Comparing Radiation After Surgery to Observation After Surgery in Patients With Clinical Low-Risk, Molecular High-Risk Meningioma, and Evaluating Observation After Surgery in Patients With Clinical and Molecular Low-Risk Meningioma

A Randomized Phase 3 Clinical Trial of Postoperative Radiotherapy Versus Postoperative Surveillance for Clinical Low-Risk, Molecular High-Risk Meningioma and Longitudinal Surveillance for Clinical and Molecular Low-Risk Meningioma

This phase III trial compares post-surgical surveillance to post-surgical radiation therapy for improving survival without disease progression in clinically low-risk patients with a grade 1 meningioma that is new or that has come back after a period of improvement (recurrent) or a new grade 2 meningioma who have undergone surgery. Post-surgical surveillance involves closely watching a patient's condition but not giving treatment unless there are changes in test results. Active surveillance avoids problems that may be caused by treatments such as radiation or surgery. It is used to find early signs that the condition is getting worse. During active surveillance, patients will be given certain exams and tests done on a regular schedule. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. The usual approach for low grade and low clinical risk meningiomas is surgery followed by radiation or no further treatment (observation) based on clinical risk factors such as tumor grade and the amount of tumor able to be removed. Clinical factors such as meningioma grade and the amount of meningioma that was removed help doctors decide whether radiation or observation is better after surgery. In this study, a patient's molecular risk, as determined using biomarkers, is also considered when assigning treatment. For patients with grade 1 or 2 meningiomas with a low clinical risk but high molecular risk of growing or coming back after surgery, this study will compare the usual approach of post-surgery observation to another usual approach of post-surgery radiation. Using high molecular risk to decide usual treatment and receiving the usual radiation could increase the amount of time without the tumor growing or coming back, but it could also cause side effects. For patients with grade 1 or 2 meningiomas with a low clinical risk and low molecular risk of growing or coming back after surgery, this study will evaluate if using molecular risk shows a greater benefit of the usual post-surgery observation.

Study Overview

• Status: Not yet recruiting
• Conditions: Grade 1 Meningioma; Grade 2 Meningioma; Recurrent Grade 1 Meningioma
• Intervention / Treatment: Procedure: Magnetic Resonance Imaging; Radiation: Intensity-Modulated Radiation Therapy; Radiation: Fractionated Stereotactic Radiation Therapy; Other: Questionnaire Administration; Procedure: Intensity-Modulated Proton Therapy; Other: Neurocognitive Assessment; Other: Patient Observation; Procedure: Biospecimen Collection

Detailed Description

PRIMARY OBJECTIVES:

I. To determine if progression free survival (PFS) is improved with postoperative radiotherapy compared to postoperative surveillance for patients with clinical low-risk, molecular high-risk meningiomas, as defined using a centralized 34-gene expression biomarker and centralized neuro-radiology review. (Cohort A) II. To determine if 5-year PFS is greater than 90% with postoperative surveillance for patients with clinical and molecular low-risk meningiomas, as defined using a centralized 34-gene expression biomarker and centralized neuro-radiology review. (Cohort B)

SECONDARY OBJECTIVES:

I. To determine if overall survival (OS) of patients with clinical low-risk, molecular high-risk meningiomas is improved with postoperative radiotherapy compared to postoperative surveillance. (Cohort A) II. To determine if the time-to-next-treatment of patients with clinical low-risk, molecular high-risk meningiomas is improved with postoperative radiotherapy compared to postoperative surveillance. (Cohort A) III. To define the safety and tolerability of postoperative radiotherapy for patients with clinical low-risk, molecular high-risk meningiomas using Common Terminology Criteria for Adverse Events (CTCAE) 5.0. (Cohort A) IV. To determine if postoperative radiotherapy leads to increased neurocognitive function (NCF) deterioration, as assessed by the Hopkins Verbal Learning Test-Revised (HVLT-R), the Controlled Oral Word Association Test (COWA), and the Trail Making Tests (TMT) A and B, as compared to postoperative surveillance for patients with clinical low-risk, molecular high-risk meningiomas. (Cohort A) V. To determine if postoperative radiotherapy leads to increased patient-reported neurological symptom burden, as measured by the MD Anderson Symptom Inventory Brain Tumor (MDASI-BT) module, as compared to postoperative surveillance for patients with clinical low-risk, molecular high-risk meningiomas. (Cohort A) VI. To define the OS of patients with clinical and molecular low-risk meningiomas with postoperative surveillance. (Cohort B) VII. To define the safety profile of postoperative surveillance for patients with clinical and molecular low-risk meningiomas using CTCAE 5.0. (Cohort B)

EXPLORATORY OBJECTIVE:

I. To explore additional biomarkers in pre-treatment tumor tissue, blood, or serum that may elucidate the efficacy, safety, or tolerability of postoperative radiotherapy compared to postoperative surveillance.

OUTLINE: Patients with a high gene expression risk score after gross total resection (GTR) or subtotal resection (STR) or intermediate gene expression risk score after STR (Cohort A) are randomized to 1 of 2 arms. Patients with low gene expression risk score after GTR or STR or intermediate gene expression risk score after GTR (Cohort B) are assigned to Arm I.

ARM I: Patients undergo surveillance on study. Patients also undergo magnetic resonance imaging (MRI) throughout the trial and undergo collection of plasma, serum, and blood samples on study.

ARM II: Patients undergo intensity-modulated radiation therapy (IMRT) or intensity-modulated proton therapy (IMPT) 5 days per week for a total of 30 fractions over 50 days or undergo fractionated stereotactic radiation therapy (FSRT) for a total of 5 fractions over 10 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI and collection of plasma, serum, and blood samples throughout the trial.

After completion of study treatment, patients are followed up at 3, 6, and 12 months, every 6 months in years 2 and 3, and then yearly in years 4 and 5.

• Study Type: Interventional
• Enrollment (Estimated): 464
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Radiologically confirmed newly diagnosed or recurrent solitary (n=1) cranial World Health Organization (WHO) grade 1 meningioma post GTR or STR based on postoperative MRI findings, or newly diagnosed solitary WHO grade 2 meningioma post GTR based on postoperative MRI findings at the enrolling institution. Somatostatin receptor (SSTR)-directed positron emission tomography (PET) imaging may not be used to define extent of resection or meningioma number
• Histologically confirmed as WHO grade 1 or 2, based on pathology findings at the enrolling institution according to WHO 2021 criteria

• Initial surgery (GTR or STR) within 180 days prior to step 1 registration (within this 180-day period, a second surgery is permitted to achieve GTR):

  • GTR is defined as the absence of gross residual meningioma, as confirmed by postoperative MRI
  • STR is defined as the presence of gross residual meningioma, as confirmed by postoperative MRI
  • Surgeon-reported Simpson grade of resection, meningioma location, and any available SSTR-directed PET imaging studies will be assembled
• Postoperative MRI prior to step 1 registration. It is additionally required that all imaging sequences obtained in all preoperative and postoperative MRI, and any computed tomography (CT) or SSTR-direct PET imaging studies used for radiotherapy planning be submitted to NRG Oncology after step 1 registration. SSTR PET imaging may be used for radiotherapy planning to ensure all disease is encompassed in the clinical target volume (CTV) but may not be used to shrink the CTV or to supersede MRI-defined extent of resection or meningioma number
• NOTE: Central review for pathology, radiology, and gene expression profiling must occur between step 1 and step 2 of registration. Once appropriate pathology and imaging data are received, central pathology and radiology review will occur within 10 business days and must confirm WHO grade 1 meningioma after GTR or STR or WHO grade 2 meningioma after GTR. Gene expression profiling will occur within 30 business days of receiving appropriate pathology specimens. Central review for pathology, radiology, and gene expression must be completed before the patient can proceed to step 2 registration/randomization. For patients with central confirmation of clinical low-risk, molecular high-risk meningioma who will be eligible for cohort A randomization, central determination of 54 gray (Gy)/30 fractions (Fx) or 25Gy/5Fx radiotherapy and recommended radiotherapy treatment volumes will be provided prior to step 2 registration. See the study-specific biospecimen collection and submission manual on the Cancer Trials Support Unit (CTSU) protocol website for details of central pathology review and gene expression biomarker testing
• Age ≥ 18
• Central radiology confirmation of solitary (n=1) cranial meningioma on preoperative MRI and extent of resection (GTR or STR) on postoperative MRI
• Central histological pathology confirmation of newly diagnosed or recurrent WHO grade 1 meningioma after GTR or STR, or newly diagnosed WHO grade 2 meningioma after GTR, according to WHO 2021 criteria

• Central gene expression profiling for calculation of the gene expression risk score:

  • Cohort A: High gene expression risk score after GTR or STR, or intermediate gene expression risk score after STR
  • Cohort B: Low gene expression risk score after GTR or STR, or intermediate gene expression risk score after GTR
• Postoperative Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

• Not pregnant and not nursing

  * Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to step 2 registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) and who is not postmenopausal

• No prior high dose radiotherapy within the last 10 years to the region of the study tumor that would result in overlap of radiotherapy fields will be allowed. High dose radiotherapy is defined as an EQD2 of 45Gy or higher, as calculated with an alpha/beta ratio of 3. Patients with known or suspected radiation-induced meningioma are eligible
• New York Heart Association Functional Classification II or better (New York Heart Association [NYHA] Functional Classification III/IV are not eligible) (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification)
• No active infection currently requiring intravenous (IV) antibiotic management
• No known history of meningioma predisposition syndrome, such as neurofibromatosis type 2 (testing is not required)

Exclusion Criteria:

-

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1 Postoperative Surveillance; Patients undergo surveillance on study. Patients also undergo MRI throughout the trial and undergo collection of plasma, serum, and blood samples on study.	Procedure: Magnetic Resonance Imaging; Undergo MRI; Other: Patient Observation; Undergo surveillance; Procedure: Biospecimen Collection; Undergo collection of plasma, serum, and blood samples
Experimental: Arm II Postoperative Radiotherapy; Patients undergo IMRT or IMPT 5 days per week for a total of 30 fractions over 50 days or undergo FSRT for a total of 5 fractions over 10 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI and collection of plasma, serum, and blood samples throughout the trial.	Procedure: Magnetic Resonance Imaging; Undergo MRI; Radiation: Intensity-Modulated Radiation Therapy; Undergo IMRT; Radiation: Fractionated Stereotactic Radiation Therapy; Undergo FSRT; Other: Questionnaire Administration; Ancillary Studies; Procedure: Intensity-Modulated Proton Therapy; Undergo IMPT; Other: Neurocognitive Assessment; Ancillary studies; Procedure: Biospecimen Collection; Undergo collection of plasma, serum, and blood samples

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (Cohort A)	The log-rank test will be used to test the difference in PFS between the arms. Will estimate progression free survival by arm using the method of Kaplan-Meier. Cox proportional hazards model will be used to estimate the treatment hazard ratio and 95% confidence interval.	From randomization until the first documented disease progression or death, assessed up to 5 years
Progression free survival (Cohort B)	A one-sided 5% level Wald test will be used to determine if the observed hazard for progression free survival is better than that specified under the null hypothesis. Will estimate progression free survival using the method of Kaplan-Meier. Greenwood's formula will be used to estimate the confidence intervals for 5-year progression free survival.	From randomization until the first documented disease progression or death, assessed up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (Cohort A)	Analysis for overall survival will consist of estimation of its distribution for each study arm via the Kaplan-Meier method and a stratified log-rank test. Additional analyses may consist of estimating the treatment hazard ratio via the Cox proportional hazards model adjusting for randomization stratification factors, evaluating whether the proportional hazards assumption holds or whether any treatment effect is notably time-varying, and evaluating for potential treatment by prognostic covariate interactions.	From randomization until death due to any cause, assessed up to 5 years
Overall survival (Cohort B)	Analysis for overall survival will consist of estimation of its distribution for each study arm via the Kaplan-Meier method and a stratified log-rank test. Additional analyses may consist of estimating the treatment hazard ratio via the Cox proportional hazards model adjusting for randomization stratification factors, evaluating whether the proportional hazards assumption holds or whether any treatment effect is notably time-varying, and evaluating for potential treatment by prognostic covariate interactions.	From randomization until death due to any cause, assessed up to 5 years
Time to next treatment (TTNT) (Cohort A)	Time to next treatment (TTNT) (Cohort A)	From randomization until reoperation in the prior surgical bed or prior radiotherapy field, re-irradiation in the prior surgical bed or radiotherapy field, or initiation of systemic meningioma-directed medical therapy, assessed up to 5 years
Incidence of adverse events (Cohort A)	Adverse events (AEs) will be graded according to Common Terminology Criteria for Adverse Events version 5.0. Comprehensive summaries of 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.	At months 3, 6, and 12 for the first year then every 6 months for year 2
Incidence of adverse events (Cohort B)	AEs will be graded according to Common Terminology Criteria for Adverse Events version 5.0. Comprehensive summaries of 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.	At months 3, 6, and 12 for the first year then every 6 months for year 2
Patient-reported neurological symptom burden (Cohort A)	Will determine whether postoperative radiotherapy increases patient-reported neurological symptom burden compared with postoperative surveillance in patients with clinical low-risk, molecular high-risk meningiomas. Neurological symptom burden will be assessed using the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) module, a patient-reported outcome measure in which symptom severity items are scored on a 0 to 10 numeric rating scale, where 0 = symptom not present and 10 = symptom as bad as imaginable. Higher scores indicate greater symptom burden (worse outcome). For the primary analysis evaluating between-arm differences in MDASI-BT scores over time, a general mixed-effects model for repeated measures will be fitted to assess changes in scores by treatment arm.	Every 12 months for 5 years
Neurocognitive function (Cohort A)	Neurocognitive function will be assessed using the Trail Making Test (TMT), a measure of attention, processing speed, and executive function. Neurocognitive failure will be defined according to the protocol-specified criteria for deterioration from baseline on the TMT. TTNCF analyses will be performed as described above. TMT performance is typically measured as completion time in seconds; lower completion times indicate better neurocognitive performance and higher values indicate worse performance.	Every 12 months for 5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival by sex	Estimates of the primary outcome treatment effect and the corresponding 95% confidence intervals will be provided by sex.	Up to 5 years
Progression free survival by race	Estimates of the primary outcome treatment effect and the corresponding 95% confidence intervals will be provided by race.	Up to 5 years
Progression free survival by ethnicity	Estimates of the primary outcome treatment effect and the corresponding 95% confidence intervals will be provided by ethnicity.	Up to 5 years

Collaborators and Investigators

• Sponsor: NRG Oncology

Study record dates

Study Major Dates

• Study Start (Estimated): January 28, 2027
• Primary Completion (Estimated): June 30, 2035
• Study Completion (Estimated): June 30, 2040

Study Registration Dates

• First Submitted: August 13, 2026
• First Submitted That Met QC Criteria: August 21, 2026
• First Posted (Actual): August 25, 2026

Study Record Updates

• Last Update Posted (Actual): August 25, 2026
• Last Update Submitted That Met QC Criteria: August 21, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Health Services Administration; Investigative Techniques; Therapeutics; Quality of Health Care; Behavioral Disciplines and Activities; Chemistry Techniques, Analytical; Spectrum Analysis; Radiotherapy; Outcome Assessment, Health Care; Outcome and Process Assessment, Health Care; Psychological Tests; Radiotherapy, Conformal; Radiotherapy, Computer-Assisted; Neuropsychological Tests; Magnetic Resonance Spectroscopy; Watchful Waiting; Radiotherapy, Intensity-Modulated; Mental Status and Dementia Tests
• Other Study ID Numbers: NRG-BN015; NCI-2026-05558 (Other Identifier: NCI Trial Identifier)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No