Memantine With or Without Raloxifene for Cognitive Preservation after Radiation Therapy to the Brain, The Memory RT Trial

Status: approved

This phase II trial compares the effect of memantine with or without raloxifene in preserving memory and thinking skills (cognition) in patients with brain tumors undergoing radiation therapy to the brain. Patients with brain tumors are at increased risk of cognitive dysfunction impacting a wide range of domains including attention, memory, language processing, spatial awareness, judgement, and overall executive function. These symptoms can be made worse by radiation therapy, a common treatment for these patients. Recently, high expression of the estrogen receptor (ER) has been identified as a potential protective mechanism against Alzheimer disease. Raloxifene is a type of selective estrogen receptor modulator (SERM) that is used to reduce the risk of invasive breast cancer in postmenopausal women. Raloxifene may also prevent cognitive decline in patients receiving radiation therapy to the brain. Memantine is a drug used to treat dementia caused by Alzheimer disease. It is also being studied in the treatment of side effects from whole-brain radiation therapy for cancer and other conditions. Memantine blocks the uptake of calcium by certain brain cells and decreases their activity. It is a type of N-methyl-D-asparatate (NMDA) receptor antagonist. Giving memantine and raloxifene together may be more effective than memantine alone for cognitive preservation in patients with brain tumors undergoing radiation therapy to the brain.

Inclusion Criteria

Age ≥ 18 years
Ability to provide informed written consent in either English or Spanish
All individuals of childbearing potential must have a negative serum pregnancy test and male and female subjects must agree to use effective means of contraception (surgical sterilization or the use of barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an intrauterine device [IUD]) with their partner from entry into the study through 24 weeks after the last dose of raloxifene
Patients undergoing radiation therapy to the brain as a part of solid tumor cancer therapy, using intensity modulated radiation therapy (IMRT) or whole brain radiation therapy (WBRT). Willingness to adhere to planned study drug regimen, including obtaining medication from an outside pharmacy via prescription
Patients must have a creatinine clearance ≥ 50 mL/min (using Cockcroft-Gault Equation)
Patients must not have hepatic impairment greater than Child-Pugh Score “Class A”

Exclusion Criteria

History of prior radiotherapy to the brain
Life expectancy of < 6 months
Radiation therapy planned is ≤ 5 fractions (e.g. stereotactic radiosurgery [SRS] or stereotactic radiotherapy [SRT], or 5-fraction whole brain)
Contraindications to taking memantine and/or raloxifene based on package inserts and the clinical judgement of the treating physician * Women with active or past history of venous thromboembolism * Postmenopausal women with documented coronary heart disease and postmenopausal women at increased risk for major coronary events * Premenopausal women not surgically sterilized, pregnant women, participants with significant hepatic impairment, participants with moderate or severe renal impairment, participants on concomitant estrogen therapy and participants on Cholestyramine, Warfarin, diazepam, diazoxide, and lidocaine * Individuals with a condition that raises urine pH
The subject is unable to undergo MRI scan (e.g., has an MRI incompatible pacemaker)
Conditions or situations which, in the opinion of the investigator, imply the patient will be unable or not suitable to complete trial requirements or at excessive risk from trial participation
Known allergy to either of the medications (memantine or raloxifene) used in this study or their excipients
Cognitive failure as assessed by Mini Mental State Exam (MMSE) score < 17

PRIMARY OBJECTIVE:

I. To determine in patients receiving radiation therapy to the brain, if raloxifene plus memantine (R+M), in comparison to memantine alone (M) results in increased time to cognitive failure (TTCF).

SECONDARY OBJECTIVES:

I. To determine in patients receiving radiation therapy to the brain, if raloxifene plus memantine (R+M), in comparison to memantine alone (M) results in higher learning and memory.

II. To determine in patients receiving radiation therapy to the brain, if raloxifene plus memantine, in comparison to memantine alone, results in higher processing speed.

III. To determine in patients receiving radiation therapy to the brain, if raloxifene plus memantine, in comparison to memantine alone, results in higher executive function.

IV. To determine in patients receiving radiation therapy to the brain, if raloxifene plus memantine, in comparison to memantine alone, results in higher verbal fluency.

V. To determine in patients receiving radiation therapy to the brain, if raloxifene plus memantine, in comparison to memantine alone, results in higher quality of life (QOL).

VI. To determine in patients receiving radiation therapy to the brain, if raloxifene plus memantine, in comparison to memantine alone, results in lower symptom burden.

EXPLORATORY OBJECTIVES:

I. To determine in patients with high grade glioma (HGG) receiving radiation therapy to the brain, if raloxifene plus memantine, in comparison to memantine alone, results in longer time to progression.

II. To determine in patients with HGG receiving radiation therapy to the brain, if raloxifene plus memantine, in comparison to memantine alone, results in longer survival.

III. To evaluate molecular changes (ER beta response genes, astrocyte activation genes) after use of raloxifene plus memantine when compared to memantine alone in patients with high-grade glioma in patients who undergo future tumor resection during or after participation in this study.

IV. To evaluate overall survival (OS) with subset analysis based on histology.

V. Impact on leukoencephalopathy at 12 months (change in white matter T2 hyperintensity using volumetric assessment).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive memantine orally (PO) once daily (QD) or twice daily (BID) for at least 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) during screening and magnetic resonance imaging (MRI) throughout the study.

ARM II: Patients receive memantine PO QD or BID and raloxifene PO QD for at least 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT during screening and MRI throughout the study.

After completion of study treatment, patients are followed every 3 months for 1 year.

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Memantine With or Without Raloxifene for Cognitive Preservation after Radiation Therapy to the Brain, The Memory RT Trial

Inclusion Criteria

Exclusion Criteria

United States

Texas

San Antonio

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Memantine With or Without Raloxifene for Cognitive Preservation after Radiation Therapy to the Brain, The Memory RT Trial

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