Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Menopause

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

acolbifene hydrochloride

Carol Fabian

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.

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

Individual data will not be shared; only summary assessments.

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.

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.

Change in serum concentration of estradiol from baseline to 6 months

Change in serum concentration of bioavailable estradiol (adjusted for concentration of Sex Hormone Binding Globulin), from baseline to 6 months

Change in serum concentration of Testosterone from baseline to 6 months

Problems with hot flashes were assessed by average number per day and intensity.

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.

National Cancer Institute (NCI)

University of Kansas Medical Center

Professor

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

acolbifene hydrochloride: Given orally

Prevention (Acolbifene Hydrochloride)

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Height

Weight

Projected risk of a women developing breast cancer within the next 5 years, as calculated using the Gail Risk Model.

5-Year Gail Risk

Age First Live Birth

Bruce F. Kimler Ph.D

Change in the Percentage of Breast Epithelial Cells Expressing Ki-67, From Baseline to 6 Months

One subject was without a digital file due to technical reasons. Thus, only 24 subjects were evaluated.

Change in Mammographic Breast Density

Change in Serum Estradiol Concentration

Change in Serum Concentration of Bioavailable Estradiol

Change in Serum Concentration of Testosterone

Reports of Hot Flashes as Assessed by the Loprinzi Hot Flash Scoring System

Reports of Muscle/Joint Complaints as Assessed by the Validated HAQ II Questionnaire

Overall Study

Symptoms and General Pathology

Carcinoma

Carcinoma, Ductal

Hyperplasia

Carcinoma in Situ

Carcinoma, Lobular

Carcinoma, Intraductal, Noninfiltrating

Carcinoma, Ductal, Breast

Breast Carcinoma In Situ

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Bone Density Conservation Agents

Antineoplastic Agents

All Drugs and Chemicals

Tamoxifen

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Estrogen Receptor Modulators

Selective Estrogen Receptor Modulators

Patients receive acolbifene PO QD for 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo 3D mammography and collection of blood samples during screening and at the end of acolbifene treatment. In addition, patients undergo RPFNA during screening and during day 1-10 of their menstrual cycle, or if not menstruating, at the convenience of the patient and study staff.

Patients receive tamoxifen PO QD for 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo 3D mammography and collection of blood samples during screening and at the end of tamoxifen treatment. In addition, patients undergo RPFNA during screening and day 1-10 of their menstrual cycle, or if not menstruating, at the convenience of the patient and study staff.

Acolbifene Hydrochloride

Biospecimen Collection

Mammography

Random Periareolar Fine-Needle Aspiration

Lisa D. Yee

Seema A. Khan

Carol J. Fabian

Sagar D. Sardesai

Carol J Fabian

This phase IIA trial compares the effect of acolbifene versus low dose tamoxifen in preventing breast cancer in premenopausal women at high risk for developing breast cancer. The usual approach for patients at increased risk for breast cancer is to undergo yearly breast magnetic resonance imaging (MRI) or ultrasound in addition to yearly mammogram. Premenopausal women at very high lifetime risk for breast cancer (greater than 50%) can consider preventive removal (mastectomy) of both breasts. Premenopausal women age 35 or older with a prior diagnosis of atypical hyperplasia, lobular carcinoma in situ, or an estimated 10-year risk of greater than or equal to 3% or estimated 10-year risk of greater than or equal to 2-5 times that of the average woman (depending on age) may be advised to consider five years of standard dose tamoxifen. Standard dose tamoxifen is four times the dose used in this study. Estrogen can cause the development and growth of breast cancer cells. Acolbifene and tamoxifen blocks the use of estrogen by breast cells. This study may help researchers measure the effects of acolbifene and low dose tamoxifen on markers of breast cancer risk in mammogram imaging, breast tissue, and in blood samples.

PRIMARY OBJECTIVE:

I. To determine if there is a difference in change in expression of the endocrine resistance gene anterior gradient 2 (AGR2) in benign breast tissue of premenopausal women at increased risk for breast cancer randomized to acolbifene 20 mg vs tamoxifen 5 mg orally daily for 6 months.

SECONDARY OBJECTIVES:

I. To determine if there is significant within-arm effect of 6 months of acolbifene 20 mg or tamoxifen 5 mg as assessed on the Estrogen Response Gene Index (ERGI) in benign breast tissue.

II. To determine if there is significant within-arm effect of 6 months of acolbifene 20 mg or tamoxifen 5 mg on mammographic density as measured by relative change in % dense area (LIBRA \[Trademark\]).

III. Assess the feasibility of assessment of change in absolute fibroglandular volume (FGV) and % dense volume (Volpara \[Trademark\]) in a multisite trial.

IV. To determine if there is a significant within-arm effect of 6 months of acolbifene 20 mg or tamoxifen 5 mg on Menopause-Specific Quality of Life Questionnaire (MENQOL) or Hot Flash Score.

EXPLORATORY OBJECTIVES:

I. Assess within arm change in breast epithelial cell protein expression of Ki-67 in specimens with \>= 2% baseline Ki-67.

II. Assess within arm change in bioavailable serum estradiol, testosterone, progesterone.

III. Association of baseline AMH (\>= 1 ng/ml associated with normal ovarian reserve) with 6-month serum estradiol and change in tissue estrogen responsive gene expression (ERGI and AGR2).

IV. Association of tamoxifen and acolbifene parent drug and active metabolite levels with change in tissue estrogen response genes and mammographic density.

V. Assess within arm change of AGR2, FOXA1, estrogen receptor (ER), progesterone receptor (PR) by immunohistochemistry (IHC) on residual fixed random periareolar fine needle aspiration (RPFNA) specimens processed to blocks.

VI. Assess within arm change in metabolic measures including triglycerides, measures of insulin sensitivity and thyroid binding globulin (University of Kansas Medical Center \[KUMC\] participants only).

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I: Patients receive acolbifene orally (PO) once daily (QD) for 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo three-dimensional (3D) mammography and collection of blood samples during screening and at the end of acolbifene treatment. In addition, patients undergo RPFNA during screening and on day 1-10 of their menstrual cycle, or if not menstruating, at the convenience of the patient and study staff.

GROUP II: Patients receive tamoxifen PO QD for 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo 3D mammography and collection of blood samples during screening and at the end of tamoxifen treatment. In addition, patients undergo RPFNA during screening and day 1-10 of their menstrual cycle, or if not menstruating, at the convenience of the patient and study staff.

After completion of study treatment, patients are followed up between 21-35 days.

Acolbifene Versus Low Dose Tamoxifen for the Prevention of Breast Cancer in Premenopausal Women at High Risk for Development of Breast Cancer

Phase IIA Trial of Acolbifene (20 mg) vs Low Dose Tamoxifen (5 mg) in Pre-Menopausal Women at High Risk for Development of Breast Cancer

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Will be assessed in benign breast tissue acquired by random periareolar fine-needle aspiration (RPFNA). Change over the intervention period is expressed as the ratio of the relative abundance values (6-month value: baseline value) and then this fold change (FC) value is log transformed (base 2) for analysis. For this variable, values of zero indicate no change in the relative abundance of AGR2; positive values indicate an increase in the relative abundance; and negative values a decrease in the relative abundance.

The genes assayed for this index are: ESR1, ESR2, GREB1, progesterone receptor (PGR), and TFF1. The log2-transformed values of the ratio of relative abundance (6-month value: baseline value) for GREB1, PGR, TFF1, and the ratio of ESR1:ESR2 are averaged to produce the ERGI. In cases where a specific gene or ratio cannot be evaluated for change over time, it is omitted from the average.

Will be assessed via the completely automated LIBRA (Trademark) software program. This will be performed from Digital Imaging and Communications in Medicine processed image files. Will also assess the feasibility of obtaining the Volpara (Trademark) scorecard for volumetric assessments as the volume of density (absolute or % breast volume). The volumetric measures may be less susceptible to technical variance (such as compression) than area of density. We will assess relative change between baseline and 6-month fibroglandular volume determinations.

The responses to the 32 questions (will ask about symptoms over prior week) are clustered into four domains (vasomotor, psychosocial, physical, sexual). Worsening of problems (higher scores) over the course of the intervention will assessed by average scores for each of the four individual domains as well as the total MENQOL score.

The Hot Flash Score uses the product of the average number of hot flash/night sweat episodes per day and the average intensity (0= N/A, not experienced; 1= Mild; 2= Moderate; 3= Severe; 4= Very Severe).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Acolbifene in Preventing Cancer in Premenopausal Women at High Risk of Breast Cancer	NCT00853996	Breast Cancer	acolbifene hydr...	30 Years - 55 Years	University of Kansas Medical Center
Acolbifene Versus Low Dose Tamoxifen for the Prevention of Breast Cancer in Premenopausal Women at High Risk for Development of Breast Cancer	NCT05941520	Breast Atypical... Breast Carcinom... Breast Ductal C... Breast Lobular ...	Acolbifene Hydr... Biospecimen Col... Mammography Random Periareo... Tamoxifen	35 Years -	National Cancer Institute (NCI)
Acolbifene in Preventing Cancer in Premenopausal Women at High Risk of Breast Cancer	NCT00853996	Breast Cancer	acolbifene hydr...	30 Years - 55 Years	University of Kansas Medical Center

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