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

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ClinicalTrials.gov Identifier: NCT04588246
Recruitment Status : Recruiting
First Posted : October 19, 2020
Last Update Posted : January 10, 2024
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
NRG Oncology

Study Description
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Brief Summary:
This phase III trial compares the effect of adding whole brain radiotherapy with hippocampal avoidance and memantine to stereotactic radiosurgery 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 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 to stereotactic radiosurgery may be effective in shrinking or stabilizing cancer that has spread to the brain and returned in other areas of the brain after receiving stereotactic radiosurgery.

Condition or disease Intervention/treatment Phase
Anatomic Stage IV Breast Cancer AJCC v8 Metastatic Breast Carcinoma Metastatic Digestive System Carcinoma Metastatic Lung Non-Small Cell Carcinoma Metastatic Malignant Neoplasm in the Brain Metastatic Melanoma Metastatic Renal Cell Carcinoma Prognostic Stage IV Breast Cancer AJCC v8 Recurrent Brain Neoplasm Stage IV Lung Cancer AJCC v8 Stage IV Renal Cell Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8 Drug: Memantine Other: Quality-of-Life Assessment Other: Questionnaire Administration Radiation: Stereotactic Radiosurgery Radiation: Whole-Brain Radiotherapy Phase 3

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Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 350 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
Official Title: Phase III Trial of Salvage Stereotactic Radiosurgery (SRS) or SRS + Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) for First or Second Distant Brain Relapse After Upfront SRS With Brain Metastasis Velocity >/= 4 Brain Metastases/Year
Actual Study Start Date : December 15, 2020
Estimated Primary Completion Date : January 31, 2025
Estimated Study Completion Date : January 31, 2030

Resource links provided by the National Library of Medicine

Drug Information available for: Memantine

Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm I (salvage SRS, memantine, HA-WBRT)
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. Within 1 week prior to or following HA-WBRT, patients undergo salvage SRS. 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.
 Drug: Memantine
Given PO

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Radiation: Stereotactic Radiosurgery
Undergo salvage SRS
Other Names:
  • Stereotactic External Beam Irradiation
  • stereotactic external-beam radiation therapy
  • Stereotactic Radiation Therapy
  • Stereotactic Radiotherapy
  • stereotaxic radiation therapy
  • stereotaxic radiosurgery

Radiation: Whole-Brain Radiotherapy
Undergo HA-WBRT
Other Names:
  • WBRT
  • whole-brain radiation therapy
Active Comparator: Arm II (salvage SRS)
Patients undergo salvage SRS.
 Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Radiation: Stereotactic Radiosurgery
Undergo salvage SRS
Other Names:
  • Stereotactic External Beam Irradiation
  • stereotactic external-beam radiation therapy
  • Stereotactic Radiation Therapy
  • Stereotactic Radiotherapy
  • stereotaxic radiation therapy
  • stereotaxic radiosurgery


Outcome Measures
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Primary Outcome Measures :
  1. Time to Neurologic Death [ Time Frame: From randomization until progressive neurologic decline at time of death, irrespective of status of extracranial disease, or death from inter-current disease in patients with severe neurologic dysfunction, assessed up to 3 years ]
    The primary comparison of treatment effect on neurologic deaths will be based a one-sided 0.05-level (score) test for cause-specific hazard ratio in a Cox proportional hazards model. Additional analyses will involve estimating the median time to neurologic death using the cumulative incidence function estimator in the presence of precluding events such as non-neurologic deaths in the two arms, separately. The Gray's test will be used to evaluate the difference in the distribution of neurologic deaths. These results will be interpreted in light of the competing non-neurologic deaths, which may be frequent.


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: From randomization to death from any cause, assessed up to 3 years ]
    Analysis will consist of estimation of the OS curves via the Kaplan-Meier method and a stratified log-rank test. Additional analyses may consist of estimating the hazard ratio via the Cox proportional hazards model, accounting for other prognostic covariates (and 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.

  2. Intracranial Progression-Free Survival (IPFS) [ Time Frame: From randomization to intracranial progression or death from any cause, assessed up to 3 years ]
    Analysis will consist of estimation of the IPFS curves via the Kaplan-Meier method and a stratified log-rank test. Additional analyses may consist of estimating the hazard ratio via the Cox proportional hazards model, accounting for other prognostic covariates (and 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.

  3. Brain Metastasis Velocity (BMV) at subsequent relapse [ Time Frame: Up to 3 years ]
    The Wilcoxon rank-sum test will be used to compare the distributions of BMVs between the two treatment arms at 2-sided 0.05 level.

  4. Cognitive Abilities [ Time Frame: Up to 1 year ]
    Measured by the Patient Reported Outcomes Measurement Information System Cognitive Function Short Form 4a version 2.0.

  5. Symptom Burden [ Time Frame: Up to 1 year ]
    Measured by the MD Anderson Symptom Inventory - Brain Tumor (MDASI-BT). The MDASI-BT rates symptoms on an 11- point scale (0 to 10) to indicate the presence and severity of the symptom, with 0 being "not present" and 10 being "as bad as you can imagine." Each symptom is rated at its worst in the last 24 hours.

  6. Health Status [ Time Frame: Up to 1 year ]
    Measured by the European Quality of Life Five Dimension Five Level Scale Questionnaire (EQ-5D-5L). The EQ-5D-5L uses 5 levels (no problems, slight problems, moderate problems, severe problems, and extreme problems) to assess current health status.

  7. Incidence of Adverse Events associated with the interventions [ Time Frame: Up to 3 years ]
    Adverse Events (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 arm.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have developed their first or second distant brain relapse(s) at least 8 weeks after upfront 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 magnetic resonance imaging (MRI) brain scan obtained within 21 days prior to randomization

    • 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 upfront 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 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
  • 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:

  • 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, small cell carcinoma, 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-aspartate (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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04588246


Locations
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Sponsors and Collaborators
NRG Oncology
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Vinai Gondi NRG Oncology
More Information
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Responsible Party: NRG Oncology
ClinicalTrials.gov Identifier: NCT04588246    
Other Study ID Numbers: NRG-BN009
NCI-2020-07375 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-BN009 ( Other Identifier: NRG Oncology )
NRG-BN009 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
First Posted: October 19, 2020    Key Record Dates
Last Update Posted: January 10, 2024
Last Verified: January 2024

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Breast Neoplasms
Lung Neoplasms
Neoplasms
Carcinoma, Renal Cell
Brain Neoplasms
Carcinoma, Non-Small-Cell Lung
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms by Site
Breast Diseases
Skin Diseases
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases
 Respiratory Tract Diseases
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Female Urogenital Diseases
Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
Kidney Diseases
Urologic Diseases
Male Urogenital Diseases
Central Nervous System Neoplasms
Nervous System Neoplasms
Brain Diseases
Central Nervous System Diseases