Radiosurgery Dose Reduction for Brain Metastases on Immunotherapy (RADREMI): A Prospective Pilot Study (RADREMI)

This study will evaluate the rate of radiation necrosis following treatment with immune checkpoint inhibitor (ICI) treatment and radiation therapy in subjects with metastatic brain cancer. Subjects will be treated with the standard of care immunotherapy followed by radiation therapy via stereotactic radiosurgery at a reduced dose.

Study Overview

• Status: Terminated
• Conditions: Brain Cancer; Brain Tumor; Brain Metastases
• Intervention / Treatment: Radiation: Reduced Dose SRS

Detailed Description

This is a prospective, single arm, pilot study to determine the symptomatic radiation necrosis rate at 6 months utilizing dose-reduced stereotactic radiosurgery with immunotherapy for subjects with a diagnosis of 1-10 brain metastases from MRI and tissue diagnosis of primary malignancy.

Primary end-point is 6 month symptomatic radiation necrosis, defined as a 6-month rate of clinical symptomatology requiring steroid administration (i.e. Decadron) and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis. Follow-up MRIs will be fused with the planning scan for this assessment.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health Hospital
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Methodist Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Sciences

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Brain MRI-confirmed 1-10 solid tumor brain metastases
2. Biopsy-confirmed primary malignancy
3. ds-GPA estimated median survival of at least 6 months, for histologies not included in the ds-GPA, publications or noted online at brainmetgpa.com, the PI will use either published or validated data or their best clinical judgment to determine the patient's expected survival
4. Stereotactic radiosurgery candidate per treating Radiation Oncologist
5. ≥ 18 years old at the time of informed consent
6. Ability to provide written informed consent and HIPAA (Health Insurance Portability and Accountability Act) authorization.
7. ALC > 800/ul (Ku et al., 2010)
8. Patients currently on cytotoxic chemotherapy are eligible
9. Patients receiving ICI up to 30 days prior to delivery of SRS are eligible
10. Patients having undergone operative resection for metastatic brain disease within 30 days of immune checkpoint inhibitor (ICI) administration are eligible.

Exclusion Criteria:

1. Major medical illnesses or psychiatric impairments, which in the investigator's opinion will prevent administration or completion of the protocol therapy and/or interfere with follow-up
2. Patients unable to receive MRI Brain
3. Patients with more than 10 brain metastases on MRI Brain imaging
4. Any lesion > 4 centimeter maximum diameter
5. Total volume of metastatic disease more than 30 cubic centimeters
6. Previous whole brain radiation therapy
7. For Cohort 1: Previous stereotactic radiosurgery where the 50% isodose line overlaps with current treatment field
8. For Cohort 2: Patients whose treatment will have a dose overlap within the target from prior treatments of 20% or greater
9. Already receiving chronic dexamethasone (chronic = > 2 weeks) prior to SRS
10. Not a radiosurgical candidate per Radiation Oncology discretion
11. Existing autoimmune disease
12. Patients who have an unknown primary cancer
13. Histology not amenable for SRS (i.e. lymphoma). (Small Cell Lung Cancer IS amenable.)

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: Reduced Dose Stereotactic Radiosurgery; Subjects will receive one stereotactic radiosurgery (SRS) treatment at a reduced dose based on the brain tumor size concurrently with their standard of care immunotherapy. Subjects will undergo follow up with clinical exams and brain MRI scans at 1, 3, 6, 9, and 12 months post SRS treatment	Radiation: Reduced Dose SRS; Subjects will receive SRS treatment at a reduced dose based on the brain tumor size

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptomatic Radiation Necrosis Proportion	The observed proportion of evaluable patients with symptomatic radiation necrosis by 6-months. Symptomatic radiation necrosis was defined as the rate of clinical symptomatology requiring steroid administration (i.e. Decadron) and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptomatic Radiation Necrosis Rate	Symptomatic radiation necrosis was defined as the rate of clinical symptomatology requiring steroid administration (i.e. Decadron) and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis. This measure details the estimated 6-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to the presence of symptomatic radiation necrosis was calculated. Patients who did not experience the outcome were censored at the date last known alive or at the date of death if they expired.	6 months
Symptomatic Radiation Necrosis Rate	Symptomatic radiation necrosis was defined as the rate of clinical symptomatology requiring steroid administration (i.e. Decadron) and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to the presence of symptomatic radiation necrosis was calculated. Patients who did not experience the outcome were censored at the date last known alive or at the date of death if they expired.	12 months
Symptomatic Radiation Necrosis by SRS Group	Symptomatic radiation necrosis was defined as the rate of clinical symptomatology requiring steroid administration (i.e. Decadron) and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to the presence of symptomatic radiation necrosis was calculated. Patients who did not experience the outcome were censored at the date last known alive or at the date of death if they expired.	12 months
Symptomatic Radiation Necrosis by Brain Metastases Group	Symptomatic radiation necrosis was defined as the rate of clinical symptomatology requiring steroid administration (i.e. Decadron) and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to the presence of symptomatic radiation necrosis was calculated. Patients who did not experience the outcome were censored at the date last known alive or at the date of death if they expired.	12 months
Symptomatic Radiation Necrosis by Immune Checkpoint Inhibitor (ICI) Group	Symptomatic radiation necrosis was defined as the rate of clinical symptomatology requiring steroid administration (i.e. Decadron) and/or operative intervention concomitant with advanced and routine brain imaging findings consistent with radiation necrosis. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to the presence of symptomatic radiation necrosis was calculated. Ppatients who did not experience the outcome were censored at the date last known alive or at the date of death if they expired.	12 months
Local Control	Local control was defined as the rate of any new, recurrent, or progressing tumor as defined by Response Assessment in Neuro-oncology (RANO) criteria within the planning target volume. This measure details the estimated 6-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to local failure was calculated. Patients who did not experience local failure were censored at the date last known alive or at the date of death if they expired.	6 months
Local Control	Local control was defined as the rate of any new, recurrent, or progressing tumor as defined by Response Assessment in Neuro-oncology (RANO) criteria within the planning target volume. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to local failure was calculated. Patients who did not experience local failure were censored at the date last known alive or at the date of death if they expired.	12 months
Local Control by SRS Group	Local control was defined as the rate of any new, recurrent, or progressing tumor as defined by Response Assessment in Neuro-oncology (RANO) criteria within the planning target volume. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to local failure was calculated. Patients who did not experience local failure were censored at the date last known alive or at the date of death if they expired.	12 months
Local Control by Brain Metastases Group	Local control was defined as the rate of any new, recurrent, or progressing tumor as defined by Response Assessment in Neuro-oncology (RANO) criteria within the planning target volume. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to local failure was calculated. Patients who did not experience local failure were censored at the date last known alive or at the date of death if they expired.	12 months
Local Control by Immune Checkpoint Inhibitor (ICI) Group	Local control was defined as the rate of any new, recurrent, or progressing tumor as defined by Response Assessment in Neuro-oncology (RANO) criteria within the planning target volume. This measure details the estimated 12-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to local failure was calculated. Patients who did not experience local failure were censored at the date last known alive or at the date of death if they expired.	12 months
Radiographic Radiation Necrosis Rate	Radiographic radiation necrosis was defined as brain imaging findings on magnetic resonance imaging (MRI), magnetic resonance (MR) perfusion, MR Spectroscopy, and/or positron emission tomography (PET) imaging consistent with radiation necrosis. This measure details the estimated 6-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to the presence of radiographic radiation necrosis was calculated. Patients who did not experience the outcome were censored at the date last known alive or at the date of death if they expired.	6 months
Radiographic Radiation Necrosis Rate	Radiographic radiation necrosis was defined as brain imaging findings on magnetic resonance imaging (MRI), magnetic resonance (MR) perfusion, MR Spectroscopy, and/or positron emission tomography (PET) imaging consistent with radiation necrosis. This measure details the estimated 6-month survival and associated 95% confidence interval from the Kaplan Meier method. The time from treatment start to the presence of radiographic radiation necrosis was calculated. Patients who did not experience the outcome were censored at the date last known alive or at the date of death if they expired.	12 months

Collaborators and Investigators

• Sponsor: Indiana University
• Investigators: Principal Investigator: Kevin Shiue, MD, Indiana University

Publications and helpful links

General Publications

• McClelland S 3rd, Lautenschlaeger T, Zang Y, Hanna NH, Shiue K, Kamer AP, Agrawal N, Ellsworth SG, Rhome RM, Watson GA. Radiosurgery dose reduction for brain metastases on immunotherapy (RADREMI): A prospective phase I study protocol. Rep Pract Oncol Radiother. 2020 Jul-Aug;25(4):500-506. doi: 10.1016/j.rpor.2020.04.007. Epub 2020 Apr 23.

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2019
• Primary Completion (Actual): July 25, 2023
• Study Completion (Actual): February 20, 2024

Study Registration Dates

• First Submitted: August 5, 2019
• First Submitted That Met QC Criteria: August 5, 2019
• First Posted (Actual): August 7, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 23, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Radiation; Stereotactic Radiosurgery; Immune therapy
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Neoplasms by Site; Neoplasms; Neoplastic Processes; Nervous System Neoplasms; Central Nervous System Neoplasms; Neoplasm Metastasis; Brain Neoplasms
• Other Study ID Numbers: RAON-IIR-IUSCC-0710

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No