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Clinical Trial 19296

Cancer Type: Healthy Subjects
Study Type: Prevention
NCT#: NCT03063619

Phase: Phase II
Prinicipal Investigator:

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Study Title

A Randomized, Double-blind, Placebo-controlled Study of 4-hydroxytamoxifen Topical Gel in Women with Mammographically Dense Breast


The goal of this study is to determine whether putting 4-Hydroxytamoxifen (4-OHT) gel on the breast skin lowers mammographic density (MD) compared with putting placebo gel on the breast skin.


1. OBJECTIVES: The overall objective is to evaluate whether daily application of 2mg (2mL) per breast of 4-hydroxytamoxifen (4-OHT) topical gel versus placebo lowers breast density in women with mammographically dense breast, based on the intent-to-treat principle, i.e., all participants who have MD measurements from both baseline and 52 weeks, regardless of compliance, will be included in the primary analysis. 1.1 Primary Objectives: To estimate and compare the percent change in mammographic breast density (using Cumulus software) from baseline to Month 12 in women applying 2mg 4-OHT gel per breast versus placebo. 1.2 Secondary Objectives: 1. To compare the Cumulus vs. Volpara breast density measurement methods to estimate percent change in mammographic breast density from baseline to Month 12 in women applying 2mg of 4-OHT gel per breast vs. placebo. 2. To compare the percentage of women who underwent a change in BIRADS category, comparing pre-and post- treatment measurements, for recipients of active agent versus placebo. 3. To estimate percentage of women with greater than or equal to 10% absolute decrease in quantitative mammographic density percentage between baseline and 12 months, comparing between treated group 2 mg per breast 4-OHT gel to placebo. 4. To compare the 2D vs. 3D breast density measurement methods to estimate percent change in mammographic breast density from baseline to Month 12 in women applying 2mg of 4-OHT gel per breast vs. placebo. 5. To describe symptoms assessed by 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). 6. 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. 7. 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. 8. 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.




4-hydroxytamoxifen (Afimoxifene); Placebo ()

Inclusion Criteria

  • Women age 40-55 years, or 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 equal to or less than 1 (Karnofsky >= 70%)
  • Adequate hepatic, renal and marrow function
  • Participant must have a gynecology examination within the last 5 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
  • 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
  • Unwilling to use adequate contraception during study treatment duration, 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
  • Women with a uterus and abnormal uterine bleeding, or prior diagnosis of endometrial hyperplasia, endometrial polyps, or endometrial cancer.
  • Prior use of selective estrogen receptor modulators (SERMS) and aromatase inhibitors (AIs), except for a maximum of 3 months and at least 12 months prior.
  • 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

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