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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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SRS, Brain Cancer, Brain Metastases, Melanoma, Lung Cancer, Breast Cancer, HER2-positive Breast Cancer, Colorectal Cancer, Gastrointestinal Cancer, SRT, Whole Brain Radiation, Stereotactic Radiation, AGuIX, Nanoparticle, Cystic, Brain Tumor

Intervention / Treatment
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* Radiation: Stereotactic Radiation
* Drug: AGuIX gadolinium-based nanoparticles
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stereotactic Radiation plus AGuIX gadolinium-based nanoparticles<br>Randomly assigned participants will receive: AGuIX gadolinium-based nanoparticles 3-5 days before radiation is initiated AGuIX gadolinium-based up to 2x during radiation, depending on standard of care radiation treatment. If standard of care radiation treatment involves only one day of radiation, participant will receive AGuIX gadolinium-based nanoparticles on the day of radiation. If standard of care radiation treatment involves 5 or 6 days of radiation, participant will receive AGuIX gadolinium-based nanoparticles two-times (2x) in total, on the first and third day of radiation. | Radiation: Stereotactic Radiation<br>* Focused radiation beams to treat tumors<br>* Other names: Stereotactic Radiotherapy;Drug: AGuIX gadolinium-based nanoparticles<br>* Intravenous injection<br>|
| Experimental: Stereotactic Radiation plus placebo<br>Randomly assigned participants will receive: Placebo 3-5 days before radiation is initiated Placebo up to 2x during radiation, depending on standard of care radiation treatment. If standard of care radiation treatment involves only one day of radiation participant will receive Placebo on the day of radiation. If standard of care radiation treatment involves 5 or 6 days of radiation participant will receive Placebo two-times (2x) in total, on the first and third day of radiation. | Radiation: Stereotactic Radiation<br>* Focused radiation beams to treat tumors<br>* Other names: Stereotactic Radiotherapy;Other: Placebo<br>* Intravenous infusion<br>* Other names: Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brain Cancer, Brain Metastases, Melanoma, Lung Cancer, Breast Cancer, HER2-positive Breast Cancer, Colorectal Cancer, Gastrointestinal Cancer, SRS, SRT, Whole brain radiation, Stereotactic Radiation, AGuIX, Nanoparticle, Cystic, Brain Tumor