Radiotherapy of Multiple Brain Metastases Using AGuIX®

Radiotherapy Clinical Trial

— NANORAD2  

Official title:

Radiotherapy of Multiple Brain Metastases Using AGuIX® Gadolinium-chelated Polysiloxane Based Nanoparticles: a Prospective Randomized Phase II Clinical Trial.

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03818386
• Other study ID #: 38RC18.085
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: March 26, 2019
• Est. completion date: March 26, 2025

Study information

• Verified date: August 2023
• Source: University Hospital, Grenoble
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Prospective Randomized Open Blinded Endpoint phase II clinical trial. The study will be adaptive: an interim analysis is planned after enrolment of 20 patients in each arm of treatment (WBRT and AGuIX® + WBRT), to select and continue the study with group(s) that present the best response rate to the experimental treatment (AGuIX® + WBRT).

The main endpoint will be evaluated by a blinded endpoint committee.

Description:

The occurrence of brain metastases is a common event in the history of cancer and negatively affects the life expectancy of patients. Their incidence varies between 15 and 50% according to the histologic types. Surgery, stereotactic radiosurgery, radiotherapy and chemotherapy are the main treatments currently proposed.

For patients with multiple brain metastases, whole brain radiation therapy (WBRT) remains the standard of care. However, the median overall survival is less than 6 months and new approaches need to be developed to improve treatment of these patients.

In this context, the weak control of the disease comes from three main factors: the multiplicity of the brain lesions, the radioresistance of certain histologies and the poor distribution of cytotoxic agents in brain metastases.

The use of radiosensitizing agents is here of great interest. The radiosensitizing agent chosen in this study is AGuIX®. It is a Gadolinium-chelated polysiloxane based nanoparticle developed by NH TherAguix company for its theranostic properties (radiosensitization and diagnosis by multimodal imaging). Preclinical studies have demonstrated the radiosensitizing effect of AGuIX® in vivo in 8 tumor models xenografted in rodents, and particularly in brain tumors.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 100
• Est. completion date: March 26, 2025
• Est. primary completion date: June 26, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients with brain metastases, from a histologically confirmed solid tumor, eligible for WBRT

• At least 18 years old

• Signed informed consent after informing the patient

• ECOG (Eastern Cooperative Oncology Group) performance status 0-2

• Extracranial disease:

• Complete or partial response or stability under systemic treatment

• No extracranial disease

• Or first line of treatment

• Life expectancy greater than 6 weeks

• Effective contraceptive method for all patient of childbearing potential

• Affiliated to a social security regimen

Exclusion Criteria:

• Leptomeningeal metastasis

• Evidence of metastasis with recent large hemorrhage

• Progressive and threatening extracranial disease under systemic treatment

• Previous cranial irradiation (except stereotactic irradiation)

• Known contra-indication, sensitivity or allergy to gadolinium

• Known contra-indication for Magnetic Resonance Imaging

• Renal insufficiency (glomerular filtration rate = 50 mL/min/1.73m²)

• Pregnancy or breastfeeding

• Subject under administrative or judicial control

Related Conditions & MeSH terms

• Brain Metastases, Adult
• Brain Neoplasms
• Neoplasm Metastasis
• Radiotherapy

Intervention

Drug:
• AGuIX®
3 intravenous injection at 100mg/kg D0: AGuIX® injection followed by MRI (within 7 days before commencement of WBRT) Fr1: AGuIX® injection before the first radiation session Fr6: AGuIX® injection before the sixth radiation session

Radiation:
• Whole Brain Radiation Therapy
30 Gy in 10 fractions of 3 Gy over 2-3 weeks

Locations

Country	Name	City	State
France	Centre Hospitalier Annecy Genevois	Annecy	Rhones-Alpes
France	CRLCC - Institut Bergonié	Bordeaux
France	Crlcc Francois Baclesse	Caen
France	Centre Georges François Leclerc	Dijon
France	Centre Hospitalier Universitaire Grenoble-Alpes	Grenoble	Rhones-Alpes
France	Centre Leon Berard Lyon	Lyon	Rhones Alpes
France	Hospices Civils de Lyon-Hôpital Lyon Sud	Lyon
France	Institut Régional du Cancer	Montpellier	Occitanie
France	Hôpital Européen Georges Pompidou	Paris
France	La Pitié Salpêtrière - Charles Foix	Paris
France	Institut Curie Saint Cloud	Saint-Cloud
France	Crlcc Paul Strauss	Strasbourg
France	Institut Claudius Regaud Institut Universitaire du Cancer Toulouse Oncopole Radiothérapie	Toulouse	Occitanie
France	Institut de Cancérologie de Lorraine ALEXIS VAUTRIN	Vandœuvre-lès-Nancy

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Grenoble	NH TherAguix SAS

Country where clinical trial is conducted

France, 

References & Publications (3)

Le Duc G, Miladi I, Alric C, Mowat P, Brauer-Krisch E, Bouchet A, Khalil E, Billotey C, Janier M, Lux F, Epicier T, Perriat P, Roux S, Tillement O. Toward an image-guided microbeam radiation therapy using gadolinium-based nanoparticles. ACS Nano. 2011 Dec 27;5(12):9566-74. doi: 10.1021/nn202797h. Epub 2011 Nov 9. — View Citation

Lux F, Tran VL, Thomas E, Dufort S, Rossetti F, Martini M, Truillet C, Doussineau T, Bort G, Denat F, Boschetti F, Angelovski G, Detappe A, Cremillieux Y, Mignet N, Doan BT, Larrat B, Meriaux S, Barbier E, Roux S, Fries P, Muller A, Abadjian MC, Anderson C, Canet-Soulas E, Bouziotis P, Barberi-Heyob M, Frochot C, Verry C, Balosso J, Evans M, Sidi-Boumedine J, Janier M, Butterworth K, McMahon S, Prise K, Aloy MT, Ardail D, Rodriguez-Lafrasse C, Porcel E, Lacombe S, Berbeco R, Allouch A, Perfettini JL, Chargari C, Deutsch E, Le Duc G, Tillement O. AGuIX(R) from bench to bedside-Transfer of an ultrasmall theranostic gadolinium-based nanoparticle to clinical medicine. Br J Radiol. 2019 Jan;92(1093):20180365. doi: 10.1259/bjr.20180365. Epub 2018 Sep 18. — View Citation

Verry C, Dufort S, Barbier EL, Montigon O, Peoc'h M, Chartier P, Lux F, Balosso J, Tillement O, Sancey L, Le Duc G. MRI-guided clinical 6-MV radiosensitization of glioma using a unique gadolinium-based nanoparticles injection. Nanomedicine (Lond). 2016 Sep;11(18):2405-17. doi: 10.2217/nnm-2016-0203. Epub 2016 Aug 16. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Best objective intracranial response rate - intent-to-treat	Evaluation of brain metastases response, according to RECIST v1.1 criteria (or modified RECIST) by MRI, with MRI centralized reading	at 6 weeks
Primary	Best objective intracranial response rate - intent-to-treat	Evaluation of brain metastases response, according to RECIST v1.1 criteria (or modified RECIST) by MRI, with MRI centralized reading	at 3 months
Secondary	Evaluation of the quality of life	Quality of life test score EORTC QLQ C30	at D0, 6 weeks, 3, 6, 9, 12 months
Secondary	Evaluation of the quality of life	Quality of life test score EORTC QLQ BN20	at day 0, 6 weeks, 3, 6, 9, 12 months
Secondary	Neurocognitive evaluation	Neurocognitive test (MoCA)	at Day 0, 6 weeks, 3, 6, 9, 12 months
Secondary	Best objective intracranial response rate - per-protocol	Evaluation of brain metastases response on per-protocol population, according to RECIST v1.1 criteria (or modified RECIST), by MRI with centralized reading	at 6 weeks and 3 months
Secondary	Evaluation of the intracranial response rate	Evaluation of brain metastases response, according to RANO, to RECIST v1.1 criteria, and as the evolution of the sum of longest diameters (for all metastases with a sum of diameters > 1cm), by MRI, at 6 weeks and 3, 6, 9 and 12 months	for 12 months
Secondary	Evaluation of individual metastasis response	Evaluation of individual brain metastasis response, for all metastases with the sum of diameters > 1cm, by MRI rate	at 6 weeks and 3, 6, 9 and 12 months
Secondary	Intracranial progression-free survival	Evaluation of the time between the start of the treatment and the occurence of intracranial progression or neuriologic death	at 12 months
Secondary	Intracranial progression-free survival, brain survival	Death related to brain metastases progression	at 12 months
Secondary	Overall survival	Death	at 12 months
Secondary	Change in steroid dependence	Reporting of daily steroid dose	at 6 weeks and 3, 6, 9 and 12 months
Secondary	Incidence of adverse events	Reporting of adverse events by type, frequency and severity for both treatments (WBRT and AGuIX® + WBRT)	at 6 weeks and 3, 6, 9 and 12 months
Secondary	MRI study of the distribution of the product in brain metastases	MRI evaluation of contrast enhancement at D0 after AGuIX® injection	Day 0