Single vs Multi-fraction SRS Patients on Immunotherapy

Study Overview
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Brief Summary
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This study is meant to compare different surgical approaches to brain cancer.

Official Title
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MIGRAINE: Randomized trIal of Single Versus Multifraction Radiosurgery on Immunotherapy

Conditions
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Brain Cancer, Brain Metastases

Intervention / Treatment
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* Radiation: Radiosurgery Single Treatment
* Radiation: Radiosurgery Three Treatments


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: i. Adult patients (≥ 18 years old) with an ECOG Performance Status 0-2 and a life expectancy of 3 months or more. ii. Histologically confirmed systemic malignancy with gadolinium contrast-enhanced MRI scan demonstrating 1-10 newly diagnosed intraparenchymal brain metastases. iii. Well-circumscribed, measureable intraparenchymal brain metastasis(s) with maximum tumor diameter ≤3.0 cm. If multiple metastases are present, the other(s) must not exceed 3.0 cm in maximum diameter. At least one metastasis must be ≥ 0.5 cm in maximum diameter to be considered measurable disease. iv. Negative urine or serum pregnancy test done ≤ 21 days prior to CT simulation, for women of child bearing potential only. v. Ability to understand and willingness to sign a written informed consent document. vi. Must have received immunotherapy (PD-1/PD-L1 and/or CTLA-4 inhibitor(s)) within the past 6 months or plan on receiving immunotherapy within the next 1 month. vii. Must have a Gustave Roussy Immune Score (GRIm-Score) of 0 or 1 (neutrophil-to-lymphocyte ratio > 6 = 1 point, LDH > Upper Limit of Normal = 1 point, and Albumin < 3.5 g/dL = 1 point). Exclusion Criteria: i. Diagnosis of germ cell tumor or hematologic malignancy. ii. Metastases in the brain stem, midbrain, pons, medulla, or within 7 mm of the optic apparatus (optic nerves, chiasm and optic tracts). iii. Diagnosis of leptomeningeal disease. iv. Prior SRS to an immediately adjacent lesion(s) of interest or to the current lesion(s) of interest. v. Prior history of pseudoprogression or radionecrosis from cranial radiotherapy. vi. A neurosurgical resection cavity deemed too large by the radiation oncologist to be treated with a single fraction of stereotactic radiosurgery. vii. Contraindications to gadolinium contrast-enhanced MRI (eg, non-compatible pacemaker, eGFR <30, gadolinium allergy). viii. A Gustave Roussy Immune Score (GRIm-Score) > 1 (neutrophil-to-lymphocyte ratio > 6 = 1 point, LDH > Upper Limit of Normal = 1 point, and Albumin < 3.5 g/dL = 1 point).

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br> | Radiation: Radiosurgery Three Treatments<br>* Multi-fraction SRS. Three small doses done on each brain tumor. 27 Gy in 3 fractions in the multi-fraction group<br>* Other names: SRS;|
| Active Comparator: ARM B<br> | Radiation: Radiosurgery Single Treatment<br>* Frameless single-fraction SRS. One large treatment done on each brain tumor. 20 Gy for GTVs (or resection cavity CTVs) < 2 cm, and 18 Gy for GTVs (or resection cavity CTVs) between 2-3 cm in the single-fraction.<br>* Other names: SRS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Multi-Fraction SRS superiority compared to single fraction SRS | To determine if Multi-Fraction SRS will decrease the rate of radionecrosis when compared to single-fraction SRS for patients with small metastases and are on immunotherapy. | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Target metastasis progression | Target metastasis progression will be assessed using adapted Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) consensus imaging criteria. In brief, progressive disease is defined as a ≥20% relative increase in the longest diameter (LD) of the target metastasis compared to its smallest LD recorded on study, with a minimum absolute increase of 5 mm | 4 years | 
| Overall Survival Rate | Time from randomization to death | 4 years | 
| Acute CTCAE v5.0 CNS Grade 2+ and Grade 3+ toxicities | Any acute CTCAE v5.0 CNS Grade 2+ and Grade 3+ toxicities, within 90 days of SRS completion (toxicity must be specified). | 4 years | 
| Late CTCAE v5.0 CNS Grade 2+ and Grade 3+ toxicities | Any late CTCAE v5.0 CNS Grade 2+ and Grade 3+ toxicities, greater than 90 days from SRS completion (toxicity must be specified). | 4 years | 
| rate of individual metastases radionecrosis | To compare the rates over time of individual metastases radionecrosis using a parametric survival analysis | 4 years | 
| rate of individual metastases rates of edema | To compare rates over time of individual metastases rates of edema using a parametric survival analysis. | 4 years | 
| Rates of Symptomatic Edema | To compare rates of symptomatic edema at 3 months, 6 months, and 1 year.1 | 1 year | 
| Time to any distant intracranial failure | Time to any distant intracranial failure (ie, appearance of brain metastasis at untreated site). | 4 years | 
| Time to initiation of any combination | Time to initiation of any combination of death, salvage SRS, WBRT, or neurosurgical resection for intracranial failure. | 4 years |