Donepezil in Treating Patients Who Have Undergone Radiation Therapy for Brain Tumors

OBJECTIVES:

Primary

- Compare the effect of donepezil hydrochloride vs placebo, in terms of improving
neurocognitive symptom cluster (i.e., cognitive impairment, subjective confusion, and
fatigue), in patients who have undergone partial- or whole-brain irradiation for brain
tumors.

Secondary

- Compare the effect of these regimens on mood and quality of life in these patients.

OUTLINE: This is a prospective, double-blind, placebo-controlled, randomized, multicenter
study. Patients are stratified according to prior brain irradiation type (whole-brain vs
partial-brain) and study site. Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive oral donepezil hydrochloride once or twice daily for up to 24
weeks in the absence of unacceptable toxicity.

- Arm II: Patients receive oral placebo once or twice daily for up to 24 weeks in the
absence of unacceptable toxicity.

Patients complete self-reported questionnaires (quality of life, fatigue, subjective
confusion, neurocognitive battery, and mood) at baseline and 12 and 24 weeks.

PROJECTED ACCRUAL: A total of 200 patients will be accrued for this study.

INCLUSION CRITERIA:

- Adults >18 years old.

- Life expectancy of at least > 30 weeks.

- Must have received a prior course of at least 30 Gy fractionated whole or partial
brain irradiation for treatment of a primary brain tumor or metastatic disease to the
brain.

- Must have completed radiation > 6 months prior to enrollment and have no radiographic
evidence of brain disease, or stable brain disease defined as no evidence of tumor
progression in the 3 months prior to enrollment.

- Patients who have undergone one or more treatments with single fraction stereotactic
radiosurgery (SRS) in addition to whole or partial brain irradiation are eligible, as
long as the SRS was completed > 6 months prior to registration if NED or stable
disease.

- Radiation treatment records must be available for all prior radiation treatments
(external beam and/or SRS).

- Patients who have received PCI (prophylactic cranial irradiation) are eligible.

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

- Treatment with steroids, anti-cholinergics, anti-epileptics, anti-depressants, and /or
sedatives/benzodiazepines is acceptable, but the patient must be on a stable or
decreasing dose at the time of study entry.

- Patients using narcotic analgesics on a stable dose and/or prn basis are eligible.

- Patients currently on a stable dose of Methylphenidate or Dextramphetamine are
eligible.

- For patients with brain metastases, if extracranial primary or metastatic disease is
present, it must have responded to local and/or systemic treatment. Must be stable in
the 3 months prior to enrollment.

- Must not be receiving chemotherapy at the time of enrollment.

- Patient must not have any planned therapy, including surgery, brain radiation of any
type, chemotherapy, or immunotherapy during the next 30 weeks for brain or
extracranial primary metastatic disease.

- Hormonal therapy for patients with breast or prostate cancer is acceptable.

- Breast patients receiving therapy with Herceptin are allowed.

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

- Patients must have a telephone.

EXCLUSION CRITERIA:

- Patients cannot be currently taking dementia drugs, cognitive enhancers, neuroleptics,
and/or anti-parkinsonian agents. For patients who have used these drugs in the past,
they must not have used them in the 2 weeks prior to enrolling on the study.

- Hypersensitivity to donepezil.

- Patients may not currently be taking Ketoconazole or Quindine

- Arrythmias including bradycardia or heartblock

- Patients who have received, GliaSite or other type of brain brachytherapy, (Gliadel
Wafers permitted) convection enhanced delivery of immunotoxins, and/or any other
investigational modalities for treatment of their brain tumor. The effects of
donepezil on the developing human fetus at the recommended therapeutic dose are
unknown. For this reason, women of child-bearing potential and men 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 treating 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.