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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: acolbifene hydrochloride


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prevention (acolbifene hydrochloride)<br>Patients receive oral acolbifene hydrochloride once daily for 6 months in the absence of unacceptable toxicity. | Drug: acolbifene hydrochloride<br>* Given orally<br>* Other names: SCH 57068.HCl;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Percentage of Breast Epithelial Cells Expressing Ki-67, From Baseline to 6 Months | Change in proliferation as measured by Ki-67 immunocytochemical expression in breast epithelial cells obtained by random periareolar fine needle aspiration at baseline and at 6 months. | Baseline to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mammographic Breast Density | Change in mammographic density from baseline to 6 months, The Percent Breast Density is estimated using the Cumulus computer-assisted program to define a region that is at greater density than the remainder of the breast. | Baseline to 6 months | 
| Change in Serum Estradiol Concentration | Change in serum concentration of estradiol from baseline to 6 months | Baseline to 6 months | 
| Change in Serum Concentration of Bioavailable Estradiol | Change in serum concentration of bioavailable estradiol (adjusted for concentration of Sex Hormone Binding Globulin), from baseline to 6 months | Baseline to 6 months | 
| Change in Serum Concentration of Testosterone | Change in serum concentration of Testosterone from baseline to 6 months | Baseline to 6 months | 
| Reports of Hot Flashes as Assessed by the Loprinzi Hot Flash Scoring System | Problems with hot flashes were assessed by average number per day and intensity. | Baseline to up to 2 weeks post-treatment | 
| Reports of Muscle/Joint Complaints as Assessed by the Validated HAQ II Questionnaire | The Health Assessment Questionnaire II (HAQ-II) measures interference in daily activities from arthralgias and joint pain. Range 0 - 4. A higher score indicates greater (i.e., worse) interference. | Baseline to up to 2 weeks post-treatment |