. doi: 10.1111/j.0006-341X.2000.01177.x.
    1. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010;28(11):1963–72. doi: 10.1200/JCO.2009.26.3541.

Source: PubMed

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