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

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.

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