Donepezil Hydrochloride in Improving Memory Performance in Breast Cancer Survivors after Chemotherapy

Inclusion Criteria

• History of invasive breast cancer
• Must have completed at least 4 cycles of adjuvant/neo-adjuvant cytotoxic chemotherapy between 1 and 5 years prior to registration (ongoing herceptin or other chronic human epidermal growth factor receptor [HER] 2 directed therapies are allowed)
• Patients receiving ongoing hormonal therapy for breast cancer must be on the same hormonal agent for at least 3 months prior to study registration and plan to continue for the duration of the study (9 months)
• Use of psychotropic medications (anti-depressants, anxiolytics, sleeping aids, narcotics) is permitted if the patient whose eligibility is being assessed has been on the medication for at least 12 weeks; the dose of this medication must be stable for at least 4 weeks prior to enrollment * Patients who were previously on one of these psychotropic medications and have subsequently discontinued the drug must have been off the medication for at least 4 weeks prior to enrollment * Patients who have been on a psychotropic medication for at least 12 weeks but have recently switched to a medicine in the same class (for example, switching from one selective serotonin reuptake inhibitor [SSRI] antidepressant to a different SSRI antidepressant) need to be on a stable dose of the new medication for at least 4 weeks prior to enrollment to be eligible
• Self-reported cognitive problem plus a measured memory deficit (score =< 7 on single trial of eligibility pre-screen Hopkins Verbal Learning Test-Revised [HVLT-R] form C)
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Able to understand and the willingness to sign a written informed consent document
• Must be able to speak English
• Patients currently taking a moderate risk corrected QT interval (QTc) prolongation medication are allowed if one of the following criteria are met: * The moderate risk QTc prolongation medication is stopped; the patient should be off the moderate risk QTc prolongation medication for at least 5 half-lives before starting study drug * Patients that continue using a moderate risk QTc prolongation medication must have a normal QTc interval (=< 460 milliseconds) on a screening electrocardiography (ECG) following informed consent and prior to study enrollment; these patients will also be monitored at designated study follow-up visits (monitored 3-7 days after initiating study drug, at week 3, and 3-7 days after the study drug dose increase with ECG’s to assess the QTc interval; the QTc level must be =< 500 milliseconds at these time points in order to continue on the study drug) * Moderate risk QTc prolongation medications that are only taken occasionally may be stopped at the discretion of the treating site physician; patients must be off medication for at least 5 half-lives prior to starting study drug to be eligible
• Patients currently taking a moderate risk bradycardia-causing agent are allowed if one of the following criteria are met: * The moderate risk bradycardia-causing agent is stopped; the patient should be off the moderate risk bradycardia-causing agent for at least 5 half-lives before starting study drug * Patients that continue using a moderate risk bradycardia-causing agent must have a resting heart rate >= 55 beats per minute at screening following informed consent; these patients’ resting heart rate will be monitored 3-7 days after initiating study drug, at week 3, and 3-7 days after the study drug dose increase * Moderate risk bradycardia-causing agents that are only taken occasionally may be stopped at the discretion of the treating site physician; patients must be off medication for at least 5 half-lives prior to starting study drug to be eligible

Exclusion Criteria

• Evidence or suspected recurrent or metastatic disease
• Prior brain irradiation
• Planned therapy (surgery, radiation, chemotherapy, or immunotherapy) while on the study for brain and/or extracranial primary/metastatic disease
• Hypersensitivity to donepezil or piperidine derivatives
• Current use of ceritinib
• Current use of succinylcholine/acetylcholinesterase inhibitors as listed; for patients who have used these medications, they must not have used them within 4 weeks prior to enrollment
• Current use of high-risk QTc prolonging medication(s)
• Current use of quinidine or systemic ketoconazole (topical ketoconazole is acceptable to use while on study)
• History of dementia, Alzheimer’s disease, multi-infarct dementia or clinically significant cerebrovascular accident (history of transient ischemic attack [TIA] is allowed)
• Current use of donepezil, galantamine, rivastigmine, tacrine, memantine, methylphenidate, dextroamphetamine, or any other specific cognition enhancing drug(s); for patients who have used these medications, they must not have used them within 4 weeks prior to pre-screening; patients who plan to start taking a cognition enhancing drug while on this study are also excluded
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to donepezil. Hypersensitivity to donepezil
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, recent myocardial infarction, or cardiac arrhythmia
• Major medical conditions that affect cognition, traumatic brain injury, multiple sclerosis, acute severe fatigue, chronic fatigue syndrome or fibromyalgia
• Psychiatric illness/social situations that would limit compliance with study requirements including but not limited to a history of schizophrenia, psychosis or substance abuse
• Untreated current severe depression; currently treated depression is permitted if treatment is stable
• Patients with a resting heart rate less than 55 beats per minute, seizure disorder or peptic ulcer disease (PUD)
• Screening QTc of > 460 milliseconds will make the patient ineligible
• History of congenital long QT syndrome or torsades de pointes
• Pregnant women are excluded from this study; following informed consent, women of childbearing potential will be screened with a serum or urine pregnancy test within 10 days of enrollment; the effects of donepezil on the developing human fetus at the recommended therapeutic dose are unknown; for this reason and because donepezil is known to be teratogenic, women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately
• It is unknown whether donepezil is excreted in breast milk, for this reason women who are currently breast-feeding are not eligible for this study
• On another intervention study involving medication at the time of enrollment or during participation in this study; (exception: Patients will remain eligible for this study if they are also enrolled on the Alliance for Clinical Trials in Oncology study [NCT02927249]: Aspirin in Preventing Recurrence of Cancer in Patients with HER2 Negative Stage II-III Breast Cancer After Chemotherapy, Surgery, and/or Radiation Therapy; studies that involve only blood draws or questionnaires are also permitted)
• Use of investigational drugs likely to affect cognition within 30 days prior to pre-screening visit