Memantine and Exercise for Chemotherapy-Related Cognitive Decline in Patients with Breast Cancer - PROJECT SUMMARY/ABSTRACT Chemotherapy-related cognitive decline (CRCD) is common and consequential to quality of life and function, but there is no standard of care to prevent or treat CRCD. Three major barriers to developing effective interventions include: 1) interindividual variability in pre-systemic risk factors; 2) multiple mechanisms of CRCD; and 3) a lack of investigators capable of developing mechanism-driven interventions and deploying them in complex medical settings (e.g., concurrent with chemotherapy). Memantine is a promising medication for CRCD, as it modulates pathways involving brain-derived neurotrophic factor (BDNF) and inflammation, two interrelated mechanisms of CRCD and of cognitive aging broadly. Exercise is an optimal behavioral augmentation strategy, as it also targets BDNF and inflammation, improves frailty, and is recommended for mood, fatigue, and physical function in cancer patients undergoing treatment. In the proposed K23 study, we will conduct a three-arm randomized controlled trial (RCT) of MEM+EX (combined memantine and an established cancer exercise program [Get Real & Heel]), memantine, or placebo to mitigate CRCD in 90 patients with breast cancer. Specific research aims are to: determine the feasibility and acceptability of MEM+EX during breast cancer chemotherapy (Aim 1); evaluate the preliminary efficacy of MEM+EX and memantine to mitigate cognitive decline (Aim 2) and changes in CRCD biomarkers (Aim 3); and explore the impact of frailty on changes in cognitive function and CRCD biomarkers (Exploratory Aim 4). We hypothesize that 1) our RCT will be a) feasible (≥ 40% recruitment rate; ≥85% retention rate; ≥75% adherence to ≥90% medication doses and ≥75% exercise sessions) and b) acceptable; MEM+EX and memantine will 2) exhibit lesser decline in objective and patient-reported cognition; and 3) mitigate BDNF decline and inflammation; and 4) treatment changes in cognition and CRCD biomarkers will be moderated by baseline frailty levels. The primary outcomes are feasibility and acceptability. Secondary outcomes are a composite of objective measures of attention and executive function, patient-reported cognition, BDNF, and an inflammatory composite measure. Outcomes will be assessed at baseline, 4 weeks, post-intervention (primary endpoint), and 6 month follow-up. Dr. Nakamura’s long-term goal is to become an independent investigator who develops and tests effective, mechanistically-based cognitive interventions for patients with cancer. His short- term goals for this award are to obtain training in: 1) design, conduct, and analysis of clinical trials; 2) cognitive measurement; and 3) mechanisms of CRCD. The mentorship and resources at the University of North Carolina at Chapel Hill create an ideal environment for this K23 award. The proposed research and training aims are consistent with the NIA’s goal to develop effective interventions to maintain well-being and function and reduce the burden of age-related diseases. This award provides Dr. Nakamura with the necessary education, training, and pilot data to prepare him to conduct a future definitive trial of MEM+EX and lead other large-scale RCTs of interventions targeting the pathophysiology of cognitive decline induced by cancer and its treatments.
