Trial: Stereotactic Brain-directed Radiation W…

Trial Details

Sponsor: Dana-Farber Cancer Institute (other)

Phase: 2

Start date: Sept. 15, 2021

Planned enrollment: 134

Trial ID: NCT04899908

More trial details at ClinicalTrials.gov

Show Summary from Sponsor

The purpose of this study is to determine whether AGuIX (Activation and Guidance of Irradiation by X-ray) gadolinium-based nanoparticles make radiation work more effectively in the treatment of patients with brain metastases that are more difficult to control with stereotactic radiation alone.

More details:

This research study is a double-blind, randomized phase II clinical trial of brain-directed stereotactic radiation with or without AGuIX (Activation and Guidance of Irradiation by X-ray) gadolinium-based nanoparticles in the management of brain metastases at higher-risk of local recurrence with radiation alone. The study agent (AGuIX gadolinium-based nanoparticles) has two main parts. The first is gadolinium, also known as "contrast," which is typically injected into a vein during a MRI scan. The second part is a nanoparticle (linked to the gadolinium) that may make focused radiation work more effectively. The AGuIX gadolinium-based nanoparticles are deposited within the brain metastases via the bloodstream and then the brain metastases are radiated. The U.S. Food and Drug Administration (FDA) has not approved AGuIX gadolinium-based nanoparticles as a treatment for any disease. AGuIX gadolinium-based nanoparticles have been tested in other studies for safety and efficacy in patients with brain metastases who are also receiving radiation. This study seeks to determine whether AGuIX gadolinium-based nanoparticles improve outcomes relative to placebo.Participants will be "randomized" into one of the study groups: * Group A: Radiation plus AGuIX gadolinium-based nanoparticles * Group B: Radiation plus placebo The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. NH TherAguix, the manufacturer of the AGuIX gadolinium-based nanoparticles, is supporting this research study by providing the AGuIX gadolinium-based nanoparticles that will be evaluated in this study. NH TherAguix is also covering the cost of the study. It is expected that about 134 people will take part in this research study.

Investigational Drug AI Analysis

Show for: AGuIX (AGuIX® nanoparticles)

Overview

AGuIX (Activation and Guidance of Irradiation by X‑rays) are ultrasmall, gadolinium-chelated polysiloxane nanoparticles being developed as an intravenous, MRI-visible radioenhancer to be combined with radiotherapy across multiple solid tumors (brain metastases, glioblastoma, cervical cancer, pancreatic cancer, and others). As of October 7, 2025, randomized phase II trials are ongoing; completed early-phase studies have primarily established tumor uptake, imaging guidance, and a favorable safety profile. (fdaaa.trialstracker.net)

Mechanism of action

Physical/chemical: High‑Z gadolinium within AGuIX increases local energy deposition upon irradiation, producing cascades of low‑energy (Auger) electrons and reactive oxygen species that amplify DNA damage. (pmc.ncbi.nlm.nih.gov)
Biological/immunologic: Preclinical and mechanistic reviews describe enhanced apoptosis, autophagy/ferroptosis, and features of immunogenic cell death with downstream activation of dendritic and T cells. (pubmed.ncbi.nlm.nih.gov)
Tumor delivery/imaging: After IV dosing, AGuIX accumulates in tumors via EPR, provides strong T1 MRI contrast for target delineation, and is renally cleared owing to its ultrasmall size (~3 nm hydrodynamic diameter). (pubs.acs.org)

Efficacy

Early-phase, non-randomized signals (interpret with caution):

Brain metastases (phase I, NANO‑RAD; n=15; AGuIX 15–100 mg/kg + WBRT 30 Gy/10 fx): 13/14 evaluable patients had clinical benefit with stabilization or reduction of tumor volume; MRI uptake correlated with response, supporting radiosensitization. (pubmed.ncbi.nlm.nih.gov)
Locally advanced cervical cancer (phase I; n=12; AGuIX + concurrent chemoradiation and brachytherapy): all patients achieved complete remission of the primary tumor; designed as dose‑finding with no control arm. (pubmed.ncbi.nlm.nih.gov)

Ongoing randomized studies (no efficacy readouts published yet as of the date above):

Brain metastases at high risk of local failure: double‑blind phase II SRS/SRT ± AGuIX (NCT04899908; target n=134); DSMB allowed continuation after preplanned futility analysis; interim efficacy readout had been anticipated for late 2024 but results have not been posted publicly. (fdaaa.trialstracker.net)
Multiple brain metastases with WBRT: randomized phase II (NANORAD2). (essaisclic.girci-idf.fr)
Newly diagnosed glioblastoma: phase I/II (NANO‑GBM) with radiotherapy + temozolomide; phase Ib completed with RP2D set; phase II ongoing. (pubmed.ncbi.nlm.nih.gov)
Pancreatic ductal adenocarcinoma (locally advanced/unresectable): phase Ib/II (NANO‑SMART) using MR‑guided adaptive RT ± AGuIX; pancreas cohort advanced to randomized phase II in 2024. (globenewswire.com)

Safety

Across early-phase trials, AGuIX has been well tolerated:
Brain metastases phase I: no dose‑limiting toxicities (DLTs) up to 100 mg/kg; plasma half‑life ~1.3 h. (pubmed.ncbi.nlm.nih.gov)
Cervical cancer phase I: no DLTs among 12 treated patients. (pubmed.ncbi.nlm.nih.gov)
Glioblastoma phase Ib (8 patients, up to 4 injections at 100 mg/kg): only one DLT (grade 3 lymphopenia attributed to temozolomide); RP2D = 100 mg/kg. (pubmed.ncbi.nlm.nih.gov)
Ongoing brain‑metastases phase II: DSMB continuation after mid‑study futility analysis; sponsor reports no serious AGuIX‑related adverse events to date. (businesswire.com)
Biodistribution/clearance: Preclinical/clinical imaging and PK support rapid renal clearance with minimal off‑target retention, consistent with ultrasmall size and stable gadolinium chelation. (pubs.acs.org)

Pharmacokinetics and imaging guidance

Typical clinical dosing explored: 50–100 mg/kg IV, often administered shortly before radiation fractions; tumor uptake is dose‑dependent and persists for days, enabling imaging‑based target delineation and potential dose painting. (pubmed.ncbi.nlm.nih.gov)

Regulatory and development status

FDA Fast Track designation (May 30, 2024) for malignant gliomas (including GBM). (globenewswire.com)
EU orphan designation for pancreatic cancer (EMA EU/3/22/2576; Feb 24, 2022). (ema.europa.eu)

HealthScout AI Analysis

Goal: Evaluate whether adding AGuIX gadolinium-based nanoparticles to brain-directed stereotactic radiation improves local control of high-risk brain metastases compared with stereotactic radiation alone.

Patients: Adults with biopsy-proven solid tumors and at least one measurable brain metastasis ≥5 mm that is considered at higher risk for local failure with stereotactic radiation alone. Eligible high-risk categories include melanoma progressing on immunotherapy, gastrointestinal primaries, HER2-positive breast cancer, cystic metastases, lesions ≥2 cm, or locally recurrent metastases after prior stereotactic or whole-brain radiation (with additional safety constraints for previously irradiated organs at risk). Required KPS ≥70, eGFR ≥60 mL/min/1.73m2, estimated survival ≥3 months; exclusion includes inability to undergo MRI or receive gadolinium, widespread leptomeningeal disease, very high target counts, pregnancy or breastfeeding, and specific dose proximity constraints for those with prior brain radiation.

Design: Double-blind, randomized, placebo-controlled, phase II treatment study with 1:1 allocation to stereotactic radiation plus AGuIX versus stereotactic radiation plus placebo. Approximately 134 participants will be enrolled. Blinding applies to participants and treating teams.

Treatments: All participants receive standard-of-care stereotactic radiation to brain metastases. The investigational agent is AGuIX gadolinium-based nanoparticles, a theranostic gadolinium nanoparticle designed to accumulate in tumors via the EPR effect, enhance MRI contrast, and radiosensitize tumors by increasing local radiation dose deposition with rapid renal clearance. Early-phase studies in brain metastases (NANO-RAD) combined AGuIX with whole-brain radiotherapy and showed clinical benefit signals and correlation between MRI enhancement and response without dose-limiting toxicity up to 100 mg/kg. Additional early studies in glioblastoma and cervical cancer suggest favorable safety and feasibility as a radiosensitizer. In this trial, AGuIX or placebo is administered 3–5 days before radiation and then up to two additional infusions during the radiation course, aligned with 1-day or 5–6-day stereotactic regimens.

Outcomes: Primary outcome is time to local recurrence per metastasis using RANO–Brain Metastases criteria over 6 months. Secondary outcomes through 12 months include overall survival, progression-free survival, time to progression, death due to neurologic causes, longitudinal Karnofsky performance status, EQ-5D, incidence and time to new brain metastases, radiation necrosis, leptomeningeal disease, progressive intracranial disease, salvage craniotomy, additional radiotherapy, seizures, steroid use, and one-year local control by RECIST. Neurocognitive endpoints include HVLT-R, Trail Making Test A/B, COWAT, and MMSE.

Burden on patient: Moderate. Beyond standard stereotactic radiation workflows and routine MRI-based surveillance, participants undergo additional intravenous administrations of investigational product or placebo before and during radiation, requiring extra infusion visits synchronized with treatment days. Serial MRIs and neurocognitive testing (HVLT-R, TMT, COWAT, MMSE) and patient-reported outcomes (EQ-5D) add time and testing compared with routine practice. No intensive pharmacokinetic blood draws or mandatory biopsies are described, and visit frequency largely tracks typical post-SRS follow-up, keeping burden below that of early-phase dose-escalation trials but higher than standard radiation alone due to added infusions and assessments.

Last updated: Oct 2025

Eligibility

Show Criteria

Inclusion Criteria:

* Participants must have a biopsy proven solid malignancy and at least one intracranial measurable lesion spanning ≥5mm in maximal unidimensional size and radiographically consistent with or pathologically proven to be a brain metastasis AND meet one of the following additional criteria regarding the primary site or nature of the intracranial disease:

* Melanoma with intracranial growth consistent with tumor progression despite immunotherapy

* Gastrointestinal primary

* HER2 positive breast cancer (subtype assessed using most representative tissue available in opinion of enrolling clinician and/or study PI)

* Cystic metastases

* Metastases ≥2cm in maximal unidimensional size

* Locally recurrent metastases after prior stereotactic radiation

* Locally recurrent metastases after prior whole brain radiation \*Patients with metastases from melanoma, GI primaries, or HER2+ breast cancer, as well as those with cystic metastases or metastases ≥2cm in maximal unidimensional size, who have local recurrences after prior brain-directed radiation can only be treated in the strata permitting prior radiation (last two strata above)

* Age ≥18 years at diagnosis of brain metastases

* Estimated glomerular filtration rate of ≥ 60 mL/min/1.73m2

* Karnofsky performance status of at least 70 (i.e. at minimum, "cares for self" but "unable to carry on normal activity or do active work")

* Estimated survival based on extracranial disease of at least 3 months in the opinion of the enrolling clinician and/or study PI

* Ability to understand and the willingness to sign a written informed consent document

* The effects of AGuIX on the developing human fetus are unknown. For this reason, women of child-bearing potential must agree to use adequate contraception prior to study entry and for the duration of the therapeutic component of study participation

Exclusion Criteria:

* Participants who cannot undergo a brain MRI

* Participants who cannot receive gadolinium

* Participants with widespread, definitive leptomeningeal disease

* Patients requiring radiation to either \>10 targets (if naïve to whole brain radiation) or \>20 targets (if whole brain radiation has been given previously) per the discretion of the treating clinician and/or study PI

* Pregnant women are excluded from this study because of the potential deleterious effects of gadolinium on the developing fetus. Because there is an unknown but potential risk for adverse events in nursing infants, women who are breastfeeding are not eligible for this study

* In cohorts who have received prior brain-directed radiation, patients are not eligible for this study if they have active (at the time of protocol screening) brain metastases that require radiation that are in or within 1.0cm of the brainstem, eyes, optic nerves, or optic chiasm if the juxtaposed organ at risk (i.e. brainstem, eyes, optic nerves, or optic chiasm) has previously received either \>6.0 Gy in a single fraction or, if prior radiation was fractionated, a cumulative dose in 2.0 Gy equivalents, using an alpha/beta ratio of 2, of \>40.0 Gy. In addition, all patients who have had prior brain-directed radiation, regardless of technique/dose/fractionation, are not eligible for the study until written approval is provided by the study/site PI

Sites (2)

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Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

[email protected] / 617-732-7560

Status: Recruiting

Dana Farber Cancer Institute