A Study to See if Memantine Protects the Brain During Radiation Therapy Treatment for a Brain Tumor

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT04939597
• Collaborator: (none)
• Enrollment: 162
• Locations: 38
• Arms: 2
• Anticipated Duration (Months): 70.5
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase III trial compares memantine to usual treatment in treating patients with brain tumors that are newly diagnosed or has come back (recurrent). Memantine may block receptors (parts of nerve cells) in the brain known to contribute to a decline in cognitive function. Giving memantine may make a difference in cognitive function (attention, memory, or other thought processes) in children and adolescents receiving brain radiation therapy to treat a primary brain tumor.

Condition or Disease	Intervention/Treatment	Phase
Brain Neoplasm; Recurrent Brain Neoplasm	Procedure: Cognitive Assessment; Drug: Memantine Hydrochloride; Drug: Placebo Administration	Phase 3

Detailed Description

PRIMARY OBJECTIVE:

1. To determine the efficacy, as measured by the slope of change of the Cogstate composite Z score from baseline to 12 months, of oral memantine hydrochloride (memantine administered for a period of 6 months, when compared to placebo, in children ages 4-18 receiving cranial or craniospinal radiotherapy for primary central nervous system tumors.

EXPLORATORY OBJECTIVES:

1. To determine if memantine is associated with improved cognitive function as measured for participants in the optional Children's Oncology Group (COG) Standardized Battery at 12 months.

2. To determine if memantine is associated with change in cognitive function version (vs.) placebo as measured by Cogstate composite score at end of radiation therapy (RT), 3 and 6 months.

3. To determine if memantine is associated with differences in cognitive function vs. placebo as measured by Cogstate composite score at 30 and 60 months for participants in the optional COG Standardized Battery.

4. To correlate early cognitive changes (end of RT, 3, 6, 12 months Cogstate composite score) with late cognitive function (30 and 60 months Cogstate composite score).

5. To correlate COG Standardized Battery scores to Cogstate composite scores at 12, 30, and 60 months.

6. To estimate the 36-month disease-free and overall survival (of primary brain tumor) after memantine treatment compared to placebo.

7. To correlate changes in quantitative volumetric magnetic resonance imaging (MRI) measurements of critical brain regions with cognitive function over time.

8. To evaluate impact of memantine versus placebo on molecular biomarkers associated with cognitive decline after radiotherapy.

9. To determine whether oral memantine, when compared to placebo, is associated with reduction in the incidence of decline of composite Cogstate score at 12 months in children ages 4-18 receiving cranial radiotherapy for primary central nervous system tumors.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive memantine hydrochloride orally (PO) twice daily (BID) for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also complete cognitive testing over 20-30 minutes at baseline, end of radiation therapy, and at 3, 6, 12, 30, and 60 months.

ARM II: Patients receive placebo PO BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also complete cognitive testing over 20-30 minutes at baseline, end of radiation therapy, and at 3, 6, 12, 30, and 60 months.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 162 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Randomized, Placebo-Controlled Trial Evaluating Memantine for Neurocognitive Protection in Children Undergoing Cranial Radiotherapy as Part of Treatment for Primary Central Nervous System Tumors
• Actual Study Start Date: Nov 15, 2021
• Anticipated Primary Completion Date: Sep 30, 2027
• Anticipated Study Completion Date: Sep 30, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (memantine hydrochloride) Patients receive memantine hydrochloride PO BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also complete cognitive testing over 20-30 minutes at baseline, end of radiation therapy, and at 3, 6, 12, 30, and 60 months.	Procedure: Cognitive Assessment; Complete cognitive testing; Drug: Memantine Hydrochloride; Given PO; Other Names: Ebixia Namenda
Placebo Comparator: Arm II (placebo) Patients receive placebo PO BID for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also complete cognitive testing over 20-30 minutes at baseline, end of radiation therapy, and at 3, 6, 12, 30, and 60 months.	Procedure: Cognitive Assessment; Complete cognitive testing; Drug: Placebo Administration; Given PO

Outcome Measures

Primary Outcome Measures

1. Cogstate composite Z score [At baseline, end of radiation therapy (RT), 3 months, 6 months, and 12 months after baseline]

   Cogstate composite Z score is an average of detection Z scores, Identification Z scores, and one-back Z scores calculated using cogstate age-based normative data. The difference in slopes of cogstate composite Z scores over time will be estimated via a mixed model.

Other Outcome Measures

1. Intelligence quotient score [At 12, 30, 60 months]

   Assessed by intelligence assessment.

2. Processing speed score [At 12, 30, 60 months]

   Assessed by processing speed/attention assessment).

3. Verbal memory score [At 12, 30, 60 months]

   Assessed by Children's Memory Scale (CMS) Stories assessment.

4. Verbal memory score [At 12, 30, 60 months]

   Assessed by the Wechsler Memory Scale - Fourth Edition (WMS-IV) using Logical Memory I and II.

5. Visual memory score [At 12, 30, 60 months]

   Assessed by CMS Faces assessment, using Immediate and Delayed.

6. Working memory score [At 12, 30, 60 months]

   Assessed by Wechsler Intelligence Scale for Children-Fifth Edition Digit Span.

7. Working memory score [At 12, 30, 60 months]

   Assessed by Wechsler Adult Intelligence Scale - Fourth Edition Digit Span assessments.

8. Verbal score [At 12, 30, 60 months]

   Assessed by the California Verbal Learning Test - Children's Version (CVLT-C).

9. Verbal score [At 12, 30, 60 months]

   Assessed by the 2nd Edition (CVLT-II) assessment, using the List A Trials 1-5 Total T-score.

10. Visual learning score [At 12, 30, 60 months]

    Assessed by CMS Dot Locations assessment, using Total, Learning, Delay.

11. Executive functioning score [At 12, 30, 60 months]

    Assessed by Executive Function assessment, using Cognitive Regulation Index.

12. Estimate the difference in change of cogstate composite Z scores over time between 2 treatment arms [At end of RT, 3, and 6 months post baseline]

    Cogstate composite Z score is an average of detection Z scores, Identification Z scores, and one-back Z scores calculated using cogstate age-based normative data. The difference in slopes of cogstate composite Z scores over time will be estimated via a mixed model.

13. Cogstate composite Z score [At 30 months post baseline]

    Cogstate composite Z score is an average of detection Z scores, Identification Z scores, and one-back Z scores calculated using cogstate age-based normative data.

14. Cogstate composite Z score [At 60 months post baseline]

    Cogstate composite Z score is an average of detection Z scores, Identification Z scores, and one-back Z scores calculated using cogstate age-based normative data.

15. Disease-free survival [At 36 months]

    The number of patients with disease-free survival (of primary brain tumor) after mematine treatment compared to placebo.

16. Overall survival [At 36 months]

    The number of patients with disease-free survival (of primary brain tumor) after mematine treatment compared to placebo.

17. Quantitative volumetric magnetic resonance imaging measurements of critical brain regions (hippocampus, frontal cortex) [Up to 30 months]

    Correlate changes in quantitative volumetric magnetic resonance imaging (MRI) measurements for patients treated with protcon therapy vs. photon therapy.

18. Number of patients who consented to biobanking [At baseline, end of RT, 6 months, and 12 months]

    The number of patients who agree to be in the Biobanking part of the study future research.

19. Incidence of composite cognitive score decline [At 12 months post baseline]

    The Chi-square test will be used to compare the proportion of patients having the incidence of neurocognitive function (NCF) decline between two treatment arms. A clinically meaningful NCF decline is defined as 0.5 SD or more decline in cogstate composite score between baseline and 12 months.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• = 4 and < 18 years at time of study entry

• Patients must weigh 15 kg or greater at time of study entry

• Newly diagnosed or recurrent primary brain tumors that have not received prior cranial radiotherapy

• Planned focal, cranial or craniospinal radiation treatment for a primary brain tumor

• The patient must have receptive and expressive language skills in English, French or Spanish since the neurocognitive function and quality of life (QOL) assessment instruments are available in these languages only

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

• Age: 4 to < 6 years; Maximum serum creatinine (mg/dL): 0.8 male; 0.8 female

• Age: 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 male; 1 female

• Age: 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 male; 1.2 female

• Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 male; 1.4 female

• Age: >= 16 years; Maximum serum creatinine (mg/dL): 1.7 male; 1.4 female

• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age

• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L

• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L

• The patient must be able to undergo magnetic resonance imaging

• All patients and/or their parents or legal guardians must sign a written informed consent

• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria:

• Life expectancy of less than 18 months

• Pre-existing conditions:

• Any contraindication or allergy to memantine

• Intractable seizures while on adequate anticonvulsant therapy, defined as more than one seizure per month for the past 2 months or since initiating anticonvulsant therapy

• Co-morbid systemic illnesses, psychiatric conditions, social situations, or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens or would limit compliance with the study requirements

• Patients with a motor, visual, or auditory condition that precludes computerized neurocognitive assessments are not eligible to participate

• Patients with any medical condition or taking medications that lead to alterations of urine pH towards the alkaline condition (e.g., renal tubular acidosis, carbonic anhydrase inhibitors, sodium bicarbonate)

• Personal history of prior cranial or craniospinal radiotherapy is not allowed

• Note: Prior anti-cancer therapy including surgery, chemotherapy, targeted agents are allowed as per standard of care clinical treatment guidelines

• Female patients who are pregnant are excluded since fetal toxicities and teratogenic effects have been noted for the study drug. A pregnancy test is required for female patients of childbearing potential

• Lactating females who plan to breastfeed their infants

• Sexually active patients of reproductive potential who do not agree to use an effective contraceptive method for the duration of their study participation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Alabama	Birmingham	Alabama	United States	35233
2	Kaiser Permanente-Oakland	Oakland	California	United States	94611
3	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
4	UCSF Medical Center-Mission Bay	San Francisco	California	United States	94158
5	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
6	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida	United States	32207
7	Nemours Children's Hospital	Orlando	Florida	United States	32827
8	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida	United States	33607
9	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii	United States	96826
10	Saint Luke's Cancer Institute - Boise	Boise	Idaho	United States	83712
11	University of Illinois	Chicago	Illinois	United States	60612
12	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
13	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
14	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
15	Michigan State University Clinical Center	East Lansing	Michigan	United States	48824-7016
16	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
17	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905
18	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
19	Children's Mercy Hospitals and Clinics	Kansas City	Missouri	United States	64108
20	Saint Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
21	Albany Medical Center	Albany	New York	United States	12208
22	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
23	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
24	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
25	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
26	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
27	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
28	Dayton Children's Hospital	Dayton	Ohio	United States	45404
29	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
30	Legacy Emanuel Children's Hospital	Portland	Oregon	United States	97227
31	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
32	Saint Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
33	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
34	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
35	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229
36	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
37	Children's Hospital of The King's Daughters	Norfolk	Virginia	United States	23507
38	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• Children's Oncology Group

Investigators

• Principal Investigator: Nadia N Laack, Children's Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT04939597
• Other Study ID Numbers: ACCL2031; NCI-2020-07502; ACCL2031; COG-ACCL2031; ACCL2031; U01CA246568; U24CA196173; UG1CA189955
• First Posted: Jun 25, 2021
• Last Update Posted: Aug 18, 2022
• Last Verified: Jun 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Neoplasms; Brain Neoplasms; Memantine

Study Results

No Results Posted as of Aug 18, 2022