UNIty-Based MR-Linac Guided Adaptive RadioThErapy for High GraDe Glioma-4 (UNITED-4)

UNIty-Based MR-Linac Guided Adaptive RadioThErapy for High GraDe Glioma-4 (UNITED-4): Prospective Evaluation of FLAIR-Guided Clinical Target Volume Reduction

This study builds on the results of prior studies (UNITED and UNITED-3). The goal of UNITED-4 is to test whether an adaptive radiation therapy (RT) therapy approach ('dose painting'), with reduced margins, impacts approach in participants with glioblastoma impacts local control compared to standard non-adaptive RT approach. The main questions of the study are to see how this adaptive RT approach with reduced margins compares to standard RT in terms of:

• Local control
• Overall and progression-free survival
• Patterns of failure
• Toxicity, Neurological Function, and Quality of Life
• Longitudinal imaging features

Study Overview

• Status: Recruiting
• Conditions: Astrocytoma, Grade IV; Glioblastoma (GBM)
• Intervention / Treatment: Radiation: Dose painting + Reduced Margins

Detailed Description

The UNITED-4 study is for people diagnosed with glioblastoma (GBM) or other high-grade (aggressive) brain tumors. These tumors are typically treated with radiation therapy combined with a chemotherapy agent called temozolomide. Standard radiation for these tumours uses a wide margin around the tumor to ensure that all areas potentially at risk for the presence of cancer cells are targeted, but this approach can also damage healthy brain tissue.

The UNITED-4 trial uses a new machine called an MR-Linac, which combines a radiation machine with an magnetic resonance imaging (MRI) scanner, allowing doctors to take daily images during treatment and adjust the radiation plan in real-time. This study will personalize treatment based on fluid-attenuated inversion recovery (FLAIR) MRI imaging that shows where cancer cells might be spreading while using smaller treatment margins to protect more of the normal brain. Patients will receive either 30 treatments over 6 weeks or 15 treatments over 3 weeks, with different radiation doses delivered simultaneously to high-risk areas (tumour) and lower-risk areas (normal brain). The goal of this study is to determine if this approach maintains cancer control while potentially reducing side effects and improving quality of life compared to standard treatments. Risks include radiation side effects (expected to be no worse than standard treatment) and a possibility of tumor recurrence at treatment edges.

The study will enroll 60 patients over 24 months at Sunnybrook Health Sciences Centre.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Hanbo Chen, MD; Phone Number: 416-480-6100; Email: hanbo.chen@sunnybrook.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N3M5
      • Recruiting
      • Sunnybrook Health Sciences Centre - Odette Cancer Centre
      • Contact: Aimee Theriault; Phone Number: 67364 416-480-5000; Email: aimee.theriault@sunnybrook.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histopathologically confirmed, based on biopsy or surgical resection, glioblastoma or WHO grade 4 astrocytoma (IDH wild type or mutant)
• Deemed clinically appropriate for concurrent chemoradiotherapy (with temozolomide) with definitive/radical intent
• Biopsy or surgical resection performed ≤ 12 weeks prior to study entry
• Expected survival ≥ 12 weeks
• ECOG performance status of 0, 1 or 2
• Sufficient estimated glomerular filtration rate (eGFR) of ≥ 30 mL/ min/1.73 m2 to allow administration of gadolinium-based contrast agent; patients with eGFR < 30 mL/min/1.73 m2 not on dialysis may be allowed on the study after discussion of risks and benefits and approval by study neuroradiologist(s)
• Completed written informed consent
• Patient must be accessible for treatment and follow-up
• Patients with multifocal or multicentric disease will be allowed per the discretion of the radiation oncologist

Exclusion Criteria:

• Contraindications to MRI examination as per standard MRI screening policy
• Contraindication to Gadolinium-based contrast media
• Enhancing disease involving any part of the brainstem on post-gadolinium T1-weighted MRI imaging for patients being treated using the short-course 15-fraction regimen
• Inability to lie flat in a supine position for at least 30 minutes
• Inability to tolerate immobilization in a head thermoplastic mask
• Patients > 140 kg and/or a circumference > 60 cm (MRI scanner weight and bore size limits)
• Prior therapeutic cranial irradiation
• Leptomeningeal dissemination of disease
• History of other malignancies with the exception of adequately treated non-melanoma skin cancer, or curatively treated other solid tumours with no evidence of disease for ≥ 2 years
• Patients with any condition (e.g. psychological, geographical, etc.) that does not permit compliance with the protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Adaptive RT (Dose Painting); Participants in this arm will have radiation (with reduced margins) delivered using a dose painting approach	Radiation: Dose painting + Reduced Margins; Reduced margins using a dose painting approach

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Disease worsening at 6 months	From RT start to 6 months after RT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival		Throughout study participation, anticipated 0-25 months
Type of progression	Whether the progression occurred at local, marginal, or distant location	Throughout study participation, anticipated 0-25 months
Number of participants with RT-related adverse events as assessed by CTCAE v5.0	Acute (within 3 months of RT completion) and late (> 3 months of RT completion) effects will be assessed	Throughout study participation, anticipated 0-25 months
Neurological Function	Will be assessed by your treating doctor, using the Neurological Assessment in Neuro-Oncology (NANO) scale	Throughout study participation, anticipated 0-25 months
Imaging features as correlates of treatment outcomes		Throughout study participation, anticipated 0-25 months
Changes in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)	This is one of the questionnaires that will be used to qualitatively assess the changes to your quality of life (neurological function, symptoms, and overall status), during your participation on the study. A higher scale score represents a higher response level with regards to the measured item.	Throughout study participation, anticipated 0-25 months
Changes in the European Organisation for Research and Treatment of Cancer Brain Cancer Module (EORTC QLQ-BN20)	This questionnaire is used together with QLQ-C30 to qualitatively assess changes in your symptoms during your participation on the study. A higher scale score represents more, or more severe, symptoms.	Throughout study participation, anticipated 0-25 months

Collaborators and Investigators

• Sponsor: Sunnybrook Health Sciences Centre

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2025
• Primary Completion (Estimated): October 1, 2029
• Study Completion (Estimated): October 1, 2030

Study Registration Dates

• First Submitted: November 17, 2025
• First Submitted That Met QC Criteria: March 6, 2026
• First Posted (Actual): March 9, 2026

Study Record Updates

• Last Update Posted (Actual): March 9, 2026
• Last Update Submitted That Met QC Criteria: March 6, 2026
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma
• Other Study ID Numbers: UNITED-4

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No