Clinical trial NCT03818386: Radiotherapy of Multiple Brain Metastases Using AGuIX®
Official title: Radiotherapy of Multiple Brain Metastases Using AGuIX® Gadolinium-chelated Polysiloxane Based Nanoparticles: a Prospective Randomized Phase II Clinical Trial.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Brain Metastases, Adult
Radiotherapy
Keywords: gadolinium nanoparticles
AGuIX
Lead sponsor: University Hospital, Grenoble
Sponsor class: OTHER
Collaborators: name: NH TherAguix SAS
First posted: 2019-01-28
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective Randomized Open Blinded Endpoint phase II clinical trial.
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Best objective intracranial response rate - intent-to-treat
timeFrame: at 6 weeks
measure: Best objective intracranial response rate - intent-to-treat
timeFrame: at 3 months
Secondary outcomes:
measure: Evaluation of the quality of life
timeFrame: at D0, 6 weeks, 3, 6, 9, 12 months
measure: Evaluation of the quality of life
timeFrame: at day 0, 6 weeks, 3, 6, 9, 12 months
measure: Neurocognitive evaluation
timeFrame: at Day 0, 6 weeks, 3, 6, 9, 12 months
measure: Best objective intracranial response rate - per-protocol
timeFrame: at 6 weeks and 3 months
measure: Evaluation of the intracranial response rate
timeFrame: for 12 months
measure: Evaluation of individual metastasis response
timeFrame: at 6 weeks and 3, 6, 9 and 12 months
measure: Intracranial progression-free survival
timeFrame: at 12 months
measure: Intracranial progression-free survival, brain survival
timeFrame: at 12 months
measure: Overall survival
timeFrame: at 12 months
measure: Change in steroid dependence
timeFrame: at 6 weeks and 3, 6, 9 and 12 months
measure: Incidence of adverse events
timeFrame: at 6 weeks and 3, 6, 9 and 12 months
measure: MRI study of the distribution of the product in brain metastases
timeFrame: Day 0
Other outcomes:
Locations:
city: Montpellier
country: France
facility: Institut Régional du Cancer
state: Occitanie
city: Toulouse
country: France
facility: Institut Claudius Regaud Institut Universitaire du Cancer Toulouse Oncopole Radiothérapie
state: Occitanie
city: Lyon
country: France
facility: Centre Leon Berard Lyon
state: Rhones Alpes
city: Annecy
country: France
facility: Centre Hospitalier Annecy Genevois
state: Rhones-Alpes
city: Grenoble
country: France
facility: Centre Hospitalier Universitaire Grenoble-Alpes
state: Rhones-Alpes
city: Bordeaux
country: France
facility: CRLCC - Institut Bergonié
city: Caen
country: France
facility: Crlcc Francois Baclesse
city: Dijon
country: France
facility: Centre Georges François Leclerc
city: Lyon
country: France
facility: Hospices Civils de Lyon-Hôpital Lyon Sud
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
city: Paris
country: France
facility: La Pitié Salpêtrière - Charles Foix
city: Saint-Cloud
country: France
facility: Institut Curie Saint Cloud
city: Strasbourg
country: France
facility: Crlcc Paul Strauss
city: Vandœuvre-lès-Nancy
country: France
facility: Institut de Cancérologie de Lorraine ALEXIS VAUTRIN
Study officials:
affiliation: University Hospital, Grenoble
name: Camille VERRY, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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.
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.