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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Breast Atypical Hyperplasia, Breast Carcinoma, Breast Ductal Carcinoma In Situ, Breast Lobular Carcinoma In Situ

Intervention / Treatment
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* Drug: Acolbifene Hydrochloride
* Procedure: Biospecimen Collection
* Procedure: Mammography
* Procedure: Random Periareolar Fine-Needle Aspiration
* Drug: Tamoxifen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 35 years Considered clinically premenopausal Having regular menstrual cycles (between 21 and 35 days) unless a contraceptive device such as progestin containing intrauterine device (IUD) (e.g., Mirena IUD) is being used which suppresses menstrual periods, or premenopausal women who have undergone a hysterectomy, but ovaries are intact Not considering pregnancy for at least 12 months Women of child-bearing potential must be willing to use effective birth control methods (precautions) during study and for 8 weeks prior to fine needle aspiration and for 8 weeks after study completion as tamoxifen may have teratogenic effects on the developing fetus. Reproductive and developmental toxicity studies have not been conducted with acolbifene. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately. Two of the following are recommended but woman must agree to at least one of the following methods: Hormonal-impregnated intrauterine device (IUD) or rings Non-hormonal IUD Barrier method (such as condoms and diaphragms or cervical caps with or without a spermicide) Partner has had a vasectomy Must have increased breast cancer risk as predicted by any one or more of the conditions listed below or increased model calculated risk as below: Any one or more of the following conditions associated with increased risk (condition must be documented in electronic medical record or copy of relevant pathology or genetic testing reports submitted with the eligibility checklist) A prior biopsy at any time in the past showing ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), atypical hyperplasia. (If DCIS must have been treated by mastectomy or local excision +/- radiation with this treatment completed at least 3 months prior to screening with RPFNA) High or moderate penetrance risk pathogenic or likely pathogenic germline gene mutation in ATM, BARD1, BRIP1, CDH1, CHEK2, MSH6, NBN, NF1, PTEN, PMS2, RAD51C, RAD51D, or TP53 High polygenic risk score (Life-time risk of >= 2x average or 25%) Breast cancer in a first or second degree relative (female or male) with onset under age 50. First degree relative is defined as parent, sibling, or child. Second degree relative is defined as grandparent, uncle, aunt, nephew, niece, half-sibling, grandchild or first cousin Two or more affected first or second-degree relatives from either the maternal or paternal lineage without regard to age Bilateral breast cancer or breast and ovarian cancer in the same first or second degree relative without regard to age. High mammographic density defined as either visual estimate of area of density (VAS) > 50%, or Volpara (Trademark) >= 15% dense volume (Volpara d) or Breast Imaging Reporting and Data System (BIRADS) assessment of extremely dense (BIRADs D) Alternatively, instead of Conditions listed above, , increased risk of breast cancer as calculated by standard models (Breast Cancer Risk Assessment Tool [BCRAT] Version 2, IBIS Version 8, Breast Cancer Surveillance Consortium) 5-year BCRAT Version 2.0 >= 1.66% 10-year IBIS Version 8 of >= 3% or Breast Cancer Surveillance Consortium Version 2 of >= 3% 10 -year IBIS Version 8 age specific relative risk of Age 35-39 10-year relative risk of >= 5X that for age group Age 40-44 10-year risk of >= 4X that for age group Age 45 and up 10-year risk of >= 2X IBIS Version 8 Remaining lifetime risk of >= 25% or >= 2X that of population A copy of the output of model calculations from IBIS Version 8 (http://www.emstrials.org/riskevaluator/), BCRAT Version 2.0 (https://dceg.cancer.gov/tools/riskassessment/bcra) or BCSC version 2.0 (https://tools.bcsc-scc.org/BC5yearRisk/calculator.htm) online tools, if used for qualifying risk assessment, or polygenetic risk score should be submitted with the eligibility checklist. Otherwise, these risk qualifying factors need to be documented in the medical record if that is considered the source document Women must have at least 1 unaffected untreated breast for fine needle aspiration. Women may have had prior unilateral breast radiation or mastectomy for DCIS Eastern Cooperative Oncology Group (ECOG) current performance status ≤2 as documented within 3 months prior to randomization (Karnofsky score >= 60%) Total bilirubin =< 1.5 x institutional upper limit of normal (measured within 180 days prior to randomization) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase]) =< 1.5 x institutional upper limit of normal (measured within 180 days prior to randomization) Creatinine =< 2.0 mg/dL (measured within 180 days prior to randomization) Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load Patients on chronic suppressive antiviral therapy for herpes simplex virus (HSV) are eligible Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Bilateral breast implants (danger of implant puncture with RPFNA) Women who are pregnant Currently breastfeeding (concern that tamoxifen or acolbifene may be in breast milk or nursing within the past 12 months (concern about milk fistula with RPFNA) Prior invasive breast cancer within the past 5 years Other prior invasive cancer > T1 stage (other than non-melanoma skin) within the past 5 years Pathogenic or likely pathogenic germline mutation in BRCA1/2 or PALB2 (These latter individuals are likely to undergo yearly ovarian screening and enlarging cysts could raise concern about ovarian cancer and lead to unnecessary diagnostic procedures) Type I or Type II diabetes mellitus requiring treatment with prescription medication Prior deep vein thrombosis, pulmonary embolus, or stroke History of chronic liver disease including NASH (nonalcoholic steatohepatitis) and chronic hepatitis C Current use of prescription anticoagulants such as Coumadin (warfarin), direct-acting oral anticoagulants such as Xarelto (rivaroxaban) or Eliquis (apixaban), or heparin Women who would not be able to or do not wish to discontinue daily use of aspirin (81 mg or higher) and aspirin containing products (81 mg or higher) at least 3 weeks prior to each RPFNA are not eligible. Women who would be able to stop daily use of aspirin and aspirin containing products at least 3 weeks prior to each RPFNA are eligible NOTE: Women may resume daily use of aspirin and aspirin containing products 3 days after each RPFNA procedure Starting or stopping hormonal progestin IUDs within 8 weeks of baseline RPFNA Current use or use within the prior 8 weeks of progesterone/progestin injections, progestin implants or oral contraceptives either combined estrogen + progestin or progestin only (due to concerns about high levels of progestin and lack of safety and efficacy data with low dose tamoxifen) Current use of other investigational agents Prior treatment with acolbifene for more than 2 months Prior treatment with tamoxifen for more than 2 months Current use of prescription immunosuppressive drugs History of allergic reactions attributed to tamoxifen or acolbifene or compounds of similar chemical composition Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study

Ages Eligible for Study
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Minimum Age: 35 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 (acolbifene)<br>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. | Drug: Acolbifene Hydrochloride<br>* Given PO<br>Procedure: Biospecimen Collection<br>* Undergo collection of blood<br>* Other names: Specimen Collection;Procedure: Random Periareolar Fine-Needle Aspiration<br>* Undergo RPFNA<br>* Other names: RPFNA;|
| Active Comparator: Group 2 (tamoxifen)<br>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. | Procedure: Biospecimen Collection<br>* Undergo collection of blood<br>* Other names: Specimen Collection;Procedure: Mammography<br>* Undergo 3D mammography<br>* Other names: MG;Procedure: Random Periareolar Fine-Needle Aspiration<br>* Undergo RPFNA<br>* Other names: RPFNA;Drug: Tamoxifen<br>* Given PO<br>* Other names: TMX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the relative abundance of the specific sequence of messenger ribonucleic acid (mRNA) that codes for AGR2 | 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. | Baseline up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Estrogen Response Gene Index (ERGI) | 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. | Baseline up to 6 months | 
| Relative change in mammographic percentage (%) dense area | 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. | Baseline up to 6 months | 
| Change in Menopause-Specific Quality of Life (MENQOL) | 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. | Baseline up to 6 months | 
| Change in Hot Flash 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). | Baseline up to 6 months |