The following datasets contain the data available for EPPT NWU2013-01-03. 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 34 datasets contain the raw form data received, excluding PII.

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Trial Summary

This study was performed to determine the effect of oral vs. transdermal telapristone treatment during their pre-surgical window women who were scheduled for unilateral or bilateral mastectomies. 65 volunteers were able to complete the trial with 61 being fully compliant.

Telapristone was administered to the volunteers in a dose of 24mg gel or 12mg capsule every day for 4 weeks to determine the more effective treatment.

The study concluded that plasma concentrations of telapristone were much lower in the transdermal arm. In addition, the transdermal therapy was well received by the participants and was sufficiently well tolerated over the trial to be a viable prevention drug, if efficacious.

Randomized trial with two arms:

• Arms:
  • Arm I: Telapristone gel (12 mg per breast, total 24 mg) and placebo capsule (12 mg) daily for 4 weeks.
  • Arm II: Placebo gel (12 mg per breast, total 24 mg) and telapristone capsule (12 mg) daily for 4 weeks.

Enrollment Statistics

Expected Enrollment: 85

Actual Enrollment: 82

• 75 participants randomized (75 of 82 consented)
  • 7 not randomized (ineligible, adverse event, physician decision)
• 10 dropped from study (10 of 75)
  • 8 did not receive agent (hormone use, recent history of alcoholism, surgery date, health insurance)
  • 2 dropped out (due to smell of gel or adverse events)
• 4 non-compliant (61 of 65)

Total Study Population Demographics (65 Randomized and Eligible People):

• Age (years)
  • Mean: 50
  • Range: 27 - 77
  • Median: 46
• Height (cm)
  • Mean: 163
  • IQR: 159 - 167
  • Range: 151 - 180
  • Median: 163
• Weight (kg)
  • Mean: 74
  • IQR: 60 - 82
  • Range: 41 - 156
  • Median: 69
• Sex
  • Females: 65 (100%)
  • Males: 0 (0%)

Final Analysis Population: 65

Eligibility Criteria

Inclusion Criteria

• Women scheduled for unilateral or bilateral mastectomy for breast cancer therapy, pathology confirmed stage 0-II (including ductal carcinoma in situ), or prophylaxis (BRCA1/2 mutation carriers, women with strong family history or lobular carcinoma in situ or other conditions where prophylactic mastectomy has been elected).
• Age > 18
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
• Total bilirubin < 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) < 2.5 x ULN
• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x ULN
• Creatinine < 2 x ULN
• Alkaline phosphatase < 2.5 x ULN
• Blood urea nitrogen < 2 x ULN
• Willing to use non-hormonal contraception (adequate barrier-type contraception or intrauterine device [IUD]) from the time the pregnancy test is performed for the duration of study participation, and 30 days after study drug cessation (for women of childbearing potential only)
• Ability to understand and the willingness to sign a written informed consent document
• Willing and able to schedule mastectomy 4 weeks (+/- 7days) following start of study agent
• Willing to avoid exposing breast skin to natural or artificial sunlight (e.g. tanning beds) for the duration of study agent dosing
• Negative urine pregnancy test result, for participants of child bearing potential, within 5 days prior to first dose of study medication; female of child-bearing potential is any woman (regardless of sexual orientation, whether she has undergone a tubal ligation, or remains celibate by choice) who meets the following criteria: has not undergone a hysterectomy or bilateral oophorectomy; OR has had a menstrual period at any time in the preceding 12 consecutive months)
• Willing to use alcohol in moderation while taking study agent
• Willing to refrain from using soy supplements, over the counter estrogen supplements like estroven, Chinese herbs, or other over-the-counter (OTC) herbal products

Exclusion Criteria

• The presence of skin invasion by the breast cancer, or inflammatory changes with skin edema AND erythema
• Women with skin diseases (psoriasis, eczema)
• A history of thromboembolic disorder or cerebral vascular disease
• Use of oral contraceptives or other hormonal treatments within eight weeks prior to randomization or during the period of the study; women should not have used Depo-Provera in the preceding 6 months; use of hormone coated IUD like Mirena is allowed
• Participants may not have received any other investigational agents in the previous 3 months
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to telapristone (i.e. other progesterone antagonists)
• Taken tamoxifen or other selective estrogen/progesterone receptor modulators (SERMs/SPRMs) within two years prior to entering study or been required to discontinue SERM therapy due to thromboembolic or uterine toxicity
• 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
• History of prior breast cancer-specific therapy within the previous 2 years; previous unilateral radiation in women scheduled for mastectomy of the contralateral side is allowed
• Pregnant or breastfeeding
• Currently taking spironolactone
• Recent history (within 6 months) of alcoholism or drug abuse
• Known active infection with human immunodeficiency virus (HIV), hepatitis A, B, or C

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.

Study Schema

Over the course of this study 649 biospecimens were collected.

For plasma analysis, a 100 μL sample aliquot was mixed with 600μL of methyl tert-butyl ether (MTBE) and 10 ng of mifepristone in a 2-mL microcentrifuge tube. After the sample was shaken for 10 minutes, it was then centrifuged at 4000 RPM for 10 minutes at 4°C and was then frozen for at least an hour at -70°C. The top organic layer was then extracted and placed into another 2-mL microcentrifuge tube.

Breast tissue samples were weighted and minced with surgical scalpels. Samples of approximately 30 mg were treated with 200 μL of ASTM Type I Water, 10 ng of mifepristone and 600 μL of MTBE and processed in a 1600 MiniG (SPEX SamplePrep, Metuchen, NJ) tissue homogenizer for 10 minutes using a stainless-steel ball. The MTBE extracts were dried under nitrogen flow at 30 °C for approximately 15 minutes. The sample residue was reconstituted in 500μL of cold methanol, vortexed for 5 minutes and centrifuged. 250μL of the above sample was transferred into another 2-mL microcentrifuge tube and dried under nitrogen flow at 30°C for approximately 15 minutes. The sample residue was reconstituted in 125μL of 40% acetonitrile in water, vortexed and centrifuged again before instrumental analysis.

Chromatographic separation was achieved with a Luna C18(2) 3μ column, 50×2.0 mm (Phenomenex, Torrance, CA). The mobile phase was A: 0.1% formic acid in water (v/v) and B: 0.1% formic acid in acetonitrile (v/v). After injection, initial conditions with A at 70% were held for 0.5 min, decreased to 5% in 3.5 min and held at 5% for 2 min, returning to initial conditions for approximately 6 min of re-equilibration time. The flow rate was 0.3 ml/min at 25 °C. Retention times for CDB-4124, CDB-4453, and mifepristone were 1.6, 1.1 and 1.2 min, respectively. Total run time was 12 min. A turbo ion spray interface was used as the ion source operating in positive mode. Acquisition was performed in multiple reaction monitoring mode using m/z 506.4 → 134.3, 492.2 → 120.2, and 430.2 → 372.3 at low resolution for CDB-4124, CDB-4453, and mifepristone respectively.

*No Specimen Available

Results/Findings:

Plasma and tissue concentrations, measured at five locations in the mastectomy specimen using liquid chromatography tandem mass spectrometry were compared. In 60 evaluable subjects, median drug concentration (ng/g tissue) was 103 (interquartile range (IQR): 46.3–336) in the oral vs. 2.82 (IQR: 1.4–5.5) in the transdermal group. Despite poor dermal permeation, within-breast drug distribution pattern was identical in both groups (R₂ = 0.88, P = 0.006), demonstrating that transdermally and orally delivered drug is distributed similarly through the breast, and is strongly influenced by tissue adiposity (P < 0.0001). Other skin-penetrant drugs should be tested for breast cancer prevention.