Afimoxifene in Reducing the Risk of Breast Cancer in Women With Mammographically Dense Breast

PRIMARY OBJECTIVES:

I. To estimate and compare the percent change in mammographic breast density (using Cumulus
software) from baseline to month 12 in women applying 4mg afimoxifene (4-hydroxytamoxifen
[4-OHT]) gel per breast versus placebo.

SECONDARY OBJECTIVES:

I. To compare the Cumulus versus (vs.) Volpara breast density measurement methods to estimate
percent change in mammographic breast density from baseline to month 12 in women applying 4mg
of 4-OHT gel per breast vs. placebo.

II. To compare the percentage of women who underwent a change in Breast Imaging Reporting and
Data System (BIRADS) category, comparing pre-and post- treatment measurements, for recipients
of active agent versus placebo.

III. To estimate percentage of women with >= 10% absolute decrease in quantitative
mammographic density percentage between baseline and 12 months, comparing between treated
group 4mg per breast 4-OHT gel to placebo.

IV. To describe symptoms assessed by breast cancer prevention trial (BCPT) eight symptom
scale (BESS) questionnaire and laboratory toxicity assessment (factor VIII [F VIII], Von
Willebrand [vWB] factor, sex hormone-binding globulin [SHBG], lipid profile).

V. To evaluate serum measurements of 4-OHT and related metabolite levels and factors related
to tamoxifen exposures, such as insulin-like growth factor (IGF) pathway members, C-reactive
protein (CRP), estradiol.

VI. To evaluate tissue biomarkers (among women undergoing optional pre- and post-treatment
biopsies): terminal duct lobular unit (TDLU) involution; collagen structural changes;
SETER/PR index: estrogen related transcription, Ki-67, COX-2, p16, CD68.

VII. To examine whether any reductions in mammographic density seen after 1 year of 4-OHT vs.
placebo gel application persist at 24 months, one year after gel application has stopped.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients apply placebo gel topically to each breast once daily (QD) for up to 52
weeks.

ARM B: Patients apply afimoxifene gel topically to each breast QD for up to 52 weeks.

After completion of study treatment, patients are followed up at 24 months.

Inclusion Criteria:

- Less than 40 years if 5-year breast cancer Gail risk is >= 1.66%

- Mammographically dense breast (heterogeneously dense [C] or extremely dense [D], based
on American College of Radiology [ACR] BIRADS fifth edition classification or
heterogeneously dense [3] or extremely dense [4], based on ACR BIRADS fourth edition
classification) in either breast

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- White blood cells >= 3,000/microliter

- Absolute neutrophil count >= 1,500/microliter

- Platelets >= 100,000/microliter

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 1.5 × institutional upper limit of normal (ULN)

- Creatinine within normal institutional limits

- Participant must have a gynecology examination within the last 3 years, with no
atypical hyperplasia and no cancer

- Premenopausal women taking non hormonal intra-uterine device (IUD) birth control
method will be eligible, if they have been on the same IUD for at least 3 months prior
to enrollment and plan to continue using the same method throughout the study

- Women of child-bearing potential must agree to use a reliable nonhormonal
contraceptive method during the study and for 2 months after completing study
medications; reliable nonhormonal methods of contraception include barrier
contraception and an intra-uterine device (IUD); Note: women who had tubal ligation or
had a partner who had undergone a vasectomy (and are monogamous) are eligible for the
study and are not required to use barrier contraception

- If the participant is of childbearing potential, she must have a documented negative
urine pregnancy test within 7 days prior to randomization

- Willingness to avoid exposing breast skin to natural or artificial sunlight (i.e.
tanning beds) for the duration of the study

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to 4-OHT gel

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, thromboembolic disease, or psychiatric illness/social situations that
would limit compliance with study requirements

- Pregnant, or had given birth, or nursed at any time during the last 12 months

- Women with a previous history of invasive breast cancer or bilateral ductal carcinoma
in situ (DCIS) or current untreated DCIS; women with a history of cancer within the
last 3 years, except for non-melanoma skin cancer; women with unilateral DCIS (with or
without radiation therapy) are eligible as long as they have an unaffected breast

- Prior bilateral breast surgery (mastectomy, segmental mastectomy, or breast
augmentation surgery including breast implants or breast reductions)

- Women with "mosaic mammographic screening views", i.e., whose larger breast size
precludes being imaged within a single mammographic screening view

- Women with active liver disease, abnormal uterine bleeding, or prior diagnosis of
endometrial hyperplasia

- Prior use of selective estrogen receptor modulators (SERMS) and aromatase inhibitors
(AIs) for prevention or therapy

- Skin lesions on the breast that disrupt the stratum corneum (e.g., eczema, ulceration)

- Treatment with any investigational drug or investigational biologic within 30 days of
initiating study treatment or during the study