Comparing the Addition of Radiation Either Before or After Surgery for Patients With Brain Metastases

• ClinicalTrials.gov Identifier: NCT05438212
• Recruitment Status: Recruiting
• First Posted: June 29, 2022
• Last Update Posted: January 11, 2024
• Sponsor: NRG Oncology
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): NRG Oncology

Tracking Information

• First Submitted Date: June 24, 2022
• First Posted Date: June 29, 2022
• Last Update Posted Date: January 11, 2024
• Actual Study Start Date: August 31, 2022
• Estimated Primary Completion Date: March 16, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 24, 2022)

Time to Composite Adverse Endpoint (CAE) [ Time Frame: Time from surgery (with the post-operative MRI as the 'baseline' for purposes of disease assessment) to local tumor progression (within the surgical bed), nodular meningeal disease, or radiation necrosis, whichever occurs first, assessed up to 4 years ]

Analysis for this endpoint will consist of testing the cause-specific hazard ratio in a Cox proportional hazards model.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 24, 2022)

• Overall Survival (OS) [ Time Frame: Time from randomization to death due to any cause, assessed up to 4 years ]
  Analysis for this endpoint will consist of estimation of the OS distribution of each treatment arm via the Kaplan-Meier method and a stratified log-rank test.
• Rate of local tumor progression [ Time Frame: Up to 4 years ]
  The time origin for these imaging-based endpoints will be time of surgery (with the post-operative magnetic resonance imaging [MRI] as the 'baseline' for purposes of disease assessment). These analyses will involve estimating the cumulative incidence function of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures in the presence of competing event of deaths. The Gray's test will be used to evaluate the difference in the distribution of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures between treatment arms.
• Rate of radiation necrosis [ Time Frame: Up to 4 years ]
  The time origin for these imaging-based endpoints will be time of surgery (with the post-operative MRI as the 'baseline' for purposes of disease assessment). These analyses will involve estimating the cumulative incidence function of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures in the presence of competing event of deaths. The Gray's test will be used to evaluate the difference in the distribution of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures between treatment arms.
• Rate of nodular meningeal disease [ Time Frame: Up to 4 years ]
  The time origin for these imaging-based endpoints will be time of surgery (with the post-operative MRI as the 'baseline' for purposes of disease assessment). These analyses will involve estimating the cumulative incidence function of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures in the presence of competing event of deaths. The Gray's test will be used to evaluate the difference in the distribution of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures between treatment arms.
• Rate of distant brain failures [ Time Frame: Up to 4 years ]
  The time origin for these imaging-based endpoints will be time of surgery (with the post-operative MRI as the 'baseline' for purposes of disease assessment). These analyses will involve estimating the cumulative incidence function of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures in the presence of competing event of deaths. The Gray's test will be used to evaluate the difference in the distribution of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures between treatment arms.
• Frequency of adverse events (AEs) [ Time Frame: Up to 4 years ]
  AEs will be graded according to Common Terminology Criteria for Adverse Events version 5.0. Comprehensive summaries of all AEs by treatment arm will be generated and examined. Counts and frequencies of worst (highest score) AE per patient will be presented overall and by AE type category, separately by assigned treatment group. The proportion of patients with at least one grade 3 or higher AE will be compared between treatment arms. Any frequencies to be tested will be evaluated using the chi-square or exact test as appropriate, with two-sided significance level 0.05.
• Change in MD Anderson Symptom Inventory - Brain Tumor (MDASI-BT) [ Time Frame: Baseline up to 2 years after surgery ]
  Will implement mixed effects models for repeated measures to evaluate the MDASI-BT scores longitudinally.
• Change in cognitive function [ Time Frame: Baseline up to 2 years after surgery ]
  Measured by Montreal Cognitive Assessment (MoCA). Will implement mixed effects models for repeated measures to evaluate the MoCA scores longitudinally.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: June 24, 2022)

Type of surgical resection [ Time Frame: Up to 4 years ]

Will compare if the type of surgical resection (piece-meal vs. en-bloc) may be associated with the rate of nodular meningeal disease. The competing risk approach by Gray (Gray 1988) will be used to compare the cumulative incidences of nMD by surgical type, where death prior to nMD will be treated as a competing risk event.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Comparing the Addition of Radiation Either Before or After Surgery for Patients With Brain Metastases
• Official Title: A Randomized Phase III Trial of Pre-Operative Compared to Post-Operative Stereotactic Radiosurgery in Patients With Resectable Brain Metastases
• Brief Summary: This phase III trial compares the addition of stereotactic radiosurgery before or after surgery in treating patients with cancer that has spread to the brain (brain metastases). Stereotactic radiosurgery is a type of radiation therapy that delivers a high dose of radiation only to the small areas of cancer in the brain and avoids the surrounding normal brain tissue. Surgery and radiation may stop the tumor from growing for a few months or longer and may reduce symptoms of brain metastases.

Detailed Description

PRIMARY OBJECTIVE:

I. To determine if the time to composite adverse endpoint (CAE) (defined as: 1) local tumor progression within the surgical bed; and/or 2) Adverse Radiation Effect (ARE), the imaging correlate of post-stereotactic radiosurgery (SRS) radiation necrosis; and/or 3) nodular meningeal disease (nMD) is improved in patients treated with pre-resection SRS to the intact lesion versus those treated with post-resection SRS.

SECONDARY OBJECTIVES:

I. To assess the trajectory of symptom burden in patients treated with pre-resection SRS to the intact lesion versus those treated to the post-resection surgical cavity as measured by MD Anderson Symptom Inventory for brain tumor (MDASI-BT) II. To determine whether there is improved overall survival (OS) in patients with resected brain metastases who undergo pre-resection SRS compared to patients who receive post-resection SRS.

III. To compare rates of ARE, the imaging correlate of radiation necrosis, in patients who receive pre-resection SRS to patients who receive post-resection SRS.

IV. To determine whether there is increased time to whole brain radiotherapy (WBRT) in patients who receive pre-resection SRS compared to patients who receive post-resection SRS.

V. To assess the trajectory of neuro-cognitive function in patients treated with pre-resection SRS to the intact lesion versus those treated to the post-resection surgical cavity as measured by the Montreal Cognitive Assessment (MoCA).

VI. To compare rates of nodular meningeal disease in patients who receive pre-resection SRS to patients who receive post-resection SRS.

VII. To compare rates of local recurrence in the resection cavity for patients who receive pre-resection SRS to patients who receive post-resection SRS.

VIII. To compare rates of local recurrence of intact, non-index metastases treated with SRS.

IX. To compare rates of distant brain failure in patients who receive pre-resection SRS to patients who receive post-resection SRS.

X. To assess toxicity in the two treatment arms.

EXPLORATORY OBJECTIVE:

I. To explore if the type of surgical resection (piece-meal versus [vs.] en-bloc) may be associated with the rate of nodular meningeal disease.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo surgery per standard of care. Within 10-30 days after surgery, patients undergo stereotactic radiosurgery for 1 fraction.

ARM II: Within 7 days before surgery, patients undergo stereotactic radiosurgery for 1 fraction. Patients undergo surgery per standard of care.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 2 years.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Malignant Neoplasm in the Brain

Intervention

• Procedure: Brain Surgery
  Undergo surgery per standard of care
• Other: Quality-of-Life Assessment
  Ancillary studies
• Other: Questionnaire Administration
  Ancillary studies
• Radiation: Stereotactic Radiosurgery
  Undergo stereotactic radiosurgery

Study Arms

• Active Comparator: Arm I (surgery, stereotactic radiosurgery)
  Patients undergo surgery per standard of care. Within 10-30 days after surgery, patients undergo stereotactic radiosurgery for 1 fraction.
  Interventions:

  • Procedure: Brain Surgery
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
  • Radiation: Stereotactic Radiosurgery
• Experimental: Arm II (stereotactic radiosurgery, surgery)
  Within 7 days before surgery, patients undergo stereotactic radiosurgery for 1 fraction. Patients undergo surgery per standard of care.
  Interventions:

  • Procedure: Brain Surgery
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
  • Radiation: Stereotactic Radiosurgery

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 24, 2022): 236
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 16, 2032
• Estimated Primary Completion Date: March 16, 2027 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Radiographic confirmation of 1-4 brain metastases, one of which requires resection, as defined by magnetic resonance imaging (MRI) with contrast obtained within 14 days prior to registration

  • The maximum diameter of the lesion to be resected on the post-contrast MRI, as measured on any orthogonal plane (axial, sagittal, coronal), must measure > 2.0 cm and < 5.0 cm.
  • The maximum diameter of the lesions not to be resected must measure < 4.0 cm
• Known active or history of invasive non-central nervous system (CNS) primary cancer based on documented pathologic diagnosis within the past 3 years
• All brain metastases must be located > 5 mm from the optic chiasm and outside the brainstem
• Patient is able to medically tolerate surgery and SRS
• The lesion chosen for surgical therapy must be deemed an appropriate target for safe, gross total resection by the treating surgeon
• History/physical examination within 14 days prior to registration
• Age >= 18
• Karnofsky performance status (KPS) >= 60 within 14 days prior to registration
• A negative urine or serum pregnancy test (in persons of childbearing potential) within =< 14 days prior to registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal for at least 12 consecutive months
• Participants who are sexually active must agree to use medically acceptable forms of contraception during treatment on this study to prevent pregnancy
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

Exclusion Criteria:

• Prior cranial radiotherapy, including whole brain radiotherapy, or SRS to the resection site

  • Note: The index lesion to be resected cannot have been previously treated with SRS (i.e. repeat radiosurgery to the same location/lesion is not allowed on this protocol). Previous SRS to other lesions is allowed

• Evidence of leptomeningeal disease (LMD)

  • Note: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive cerebrospinal fluid (CSF) cytology and/or unequivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator's discretion based on level of clinical suspicion
• Any medical conditions which would make this protocol unreasonably hazardous, including, but not limited to: contraindications to general endotracheal anesthesia; intracranial surgery; and stereotactic radiosurgery
• Primary histology of germ cell tumor, small cell carcinoma or lymphoma
• More than one brain metastasis planned for resection
• Inability to undergo MRI with contrast

• Planned administration of cytotoxic chemotherapy or tyrosine/multi-kinase inhibitors within the 3 days prior to, the day of, or within 3 days after the completion of SRS

  • Note: chemotherapy and immunotherapy outside of this window are allowed

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05438212
• Other Study ID Numbers: NRG-BN012; NCI-2022-04804 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); NRG-BN012 ( Other Identifier: NRG Oncology ); NRG-BN012 ( Other Identifier: CTEP ); U10CA180868 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: NRG Oncology
• Original Responsible Party: Same as current
• Current Study Sponsor: NRG Oncology
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Stuart H Burri; NRG Oncology

• PRS Account: NRG Oncology
• Verification Date: January 2024