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

Metastatic Melanoma Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04588246
• Other study ID #: NRG-BN009
• Secondary ID: NCI-2020-07375NR
• Status: Recruiting
• Phase: Phase 3
• Start date: December 15, 2020
• Est. completion date: January 31, 2030

Study information

• Verified date: January 2024
• Source: NRG Oncology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

PRIMARY OBJECTIVE:

I. To determine if salvage stereotactic radiosurgery (SRS) plus whole brain radiotherapy with hippocampal avoidance (HA-WBRT) in patients with brain metastasis velocity >= 4 new brain metastases/year at time of first or second distant brain failure following upfront SRS prolongs time to neurologic death as compared to salvage SRS alone.

SECONDARY OBJECTIVES:

I. To determine if salvage SRS + HA-WBRT in patients with brain metastasis velocity >= 4 new brain metastases/year at time of first or second distant brain failure following upfront SRS prolongs overall survival as compared to salvage SRS alone.

II. To evaluate if salvage SRS + HA-WBRT in patients with brain metastasis velocity >= 4 new brain metastases/year at time of first or second distant brain failure following upfront SRS prolongs intracranial progression-free survival as compared to salvage SRS alone.

III. To evaluate if salvage SRS + HA-WBRT in patients with brain metastasis velocity >= 4 new brain metastases/year at time of first or second distant brain failure following upfront SRS improves brain metastasis velocity at subsequent relapse as compared to salvage SRS alone.

IV. To assess perceived difficulties in cognitive abilities, symptom burden and health status after salvage SRS + HA-WBRT, as compared to salvage SRS alone, in patients with brain metastasis velocity >= 4 new brain metastases/year at time of first or second distant brain failure following upfront SRS.

V. To compare neurocognitive function outcomes following salvage SRS + HA-WBRT, as compared to salvage SRS alone, in patients with brain metastasis velocity >= 4 new brain metastases/year at time of first or second distant brain failure following upfront SRS.

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 salvage SRS + HA-WBRT in patients with brain metastasis velocity >= 4 new brain metastases/year at time of first or second distant brain failure following upfront SRS improves brain metastasis velocity and/or overall survival at subsequent relapse as compared to salvage SRS.

VI. To compare the estimated cost of brain-related therapies and quality-adjusted life years in patients who receive salvage SRS + HA-WBRT, as compared to salvage SRS alone, in patients with metastasis velocity >= 4 new brain metastases/year at time of first or second distant brain failure following upfront SRS.

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. 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 orally (PO) once daily (QD) or twice daily (BID) for 24 weeks in the absence of disease progression or unacceptable toxicity.

ARM II: Patients undergo salvage SRS.

After completion of study treatment, patients are followed up every 2-3 months for at least 1 year.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 350
• Est. completion date: January 31, 2030
• Est. primary completion date: January 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Anatomic Stage IV Breast Cancer AJCC v8
• Brain Neoplasms
• Breast Neoplasms
• Carcinoma
• Carcinoma, Non-Small-Cell Lung
• Carcinoma, Renal Cell
• Lung Neoplasms
• 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
• Neoplasms
• 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

Intervention

Drug:
• Memantine
Given PO

Other:
• Quality-of-Life Assessment
Ancillary studies
• Questionnaire Administration
Ancillary studies

Radiation:
• Stereotactic Radiosurgery
Undergo salvage SRS
• Whole-Brain Radiotherapy
Undergo HA-WBRT

Locations

Country	Name	City	State
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	MedStar Franklin Square Medical Center/Weinberg Cancer Institute	Baltimore	Maryland
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	UM Upper Chesapeake Medical Center	Bel Air	Maryland
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Tufts Medical Center	Boston	Massachusetts
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Christiana Care Health System-Concord Health Center	Chadds Ford	Pennsylvania
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Saint Joseph Mercy Chelsea	Chelsea	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Central Maryland Radiation Oncology in Howard County	Columbia	Maryland
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	UM Sylvester Comprehensive Cancer Center at Coral Gables	Coral Gables	Florida
United States	City of Hope Corona	Corona	California
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Carle at The Riverfront	Danville	Illinois
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	UM Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida
United States	Northwestern Medicine Cancer Center Kishwaukee	DeKalb	Illinois
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois
United States	UM Baltimore Washington Medical Center/Tate Cancer Center	Glen Burnie	Maryland
United States	UPMC Cancer Centers - Arnold Palmer Pavilion	Greensburg	Pennsylvania
United States	Prisma Health Cancer Institute - Faris	Greenville	South Carolina
United States	City of Hope at Irvine Lennar	Irvine	California
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	Northwell Health/Center for Advanced Medicine	Lake Success	New York
United States	City of Hope Antelope Valley	Lancaster	California
United States	Geisinger Medical Oncology-Lewisburg	Lewisburg	Pennsylvania
United States	Covenant Medical Center-Lakeside	Lubbock	Texas
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	Riddle Memorial Hospital	Media	Pennsylvania
United States	Froedtert Menomonee Falls Hospital	Menomonee Falls	Wisconsin
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	West Virginia University Healthcare	Morgantown	West Virginia
United States	Christiana Care Health System-Christiana Hospital	Newark	Delaware
United States	Delaware Clinical and Laboratory Physicians PA	Newark	Delaware
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	Drexel Town Square Health Center	Oak Creek	Wisconsin
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Memorial Hospital West	Pembroke Pines	Florida
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	UPMC-Shadyside Hospital	Pittsburgh	Pennsylvania
United States	Geisinger Cancer Services-Pottsville	Pottsville	Pennsylvania
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	University of Rochester	Rochester	New York
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	Siteman Cancer Center at Christian Hospital	Saint Louis	Missouri
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	City of Hope South Pasadena	South Pasadena	California
United States	City of Hope South Bay	Torrance	California
United States	Banner University Medical Center - Tucson	Tucson	Arizona
United States	University of Arizona Cancer Center-North Campus	Tucson	Arizona
United States	City of Hope Upland	Upland	California
United States	Carle Cancer Center	Urbana	Illinois
United States	The Carle Foundation Hospital	Urbana	Illinois
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	Froedtert West Bend Hospital/Kraemer Cancer Center	West Bend	Wisconsin
United States	Asplundh Cancer Pavilion	Willow Grove	Pennsylvania
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	Lankenau Medical Center	Wynnewood	Pennsylvania
United States	UPMC Memorial	York	Pennsylvania
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
NRG Oncology	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to Neurologic Death	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.	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
Secondary	Overall Survival (OS)	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.	From randomization to death from any cause, assessed up to 3 years
Secondary	Intracranial Progression-Free Survival (IPFS)	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.	From randomization to intracranial progression or death from any cause, assessed up to 3 years
Secondary	Brain Metastasis Velocity (BMV) at subsequent relapse	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.	Up to 3 years
Secondary	Cognitive Abilities	Measured by the Patient Reported Outcomes Measurement Information System Cognitive Function Short Form 4a version 2.0.	Up to 1 year
Secondary	Symptom Burden	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.	Up to 1 year
Secondary	Health Status	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.	Up to 1 year
Secondary	Incidence of Adverse Events associated with the interventions	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.	Up to 3 years