The following datasets contain the data available for EPPT NWU2015-06-04. The description and documentation for each file is listed below. SAS7bdat and CSV versions of the actual data will be available to CDAS projects approved to use this study's data.

Analysis Datasets

Raw Datasets

These 39 datasets contain the raw form data received, excluding PII.

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Trial Summary

This Phase IIB randomized, double blind clinical trial tested oral tamoxifen against 4-hydroxytamoxifen gel in women with DCIS of the breast. The goal was 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.

Patients received either 2mg once daily per breast of 4-OHT topical gel, or 20mg daily oral TAM for 4 to 10 weeks.

Enrollment Statistics

Target Enrollment: 100

Actual Enrollment: 120

Actual Registration: 120

• 120 were evaluated for eligibility
• 13 were excluded for not meeting inclusion/exclusion criteria
• 107 were registered for 4 to 10 weeks of intervention
• 90 completed study
• 10 participant withdrawal
• 1 physician decision
• 1 protocol violation
• 5 other specify

Participant Statistics:

• Age (years):
  • Mean: 55.0
  • Median: 53.0
  • Range: 30 - 82
• Sex
  • Female: 120 (100%)
• BMI:
  • Mean: 29.6
  • Median: 27.5
  • Range: 19.0 - 46.3

Eligibility Criteria

Inclusion Criteria

• Screen-detected, ER positive DCIS of the breast proven on core needle biopsy, defined as 10% ER positive cells. Microinvasion will be allowed. The size of the DCIS in the core biopsy sample must be at least 4mm for a single core or total at least 5 mm if multiple cores are summed and must be estimated on the deepest step section (if step sections are taken).
• Age ≥18 years. DCIS of the breast is almost exclusively an adult condition. Because no dosing or adverse event (AE) data are currently available on the use of tamoxifen in participants <18 years of age, children are excluded from this study.
• 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
• Platelets ≥100,000/microliter
• Total bilirubin ≤1.5 x institutional upper limit of normal (ULN)
• AST (SGOT)/ALT (SGPT) ≤1.5 x ULN
• Creatinine ≤1.5 x ULN
• The effects of topical 4-OHT gel on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because tamoxifen is known to be teratogenic, all heterosexually active women who may become pregnant must agree to use a reliable non-hormonal contraceptive method or a hormonal IUD 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). Hormonal IUDs are also allowable methods of birth control. [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.]
• 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

• Exogenous sex steroid use within 4 weeks prior to diagnostic core needle biopsy (DCNB). Use of vaginally administered estrogens and hormone coated IUD such as Mirena is permitted and use should continue until surgery.
• History of any prior ipsilateral breast radiotherapy. Previous unilateral radiation of the contralateral side is allowed.
• History of other prior breast cancer-specific therapy within the previous 2 years (chemotherapy, anti-HER2 agents, endocrine agents, everolimus, CDK4-6 inhibitors).
• 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 willing and able to discontinue use and switch to an alternative medication for the duration of participation, under the advice of their physician. If the physician believes the current medication is medically necessary, the participant will not be eligible. The potent inhibitors of tamoxifen metabolism are: bupropion, cinacalcet, fluoxetine, paroxetine, quinidine.
• 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. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with tamoxifen, 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).

The Schema is a timeline of the study. It indicates start/end points, visits expected, major testing to be done, and any other information that is crucial to understanding how the study was completed.

Of 90 participants completing treatment (mean age 55 years, 62% white), 15 lacked residual DCIS in the surgical sample, leaving 75 evaluable for the primary endpoint (oral-TAM N=40, 4OHT-gel N=35). Post-treatment Ki67-LI was 3.3% higher (80% CI 2.1%-4.6%) in the 4OHT-gel compared to oral-TAM arm, exceeding the noninferiority margin (M=2.6); DCIS Score decreased more with oral-TAM treatment (-16, 95% CI -22, -9.4) than with 4OHT-gel (-1.8, 95% CI -5.8, 2.3). Median 4-OHTconcentrations (ng/g) deep in the breast were non-significantly higher in the oral-TAM arm (5.7, IQR 4.0,7.9 vs. 3.8 IQR 1.3,7.9), whereas endoxifen was abundant in the oral-TAM and minimal in the 4OHT-gel arm (13 vs. 0.3, p<0.001). Oral-TAM caused expected adverse changes in plasma proteins and vasomotor symptoms, with minimal changes in the transdermal arm.¹