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Comparing single and multiple doses of radiation for cancer patients with brain metastasis receiving immunotherapy

Hypofractionated Radiotherapy vs Single Fraction Radiosurgery for Brain Metastasis Patients on Immunotherapy (HYPOGRYPHE)

Not applicable Interventional Wake Forest University Health Sciences · NCT05703269

This study is testing whether giving cancer patients with brain metastases multiple smaller doses of radiation instead of one large dose can help reduce side effects while they receive immunotherapy.

Quick facts

PhaseNot applicable
Study typeInterventional
Enrollment244 (estimated)
Ages18 Years and up
SexAll
SponsorWake Forest University Health Sciences Academic / other
Drugs / interventionsbevacizumab, radiation, immunotherapy
Locations37 sites (Decatur, Illinois and 36 other locations)
Trial IDNCT05703269 on ClinicalTrials.gov

What this trial studies

This clinical trial aims to determine whether fractionated stereotactic radiosurgery (FSRS) can reduce the incidence of adverse radiation effects compared to single fraction stereotactic radiosurgery (SSRS) in patients with brain metastases from various cancers who are also receiving immune checkpoint inhibitor therapy. Participants will be randomly assigned to receive either SSRS or FSRS, with a focus on measuring side effects over a nine-month period. The study will consider multiple prognostic factors to ensure balanced groups for comparison. The goal is to find a treatment approach that minimizes side effects while effectively managing brain metastases.

Who should consider this trial

Good fit: Ideal candidates include adults with intact brain metastases or resection cavities who are receiving or have recently received immune checkpoint inhibitor therapy.

Not a fit: Patients with brain metastases that are not suitable for stereotactic radiosurgery or those who are not receiving immunotherapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could lead to a safer radiation treatment option for cancer patients with brain metastases, potentially reducing side effects associated with radiation therapy.

How similar studies have performed: Other studies have explored the use of fractionated stereotactic radiosurgery, but this specific comparison with immune checkpoint inhibitors is relatively novel.

Eligibility criteria

Show full inclusion / exclusion criteria 
Inclusion Criteria:

* At least one intact brain metastasis or resection cavity ≥ 2 cm in diameter or ≥ 4 cc volume.

  * Patients at initial diagnosis of brain metastases and patients with known brain metastasis treated with systemic therapy alone are eligible.
  * Patients who have previously undergone SRS for brain metastases are eligible if all MRIs and DICOM-RT files from prior SRS courses are available for upload to TRIAD and there are no lesions requiring re-irradiation. Prior SRS data upload is NOT required prior to enrollment and randomization. Both SSRS and FSRS are acceptable.
  * Lesion volume will be approximated by measuring the lesion's three perpendicular diameters on contrast-enhanced, T1-weighted MRI and the product of those diameters will be divided by 2 to estimate the lesion volume (e.g., xyz/2). Alternatively, direct volumetric measurements via slice-by-slice contouring on a treatment planning software package can be used to calculate the total tumor volume.
  * Any extent of non-CNS disease is allowed. There is no requirement for non-CNS disease to be controlled prior to study entry.
  * For patients considered to be borderline or potentially eligible by size or volume criteria, sites have the option to send in DICOM films for central review screening.
* Age ≥ 18 years at the time of enrollment.
* Total number of brain metastases (including resection cavities) ≤ 15 on diagnostic MRI; all lesions must be amenable to SSRS and FSRS as determined by the treating radiation oncologist. Treatment must take place at a facility credentialed by the Imaging and Radiation Oncology Core (IROC) for SRS and that offers both SSRS and FSRS as treatment options.
* Total gross tumor volume must be ≤ 30 cc. Lesion volume will be approximated by measuring each lesion's three perpendicular diameters on contrast-enhanced T1 MRI and the product of those diameters will be divided by 2 (V = xyz/2). Direct volumetric measurements by contouring all lesions on all visible slices on treatment planning software is also acceptable. If there is a cavity, only gross residual disease within or adjacent to the cavity is counted toward the 30 cc total volume.
* Ability to tolerate MRI brain with gadolinium-based contrast.
* Pathologically confirmed melanoma, renal cell carcinoma, non-small cell lung cancer, small cell lung cancer, or breast cancer.
* Has received, is currently receiving, or is planned to receive immune checkpoint inhibitor therapy (defined as agent targeted to PD-1/PD-L1 axis) within 30 days of the planned first day of SSRS/FSRS. Dual ICI therapy with PD-1/PD-L1 and CTLA-4 targeted agents are allowed, but patients treated with a single agent CTLA-4 targeted agent only are ineligible.

  o It is not mandatory to wait for the results of next generation sequencing (NGS) or other molecular tumor testing to determine if the patient is planned to receive ICI if the enrolling physician feels that identification of a mutation that would preclude ICI therapy (such as an EGFR mutation in a patient with NSCLC) is unlikely to be identified.
* Karnofsky Performance Status (KPS) ≥ 50. Refer to Appendix A.
* Negative serum or urine pregnancy test within 14 days of randomization for women of child-bearing potential.
* Ability to understand and the willingness to sign written informed consent.
* Patients must be able to provide informed consent.
* Must be able to speak, read and understand English or Spanish

Exclusion Criteria:

* Prior fractionated, whole, or partial brain radiation therapy. Prior fractionated SRS is acceptable.
* Prior courses of SRS for benign tumors such as meningiomas, pituitary adenomas, schwannomas may be acceptable if the treatment is \> 2cm away from the site of a metastatic lesion that would be treated on this study. The study PI or a designated co-PI must review this type of case to confirm eligibility prior to enrollment.
* Prior diagnosis ARE, including pseudoprogression or radiation necrosis/radionecrosis, or previously treated lesions being actively evaluated for possible ARE or local failure such as concerning imaging findings currently being tracked with short interval MRI.
* Leptomeningeal carcinomatosis established by lumbar puncture cytology, or MRI imaging. In the absence of a clinical indication, a lumbar puncture is not required to confirm eligibility.
* A brain metastasis that is 5 mm or less from the optic chiasm or optic nerves
* Inability to tolerate brain MRI or receive gadolinium-based contrast
* Planned or prior therapy with bevacizumab (or bevacizumab biosimilar) within 30 days of the planned first day of SRS as part of a systemic therapy regimen at study enrollment.
* Serious intercurrent illness or medical condition judged by the local investigator to compromise the patient's safety, preclude safe administration of the planned protocol treatment, or would not permit the patient to be managed according to the protocol guidelines.

Where this trial is running

Decatur, Illinois and 36 other locations

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions NSCLCRenal Cell CarcinomaBreast CarcinomaMelanomaBrain Metastases, AdultNon-small Cell Lung CancerSCLCSmall-cell Lung Cancer
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.