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

Sponsor

NRG Oncology (Other)

Overall Status

Recruiting

CT.gov ID

NCT04588246

Collaborator

National Cancer Institute (NCI) (NIH)

350

Enrollment

Locations

Arms

109.5

Anticipated Duration (Months)

7.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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

Detailed Description

PRIMARY OBJECTIVE:

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:

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.
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.
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.
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.
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.
To tabulate and descriptively compare the adverse events associated with the interventions.
To tabulate and descriptively compare the number of salvage procedures used to manage recurrent intracranial disease following the interventions.

EXPLORATORY OBJECTIVES:

To collect serum, plasma, and whole blood for translational research analyses.
To collect baseline and all follow-up magnetic resonance (MR) imaging for hippocampal volume, memory center substructures, axial T2 volumes, and quantitative texture analysis.
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.
To evaluate dose-volume histogram parameters to correlate with radiation toxicity.
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.
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.

Study Design

Study Type:

Interventional

Anticipated 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 :

Dec 15, 2020

Anticipated Primary Completion Date :

Jan 31, 2025

Anticipated Study Completion Date :

Jan 31, 2030

Arms and Interventions

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 Names: 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 Names: 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

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 Names:

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 Names:

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

Primary Outcome Measures

Time to Neurologic Death [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

Overall Survival (OS) [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.
Intracranial Progression-Free Survival (IPFS) [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.
Brain Metastasis Velocity (BMV) at subsequent relapse [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.
Cognitive Abilities [Up to 1 year]
Measured by the Patient Reported Outcomes Measurement Information System Cognitive Function Short Form 4a version 2.0.
Symptom Burden [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.
Health Status [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.
Incidence of Adverse Events associated with the interventions [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

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Banner University Medical Center - Tucson	Tucson	Arizona	United States	85719
2	University of Arizona Cancer Center-North Campus	Tucson	Arizona	United States	85719
3	UM Sylvester Comprehensive Cancer Center at Coral Gables	Coral Gables	Florida	United States	33146
4	UM Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida	United States	33442
5	Mayo Clinic in Florida	Jacksonville	Florida	United States	32224-9980
6	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
7	Memorial Hospital West	Pembroke Pines	Florida	United States	33028
8	Northwestern University	Chicago	Illinois	United States	60611
9	Carle on Vermilion	Danville	Illinois	United States	61832
10	Northwestern Medicine Cancer Center Kishwaukee	DeKalb	Illinois	United States	60115
11	Carle Physician Group-Effingham	Effingham	Illinois	United States	62401
12	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois	United States	60134
13	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois	United States	61938
14	Carle Cancer Center	Urbana	Illinois	United States	61801
15	The Carle Foundation Hospital	Urbana	Illinois	United States	61801
16	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois	United States	60555
17	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
18	MedStar Franklin Square Medical Center/Weinberg Cancer Institute	Baltimore	Maryland	United States	21237
19	UM Upper Chesapeake Medical Center	Bel Air	Maryland	United States	21014
20	Central Maryland Radiation Oncology in Howard County	Columbia	Maryland	United States	21044
21	UM Baltimore Washington Medical Center/Tate Cancer Center	Glen Burnie	Maryland	United States	21061
22	Tufts Medical Center	Boston	Massachusetts	United States	02111
23	Saint Joseph Mercy Hospital	Ann Arbor	Michigan	United States	48106
24	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan	United States	48114
25	Saint Joseph Mercy Chelsea	Chelsea	Michigan	United States	48118
26	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan	United States	48118
27	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan	United States	48197
28	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
29	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri	United States	63141
30	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
31	Siteman Cancer Center-South County	Saint Louis	Missouri	United States	63129
32	Siteman Cancer Center at Christian Hospital	Saint Louis	Missouri	United States	63136
33	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri	United States	63376
34	Sanford Bismarck Medical Center	Bismarck	North Dakota	United States	58501
35	Sanford Broadway Medical Center	Fargo	North Dakota	United States	58122
36	Sanford Roger Maris Cancer Center	Fargo	North Dakota	United States	58122
37	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
38	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
39	UPMC Cancer Centers - Arnold Palmer Pavilion	Greensburg	Pennsylvania	United States	15601
40	Geisinger Medical Oncology-Lewisburg	Lewisburg	Pennsylvania	United States	17837
41	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
42	UPMC-Shadyside Hospital	Pittsburgh	Pennsylvania	United States	15232
43	Geisinger Cancer Services-Pottsville	Pottsville	Pennsylvania	United States	17901
44	Asplundh Cancer Pavilion	Willow Grove	Pennsylvania	United States	19090
45	UPMC Memorial	York	Pennsylvania	United States	17408
46	Prisma Health Cancer Institute - Faris	Greenville	South Carolina	United States	29605
47	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
48	West Virginia University Healthcare	Morgantown	West Virginia	United States	26506
49	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226