The following datasets contain the data available for EPPT NWU2017-09-01. 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 40 datasets contain the raw form data received, excluding PII.

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Trial Summary

This three-cohort study looks to establish the dermal tolerability and safety of Endoxifen (ENX) gel administered topically to both breasts, to be used for breast cancer therapy.

Trial with three cohorts:

• Cohort 1: 10mg daily Endoxifen gel vs. placebo gel
• Cohort 2: 20mg daily Endoxifen gel vs. placebo gel
• Cohort 3: 10mg Endoxifen gel only

Target Registration: 38

Enrollment Statistics

Actual Enrollment: 36

• 33 people were registered (33 of 36)
• 1 person was registered but withdrew from the study (1 of 33)
• 12 people were in Cohort 1 (12 of 33)
• 8 people were given 10mg Endoxifen gel (8 out of 12)
• 7 people completed the study (7 out of 8)
• 1 person discontinued treatment but stayed on follow-up (1 out of 8)
• 4 people were given 10mg placebo gel (4 out of 12)
• 3 people completed the study (3 out of 4)
• 1 person discontinued treatment but stayed on follow-up (1 out of 4)
• 12 people were in Cohort 2 (12 of 33)
• 8 people were given 20mg Endoxifen gel (8 out of 12)
• 7 people completed the study (7 out of 8)
• 1 person discontinued treatment but stayed on follow-up (1 out of 8)
• 4 people were given 20mg placebo gel (4 out of 12)
• 4 people completed the study (4 out of 4)
• 8 people were in Cohort 3 (8 of 33)
• 8 people were given 10mg Endoxifen gel (8 out of 12)
• 8 people completed the study (8 out of 8)
• 3 people were not registered (3 of 36)
• 1 person was not eligible (1 of 3)
• 1 person withdrew from the study (1 of 3)
• 1 person decided to have surgery elsewhere (1 of 3)

Eligibility Criteria

Inclusion Criteria

• Women scheduled for unilateral or bilateral mastectomy for breast cancer therapy, pathology confirmed stage 0-III (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 years (since breast cancer is not a pediatric disease and no safety data are available for ENX use in children).
• ECOG performance status <=1 (Karnofsky >=70%).
• Participants must have adequate hepatic and renal function tests, as defined below. Upper limits of normal (ULN) refer to those existing at each accruing institution.
• Total bilirubin < 1.5 X ULN (in women with prior documented bilirubin elevations consistent with Gilbert's syndrome, total bilirubin up to 3X ULN will be allowed).
• AST (SGOT) < 2.5 X ULN
• ALT (SGPT) < 2.5 X ULN
• Creatinine < 2 X ULN
• Alkaline phosphatase < 2.5 X ULN
• Blood Urea Nitrogen < 2 X ULN
• Ability to understand and the willingness to sign a written informed consent document which includes a requirement to apply study agent to sensitive body parts daily.
• Willingness and ability to schedule mastectomy 21-28 days following start of study agent. Women with breast implants may participate.
• Willingness to avoid exposing breast skin to natural or artificial sunlight (i.e. tanning beds) for the duration of study agent dosing.
• Negative urine or serum pregnancy test result, for participants of child bearing potential. 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; AND has had a menstrual period at any time in the preceding 12 consecutive months).
• The effects of topical ENX gel on the developing human fetus are unknown. For this reason, women of child-bearing potential and their male partners must agree to use effective forms of birth control (abstinence is not an allowed method) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately.

Exclusion Criteria

• The presence of gross skin invasion/ulceration by the breast cancer, or inflammatory changes with skin edema AND erythema. Note: Paget's disease is permitted.
• Women receiving a "nipple delay" procedure prior to mastectomy.
• Women with skin diseases (psoriasis, eczema).
• A history of thromboembolic disorder.
• Endometrial intraepithelial neoplasia (also known as atypical hyperplasia) or a high risk of uterine cancer, defined here as known carriers of Lynch syndrome mutations (MLH1, MSH2, MSH6, PMS2).
• 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 tamoxifen.
• 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 (chemotherapy, radiation, anti-HER2 agents, endocrine agents, everolimus, CDK4-6 inhibitors). Previous unilateral radiation of the contralateral side in women scheduled for mastectomy is allowed. Study gel will be applied to both breasts.
• History of prior mastectomy.
• Pregnant or breastfeeding.
• Patients receiving neoadjuvant chemotherapy with curative intent.
• Men are excluded from this study since breast cancer is men is rare and there are no data regarding skin penetration of topical breast cancer prevention agents through male chest wall skin (which is thicker and harrier than female chest wall skin).
• Current users of other topical medications on the breast skin must be willing and able to discontinue use for the duration of participation. Body lotion and other non-medicinal topical compounds may be applied >4 hours after study gel application.

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.

Over the course of this study 814 biospecimens were collected.

Blood samples were collected twice during the study, once at baseline and once at the second study visit around 4 weeks after. Blood was collected into either blue top tubes or lavender top tubes. For the blue top tubes, 2 x 2.7 mL draw tubes, Sodium Citrate vacutainer®, were filled completely. After gently mixing, the tubes were centrifuged for 15 minutes at 1500g at 22°C. After centrifugation, the separated plasma was aliquoted to 2 mL cryogenic vials, 1 mL in each. If there was not 2 mL of plasma to fill the second vial, it should be filled with the remaining plasma available and noted. Plasma samples were then frozen at - 80°C in a non-frost free freezer. The lavender top tube, K2-EDTA vacutainer®, were filled, gently mixed, then placed at 4°C or on wet ice until they were centrifuged for 10 minutes at 1300g and 4°C. The plasma was then aliquoted similarly to the blue top tubes. After consent for biobank is verified, the buffy coat layer was collected and transferred to a separate 2 mL vial and then frozen at - 80°C in a non-frost free freezer.

Tissue samples were taken twice during the study, once at baseline and once at the second study visit around 4 weeks later. The tissue samples were taken from a biopsy at the baseline visit and then from the mastectomy specimen at the week 4 visit. After the samples were taken and weighed they were split in the following manner:

• A slice of tissue about 3 mm thick was taken from one face, weighed, placed into a cassette labelled with pencil and placed in formalin (was done as soon as possible to preserve antigenicity) for a minimum of 6 hours. After formalin fixation, it was processed within 72 hours and embedded in paraffin.
• The remaining tissue pieces were weighed together, placed into the same cryovial and flash-frozen in liquid nitrogen.
• For the lymph node tissue, if the specimen was less than 100mg, it was not split and was snap-frozen in liquid nitrogen. If the sample was greater than 100 mg, it was split into sections and processed in the same way samples were processed as outlined above.

All research tissue frozen samples and FFPE blocks from the mastectomy procedure were be stored at -80°C and room temperature, respectively.

*No Specimen Available

Thirty-two intent-to-treat participants were evaluated for local dermal toxicity. No drug-related dermal toxicity was observed in the placebo group and 25% of participants (6/24) receiving endoxifen experienced at least one Grade 1 toxicity (4/16 and 2/8 in endoxifen 10 mg and 20 mg groups, respectively). The most common toxicity was dry or itching skin and lasted for minutes to days. symptoms did not lead to discontinuation of treatment.