Acolbifene in Preventing Cancer in Premenopausal Women at High Risk of Breast Cancer

PRIMARY OBJECTIVES:

I. To determine the effect of six months of acolbifene 20 mg/day on Ki-67 in high risk
premenopausal women with baseline hyperplasia +/- atypia and Ki-67 positivity of >= 2%..

SECONDARY OBJECTIVES:

I. To determine the effect of six months of acolbifene 20 mg/day on mammographic breast
density in high risk premenopausal women.

II. To determine the effect of six months of acolbifene 20 mg/day on serum levels of
follicular phase bioavailable estradiol, and luteal phase progesterone, testosterone, and
fasting IGF-1/IGFBP-3.

III. To determine the effect of six months of acolbifene 20 mg/day on epithelial cell
cytomorphology and molecular markers such as ER, PgR, and pS2.

IV. To determine the effect of six months of acolbifene on markers of cardiovascular risk
(C-reactive protein, functional AntiThrombin III, and fasting lipid profile) and bone
turnover markers associated with bone mineral density gain or loss (serum osteocalcin and
N-telopeptide crosslinks).

V. To assess any increase in reported hot flashes, menstrual cycle irregularities, pelvic
pain, musculoskeletal complaints, and fatigue from baseline.

OUTLINE:

Patients receive oral acolbifene hydrochloride once daily for 6 months in the absence of
unacceptable toxicity.

Patients undergo symptom assessment (hot flashes, menstrual abnormalities, pelvic pain,
muscle and joint pain, and fatigue) at baseline, 6-8 weeks, monthly for 6 months, and then at
2 weeks after completion of study treatment.

Patients undergo random periareolar fine needle aspiration between days 1-10 of menstrual
cycle at baseline and at 6 months. Patients also undergo blood sample collection between days
1-10 and days 20-24 of menstrual cycle at baseline and at 6 months. Samples taken between
days 1-10 of menstrual cycle are analyzed for Ki-67 expression, cytomorphology, molecular
markers (estrogen receptor, progesterone receptor, and pS2 expression), and bioavailable
estradiol levels. Samples taken between days 20-24 of menstrual cycle are analyzed for
progesterone, testosterone, IGF-1, IGFBP-3, lipid profile, bone-turnover markers (osteocalcin
and N-telopeptide crosslinks), C-reactive protein, and functional antithrombin III.

After completion of study treatment, patients are followed at 2 weeks.

Inclusion Criteria:

- Gail risk >= 1.7% and/or relative risk >= 3 times that for 5-year age group

- Premenopausal

- More than 6 months since initiating or discontinuing oral contraceptives

- At increased risk for breast cancer, as indicated by >= 1 of the following risk
factors:

- BRCA1/2 mutation characterized as deleterious or of uncertain significance

- Prior atypical ductal hyperplasia, ductal carcinoma in situ, or lobular carcinoma in
situ

- Prior random periareolar fine needle aspiration (RPFNA) showing atypical hyperplasia

- Family history consistent with hereditary breast cancer, as indicated by 1 of the
following criteria:

- >= 4 relatives with breast cancer

- >= 2 relatives diagnosed with breast cancer at ≤ 50 years of age

- Breast and ovarian cancer diagnosed in same relative

- No suspicion for breast cancer on baseline mammogram performed between days 1-10 of
menstrual cycle within 3 months prior to screening baseline RPFNA

- Exhibits hyperplasia with or without atypia (Masood score >= 14) with >= 500 cells AND
Ki-67 positivity >= 2% by RPFNA performed within 6 months prior to initiation of study
drug

- Estimated visual mammographic breast density category >= 5% on mammogram performed
within 6 months prior to initiation of study drug

- Has regular menstrual cycles (between 21 and 35 days) unless using extended regimen
oral contraceptives or a contraceptive device (e.g., Mirena IUD) Values for metabolic
profile and blood count within normal limits

- Absolute granulocyte count > 1,000/mm^3

- Platelets > 100,000/mm^3

- Hemoglobin > 10 g/dL

- Bilirubin < 2.0 mg/dL

- AST < 2 times upper limit of normal (ULN)

- Albumin > 3.0 g/dL

- Creatinine < 1.5 mg/dL

- Alkaline phosphatase < 2 times ULN

- Concurrent hormonal contraceptives allowed provided patient remains on the same
hormonal regimen from 3 months prior to baseline aspiration until the completion of
study treatment

- Fertile patients must use effective contraception during and for 3 months after
completion of study treatment

- Willing to ingest recommended dose of calcium and vitamin D for premenopausal bone
health (1,200 mg calcium and 800 IU vitamin D daily)

- Negative pregnancy test prior to receiving study agent

Exclusion Criteria

- pregnant or nursing

- nursing within the past 6 months

- Known osteoporosis or severe osteopenia (T-score -2 or worse by DEXA)

- History of symptomatic endometriosis with pelvic pain, poorly controlled migraines, or
hot flashes

- History of deep venous thrombosis

- History of allergic reactions attributed to compounds of similar chemical or
biological composition to the study agent

- Other condition or concurrent illness that, in the opinion of the investigator, would
make the patient a poor candidate for RPFNA

- Less than 1 year since prior use of aromatase inhibitors (e.g., anastrozole,
exemestane, or letrozole) or selective estrogen receptor modulators (e.g., tamoxifen
citrate, raloxifene, or arzoxifene hydrochloride)

- Other concurrent chemopreventive agents

- Concurrent anticoagulants

- Other concurrent investigational agents

- Bilateral breast implants