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

Phase II Study of Acolbifene in Pre-Menopausal Women at High Risk for Breast Cancer

This phase II trial is studying how well acolbifene works in preventing cancer in premenopausal women at high risk of breast cancer. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of acolbifene may stop cancer from growing or coming back.

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