Testing an Active Form of Tamoxifen (4-hydroxytamoxifen) Delivered Through the Breast Skin to Control Ductal Carcinoma in Situ (DCIS) of the Breast

Study Overview
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Brief Summary
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This randomized phase IIB trial studies how well tamoxifen or afimoxifene works in treating patients with estrogen receptor positive breast cancer. Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen citrate or afimoxifene may fight breast cancer by blocking the use of estrogen by the tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To demonstrate that 2 mg once daily per breast of 4-hydroxytamoxifen (4-OHT) topical gel results in a reduction in the Ki-67 labeling index of ductal breast carcinoma in situ (DCIS) lesions that is not inferior to that seen with 20 mg daily oral tamoxifen citrate (TAM) for 4-10 weeks, when comparing the base-line diagnostic core biopsy to the therapeutic surgical excision sample. SECONDARY OBJECTIVES: I. To compare post-therapy changes in the oncotype DCIS-score between arms (this is a validated reverse transcriptase-polymerase chain reaction [RT-PCR] assay for Ki67, STK15, survivin, cyclin B1, MYBL2, PR, GSTM1). II. To compare between-group post-therapy changes in immunohistochemistry (IHC) markers: CD-68 macrophage marker as a surrogate for response to therapy, p16 and COX-2. III. To compare post-therapy changes in breast density, quantitative estimate, between arms. IV. To compare post-therapy breast tissue and plasma levels of TAM and its metabolites (N-desmethyl tamoxifen [NDT], [E] and [Z] isomers of 4-hydroxytamoxifen [4-OHT], N-desmethyl-4-hydroxytamoxifen [endoxifen]). V. To compare post-therapy breast tissue and plasma levels of estradiol and progesterone between arms (optional). VI. To compare the post-therapy fraction of participants demonstrating no residual DCIS. VII. To compare post-therapy changes in plasma proteins involved in coagulation: factors VIII and IX, von Willebrand factor, total protein S between arms. VIII. To compare post-therapy changes in plasma markers of systemic estrogenic effect (IGF-1, SHBG). IX. To compare post-therapy changes in symptoms as captured in the breast cancer prevention trial (BCPT) Eight Symptom Scale (BESS) questionnaire and skin reactions to 4-OHT gel. OUTLINE: Patients are randomized into 1 of 2 arms. ARM I: Patients apply afimoxifene gel to both breasts and receive placebo orally (PO) daily for 4-10 weeks in the absence of disease progression or unexpected toxicity. ARM II: Patients apply placebo gel to both breasts and receive tamoxifen citrate orally PO daily for 4-10 weeks in the absence of disease progression or unexpected toxicity. After completion of study treatment, patients are followed up at 1-2 weeks and 1 month after surgery.

Official Title
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Phase IIB Pre-Surgical Trial of Oral Tamoxifen Versus Transdermal 4-hydroxytamoxifen in Women With DCIS of the Breast

Conditions
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Ductal Breast Carcinoma In Situ, Estrogen Receptor Positive

Intervention / Treatment
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* Drug: Afimoxifene
* Other: Laboratory Biomarker Analysis
* Other: Placebo
* Other: Placebo
* Drug: Tamoxifen Citrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Screen-detected, estrogen receptor (ER) positive DCIS of the breast proven on core needle biopsy, defined as 10% positive cells; the presence of a focus suspicious for microinvasion will be allowed; the size of the DCIS in the core biopsy sample must total 5 mm (multiple cores can be summed) and must be estimated on the deepest step section (if step sections are taken) Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) Participants must have acceptable organ and marrow function as defined below: Baseline lab parameters are not standard of care for initiation of tamoxifen therapy; a minimal panel will therefore be appropriate. Leukocytes >= 3,000/microliter Absolute neutrophil count >= 1,500/microliter Platelets >= 100,000/microliter Total bilirubin within ≤1.5 x institutional upper limit of normal (ULN)institutional limits Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x institutional upper limit of normal (ULN) Creatinine within ≤1.5 x institutional upper limit of normal (ULN) institutional limits Women of childbearing potential and their male partners must agree to use TWO effective forms of birth control (abstinence is not an allowed method) prior to study entry and for the duration of study participation, and for two months following the last dose of study medications; effective birth control methods are: copper IUD [intrauterine device], diaphragm/cervical cap/shield, spermicide, contraceptive sponge, condoms; women of childbearing potential must have a negative urine pregnancy test within seven 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 Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: DCIS presentation as a palpable mass Exogenous sex steroid use within 4 weeks prior to core needle biopsy Prior ipsilateral breast cancer radiotherapy will be excluded; prior contralateral breast cancer therapy within 2 years will also be excluded Skin lesions on the breast that disrupt the stratum corneum (eg eczema, ulceration) History of endometrial neoplasia History of thromboembolic disease (history of varicose veins and superficial phlebitis is allowed) Current smokers Current users of potent inhibitors of tamoxifen metabolism must be able to discontinue their use and switch to an alternative medication for the duration of participation, under the advice of their physician; if the physician feels that an alternative medication is not appropriate for the subject and the current medication is medically necessary, the subject will not be eligible; the drugs are listed below; many of these are not in clinical use at the moment; bupropion, celecoxib, chlorpheniramine, chlorpromazine, cimetidine, citalopram, clemastine, clomipramine, clozapine, cocaine, delavirdine, desipramine, diphenhydramine, doxepin, duloxetine, escitalopram, fluoxetine, haloperidol, halofantrine, hydroxyzine, imipramine, isoniazid, ketoconazole, methadone, methimazole, mibefradil, miconazole, nicardipine, paroxetine, pergolide, perphenazine, pioglitazone, pyrimethamine, quinidine, quinine, ranitidine, ritonavir, ropinirole, sertraline, terbinafine, thioridazine, ticlopidine, tranylcypromine, trazodone, tripelennamine Prior use of SERMS or AIs including tamoxifen, raloxifene, anastrozole, letrozole, or exemestane for prevention or therapy within 5 years Participants may not be receiving any other investigational agents within 30 days of enrollment or during this study History of allergic reactions attributed to tamoxifen or compounds of similar chemical or biologic 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 requirements Pregnant women are excluded from this study; breastfeeding should be discontinued by nursing mothers who agree to participate in the study Men are excluded from this study since DCIS of the breast is exceedingly rare in men, and there are no data regarding skin penetration of 4-OHT though male chest wall skin (which is thicker and hairier than female chest wall skin)

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (afimoxifene, placebo)<br>Patients apply afimoxifene gel to both breasts and receive placebo PO daily for 4-10 weeks in the absence of disease progression or unexpected toxicity. | Drug: Afimoxifene<br>* Applied to the breast<br>* Other names: 4-OHT;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Placebo<br>* Given PO<br>* Other names: sham therapy;|
| Active Comparator: Arm II (placebo, tamoxifen citrate)<br>Patients apply placebo gel to both breasts and receive tamoxifen citrate orally PO daily for 4-10 weeks in the absence of disease progression or unexpected toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Placebo<br>* Applied to the breast<br>* Other names: sham therapy;Drug: Tamoxifen Citrate<br>* Given PO<br>* Other names: Zemide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ki67 labeling assessed by standard immunohistochemistry |  | Up to 1 month after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CD68, p16, and COX2 assessed by IHC | Analysis will be pilot in nature and will provide descriptive statistics for each group or subgroup of subjects, supplying results which may be used to plan future studies. | Up to 1 month after surgery | 
| Estradiol and progesterone levels in breast tissue and plasma assessed by liquid chromatography/tandem mass spectrometry | Analysis will be pilot in nature and will provide descriptive statistics for each group or subgroup of subjects, supplying results which may be used to plan future studies. | Up to 1 month after surgery | 
| Fraction of subjects with no residual DCIS in surgical sample assessed by core needle biopsy | Analysis will be pilot in nature and will provide descriptive statistics for each group or subgroup of subjects, supplying results which may be used to plan future studies. | Up to 1 month after surgery | 
| Oncotype DCIS-score assessed by RT-PCR | Analysis will be pilot in nature and will provide descriptive statistics for each group or subgroup of subjects, supplying results which may be used to plan future studies. | Up to 1 month after surgery | 
| Pathologic complete response defined as absence of residual DCIS or residual DCIS responded completely to therapy |  | Up to 1 month after surgery | 
| Plasma markers of systemic estrogenic effect (IGF-1, SHBG) | Analysis will be pilot in nature and will provide descriptive statistics for each group or subgroup of subjects, supplying results which may be used to plan future studies. | Up to 1 month after surgery | 
| Plasma proteins involved in coagulation (factors VIII and IX, von Willebrand factor, and total protein S) | Analysis will be pilot in nature and will provide descriptive statistics for each group or subgroup of subjects, supplying results which may be used to plan future studies. | Up to 1 month after surgery | 
| Symptoms assessed by BESS questionnaire | Will evaluate hot flashes, vaginal discharge/dryness, skin reactions to afimoxifene gel. Analysis will be pilot in nature and will provide descriptive statistics for each group or subgroup of subjects, supplying results which may be used to plan future studies. | Up to 1 month after surgery | 
| TAM and its metabolites levels in breast tissue and plasma | Analysis will be pilot in nature and will provide descriptive statistics for each group or subgroup of subjects, supplying results which may be used to plan future studies. | Up to 1 month after surgery |