Oral Tamoxifen vs. TamGel vs. Control in Women With Atypical Hyperplasia or Lobular Carcinoma In Situ

Study Overview
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Brief Summary
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The investigators plan to prospectively study breast tissue changes after a short course of Tamoxifen (Tam).

Detailed Description
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Women with atypical hyperplasia (AH) and lobular carcinoma in situ (LCIS) are at increased risk of breast cancer (BC) ( 1-2 % per year). Over two decades ago, placebo-controlled randomized trials established that oral tamoxifen (20 mg/day) reduces breast cancer risk by 50% in generally defined high risk women, with  70% reduction in women at high risk specifically due to atypical hyperplasia.[1] Years later, the side effects and toxicity of oral tamoxifen at 20 mg/day remain a significant barrier to its uptake and longterm compliance.[2, 3] To address the issue of toxicity, two main strategies have been pursued: 1) using a lower dose of oral tamoxifen, and 2) using a topical formulation of tamoxifen to avoid systemic side effects. The investigators will perform a prospective study of women with AH or LCIS who will take a short course of prevention therapy; breast tissue samples will be evaluated pre- and post-therapy to identify and evaluate very early biomarkers of response. The overall goal of the study is to evaluate short-term changes in background breast tissue induced by either low-dose oral tamoxifen or topical 4-OHT gel in women with AH or LCIS.

Official Title
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A Phase IIB Randomized Trial of Oral Tamoxifen vs. Topical 4-hydroxytamoxifen Gel vs. Control in Women With Atypical Hyperplasia or Lobular Carcinoma In Situ

Conditions
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Breast Atypical Hyperplasia, Breast Lobular Carcinoma in Situ, Breast Atypical Lobular Hyperplasia

Intervention / Treatment
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* Drug: Tamoxifen
* Drug: Topical 4-OHT( 4-hydroxytamoxifen)gel 4 mg/each breast/day
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing to return to enrolling institution for follow-up Willing to complete required testing Ability to complete questionnaire by themselves or with assistance Female (sex that was assigned at birth) Ipsilateral intact breast with histology confirmation of atypical ductal or lobular hyperplasia, or LCIS, within the last 5 years, whether surgically excised or not. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 The effects of topical afimoxifene (4-OHT) gel on the developing human fetus at the recommended therapeutic dose are unknown. However, oral tamoxifen is Pregnancy Category D-positive evidence of human fetal risk. For this reason, and because triphenylethylene antiestrogens, including tamoxifen, are known to be teratogenic, women of childbearing potential and their male partners must agree to use at least one effective form of birth control (abstinence is not an allowed method) prior to study entry and for the duration of study participation, and for 2 months following the last dose of study medications (participant can resume oral birth control pills for effective birth control measures after post-treatment biopsy is done). Effective birth control methods during treatment are: copper and Mirena intrauterine device (IUD), diaphragm/cervical cap/shield, spermicide, contraceptive sponge, condoms. Tubal Ligation is an acceptable method of birth control. Women of childbearing potential must have a negative pregnancy test within five days before starting study medications. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately. Willingness to avoid exposing breast skin to natural or artificial sunlight (i.e. tanning beds) for the duration of the study. Participants must have acceptable organ and marrow function as judged by treating physician's evaluation of baseline laboratory data. Negative pregnancy (serum or urine) test if of childbearing potential and/or follicle stimulating hormone (FSH) to verify menopausal status. Exclusion Criteria: Clinically suspicious mass/lesions Breast cancer in the past 5 years. Patients with any history of venous thromboembolic disease, regardless of timeframe (history of varicose veins and superficial phlebitis is allowed). Cytotoxic chemotherapy for any indication in last 2 years. Current pregnancy or lactation. History of other prior breast cancer-specific therapy within the previous 2 years (chemotherapy, anti-HER2 agents, endocrine agents, everolimus, CDK4-6 inhibitors). Cytotoxic chemotherapy for any indication in last 2 years. Prior use of selective estrogen receptor modulator (SERMS) or AIs including tamoxifen, raloxifene, anastrozole, letrozole, or exemestane for prevention or therapy within 5 years. Exogenous sex steroid, including oral contraceptive pill use within 1 month prior to pretreatment breast biopsy. Use of vaginally administered estrogens and hormone coated IUD such as Mirena is permitted. History of any prior ipsilateral breast radiotherapy. Previous unilateral radiation of the contralateral side is allowed. Skin lesions on the breast that disrupt the stratum corneum (e.g., eczema, ulceration). History of endometrial neoplasia Current smoker. Cessation for at least 6 weeks Current users of potent inhibitors of tamoxifen metabolism. The potent inhibitors of tamoxifen metabolism are: bupropion, cinacalcet, fluoxetine, paroxetine, quinidine. Participants may not be receiving any other investigational agents within 90 days of enrollment or during this study. History of allergic reactions to tamoxifen. Uncontrolled intercurrent illness that in the judgement of the treating physician would make them unsuitable for study participation Current use of anticoagulation medications. Patients who are breastfeeding. Hemoglobin < 10 g/dL (within 30 days of randomization). Leukocytes < 3,000/microliter (within 30 days of randomization). Platelets < 100,000/microliter (within 30 days of randomization). Total bilirubin > 1.5 x institutional upper limit of normal (ULN) (within 30 days of randomization). Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT) > 1.5 x ULN (within 30 days of randomization). Alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (SGPT) > 1.5 x ULN (within 30 days of randomization). Alkaline phosphatase, S > 1.5 x ULN (within 30 days of randomization). Albumin, S > 1.5 x ULN (within 30 days of randomization). Protein, total, S > 1.5 x ULN (within 30 days of randomization). Creatinine > 1.5 x ULN (within 30 days of randomization). Patients who are taking any medications, herbal products, or over the counter (OTC) products that are moderate or strong CYP2D6 inhibitors or CYP3A inducers. Patients should also refrain from starting any drug or product with these properties during the study. This is to avoid any potential interactions with tamoxifen or 4-OHT. Identification of a clinically suspicious mass on examination.

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects will be randomized 2:2:1 with either Oral Tamoxifen 10 mg/day gel placebo, Topical 4-OHT gel 4 mg/each breast/day oral placebo, or Control Oral and gel placebo for 4 weeks of treatment.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral Tamoxifen 10 mg/day<br>Oral Tamoxifen 10 mg/day | Drug: Tamoxifen<br>* Oral Tamoxifen 10 mg/day<br>* Other names: Oral tamoxifen;|
| Experimental: Topical 4-OHT (4-hydroxytamoxifen) gel 4 mg/each breast/day<br>Topical 4-OHT (4-hydroxytamoxifen) gel 4 mg/each breast/day +oral placebo | Drug: Topical 4-OHT( 4-hydroxytamoxifen)gel 4 mg/each breast/day<br>* Topical 4-OHT (4-hydroxytamoxifen) gel 4 mg/each breast/day<br>* Other names: Topical gel;|
| Experimental: Control<br>Oral and gel placebo | Drug: Placebo<br>* placebo pill or placebo gel<br>* Other names: placebo gel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The purpose of this research is to evaluate short-term changes in background breast tissue induced by oral tamoxifen or 4-OHT gel in women with atypical hyperplasia or lobular carcinoma in situ (LCIS). | Treatment Evaluation/Measurement of Effect | 48 months |