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

• ClinicalTrials.gov Identifier: NCT04899908
• Recruitment Status: Recruiting
• First Posted: May 25, 2021
• Last Update Posted: September 25, 2023
• Sponsor: Dana-Farber Cancer Institute
• Collaborator: NH TherAguix SAS
• Information provided by (Responsible Party): Ayal Aizer, MD, Dana-Farber Cancer Institute

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
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	Radiation: Stereotactic Radiation; Drug: AGuIX gadolinium-based nanoparticles; Other: Placebo	Phase 2

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 134 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: September 15, 2021
• Estimated Primary Completion Date: February 2025
• Estimated Study Completion Date: February 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Stereotactic Radiation plus AGuIX gadolinium-based nanoparticles; 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; Focused radiation beams to treat tumors; Other Name: Stereotactic Radiotherapy; Drug: AGuIX gadolinium-based nanoparticles; Intravenous injection
Experimental: Stereotactic Radiation plus placebo; 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; Focused radiation beams to treat tumors; Other Name: Stereotactic Radiotherapy; Other: Placebo; Intravenous infusion; Other Name: Saline

Outcome Measures

Primary Outcome Measures :

1. Local Recurrence [ Time Frame: From enrollment to 6 months ]
   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.

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: Ayal Aizer, MD, MHS; (617) 732-7560; aaaizer@partners.org

Contact: Ivy Ricca, BA; 6175828927; iricca@mgb.org

Locations

United States, Massachusetts

Brigham and Women's Hospital; Recruiting

Boston, Massachusetts, United States, 02115

Contact: Ayal Aizer 617-732-7560 aaaizer@partners.org

Principal Investigator: Ayal Aizer, MD, MHS

Dana Farber Cancer Institute; Recruiting

Boston, Massachusetts, United States, 02115

Contact: Ayal Aizer, MD, MPH 617-732-7560 aaaizer@partners.org

Principal Investigator: Ayal Aizer, MD, MPH

Sponsors and Collaborators

Dana-Farber Cancer Institute

NH TherAguix SAS

Investigators

• Principal Investigator: Ayal Aizer, MD, MHS; Brigham and Women's Hospital

More Information

• Responsible Party: Ayal Aizer, MD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT04899908
• Other Study ID Numbers: 20-240
• First Posted: May 25, 2021
• Last Update Posted: September 25, 2023
• Last Verified: September 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Ayal Aizer, MD, Dana-Farber Cancer Institute:

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

Additional relevant MeSH terms:

Breast Neoplasms; Colorectal Neoplasms; Melanoma; Neoplasm Metastasis; Brain Neoplasms; Gastrointestinal Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Intestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplastic Processes; Pathologic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases