Phase 3 Randomized Placebo Controlled Clinical Trial of Donepezil

Inclusion Criteria:

• Women ≥18 years old with history of invasive breast cancer
• Must have completed at least 4 cycles of adjuvant/neo-adjuvant cytotoxic chemotherapybetween 1 and 5 years prior to registration (Ongoing herceptin or other chronic humanepidermal growth factor receptor 2 (HER2) directed therapies are allowed).
• Patients receiving ongoing hormonal therapy for breast cancer must be on the samehormonal agent for at least 3 months prior to study registration and plan to continuefor the duration of the study (9 months)
• Use of psychotropic medications (anti-depressants, anxiolytics, sleeping aids,narcotics) is permitted (patient will be asked to list any that have been taken withinthe last 3 days on the recent medication sheet) if dose is stable over previous 12weeks. Patients who were previously on one of these psychotropic medications and havesubsequently discontinued the drug must have been off the medication for at least 4weeks prior to enrollment. Patients who have been on a psychotropic medication for atleast 12 weeks but have recently switched to a medicine in the same class (forexample, switching from one selective serotonin reuptake inhibitor (SSRI)antidepressant to a different SSRI antidepressant) need to be on a stable dose of thenew medication for at least 4 weeks prior to enrollment to be eligible.
• Self-reported cognitive problem plus a measured memory deficit (score <7 on singletrial of Eligibility Pre-screen Hopkins Verbal Learning Test - Revised (HVLT-R) Form 3).
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Ability 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) prolongationmedication (see Appendix A) are allowed if one of the following criteria are met: 1)The moderate risk QTc prolongation medication is stopped. The patient should be offthe moderate risk QTc prolongation medication for at least 5 half-lives beforestarting study drug. 2) Patients that continue using a moderate risk QTc prolongationmedication must have a normal QTc interval (≤ 460 milliseconds) on a screening ECGfollowing informed consent and prior to study enrollment. These patients will also bemonitored at designated study follow-up visits per Section 7.5 (monitored 3-7 daysafter initiating study drug, at week 3, and 3-7 days after the study drug doseincrease with ECG's to assess the QTc interval; the QTc level must be ≤ 500milliseconds at these time points in order to continue on the study drug). 3) Moderaterisk QTc prolongation medications that are only taken occasionally may be stopped atthe discretion of the treating site physician. Patients must be off medication for atleast 5 half-lives prior to starting study drug to be eligible.
• Patients currently taking a moderate risk bradycardia-causing agent (see Appendix B)are allowed if one of the following criteria are met: 1) The moderate riskbradycardia-causing agent is stopped. The patient should be off the moderate riskbradycardia-causing agent for at least 5 half-lives before starting study drug. 2)Patients that continue using a moderate risk bradycardia-causing agent must have aresting heart rate ≥ 55 beats per minute at screening following informed consent.These patients' resting heart rate will be monitored 3-7 days after initiating studydrug, at week 3, and 3-7 days after the study drug dose increase per Section 7.5. 3)Moderate risk bradycardia-causing agents that are only taken occasionally may bestopped at the discretion of the treating site physician. Patients must be offmedication 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 is not allowed.
• Planned therapy (surgery, radiation, chemotherapy, or immunotherapy) while on thestudy 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 in AppendixC). 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). See Appendix D
• Current use of quinidine or systemic ketoconazole (topical ketoconazole is acceptableto use while on study).
• History of dementia, Alzheimer's disease, multi-infarct dementia or clinicallysignificant Cerebrovascular Accident (history of transient ischemic attack (TIA) isallowed).
• 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 4weeks prior to pre-screening. Patients who plan to start taking a cognition enhancingdrug while on this study are also excluded.
• History of allergic reactions attributed to compounds of similar chemical or biologiccomposition to donepezil. Hypersensitivity to donepezil.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, recentmyocardial infarction, cardiac arrhythmia.
• Major medical conditions that affect cognition, traumatic brain injury, multiplesclerosis, acute severe fatigue, chronic fatigue syndrome or fibromyalgia.
• Psychiatric illness/social situations that would limit compliance with studyrequirements including but not limited to a history of schizophrenia, psychosis orsubstance abuse.
• Untreated current severe depression. Currently treated depression is permitted iftreatment is stable.
• Patients with a resting heart rate less than 55 beats per minute, seizure disorder orpeptic ulcer disease (PUD).
• History of congenital long QT syndrome or torsades de pointes.
• Screening QTc of > 460 milliseconds will make the patient ineligible.
• Pregnant women are excluded from this study. Following informed consent, women ofchild-bearing 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 therecommended therapeutic dose are unknown. For this reason and because donepezil isknown to be teratogenic, women of child-bearing potential must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) prior to studyentry and for the duration of study participation. Should a woman become pregnant orsuspect she is pregnant while participating in this study, she should inform her studyphysician immediately.
• It is unknown whether donepezil is excreted in breast milk, for this reason women whoare currently breast-feeding are not eligible for this study.
• On another intervention study involving medication at the time of enrollment or duringparticipation in this study. (Exception: Patients will remain eligible for this studyif they are also enrolled on the Alliance for Clinical Trials in Oncology study (NCT02927249): Aspirin in Preventing Recurrence of Cancer in Patients with HER2Negative Stage II-III Breast Cancer After Chemotherapy, Surgery, and/or RadiationTherapy. Studies that involve only blood draws or questionnaires are also permitted.)
• Use of investigational drugs likely to affect cognition within 30 days prior topre-screening visit.