Phase 3
N=518
Memantine Hydrochloride and Whole-Brain Radiotherapy With or Without Hippocampal Avoidance in Reducing Neurocognitive Decline in Patients With Brain Metastases
Cognitive Impairment · Metastatic Malignant Neoplasm in the Brain · Solid Neoplasm
Bottom Line
View on ClinicalTrials.gov: NCT02360215 ↗Enrolled (actual)
518
Serious AEs
44.8%
Results posted
Mar 2020
Primary outcome: Primary: Time to Neurocognitive Failure — 68.2; 59.3 percentage of participants — p=0.029
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 3
- Interventions
- Whole brain radiation therapy with hippocampal avoidance (Radiation); Memantine (Drug); Whole brain radiation therapy (Radiation)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- NRG Oncology
- Primary completion
- Apr 2018
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Time to Neurocognitive Failure |
68.2; 59.3 | 0.029 sig |
| SECONDARY Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall Score (Neurocognitive Decline) |
-0.63; -0.47; -0.68; -0.36; -0.34; -0.06 | 0.0586 |
| SECONDARY Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recall Score (Neurocognitive Decline) |
-0.75; -0.73; -0.88; -0.68; -0.54; -0.30 | 0.2656 |
| SECONDARY Change From Baseline in the Hopkins Verbal Learning Test -Revised (HVLT-R) Delayed Recognition (Neurocognitive Decline) |
-0.69; -0.70; -0.11; -0.12; -0.55; -0.06 | 0.0993 |
| SECONDARY Change From Baseline in the Trail Making Test (TMT) Part A (Neurocognitive Decline) |
-1.42; -1.31; -0.28; 0.03; -2.09; 0.17 | 0.5988 |
| SECONDARY Change From Baseline in the Trail Making Test (TMT) Part B (Neurocognitive Decline) |
-2.86; -2.27; -3.38; -0.89; -0.47; -1.06 | 0.9226 |
| SECONDARY Change From Baseline in the Controlled Oral Word Association (COWA) Test (Neurocognitive Decline) |
-0.28; -0.29; -0.06; -0.08; -0.15; -0.11 | <0.0001 sig |
| SECONDARY Change From Baseline in the Clinical Trial Battery Composite (CTB COMP) Score [Neurocognitive Decline] |
-1.09; -0.87; -0.81; -0.27; -0.44; -0.21 | 0.2552 |
| SECONDARY Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score |
0.48; 0.61; 0.29; 0.36; 0.24; -0.09 | 0.57 |
| SECONDARY Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Interference Score |
0.84; 1.09; 0.35; 0.51; 0.57; 0.01 | 0.9118 |
| SECONDARY Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Cognitive Factor Score |
0.45; 0.50; 0.52; 0.32; 0.57; 0.01 | 0.1964 |
| SECONDARY Change in M. D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Neurologic Factor Score |
0.17; 0.28; 0.13; 0.24; 0.23; 0.15 | 0.8877 |
| SECONDARY Change in EQ-5D-5L Index Score at 2 Months |
-0.04; -0.05 | 0.86 |
| SECONDARY Change in EQ-5D-5L Index Score at 4 Months |
-0.03; -0.03 | — |
| SECONDARY Change in EQ-5D-5L Index Score at 6 Months |
-0.03; -0.03 | 0.95 |
| SECONDARY Change in EQ-5D-5L Index Score at 12 Months |
-0.03; -0.01 | 0.66 |
| SECONDARY Change in EQ-5D-5L VAS Score at 2 Months |
-5.64; -1.41 | 0.18 |
| SECONDARY Change in EQ-5D-5L VAS Score at 4 Months |
-1.35; -2.98 | 0.64 |
| SECONDARY Change in EQ-5D-5L VAS Score at 6 Months |
3.97; 3.49 | 0.91 |
| SECONDARY Change in EQ-5D-5L VAS Score at 12 Months |
2.86; 2.42 | 0.92 |
| SECONDARY Intracranial Progression-Free Survival |
43.9; 44.8 | 0.076 |
| SECONDARY Overall Survival |
54.9; 50.6 | 0.242 |
| SECONDARY Number of Patients With a Grade 3+ Adverse Event (AE) Regardless of Relationship to Treatment |
144; 131 | 0.47 |
Summary
This randomized phase III trial compares memantine hydrochloride and whole-brain radiotherapy with or without hippocampal avoidance in reducing neurocognitive decline in patients with cancer that has spread from the primary site (place where it started) to the brain. Whole brain radiotherapy (WBRT) is the most common treatment for brain metastasis. Unfortunately, the majority of patients with brain metastases experience cognitive (such as learning and memory) deterioration after WBRT. Memantine hydrochloride may enhance cognitive function by binding to and inhibiting channels of receptors located in the central nervous system. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Using radiation techniques, such as intensity modulated radiotherapy to avoid the hippocampal region during WBRT, may reduce the radiation dose to the hippocampus and help limit the radiation-induced cognitive decline. It is not yet known whether giving memantine hydrochloride and WBRT with or without hippocampal avoidance works better in reducing neurocognitive decline in patients with brain metastases.
Eligibility Criteria
Inclusion Criteria
- PRIOR TO STEP 1 REGISTRATION:
- Brain metastases outside a 5-mm margin around either hippocampus must be visible on contrast-enhanced magnetic resonance imaging (MRI) performed = = 70 within 28 days prior to Step 2 registration
- Serum creatinine = = 30 ml/min
- Blood urea nitrogen (BUN) within institutional upper limit of normal (e.g. = 200 cells/microliter within 30 days prior to registration; 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
- Prior allergic reaction to memantine (memantine hydrochloride)
- Current alcohol or drug abuse (may exacerbate lethargy/dizziness with memantine)
- Intractable seizures while on adequate anticonvulsant therapy-more than 1 seizure per month for the past 2 months
- Patients with definitive leptomeningeal metastases
- Patients with brain metastases from primary germ cell tumors, small cell carcinoma, unknown primary, or lymphoma
- Contraindication to magnetic resonance (MR) imaging such as implanted metal devices or foreign bodies
- Contraindication to gadolinium contrast administration during MR imaging, such as allergy or insufficient renal function
- Current use of (other N-methyl D-aspartate [NMDA] antagonists) amantadine, ketamine, or dextromethorphan
Data sourced from ClinicalTrials.gov (NCT02360215). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.