Observation or Radiation Therapy in Treating Patients With Newly Diagnosed Grade II Meningioma That Has Been Completely Removed by Surgery

Phase 3

Recruiting

• Conditions: Grade 2 Meningioma; Intracranial Meningioma

• Registration Number: NCT03180268
• Lead Sponsor: NRG Oncology

Brief Summary

This randomized phase III trial studies how well radiation therapy works compared with observation in treating patients with newly diagnosed grade II meningioma that has been completely removed by surgery. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors.

Detailed Description

PRIMARY OBJECTIVE:

I. To determine the extent of clinical benefit of the addition of adjuvant radiotherapy (RT) to gross total resection (GTR) for patients with newly diagnosed World Health Organization (WHO) grade II meningioma.

SECONDARY OBJECTIVES:

I. Overall survival (OS). II. Disease-specific survival (DSS). III. Toxicity (grade 3+, exclusive of expected alopecia). IV. Neurocognitive function (NCF). V. Patient reported outcomes (PRO) measurements. VI. Adherence to protocol-specific target and normal tissue parameters. VII. Concordance measurements of central versus parent-institution pathology. VIII. Assessment of pHH3 mitotic index and its correlation with progression-free survival (PFS) and OS.

IX. Validation of the prognostic value of a 34-gene expression biomarker. X. Validation of the predictive value of a 34-gene expression biomarker in predicting the benefit of radiotherapy.

XI. Tissue and specimen collection for future translational research.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo observation. Additionally, patients undergo magnetic resonance imaging (MRI) and blood collection throughout the study.

ARM II: Patients undergo intensity-modulated radiation therapy (IMRT) or proton beam radiation therapy 5 days a week over 6.5-7 weeks for a total of 33 fractions in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI and blood collection throughout the study.

After completion of study treatment, patients are followed up at 3, 6, and 12 months, every 6 months for year 2 and 3, then yearly for 10 years.

Study Timeline

• Study First Submitted: 2017-06-06
• Study First Submitted QC: 2017-06-06
• Study First Posted: 2017-06-08
• Study Start: 2017-09-12
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-14
• Last Update Posted: 2025-07-15
• Primary Completion: 2027-06-15
• Study Completion: 2027-06-15

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 163

Inclusion Criteria

• PRIOR TO STEP 1 REGISTRATION:
• The patient must have a newly diagnosed unifocal intracranial meningioma, gross totally resected, and histologically confirmed as WHO grade II based upon pathology findings at the enrolling institution. WHO grade will be assigned according to WHO 2016 criteria
• Gross total resection (GTR) will be interpreted as modified Simpson grade 1-3 without gross residual dural-based or extradural tumor. GTR must be confirmed both by modified Simpson grade and by post-operative magnetic resonance imaging (MRI) findings. The modified Simpson grade can be inferred from the operative report (surgeon does not need to explicitly describe the Simpson grade for the purposes of eligibility)
• Step 1 registration must occur within 180 days of the initial surgery; this will provide sufficient time for post-operative imaging confirmation of resection extent after resolution of operative changes. Moreover, it will permit additional surgery if needed to achieve a GTR. Within this 180 day interval, a second surgery is permitted in order to achieve GTR, but even with a second surgery, Step 1 registration must occur within 180 days of the initial resection
• GTR must be confirmed on post-operative imaging following the most recent surgery. For protocol enrollment, the assessment of GTR will be made at each site. However, submission of both pre-operative and post-operative MRIs is required for patients. If a second surgery is performed, submission of post-operative MRI is required and pre-operative MRI is required only if obtained. All sequences obtained in the pre- and post-operative MR imaging are to be submitted to National Radiology Group (NRG) Oncology for study registration. The post-operative MRI must be completed within sufficient time to permit step 1 registration within 180 days of the initial resection. These same conditions apply in the setting of a second surgical procedure, although if a second surgery is completed, step 1 registration must still occur with 180 days of initial surgery. Computed tomography (CT) imaging is not required, but may be obtained if desired clinically, for instance to assess calcifications or hyperostosis
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
• NOTE: Central pathology review must occur between steps 1 and 2 of registration. Once appropriate pathology specimens are received, central pathology review will occur within 10 business days, and must confirm WHO grade II meningioma before the patient can proceed to step 2 registration and randomization
• PRIOR TO STEP 2 REGISTRATION:
• Histologically confirmed diagnosis of WHO grade II meningioma confirmed by central pathology review prior to step 2 registration
• Age >= 18
• History/physical examination, including neurologic examination within 60 days prior to step 2 registration
• Post-operative Zubrod performance status 0-1 within 60 days prior to step 2 registration
• If the patient is a woman is of childbearing potential, a serum pregnancy test, obtained within 14 days prior to step 2 registration, must be negative, and, if randomized to receive radiation therapy, the woman must agree to use contraception

Exclusion Criteria

• Optic nerve sheath meningioma, spinal or other extracranial meningioma, multiple meningiomas, hemangiopericytoma

• Definitive evidence of metastatic meningioma (metastasis, although rare, can occur and is exclusionary)

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (carcinoma in situ of the breast, oral cavity, cervix, melanoma in situ, or other non-invasive malignancies are permissible)

• Previous radiotherapy to the scalp, cranium, brain, or skull base and radiation-induced meningiomas

• Major medical illnesses or psychiatric impairments, which in the investigators opinion, will prevent administration or completion of the protocol therapy and/or preclude informed consent; these include, but are not restricted to:

  • Unstable angina and/or congestive heart failure requiring hospitalization at the time of step 2 registration
  • Transmural myocardial infarction within the last 6 months prior to step 2 registration
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of step 2 registration
  • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of step 2 registration
  • Type II neurofibromatosis (NF2)
  • Ailments entailing substantial increases in sensitivity and side effect risk from radiation therapy (ataxia telangiectasia, Nijmegen breakage syndrome, and human immunodeficiency virus (HIV) with CD4 count < 200 cells/microliter); HIV testing is not required for eligibility for this protocol, and known HIV positive patients are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count >= 200 cells/microliter within 30 days prior to step 2 registration
  • Inability to undergo MRI with and without contrast (e.g. claustrophobia, non-MRI compatible implant or foreign body, gadolinium allergy or renal dysfunction preventing the patient from receiving gadolinium- institutional guidelines should be used to determine if patients are at risk for renal dysfunction). Note that patients with severe claustrophobia are permitted on this study if they are willing and able to undergo MRI with adequate sedation or anesthesia

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Progression free survival (PFS)	From randomization to the first documented disease progression, or death due to any cause, whichever comes first, assessed up to 10 years	Kaplan-Meier method will be used to calculate the PFS rates for each of the two arms. Hazard ratio (HR) on the treatment effect will be calculated using the Cox proportional hazard model. A one-sided log-rank test will be used to test the difference in PFS between the two arms.

Secondary Outcome Measures

Name	Time	Method
PFS	From randomization to the first documented disease progression, or death due to any cause, whichever comes first, assessed up to 5 years	Will be calculated based on the Kaplan-Meier curve. Cox proportional hazard model will be used to determine the adjusted treatment effect on PFS, with patient pretreatment characteristics as covariates.
Disease-specific survival (DSS)	From randomization to disease-related death, assessed up to 10 years	Will be calculated using the cumulative incidence function for each arm. The HR for the treatment effect on DSS will be calculated using Gray's method under the competing risk approach, with death due to non-disease related cause treated as the competing risk. Multivariate analysis on DSS will be performed using the Fine-Gray model, with patient pretreatment characteristics as covariates.
DSS rates	At 5 years	Will be calculated using the cumulative incidence function for each arm. The HR for the treatment effect on DSS will be calculated using Gray's method under the competing risk approach, with death due to non-disease related cause treated as the competing risk. Multivariate analysis on DSS will be performed using the Fine-Gray model, with patient pretreatment characteristics as covariates.
Overall survival (OS)	From randomization to death due to any cause, assessed up to 10 years	Cox proportional hazard model will be used to determine the adjusted treatment effect on OS, with patient pretreatment characteristics as covariates.
Incidence of adverse events (exclusive of alopecia)	Up to 3 years	Will be measured by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4 (version 5 beginning April 5, 2018).
Adherence rate to protocol-specific target and normal tissue parameters	Up to 10 years
Concordance rate of central versus parent-institution pathology	Up to 10 years
Prognostic value of 34-gene expression biomarker	Up to 5 years	Will generate Kaplan-Meier curves for different risk subgroups defined by the risk scores, separately for post-operative observation and post-operative radiotherapy arms. The log-rank test will be used to test the difference in clinical outcomes (PFS and OS) between molecular risk subgroups (separately for the post-operative observation arm and post-operative radiotherapy arm). Cox proportional hazard model will be used to estimate the prognostic effect of the gene expression defined risk groups on clinical outcomes adjusting for pre-treatment patient characteristics as well as treatment arm.
Change in patient reported outcomes (PRO) as assessed by MDASI-BT	Baseline up to 60 months	Will use a 2-sample t-test with a one-sided significance level of 0.05, with a Bonferroni adjustment to account for the neurocognitive function and symptom assessments resulting in an overall type I error of 0.1, there will be 72% statistical power to detect a medium effect size of 0.5 standard deviation for a comparison of the change from baseline to 6 months after randomization between the experimental and the control arm. Will compare PRO outcomes between IMRT to proton therapy.
OS rates	At 5 years	Will be calculated based on the Kaplan-Meier curve. Cox proportional hazard model will be used to determine the adjusted treatment effect on OS, with patient pretreatment characteristics as covariates.
Predictive value of 34-gene expression biomarker	Up to 5 years	Will be evaluated formally through the test of a statistical interaction between molecular risk group (low/intermediate versus high) and treatment (observation versus radiotherapy). The Kaplan-Meier curves of PFS and OS between treatment arms will be displayed separately among low/intermediate risk and high-risk groups. A Cox proportional hazards model will be built including treatment group, gene expression risk group, an interaction term between treatment and gene expression risk group, as well as other pre-treatment patient characteristics. The interaction test will be based on a two-sided 0.05 level Wald test in the Cox proportional hazards model. The treatment difference between radiation therapy and observation will also be tested within each gene expression risk subgroup in a multivariable Cox proportional hazards model, adjusting for other patient characteristics.
Change in neurocognitive function (NCF) assessed by MD Anderson Symptom Inventory with Brain Tumor (MDASI-BT)	Baseline up to 60 months	Will use a 2-sample t-test with a one-sided significance level of 0.05, with a Bonferroni adjustment to account for the neurocognitive function and symptom assessments resulting in an overall type I error of 0.1, there will be 72% statistical power to detect a medium effect size of 0.5 standard deviation (SD) for a comparison of the change from baseline to 6 months after randomization between the experimental and the control arm. Will compare NCF outcomes between IMRT to proton therapy.

Trial Locations

Locations (209)

University of Alabama at Birmingham Cancer Center; 🇺🇸 Birmingham, Alabama, United States

Saint Joseph's Hospital and Medical Center; 🇺🇸 Phoenix, Arizona, United States

Mayo Clinic Hospital in Arizona; 🇺🇸 Phoenix, Arizona, United States

Mayo Clinic in Arizona; 🇺🇸 Scottsdale, Arizona, United States

University of Arizona Cancer Center-Orange Grove Campus; 🇺🇸 Tucson, Arizona, United States

Banner University Medical Center - Tucson; 🇺🇸 Tucson, Arizona, United States

University of Arizona Cancer Center-North Campus; 🇺🇸 Tucson, Arizona, United States

Kaiser Permanente-Anaheim; 🇺🇸 Anaheim, California, United States

Sutter Cancer Centers Radiation Oncology Services-Auburn; 🇺🇸 Auburn, California, United States

Kaiser Permanente-Bellflower; 🇺🇸 Bellflower, California, United States

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