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

• ClinicalTrials.gov Identifier: NCT03180268
• Recruitment Status: Recruiting
• First Posted: June 8, 2017
• Last Update Posted: February 7, 2024
• Sponsor: NRG Oncology
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): NRG Oncology

Tracking Information

• First Submitted Date: June 6, 2017
• First Posted Date: June 8, 2017
• Last Update Posted Date: February 7, 2024
• Actual Study Start Date: June 14, 2017
• Estimated Primary Completion Date: June 15, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 6, 2017)

Progression-Free Survival (PFS) [ Time Frame: 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 (Kaplan 1958). Hazard ratio (HR) on the treatment effect will be calculated using the Cox proportional hazard model (Cox 1972). A one-sided log-rank test will be used to test the difference in PFS between the two arms (Peto 1972).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 6, 2017)

• Overall Survival (OS) [ Time Frame: From randomization to death due to any cause, assessed up to 10 years ]
  Kaplan-Meier method will be used to calculate the OS rates for each of the two arms (Kaplan 1958). Hazard ratio (HR) on the treatment effect will be calculated using the Cox proportional hazard model (Cox 1972). A one-sided log-rank test will be used to test the difference in OS between the two arms (Peto 1972). Cox proportional hazard model will be used to determine the adjusted treatment effect on OS, with patient pretreatment characteristics as covariates.
• 5 Year Overall Survival (OS) [ Time Frame: At 5 years after randomization ]
  Will be calculated based on the Kaplan-Meier curve.
• Disease-Specific Survival (DSS) [ Time Frame: 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 (Gray 1988). Multivariate analysis on DSS will be performed using the Fine-Gray model, with patient pretreatment characteristics as covariates (Fine 1999).
• 3 Year Disease-Specific Survival (DSS) [ Time Frame: At 3 years after randomization ]
  Will be calculated using the cumulative incidence function for each arm.
• 5 Year Disease-Specific Survival (DSS) [ Time Frame: At 5 years after randomization ]
  Will be calculated using the cumulative incidence function for each arm.
• 3 Year Progression-Free Survival (PFS) [ Time Frame: From randomization to the first documented disease progression, or death due to any cause, whichever comes first, assessed at 3 years after randomization. ]
  Will be calculated based on the Kaplan-Meier curve.
• 5 Year Progression-Free Survival (PFS) [ Time Frame: From randomization to the first documented disease progression, or death due to any cause, whichever comes first, assessed up to 5 years after randomization. ]
  Will be calculated based on the Kaplan-Meier curve.
• Neurocognitive Function (NCF) [ Time Frame: Baseline up to 60 months after randomization ]
  Longitudinal analysis will be performed to compare NCF over time between the 2 arms, using the NCF Clinical Trial Battery (CTB) composite score. Early change from baseline in CTB composite score will be evaluated and compared between the 2 arms using 2-sample t tests.
• Patient Reported Outcomes (PRO) as assessed by MDASI-BT [ Time Frame: Baseline up to 60 months after randomization ]
  Longitudinal analysis will be performed to compare symptom burden over time between the 2 arms, using the MDASI-BT. Early change from baseline in symptom burden will be evaluated and compared between the 2 arms using 2-sample t tests.
• Assessment of pHH3 mitotic index [ Time Frame: Up to 10 years after randomization ]
  The Kaplan-Meier method will be used to estimate the PFS and OS rates by pHH3 category. The HRs on the effect of pHH3 on PFS and OS, respectively will be calculated using the Cox proportional hazard model and will be tested using the log-rank test. Multivariate analyses will be conducted with patient pretreatment characteristics, such as age and Simpson resection grade, included as covariates.
• Incidence of adverse events as measured by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4 (exclusive of alopecia) [ Time Frame: Up to 3 years after randomization ]
  The number of adverse events will be measured using the CTCAE, version 4

• 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: Observation or Radiation Therapy in Treating Patients With Newly Diagnosed Grade II Meningioma That Has Been Completely Removed by Surgery
• Official Title: Phase III Trial of Observation Versus Irradiation for a Gross Totally Resected Grade II Meningioma
• 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 OBJECTIVES:

I. To determine, in terms of progression-free survival (PFS), 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. Outcomes and 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. Tissue microarray construction, and assessment of pHH3 mitotic index and molecular correlates to OS.

OUTLINE: Patients are randomized to 1 of 2 arms after undergoing gross total resection.

ARM I: Patients undergo observation.

ARM II: Patients undergo radiation therapy 5 days a week over 6.5-7 weeks for a total of 33 fractions (59.4 Gy in 33 daily fractions of 1.8 Gy each).

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 Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Grade II Meningioma
• Intracranial Meningioma

Intervention

• Other: Clinical Observation
  Undergo observation
• Radiation: Radiation Therapy
  Undergo radiation therapy
  Other Names:

  • Cancer Radiotherapy
  • Irradiate
  • Irradiated
  • Irradiation
  • RADIATION
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation

Study Arms

• Arm I (Clinical Observation)
  Patients undergo observation after gross total resection.
  Intervention: Other: Clinical Observation
• Experimental: Arm II (Radiation Therapy)
  Patients undergo radiation therapy 5 days a week over 6.5-7 weeks for a total of 33 fractions after gross total resection.
  Intervention: Radiation: Radiation Therapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 6, 2017): 148
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: August 31, 2027
• Estimated Primary Completion Date: June 15, 2027 (Final data collection date for primary outcome measure)

Eligibility Criteria

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
• Step 1 registration must occur within 180 days of the initial surgery; 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
• For step 1 registration the operating neurosurgeon must provide the modified Simpson grade
• GTR must be confirmed on post-operative imaging following the most recent surgery; 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; imaging subsequent to enrollment must include pre and post gadolinium contrast-enhanced three-dimensional spoiled gradient (SPGR), magnetization-prepared rapid gradient echo (MP-RAGE), or turbo field echo (TFE) MRI scan and an axial T2 fluid attenuated inversion recovery (FLAIR) sequence; to yield acceptable image quality, the gadolinium contrast-enhanced three-dimensional SPGR, MP-RAGE, or TFE axial MRI scan should use the smallest possible axial slice thickness not exceeding 1.5 mm; 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
• If the patient is a primary English speaker, the patient must participate in the NCF and patient reported outcomes part of the study; if the patient is a primary French or Spanish speaker, the patient must participate in the patient reported outcomes part of the study
• 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 15 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
• 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
• 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, etc) or receive gadolinium; 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
• Pregnancy and/or nursing females

Sex/Gender

• Sexes Eligible for Study: All

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

Contacts

Contact: C. Leland Rogers, MD; 602-406-6761; leland.rogers@dignityhealth.org

• Listed Location Countries: Canada, India, Japan, Saudi Arabia, United States

Administrative Information

• NCT Number: NCT03180268
• Other Study ID Numbers: NRG-BN003; NCI-2016-01619 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); NRG-BN003; NRG-BN003 ( Other Identifier: NRG Oncology ); NRG-BN003 ( 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

• Plan to Share IPD: No

• 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: C. Leland Rogers, MD; NRG Oncology

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