Stereotactic Brain-directed Radiation With or Without Aguix Gadolinium-Based Nanoparticles in Brain Metastases

Breast Cancer Clinical Trial

Official title:

A Double-blind, Phase II Randomized Study of Brain-directed Stereotactic Radiation With or Without AGuIX Gadolinium-based Nanoparticles in the Management of Brain Metastases at Higher Risk of Local Recurrence With Radiation Alone

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04899908
• Other study ID #: 20-240
• Status: Recruiting
• Phase: Phase 2
• Start date: September 15, 2021
• Est. completion date: February 2026

Study information

• Verified date: September 2023
• Source: Dana-Farber Cancer Institute
• Contact: Ayal Aizer, MD, MHS
• Phone: (617) 732-7560
• Email: aaaizer[@]partners.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 134
• Est. completion date: February 2026
• Est. primary completion date: February 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Brain Cancer
• Brain Metastases
• Brain Neoplasms
• Brain Tumor
• Breast Cancer
• Breast Neoplasms
• Colorectal Cancer
• Colorectal Neoplasms
• Cystic
• Gastrointestinal Cancer
• Gastrointestinal Neoplasms
• HER2-positive Breast Cancer
• Lung Cancer
• Melanoma
• Neoplasm Metastasis
• SRS

Intervention

Radiation:
• Stereotactic Radiation
Focused radiation beams to treat tumors

Drug:
• AGuIX gadolinium-based nanoparticles
Intravenous injection

Other:
• Placebo
Intravenous infusion

Locations

Country	Name	City	State
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Dana Farber Cancer Institute	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Dana-Farber Cancer Institute	NH TherAguix SAS

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Local Recurrence	Assessed with Response Assessment in Neuro-Oncology (RANO) - Brain Metastasis Guidelines Time to local failure on a per metastasis basis will be performed using the log-rank test.	From enrollment to 6 months
Secondary	Overall Survival (OS)	Assessed with log-rank test	Time from enrollment to 12 months
Secondary	Progression-Free Survival (PFS)	Assessed with log-rank test	Time from enrollment to 12 months
Secondary	Time to Progression (TTP)	Assessed with log-rank test	Time from enrollment to 12 months
Secondary	Death due to neurologic causes	Assessed with Gray's test	From enrollment to 12 months
Secondary	Performance status	Karnofsky performance status, assessed longitudinally (longitudinal regression)	From enrollment to 12 months
Secondary	Ability to complete activities of daily living	Questionnaire - EQ-5D, assessed longitudinally (longitudinal regression)	From enrollment to 12 months
Secondary	Incidence and time to detection of new brain metastases	Assessed with log-rank test	From enrollment to 12 months
Secondary	Incidence and time to detection of radiation necrosis	Assessed with log-rank test	From enrollment to 12 months
Secondary	Incidence and time to detection of leptomeningeal disease	Assessed with log-rank test	From enrollment to 12 months
Secondary	Incidence and time to detection of progressive intracranial disease	Assessed with log-rank test	From enrollment to 12 months
Secondary	Incidence and time to detection of salvage craniotomy	Assessed with log-rank test	From enrollment to 12 months
Secondary	Incidence and time to additional radiotherapeutic treatments	Assessed with log-rank test	From enrollment to 12 months
Secondary	Incidence and time to the development of seizures	Assessed with log-rank test	From enrollment to 12 months
Secondary	Steroid use	Assessed longitudinally (longitudinal regression)	From enrollment to 12 months
Secondary	Local recurrence at one year in metastases treated radiotherapeutically	Assessed using RECIST (response evaluation criteria in solid tumors) criteria	From enrollment to 12 months
Secondary	Neurocognitive function: verbal learning and memory	Hopkins Verbal Learning Test - Revised (HVLT-R)	From enrollment to 12 months
Secondary	Neurocognitive function: visual attention and task switching	Trail Making Test Part A and B (TMT)	From enrollment to 12 months
Secondary	Neurocognitive function: verbal fluency	Controlled Word Association Test (COWAT)	From enrollment to 12 months
Secondary	Neurocognitive function: cognitive impairment	Mini Mental Status Examination (MMSE)	From enrollment to 12 months