Study of Donepezil in Female Breast Cancer Survivors With Cognitive Dysfunction

OBJECTIVES:

Primary

- Determine the feasibility of conducting a randomized placebo-controlled clinical trial
for cognitive symptoms in female breast cancer survivors.

Secondary

- Estimate the variability of the clinical outcomes (FACT-Cognition Perceived Cognitive
Impairment subscale, neurocognitive battery, FACIT-Fatigue, FACT Cog Total Score,
PROMIS Fatigue, Epworth Sleepiness Scale, Beck Depression Inventory, Beck Anxiety
Inventory, and RAND Short Form-36).

- Estimate the within patient correlation over time of the clinical outcomes.

- Obtain preliminary estimates of the effect of donepezil on the primary and secondary
outcome variables.

- Correlate the reports of fatigue, sleep disturbance, and mood with measures of
cognitive symptoms and neurocognitive test performance.

- Document the severity of cognitive symptoms and functional impairment in female breast
cancer survivors who enroll on this pilot study.

- Correlate cognitive symptoms with cognitive test performance.

- Document the toxicities associated with donepezil hydrochloride use.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients
are stratified according to menopausal status (pre- vs peri-/post-menopausal) and time since
end of chemotherapy (12-36 months vs 36.01-60 months).

Arm I: Patients receive donepezil hydrochloride orally (PO) once daily (QD).

Arm II: Patients receive placebo PO QD.

In both arms treatment continues for 24 weeks.

Patients complete the entire battery of neurocognitive tests and questionnaires
(FACT-Cognition Perceived Cognitive Impairment subscale, neurocognitive battery,
FACIT-Fatigue, FACT Cog Total Score, PROMIS Fatigue, Epworth Sleepiness Scale, Beck
Depression Inventory, Beck Anxiety Inventory, and RAND Short Form-36) at baseline
(pre-treatment), 24 weeks (end of medication), and 36 weeks (end of wash-out).

After completion of therapy, patients are followed at 12 weeks.

INCLUSION CRITERIA:

- Adults >18 years old.

- Female with history of invasive breast cancer

- Must have completed adjuvant chemotherapy between 1 and 5 years prior to registration

- Received at least 4 cycles of cytotoxic chemotherapy

- Documentation of prior chemotherapy

- 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 continue for the
duration of the study (9 months)

- Karnofsky Performance Status must be > 60 or ECOG 0-2.

- Use of psychotropic medications (anti-depressants, anxiolytics, sleeping aids,
narcotics) is permitted. Patient will be asked to list any that have been taken
within the last 3 days on the recent medication sheet.

- Patients must be able to give informed consent to participate in the study, including
signing the consent form.

- Self-reported cognitive disruption (FACT-Cog Version 3 Perceived Cognitive
Impairments sub-score of < 63)

- Negative serum pregnancy test within 10 days prior to registration for women of
child-bearing potential.

EXCLUSION CRITERIA:

- Evidence or suspected recurrent or metastatic disease

- History of dementia, Alzheimer's disease, multi-infarct dementia or CVA (history of
transient ischemic attack (TIA is allowed)

- Current use of donepezil, galantamine, rivastigmine, tacrine, memantine,
methylphenidate, dextroamphetamine, or any other specific cognition enhancing
drugs.are not allowed. For patients who have used these medications they must not
have used them within 4 weeks prior to registration.

Patients may not currently be taking Ketoconazole or Quinidine

- Hypersensitivity to donepezil.

- Use of investigational medications within the last 30 days.

- Prior brain metastasis

- Traumatic brain injury, multiple sclerosis or recent myocardial infarction

- History of schizophrenia, psychosis or substance abuse

- Untreated current severe depression. (Currently treated depression is permitted if
treatment is stable.)

- Acute severe fatigue, chronic fatigue syndrome or fibromyalgia.

- History of hepatic or renal dysfunction or disease

- Pregnant women are excluded from this study. 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 child-bearing
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.