Comparing Whole Brain Radiotherapy Using a Technique That Avoids the Hippocampus to Stereotactic Radiosurgery in Patients With Cancer That Has Spread to the Brain and Come Back in Other Areas of the Brain After Earlier Stereotactic Radiosurgery

Phase 3

Terminated

Conditions: Anatomic Stage IV Breast Cancer AJCC v8
Metastatic Malignant Solid Neoplasm
Metastatic Lung Non-Small Cell Carcinoma
Metastatic Lung Small Cell Carcinoma
Metastatic Malignant Neoplasm in the Brain
Stage IV Renal Cell Cancer AJCC v8
Metastatic Malignant Breast Neoplasm
Metastatic Melanoma
Metastatic Renal Cell Carcinoma
Recurrent Brain Neoplasm

Interventions: Procedure: Biospecimen Collection
Procedure: Computed Tomography
Procedure: Magnetic Resonance Imaging
Drug: Memantine
Other: Quality-of-Life Assessment
Other: Questionnaire Administration
Radiation: Stereotactic Radiosurgery
Radiation: Whole-Brain Radiotherapy

Registration Number: NCT04588246

Lead Sponsor: NRG Oncology

Brief Summary: This phase III trial compares the effect of adding whole brain radiotherapy with hippocampal avoidance and memantine versus stereotactic radiosurgery alone in treating patients with cancer that has spread to the brain and come back in other areas of the brain after earlier stereotactic radiosurgery. Hippocampus avoidance during whole-brain radiation therapy decreases the amount of radiation that is delivered to the hippocampus, which is a brain structure that is important for memory. The medicine memantine is also often given with whole brain radiation therapy because it may decrease the risk of side effects of radiation on neurocognitive function (including thinking and memory). Stereotactic radiosurgery delivers a high dose of radiation only to the small areas of cancer in the brain and avoids the surrounding normal brain tissue. Adding whole brain radiotherapy with hippocampal avoidance and memantine may be effective in reducing the size of the cancer or keeping the cancer the same size when it has spread to the brain and/or come back in other areas of the brain compared to stereotactic radiosurgery.

Detailed Description: PRIMARY OBJECTIVE:

I. To determine if hippocampal-avoidant plus whole brain radiotherapy (HA-WBRT) in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year prolongs time to neurologic death as compared to stereotactic radiosurgery (SRS).

SECONDARY OBJECTIVES:

I. To determine if HA-WBRT in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year prolongs overall survival as compared to SRS.

II. To evaluate if HA-WBRT in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year prolongs intracranial progression-free survival as compared to SRS.

III. To evaluate if HA-WBRT in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year improves brain metastasis velocity at subsequent relapse as compared to SRS.

IV. To assess perceived difficulties in cognitive abilities, symptom burden and health status after HA-WBRT, as compared to SRS, in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year.

V. To compare neurocognitive function outcomes following HA-WBRT, as compared to SRS, in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year.

VI. To tabulate and descriptively compare the adverse events associated with the interventions.

VII. To tabulate and descriptively compare the number of salvage procedures used to manage recurrent intracranial disease following the interventions.

EXPLORATORY OBJECTIVES:

I. To collect serum, plasma, and whole blood for translational research analyses.

II. To collect baseline and all follow-up magnetic resonance (MR) imaging for hippocampal volume, memory center substructures, axial T2 volumes, and quantitative texture analysis.

III. To collect baseline and follow-up MR imaging to extract whole brain volume, white matter volume and volume of metastatic disease to correlate with cognitive change at 4 months.

IV. To evaluate dose-volume histogram parameters to correlate with radiation toxicity.

V. To assess in patients receiving immunotherapy or targeted therapy, if HA-WBRT in patients with distant brain failure with brain metastasis velocity \>= 4 new brain metastases/year at time improves brain metastasis velocity and/or overall survival at subsequent relapse as compared to SRS.

VI. To compare the estimated cost of brain-related therapies and quality-adjusted life years in patients who receive HA-WBRT, as compared to SRS, in patients with distant brain failure with metastasis velocity \>= 4 new brain metastases/year.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine orally (PO) once daily (QD) or twice daily (BID) for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) and magnetic resonance imaging (MRI) and may undergo blood sample collection throughout the trial.

ARM II: Patients undergo single fraction SRS or fractionated SRS (fSRS) on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.

Patients are followed up at 2, 4, 6, 9, and 12 months from the start of SRS/fSFS or HA-WBRT and then every 6 months after month 12 and within 21 days after patient death.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 350

Inclusion Criteria

Patients must have developed their distant brain relapse(s) at least 8 weeks after last SRS and within 21 days prior to randomization
- Distant brain relapse lesions to be treated must measure =< 3.0 cm in maximal extent and total volume of distant brain relapses to be treated must measure < 30 mL on the contrast-enhanced diagnostic MRI brain scan obtained within 21 days prior to randomization
- "last SRS" refers to the most recent SRS procedure that the patient received prior to enrollment on this study
- Distant brain relapse lesions must be diagnosed on MRI, which will include the following elements:
  - REQUIRED MRI ELEMENTS
    - Post gadolinium contrast-enhanced T1-weighted three-dimensional (3D) spoiled gradient (SPGR). Acceptable 3D SPGR sequences include magnetization-prepared 3D gradient recalled echo (GRE) rapid gradient echo (MP-RAGE), turbo field echo (TFE) MRI, BRAVO (brain volume imaging) or 3D fast FE (field echo). The T1-weighted 3D scan should use the smallest possible axial slice thickness, not to exceed 1.5 mm
    - Pre-contrast T1 weighted imaging (3D imaging sequence strongly encouraged)
    - A minimum of one axial T2 fluid attenuated inversion recovery (FLAIR) (preferred) or T2 sequence is required. This can be acquired as a 2D or 3D image. If 2D, the images should be obtained in the axial plane
  - ADDITIONAL RECOMMENDATIONS
    - Recommendation is that an axial T2 FLAIR (preferred) sequence be performed instead of a T2 sequence
    - Recommendation is that that pre-contrast 3D T1 be performed with the same parameters as the post-contrast 3D T1
    - Recommendation is that imaging be performed on a 3 Tesla (3T) MRI
    - Recommendation is that the study participants be scanned on the same MRI instrument at each time point
    - Recommendation is that if additional sequences are obtained, these should meet the criteria outlined in Kaufmann et al., 2020
    - If additional sequences are obtained, total imaging time should not exceed 60 minutes
Brain metastasis velocity (BMV) since last SRS must be >= 4 brain metastases/year
The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
Pathologically (histologically or cytologically) proven diagnosis of small cell cancer, non-small cell lung cancer, melanoma, breast cancer, renal cell carcinoma, or gastrointestinal cancer within 10 years prior to randomization. If the original histologic proof of malignancy is greater than 10 years, then pathological (i.e., more recent) confirmation is required (e.g., from a systemic metastasis or brain metastasis)
- Other histologies are not permitted
History and physical examination within 28 days prior to randomization
Age >= 18
Karnofsky performance status of >= 70 within 28 days prior to randomization
Calculated creatinine clearance (CrCl) >= 30 ml/min (within 28 days prior to randomization)
Blood urea nitrogen (BUN) within 1.5 times the institutional upper limit of normal (ULN) (e.g., if the ULN is 20 mg/dL, then BUN up to 30 mg/dL is permitted) (within 28 days prior to randomization)
Negative urine or serum pregnancy test (in women of childbearing potential) within 14 days prior to randomization

Exclusion Criteria

BMV >= 4 brain metastases/year at time of any SRS prior to enrollment.
- Patients are permitted to have undergone multiple SRS treatments to different brain metastases so long as prior BMV has been less than 4 brain metastases/year
Prior WBRT or prophylactic cranial irradiation
Local relapse of metastasis previously treated with upfront SRS (i.e., relapse outside previously SRS-treated metastases is allowed)
Brain metastases from primary germ cell tumor or lymphoma
Definitive leptomeningeal metastasis
Planned cytotoxic chemotherapy on the same day as SRS or HA-WBRT; concurrent immunotherapy is permitted
Radiographic evidence of enlargement or other architectural distortion of the lateral ventricles, including placement of external ventricular drain or ventriculoperitoneal shunt
Known history of demyelinating disease such as multiple sclerosis
Inability to swallow pills
Contraindication to MR imaging such as non-MR conditional implanted metal devices or unknown metallic foreign bodies, or contraindication to gadolinium contrast administration during MR imaging, such as anaphylactic allergy that cannot be adequately addressed with pre-contrast medications or acute kidney injury
Contraindications to memantine, including:
- Allergy, including prior allergic reaction to memantine
- Intractable seizures on adequate anticonvulsive therapy-more than 1 seizure per month for the past 2 months
- Current use of N-methyl-D-asparatate (NMDA) agonist
- Current alcohol or drug abuse, which can exacerbate lethargy/dizziness with memantine
Severe, active co-morbidity defined as follows:
- Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
- Transmural myocardial infarction within the last 6 months
- Acute bacterial or fungal infection requiring intravenous antibiotics at the time of randomization
- Chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy at the time of randomization
- Severe hepatic disease defined as a diagnosis of Child-Pugh class B or C hepatic disease
- Renal tubular acidosis or metabolic acidosis
- Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive 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 randomization. Note also that HIV testing is not required for eligibility for this protocol
Pregnant or lactating women, or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the medication and radiation involved in this study has unknown effects on the unborn fetus

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (memantine, HA-WBRT)	Computed Tomography	Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
Arm I (memantine, HA-WBRT)	Biospecimen Collection	Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
Arm II (SRS/fSRS)	Biospecimen Collection	Patients undergo single fraction SRS or fSRS on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
Arm I (memantine, HA-WBRT)	Magnetic Resonance Imaging	Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
Arm I (memantine, HA-WBRT)	Memantine	Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
Arm I (memantine, HA-WBRT)	Quality-of-Life Assessment	Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
Arm I (memantine, HA-WBRT)	Questionnaire Administration	Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
Arm I (memantine, HA-WBRT)	Whole-Brain Radiotherapy	Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total of 10 fractions in the absence of disease progression or unacceptable toxicity. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine PO QD or BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
Arm II (SRS/fSRS)	Computed Tomography	Patients undergo single fraction SRS or fSRS on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
Arm II (SRS/fSRS)	Magnetic Resonance Imaging	Patients undergo single fraction SRS or fSRS on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
Arm II (SRS/fSRS)	Quality-of-Life Assessment	Patients undergo single fraction SRS or fSRS on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
Arm II (SRS/fSRS)	Questionnaire Administration	Patients undergo single fraction SRS or fSRS on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.
Arm II (SRS/fSRS)	Stereotactic Radiosurgery	Patients undergo single fraction SRS or fSRS on study. Patients also undergo CT and MRI and may undergo blood sample collection throughout the trial.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Neurologic Death	From baseline to neurologic death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.	Neurologic death defined as 1) Progressive neurologic decline or new neurologic symptoms/signs at time of death irrespective of status of extracranial disease OR 2) Death from inter-current disease in patients with severe neurologic dysfunction. Neurologic death rates were to be estimated using the cumulative incidence method, treating non-neurologic deaths as competing risks, and otherwise censoring participants alive at time of analysis. Analysis was to occur after 127 neurologic death events overall. The primary comparison of treatment arms would be a one-sided 0.05-level test for cause-specific hazard ratio (CHR) in a Cox proportional hazards model. Given the small number of participants due to early study closure, only the number of patients with neurologic death is reported and no statistical testing was done.

Secondary Outcome Measures

Name	Time	Method
Overall Survival	Baseline to death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.	Survival rates were to be estimated using the Kaplan-Meier method and the treatment arms were to be compared using a stratified log-rank test. Given the small number of participants due to early study closure, only the number of patients alive at time of study termination is reported, and no statistical testing was done.
Intracranial Progression-Free Survival (IPFS)	Baseline to intracranial progression, death, or last follow-up. Maximum follow-up at time of study termination was 29.7 months.	IPFS rates were to be estimated using the Kaplan-Meier method and the treatment arms were to be compared using a stratified log-rank test. Given the small number of participants due to early study closure, only the number of patients with alive without intracranial progression is reported, and no statistical testing was done. Per the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, intracranial progression is defined as local progression of lesions treated with prior radiation or distant progression/development of a new brain lesion. Given the small number of participants due to early study closure, only the number of patients alive without intracranial progression is reported and no statistical testing was done.
Brain Metastasis Velocity at Subsequent Relapse (BMVs)	Baseline to death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.	BMVs = \[total number of new brain metastases since on-study SRS/HA-WBRT\] / (years since on-study SRS/HA-WBRT). BMVs is calculated at the time of distant brain relapse. Higher BMVs is associated with lower rates of survival and higher rates of neurologic death.
Change From Baseline in the M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) Symptom Severity Score	Baseline and 4 months from treatment start	The MD Anderson Symptom Inventory for brain tumor (MDASI-BT) is a 28-item multi-symptom patient-reported outcome measure assessing the presence and severity of symptoms experienced by cancer patients and the interference with daily living caused by these symptoms, with 9 items specific to brain tumors. Each item ranges from 0 ("not present") to 10 ("as bad as you can imagine") and is rated as the worst occurrence in the last 24 hours. The Symptom Severity subscale score is the average of the symptom severity items, ranging from 0 (best) to 10 (worst). Change from baseline is calculated as score at 4 months minus score at baseline. A negative change value indicates improvement in symptom severity, while a positive change value indicates worsening.
Number of Participants With a Grade 3 or Higher Adverse Event	Baseline to last follow-up. Maximum follow-up at time of study termination was 29.7 months.	Common Terminology Criteria for Adverse Events (version 5.0) grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Adverse events reported as possibly, probably, or definitely related to treatment are considered to be treatment-related adverse events. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Number of Participants Who Received Salvage Procedures	Baseline to last follow-up. Maximum follow-up at time of study termination was 29.7 months.	Salvage procedures are defined as procedures for the purpose of managing recurrent intracranial disease following protocol treatment.

Trial Locations

Locations (81): Banner University Medical Center - Tucson
🇺🇸
Tucson, Arizona, United States
University of Arizona Cancer Center-North Campus
🇺🇸
Tucson, Arizona, United States
City of Hope Corona
🇺🇸
Corona, California, United States
City of Hope Comprehensive Cancer Center
🇺🇸
Duarte, California, United States
City of Hope at Irvine Lennar
🇺🇸
Irvine, California, United States
City of Hope Antelope Valley
🇺🇸
Lancaster, California, United States
Sutter Cancer Centers Radiation Oncology Services-Roseville
🇺🇸
Roseville, California, United States
Sutter Roseville Medical Center
🇺🇸
Roseville, California, United States
Sutter Medical Center Sacramento
🇺🇸
Sacramento, California, United States
California Pacific Medical Center-Pacific Campus
🇺🇸
San Francisco, California, United States
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Banner University Medical Center - Tucson
🇺🇸Tucson, Arizona, United States