Trial: Stereotactic Brain-directed Radiation W…

Trial Details

Sponsor: Dana-Farber Cancer Institute (other)

Phase: 2

Start date: Sept. 15, 2021

Planned enrollment: 134

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® nanoparticles are gadolinium-based theranostic agents designed to enhance the efficacy of radiotherapy by acting as radiosensitizers and providing improved magnetic resonance imaging (MRI) contrast. They are under investigation for treating various cancers, including brain metastases, glioblastoma, and cervical cancer.

Mechanism of Action

AGuIX® nanoparticles accumulate selectively in tumor tissues due to the enhanced permeability and retention (EPR) effect. This accumulation allows for enhanced MRI visualization and increases the local radiation dose during radiotherapy, thereby improving tumor control. The nanoparticles are rapidly eliminated via renal excretion, minimizing systemic exposure. (pubmed.ncbi.nlm.nih.gov)

Efficacy

Brain Metastases:

In the phase I NANO-RAD trial, 15 patients with multiple brain metastases received escalating doses of AGuIX® (15 to 100 mg/kg) combined with whole-brain radiotherapy (WBRT). Thirteen of 14 evaluable patients experienced clinical benefits, including tumor stabilization or reduction. MRI analyses showed a significant correlation between contrast enhancement and tumor response, supporting the radiosensitizing effect of AGuIX®. (pubmed.ncbi.nlm.nih.gov)

Glioblastoma:

The phase I/II NANO-GBM trial evaluated AGuIX® in combination with radiotherapy and temozolomide in newly diagnosed glioblastoma patients. In the phase I portion, eight patients received up to 100 mg/kg of AGuIX®. The recommended phase II dose was established at 100 mg/kg, with widespread nanoparticle distribution observed throughout glioblastoma tissues. (pubmed.ncbi.nlm.nih.gov)

Cervical Cancer:

A phase I clinical trial involving 12 patients with locally advanced cervical cancer demonstrated that AGuIX® nanoparticles, when combined with chemoradiation and brachytherapy, were safe and well-tolerated. All patients achieved complete remission of the primary tumor, with only one instance of distant tumor recurrence, suggesting a potential improvement over historical recurrence rates. (globenewswire.com)

Safety

Across multiple clinical trials, AGuIX® has exhibited a favorable safety profile. In the NANO-RAD trial, no dose-limiting toxicities were observed up to 100 mg/kg. Reported adverse events were primarily mild to moderate, including headaches, nausea, and increased intracranial pressure. (pubmed.ncbi.nlm.nih.gov) Similarly, in the NANO-GBM trial, only one dose-limiting toxicity (grade 3 lymphopenia) was reported, which was attributed to temozolomide rather than AGuIX®. (pubmed.ncbi.nlm.nih.gov)

More Resources

Trial ID: NCT04899908

More trial details at ClinicalTrials.gov

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HealthScout AI Analysis

Goal: To assess whether AGuIX gadolinium-based nanoparticles enhance the efficacy of stereotactic radiation in patients with brain metastases that are at higher risk for local recurrence with radiation alone.

Patients: Adult patients (≥18 years) with solid tumor malignancy and at least one measurable brain metastasis (≥5 mm), meeting high-risk criteria such as melanoma refractory to immunotherapy, gastrointestinal primaries, HER2-positive breast cancer, cystic metastases, large metastases (≥2 cm), or local recurrence after prior brain radiation. Patients must have a KPS ≥70, preserved renal function, and an estimated survival of at least 3 months.

Design: Double-blind, randomized, placebo-controlled, phase II trial. Patients are randomized to receive stereotactic radiation with either AGuIX nanoparticles or placebo. Planned enrollment is 134 patients, with study procedures including eligibility screening, treatment, and longitudinal follow up.

Treatments: The experimental arm receives stereotactic radiation plus intravenous AGuIX gadolinium-based nanoparticles administered 3-5 days before and up to twice during radiation, depending on fractionation. The control arm receives stereotactic radiation with placebo on the same schedule. AGuIX nanoparticles function as radiosensitizers and MRI contrast agents; they preferentially accumulate in tumors, enhancing local radiation effects via the EPR effect. Early clinical trial data in brain metastases and other solid tumors indicate a favorable safety profile and promising evidence for improved local control. The standard arm uses stereotactic radiation, which is established for local control of brain metastases.

Outcomes: Primary outcome is local recurrence per metastasis at 6 months assessed by RANO criteria. Secondary outcomes include overall survival, progression-free survival, time to disease progression, neurologic mortality, neurocognitive function, steroid use, new brain metastases, radiation necrosis, leptomeningeal disease, salvage interventions, activities of daily living, and patient-reported quality of life, evaluated up to 12 months from enrollment.

Burden on patient: Patient burden is moderate and primarily comparable to standard care for brain metastases. The main additional procedures are intravenous administration of the investigational or placebo agent 3-5 days prior to and during radiation treatments (up to two IV infusions during radiotherapy). Safety monitoring, regular MRI scans, and neurocognitive/quality of life assessments are part of the study but represent standard follow-up for this population. There are no additional invasive procedures or intense pharmacokinetic sampling. The main burden relates to scheduling additional infusions and repeated neurocognitive testing.

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