Trial Outcomes & Findings for 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 (NCT NCT04588246)

Last Updated: 2025-06-06

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

19 participants

Primary outcome timeframe

From baseline to neurologic death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.

Results posted on

2025-06-06

Participant Flow

Participant milestones

Participant milestones
Measure	Arm I (Memantine, HA-WBRT) Patients undergo hippocampal-avoidant whole brain radiotherapy (HA-WBRT) daily (5 times weekly) for 2 weeks for a total 30 Gy in 10 fractions in the absence of disease progression or unacceptable toxicity. Consolidative stereotactic radiosurgery (SRS) boost following HA-WBRT is permitted during the follow-up period before progression. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine target twice daily (BID) dose 20 mg/day or target extended-release dose 28 mg/day in the absence of disease progression or unacceptable toxicity.	Arm II (SRS/fSRS) Patients undergo salvage SRS or fractionated stereotactic radiosurgery(fSRS).
Overall Study STARTED	10	9
Overall Study COMPLETED	10	9
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm I (Memantine, HA-WBRT) n=10 Participants Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total 30 Gy in 10 fractions in the absence of disease progression or unacceptable toxicity. Consolidative SRS boost following HA-WBRT is permitted during the follow-up period before progression. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine target BID dose 20 mg/day or target extended-release dose 28mg/day in the absence of disease progression or unacceptable toxicity.	Arm II (SRS/fSRS) n=9 Participants Patients undergo salvage SRS or fSRS.	Total n=19 Participants Total of all reporting groups
Age, Continuous	63.5 years n=5 Participants	60 years n=7 Participants	63 years n=5 Participants
Sex: Female, Male Female	6 Participants n=5 Participants	8 Participants n=7 Participants	14 Participants n=5 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	9 Participants n=5 Participants	9 Participants n=7 Participants	18 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) White	7 Participants n=5 Participants	9 Participants n=7 Participants	16 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Karnofsky performance status 70	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Karnofsky performance status 80	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Karnofsky performance status 90	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Brain Metastasis Velocity (BMV) 4 - 13	2 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants
Brain Metastasis Velocity (BMV) >13	8 Participants n=5 Participants	5 Participants n=7 Participants	13 Participants n=5 Participants
Is participant receiving immunotherapy? No	8 Participants n=5 Participants	8 Participants n=7 Participants	16 Participants n=5 Participants
Is participant receiving immunotherapy? Yes	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Diagnosis-specific graded prognostic assessment (DS-GPA) 0-2	9 Participants n=5 Participants	6 Participants n=7 Participants	15 Participants n=5 Participants
Diagnosis-specific graded prognostic assessment (DS-GPA) 3-4	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants

PRIMARY outcome

Timeframe: From baseline to neurologic death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.

Population: Randomized participants

Outcome measures

Outcome measures
Measure	Arm I (Memantine, HA-WBRT) n=10 Participants Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total 30 Gy in 10 fractions in the absence of disease progression or unacceptable toxicity. Consolidative SRS boost following HA-WBRT is permitted during the follow-up period before progression. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine target BID dose 20 mg/day or target extended-release dose 28mg/day in the absence of disease progression or unacceptable toxicity.	Arm II (SRS/Fractionated Stereotactic Radiosurgery(fSRS)) n=9 Participants Patients undergo salvage SRS or fSRS.
Percentage of Participants With Neurologic Death	3 Participants	3 Participants

SECONDARY outcome

Timeframe: Baseline to death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.

Population: Randomized participants

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.

Outcome measures

Outcome measures
Measure	Arm I (Memantine, HA-WBRT) n=10 Participants Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total 30 Gy in 10 fractions in the absence of disease progression or unacceptable toxicity. Consolidative SRS boost following HA-WBRT is permitted during the follow-up period before progression. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine target BID dose 20 mg/day or target extended-release dose 28mg/day in the absence of disease progression or unacceptable toxicity.	Arm II (SRS/Fractionated Stereotactic Radiosurgery(fSRS)) n=9 Participants Patients undergo salvage SRS or fSRS.
Overall Survival	5 Participants	5 Participants

SECONDARY outcome

Timeframe: Baseline to intracranial progression, death, or last follow-up. Maximum follow-up at time of study termination was 29.7 months.

Population: Randomized participants

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.

Outcome measures

Outcome measures
Measure	Arm I (Memantine, HA-WBRT) n=10 Participants Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total 30 Gy in 10 fractions in the absence of disease progression or unacceptable toxicity. Consolidative SRS boost following HA-WBRT is permitted during the follow-up period before progression. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine target BID dose 20 mg/day or target extended-release dose 28mg/day in the absence of disease progression or unacceptable toxicity.	Arm II (SRS/Fractionated Stereotactic Radiosurgery(fSRS)) n=9 Participants Patients undergo salvage SRS or fSRS.
Intracranial Progression-Free Survival (IPFS)	5 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline to death or last follow-up. Maximum follow-up at time of study termination was 29.7 months.

Population: Randomized participants who subsequently relapsed with new brain metastases

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.

Outcome measures

Outcome measures
Measure	Arm I (Memantine, HA-WBRT) Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total 30 Gy in 10 fractions in the absence of disease progression or unacceptable toxicity. Consolidative SRS boost following HA-WBRT is permitted during the follow-up period before progression. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine target BID dose 20 mg/day or target extended-release dose 28mg/day in the absence of disease progression or unacceptable toxicity.	Arm II (SRS/Fractionated Stereotactic Radiosurgery(fSRS)) n=5 Participants Patients undergo salvage SRS or fSRS.
Brain Metastasis Velocity at Subsequent Relapse (BMVs)	—	33.18 brain metastases/year Interval 21.9 to 104.29

SECONDARY outcome

Timeframe: Baseline and 4 months from treatment start

Population: Randomized participants with data at baseline and 4 months from start of treatment

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.

Outcome measures

Outcome measures
Measure	Arm I (Memantine, HA-WBRT) n=5 Participants Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total 30 Gy in 10 fractions in the absence of disease progression or unacceptable toxicity. Consolidative SRS boost following HA-WBRT is permitted during the follow-up period before progression. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine target BID dose 20 mg/day or target extended-release dose 28mg/day in the absence of disease progression or unacceptable toxicity.	Arm II (SRS/Fractionated Stereotactic Radiosurgery(fSRS)) n=4 Participants Patients undergo salvage SRS or fSRS.
Change From Baseline in the M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) Symptom Severity Score	-0.82 score on a scale Standard Deviation 1.29	0.53 score on a scale Standard Deviation 1.61

SECONDARY outcome

Timeframe: Baseline to last follow-up. Maximum follow-up at time of study termination was 29.7 months.

Population: Randomized participants who started treatment

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.

Outcome measures

Outcome measures
Measure	Arm I (Memantine, HA-WBRT) n=8 Participants Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total 30 Gy in 10 fractions in the absence of disease progression or unacceptable toxicity. Consolidative SRS boost following HA-WBRT is permitted during the follow-up period before progression. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine target BID dose 20 mg/day or target extended-release dose 28mg/day in the absence of disease progression or unacceptable toxicity.	Arm II (SRS/Fractionated Stereotactic Radiosurgery(fSRS)) n=8 Participants Patients undergo salvage SRS or fSRS.
Number of Participants With a Grade 3 or Higher Adverse Event	4 Participants	3 Participants

SECONDARY outcome

Timeframe: Baseline to last follow-up. Maximum follow-up at time of study termination was 29.7 months.

Population: Randomized participants who started treatment

Salvage procedures are defined as procedures for the purpose of managing recurrent intracranial disease following protocol treatment.

Outcome measures

Outcome measures
Measure	Arm I (Memantine, HA-WBRT) n=8 Participants Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total 30 Gy in 10 fractions in the absence of disease progression or unacceptable toxicity. Consolidative SRS boost following HA-WBRT is permitted during the follow-up period before progression. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine target BID dose 20 mg/day or target extended-release dose 28mg/day in the absence of disease progression or unacceptable toxicity.	Arm II (SRS/Fractionated Stereotactic Radiosurgery(fSRS)) n=8 Participants Patients undergo salvage SRS or fSRS.
Number of Participants Who Received Salvage Procedures	2 Participants	1 Participants

Adverse Events

Arm I (Memantine, HA-WBRT)

Serious events: 4 serious events

Other events: 6 other events

Deaths: 5 deaths

Arm II (SRS/Fractionated Stereotactic Radiosurgery(fSRS))

Serious events: 1 serious events

Other events: 6 other events

Deaths: 4 deaths

Serious adverse events

Serious adverse events
Measure	Arm I (Memantine, HA-WBRT) n=8 participants at risk Patients undergo HA-WBRT daily (5 times weekly) for 2 weeks for a total 30 Gy in 10 fractions in the absence of disease progression or unacceptable toxicity. Consolidative SRS boost following HA-WBRT is permitted during the follow-up period before progression. Prior to HA-WBRT or no later than the 4th treatment, patients also receive memantine target BID dose 20 mg/day or target extended-release dose 28mg/day in the absence of disease progression or unacceptable toxicity.	Arm II (SRS/Fractionated Stereotactic Radiosurgery(fSRS)) n=8 participants at risk Patients undergo salvage SRS or fSRS.
Blood and lymphatic system disorders Blood and lymphatic system disorders - Other	12.5% 1/8 • Baseline to last follow-up. Maximum follow-up was 29.7 months. All-cause mortality was assessed in eligible participants. Adverse events were assessed in eligible participants who started protocol treatment.	0.00% 0/8 • Baseline to last follow-up. Maximum follow-up was 29.7 months. All-cause mortality was assessed in eligible participants. Adverse events were assessed in eligible participants who started protocol treatment.
Blood and lymphatic system disorders Leukocytosis	12.5% 1/8 • Baseline to last follow-up. Maximum follow-up was 29.7 months. All-cause mortality was assessed in eligible participants. Adverse events were assessed in eligible participants who started protocol treatment.	0.00% 0/8 • Baseline to last follow-up. Maximum follow-up was 29.7 months. All-cause mortality was assessed in eligible participants. Adverse events were assessed in eligible participants who started protocol treatment.
Gastrointestinal disorders Small intestinal obstruction	12.5% 1/8 • Baseline to last follow-up. Maximum follow-up was 29.7 months. All-cause mortality was assessed in eligible participants. Adverse events were assessed in eligible participants who started protocol treatment.	0.00% 0/8 • Baseline to last follow-up. Maximum follow-up was 29.7 months. All-cause mortality was assessed in eligible participants. Adverse events were assessed in eligible participants who started protocol treatment.
General disorders Fatigue	12.5% 1/8 • Baseline to last follow-up. Maximum follow-up was 29.7 months. All-cause mortality was assessed in eligible participants. Adverse events were assessed in eligible participants who started protocol treatment.	0.00% 0/8 • Baseline to last follow-up. Maximum follow-up was 29.7 months. All-cause mortality was assessed in eligible participants. Adverse events were assessed in eligible participants who started protocol treatment.
Infections and infestations Lung infection	0.00% 0/8 • Baseline to last follow-up. Maximum follow-up was 29.7 months. All-cause mortality was assessed in eligible participants. Adverse events were assessed in eligible participants who started protocol treatment.	12.5% 1/8 • Baseline to last follow-up. Maximum follow-up was 29.7 months. All-cause mortality was assessed in eligible participants. Adverse events were assessed in eligible participants who started protocol treatment.
Injury, poisoning and procedural complications Fall	12.5% 1/8 • Baseline to last follow-up. Maximum follow-up was 29.7 months. All-cause mortality was assessed in eligible participants. Adverse events were assessed in eligible participants who started protocol treatment.	0.00% 0/8 • Baseline to last follow-up. Maximum follow-up was 29.7 months. All-cause mortality was assessed in eligible participants. Adverse events were assessed in eligible participants who started protocol treatment.
Musculoskeletal and connective tissue disorders Generalized muscle weakness	12.5% 1/8 • Baseline to last follow-up. Maximum follow-up was 29.7 months. All-cause mortality was assessed in eligible participants. Adverse events were assessed in eligible participants who started protocol treatment.	12.5% 1/8 • Baseline to last follow-up. Maximum follow-up was 29.7 months. All-cause mortality was assessed in eligible participants. Adverse events were assessed in eligible participants who started protocol treatment.
Nervous system disorders Encephalopathy	12.5% 1/8 • Baseline to last follow-up. Maximum follow-up was 29.7 months. All-cause mortality was assessed in eligible participants. Adverse events were assessed in eligible participants who started protocol treatment.	0.00% 0/8 • Baseline to last follow-up. Maximum follow-up was 29.7 months. All-cause mortality was assessed in eligible participants. Adverse events were assessed in eligible participants who started protocol treatment.
Nervous system disorders Memory impairment	12.5% 1/8 • Baseline to last follow-up. Maximum follow-up was 29.7 months. All-cause mortality was assessed in eligible participants. Adverse events were assessed in eligible participants who started protocol treatment.	0.00% 0/8 • Baseline to last follow-up. Maximum follow-up was 29.7 months. All-cause mortality was assessed in eligible participants. Adverse events were assessed in eligible participants who started protocol treatment.

Other adverse events

Additional Information

Wendy Seiferheld

NRG Oncology

Phone: 215-574-3208

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.
Publication restrictions are in place

Restriction type: OTHER