Comparing Single vs Multiple Dose Radiation for Cancer Patients With Brain Metastasis and Receiving Immunotherapy (HYPOGRYPHE)

• ClinicalTrials.gov Identifier: NCT05703269
• Recruitment Status: Recruiting
• First Posted: January 30, 2023
• Last Update Posted: April 19, 2024
• Sponsor: Wake Forest University Health Sciences
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Wake Forest University Health Sciences

Tracking Information

• First Submitted Date: January 18, 2023
• First Posted Date: January 30, 2023
• Last Update Posted Date: April 19, 2024
• Actual Study Start Date: July 11, 2023
• Estimated Primary Completion Date: March 31, 2028 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 18, 2023)

Occurrence of a Grade 2 or higher Adverse Radiation Effect (ARE) [ Time Frame: 9 months ]

To compare the proportion of participants experiencing Grade 2 or higher Adverse Radiation Effects (ARE) within 9 months following randomization to single fraction stereotactic radiosurgery (SSRS) vs fractionated stereotactic radiosurgery (FSRS) in patients with brain metastases ≥ 2 cm in diameter or ≥ 4cc in volume treated with concurrent immune checkpoint inhibitor (ICI) therapy.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 18, 2023)

• Compare time to composite end point [ Time Frame: 9 months ]
  To compare the time to the composite endpoint of either local failure of a metastasis treated with SRS (as defined in Section 8.2) or first Grade 2 or higher ARE between SSRS and FSRS groups.
• Compare time to local failure between SSRS and FSRS groups [ Time Frame: 9 months ]
  To compare time to local failure between SSRS and FSRS groups.
• Compare time to neurologic death between groups [ Time Frame: 9 months ]
  To compare time to neurologic death between groups.
• Compare patient-reported brain tumor specific symptom burden [ Time Frame: 9 months ]
  To compare patient-reported brain tumor specific symptom burden using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) between SRSS or FSRS groups at 9 months.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Comparing Single vs Multiple Dose Radiation for Cancer Patients With Brain Metastasis and Receiving Immunotherapy
• Official Title: Hypofractionated Radiotherapy vs Single Fraction Radiosurgery for Brain Metastasis Patients on Immunotherapy (HYPOGRYPHE)
• Brief Summary: This study is designed to see if we can lower the chance of side effects from radiation in patients with breast, kidney, small cell lung cancer, non-small cell lung cancer or melanoma that has spread to the brain and who are also being treated with immunotherapy, specifically immune checkpoint inhibitor (ICI) therapy. This study will compare the usual care treatment of single fraction stereotactic radiosurgery (SSRS) given on one day versus fractionated stereotactic radiosurgery (FSRS), which is a lower dose of radiation given over a few days to determine if FSRS is better or worse at reducing side effects than usual care treatment.
• Detailed Description: This study is an open-label, randomized, Phase III trial designed to ascertain whether fractionated stereotactic radiosurgery (FSRS) results in lower incidence of Grade 2 or higher adverse radiation effect (ARE) by 9 months compared to single fraction stereotactic radiosurgery (SSRS) in patients with large brain metastases who have received or will receive immune checkpoint inhibitor (ICI) targeted to the PD-1/PD-L1 axis within 30 days of stereotactic radiosurgery (SRS). Participants will be randomized 1:1 to either SSRS or FSRS, using a minimization randomization strategy considering 5 prognostic factors of interest: radiosurgery platform (gamma knife vs. LINAC), timing of immunotherapy relative to radiation (ICI within 30 days prior to Day 1 of SRS or not), surgical status (any resection cavity vs intact metastases only), predominant tumor type (Melanoma vs. all others), and prior courses of SRS for brain metastases (yes vs. no).
• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

Participants will be randomized 1:1 to either SSRS or FSRS, using minimization randomization strategy considering 5 prognostic factors of interest: radiosurgery platform (GK vs. LINAC), timing of immunotherapy relative to radiation (ICI within 30 days of Day 1 prior to SRS or not), surgical status (any resection cavity vs. intact metastases only), predominant tumor type (Melanoma vs. all others), and prior courses of SRS for brain metastases (yes vs. no). All baseline patient-reported outcomes and neurocognitive assessments will be collected prior to randomization to minimize bias.

Masking: None (Open Label)
Primary Purpose: Supportive Care

Condition

• NSCLC
• Renal Cell Carcinoma
• Breast Carcinoma
• Melanoma
• Brain Metastases, Adult
• Non-small Cell Lung Cancer
• SCLC
• Small-cell Lung Cancer

Intervention

• Radiation: single fraction stereotactic radiosurgery (SSRS)
  SSRS is an advanced radiation technique that delivers high dose precision radiation in a single dose to discrete intracranial lesions.
• Radiation: fractionated stereotactic radiosurgery (FSRS)
  FSRS is an advanced radiation technique that uses a lower dose precision radiation delivered over 3 to 5 treatments given daily or every other day to intracranial lesions.

Study Arms

• Active Comparator: SSRS = single fraction stereotactic radiosurgery
  SSRS is an advanced radiation technique that delivers high dose precision radiation in a single dose to discrete intracranial lesions. SSRS has recently become a standard-of-care treatment for patients with 1-4 brain metastases and is also commonly used for patients with up to 15 metastases, due to improved neurocognitive outcomes compared to whole brain radiotherapy.
  Intervention: Radiation: single fraction stereotactic radiosurgery (SSRS)
• Experimental: FSRS = fractionated stereotactic radiosurgery
  FSRS is an advanced radiation technique that uses a lower dose precision radiation delivered over 3 to 5 treatments given daily or every other day to intracranial lesions.
  Intervention: Radiation: fractionated stereotactic radiosurgery (FSRS)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 18, 2023): 244
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 31, 2028
• Estimated Primary Completion Date: March 31, 2028 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Karen Craver, MT, MHA; 336-716-0891; NCORP@wakehealth.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05703269
• Other Study ID Numbers: IRB00092505; 5UG1CA189824-08 ( U.S. NIH Grant/Contract ); NCI-2022-10836 ( Registry Identifier: Registry ID: NCI CTRP ); WF-2201 ( Other Identifier: Wake Forest NCORP Research Base )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Wake Forest NCORP Research Base is committed to following the NIH Statement on Sharing Research Data (http://grants.nih.gov/grants/guide/ notice-files/NOT-OD-03-032.html). As of July 2018, the WF NCORP RB signed an agreement with NCI to contribute de-identified data and data dictionaries from clinical trials conducted through our RB to the NCI NCTN/NCORP data archive within 6 months of primary and non-primary publications of phase II/III and phase III trials to https://nctn-data-archive.nci.nih.gov/. This will become the primary means for sharing raw data, and we will adhere to the guidelines spelled out in the NCTN/NCORP Data Archive Usage Guide. De-identified data from studies not covered by the agreement (e.g., phase II and observational studies) will be made available upon request. All data files will be de-identified.

De-identification procedures will meet the HIPAA criteria as detailed in the Code of Federal Regulations, Part 45, Section 164.514.

• Time Frame: 6 months after publication for a 2 year duration
• Access Criteria: upon request to NCORP@wakehealth.edu

• Current Responsible Party: Wake Forest University Health Sciences
• Original Responsible Party: Same as current
• Current Study Sponsor: Wake Forest University Health Sciences
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Christina K Cramer, MD; Wake Forest University Health Sciences

• PRS Account: Wake Forest University Health Sciences
• Verification Date: April 2024