SMART Trial: Cognitive Sparing Brain Radiotherapy for Multiple Brain Metastases

NCT07505979 | Not Yet Recruiting Phase 2 DMC

• 1 other identifier: 202510164MIFD
• Study Type: interventional
• Target: 90
• Locations: 0 countries
• Sites: N/A

Brief Summary

The goal of this phase II randomized trial is to determine if Stereotactic Radiosurgery (SRS) or Cognitive Sparing WBRT (CS-WBRT) better preserves neurocognitive function than standard Hippocampal Avoidance WBRT (HA-WBRT) in patients with multiple brain metastases ( $\\ge6$ lesions). The main questions it aims to answer are:

• Which treatment best preserves cognitive function (memory and executive tasks) at 6 months post-intervention?
• Can sparing the left hippocampus and corpus callosum (CS-WBRT) or using focal SRS reduce cognitive decline compared to bilateral sparing? Comparison Groups Researchers will compare three arms to evaluate their impact on cognition and disease control:
• Arm A (SRS): Focal high-dose radiation (15-20 Gy in 1 fraction) to intracranial lesions.
• Arm B (CS-WBRT): Whole-brain radiation (30 Gy in 10 fractions) sparing the left hippocampus and corpus callosum plus Memantine.
• Arm C (HA-WBRT): Whole-brain radiation (30 Gy in 10 fractions) with bilateral hippocampal avoidance plus Memantine. Participant Tasks Participants will:
• Complete neurocognitive and neuropsychological tests (HVLT-R, TMT, COWAT, CANTAB) at baseline and follow-up.
• Undergo contrast-enhanced brain MRI for planning and tracking tumor progression.
• Take Memantine HCL daily for 24 weeks if assigned to the WBRT arms (B or C).
• Provide blood samples for biomarker and genetic analysis (e.g., APOE, Tau).
• Undergo olfactory function testing and complete quality-of-life questionnaires.

Conditions

Brain Metastases From Solid Tumors

Keywords

Brain metastases; Cognitive Preservation; Hippocampal Avoidance Whole Brain Radiotherapy; Stereotactic Radiosurgery

Outcome Measures

Primary Outcomes (1)

• Preservation in neurocognitive function at 6 months after the start of brain radiotherapy for patients with multiple brain metastases

  The primary endpoint is defined as the z-scores of changes in HVLT-R memory score, and CANTAB® tasks at 6 months after the start of cranial radiotherapy or radiosurgery for multiple brain metastases. Investigators hypothesize that at least one of the three treatment arms will outperform the others in preserving neurocognitive function at 6 months

  From enrollment to 6 months after the start of brain radiotherapy

Study Arms (3)

SRS

EXPERIMENTAL

Radiation: SRS

CS-WBRT

EXPERIMENTAL

Radiation: CS-WBRT

HA-WBRT

ACTIVE COMPARATOR

Radiation: HA-WBRT

Interventions

CS-WBRT RADIATION

Conformal Whole Brain Radiotherapy 3000 cGy in 10 fractions with Left Hippocampal Avoidance \& Corpus Callosum Sparing using RapidArc

CS-WBRT

HA-WBRT RADIATION

Conformal Whole Brain Radiotherapy 3000 cGy in 10 fractions with Bilateral Hippocampal Avoidance using RapidArc

HA-WBRT

SRS RADIATION

Focal high-dose radiation (15-20 Gy in 1 fraction) to intracranial lesions

SRS

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with a histologic diagnosis of non-hematopoietic malignancy and radiographic evidence of brain metastases
• Patients with brain metastasis outside a 5-mm margin around either hippocampus or corpus callosum on gadolinium contrast-enhanced MRI obtained within 30 days prior to registration
• Patients with 6 or more active or progressive brain metastases that have not been treated by radiotherapy or radiosurgery
• No evidence of diffuse leptomeningeal metastasis on gadolinium-enhanced MRI within 30 days prior registration
• Age ≥ 18 years
• Karnofsky Performance Status ≥ 60%
• Life expectancy ≥ 6 months.
• Women of childbearing potential and male participants must practice adequate contraception
• Patients must be able to comply with the study protocol and follow-up schedules and provide study-specific informed consent

You may not qualify if:

• Prior radiotherapy to brain or radiosurgery to \> 5 intracranial metastatic lesion(s)
• Clinical diagnosis of symptomatic leptomeningeal metastsases
• Contraindication to MR imaging such as implanted metal devices or foreign bodies, severe claustrophobia
• Severe, active comorbidities which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and adverse events of the protocol, or limit compliance with study requirements, defined as follows:
• Uncontrolled active infection requiring intravenous antibiotics at the time of registration
• Transmural myocardial infarction ≤ 6 months prior to registration
• Unstable angina or congestive heart failure requiring hospitalization ≤ 6 months prior to registration
• Life-threatening uncontrolled clinically significant cardiac arrhythmias
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
• Uncontrolled psychiatric disorder
• Will receive any other investigation agent or chemotherapy during cranial radiotherapy or radiosurgery
• Current use of Memantine HCL or Allergy to Memantine HCL
• Pregnant or breast-feeding women

Sponsors & Collaborators

• National Taiwan University Hospital: lead

MeSH Terms

Conditions

Brain Neoplasms

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Central Study Contacts

Wen-Chi Yang, MD, PhD

CONTACT

+886912545812; claireds23@ntuh.gov.tw

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 24, 2026
• First Posted: April 1, 2026
• Study Start: April 1, 2026
• Primary Completion (Estimated): April 1, 2029
• Study Completion (Estimated): April 1, 2031
• Last Updated: April 13, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share