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

Non-small Cell Lung Cancer Clinical Trial

— HYPOGRYPHE  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05703269
• Other study ID #: IRB00092505
• Secondary ID: 5UG1CA189824-08N
• Status: Recruiting
• Phase: N/A
• Start date: July 11, 2023
• Est. completion date: March 31, 2028

Study information

• Verified date: April 2024
• Source: Wake Forest University Health Sciences
• Contact: Karen Craver, MT, MHA
• Phone: 336-716-0891
• Email: NCORP[@]wakehealth.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 244
• Est. completion date: March 31, 2028
• Est. primary completion date: March 31, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Brain Metastases, Adult
• Brain Neoplasms
• Breast Carcinoma
• Breast Neoplasms
• Carcinoma
• Carcinoma, Renal Cell
• Lung Neoplasms
• Melanoma
• Neoplasm Metastasis
• Non-small Cell Lung Cancer
• NSCLC
• Renal Cell Carcinoma
• SCLC
• Small Cell Lung Carcinoma
• 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.
• 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.

Locations

Country	Name	City	State
United States	Lovelace Medical Center-Saint Joseph Square	Albuquerque	New Mexico
United States	Lovelace Radiation Oncology	Albuquerque	New Mexico
United States	Trinity Health Saint Joseph Mercy Hospital Ann Arbor	Ann Arbor	Michigan
United States	Aspirus Langlade Hospital	Antigo	Wisconsin
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Montefiore Medical Center-Einstein Campus	Bronx	New York
United States	Montefiore Medical Center-Weiler Hospital	Bronx	New York
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Gibbs Cancer Center-Pelham	Greer	South Carolina
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	Aspirus Cancer Care - James Beck Cancer Center	Rhinelander	Wisconsin
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Mercy Hospital South	Saint Louis	Missouri
United States	Spartanburg Medical Center	Spartanburg	South Carolina
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Aspirus Cancer Care - Stevens Point	Stevens Point	Wisconsin
United States	Overlook Medical Center	Summit	New Jersey
United States	Aspirus Regional Cancer Center	Wausau	Wisconsin
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	Aspirus Cancer Care - Wisconsin Rapids	Wisconsin Rapids	Wisconsin
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
Wake Forest University Health Sciences	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Occurrence of a Grade 2 or higher Adverse Radiation Effect (ARE)	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.	9 months
Secondary	Compare time to composite end point	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.	9 months
Secondary	Compare time to local failure between SSRS and FSRS groups	To compare time to local failure between SSRS and FSRS groups.	9 months
Secondary	Compare time to neurologic death between groups	To compare time to neurologic death between groups.	9 months
Secondary	Compare patient-reported brain tumor specific symptom burden	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.	9 months