Transdermal or Oral Telapristone Acetate in Treating Patients Undergoing Mastectomy

PRIMARY OBJECTIVES:

I. To demonstrate that mean levels of telapristone (telapristone acetate) in breast tissue
following gel application will result in levels that are not more than 50% lower than those
following oral administration.

SECONDARY OBJECTIVES:

I. To assess whether plasma concentrations of telapristone are significantly lower with
transdermal than oral therapy.

II. To compare within-breast variation of breast tissue concentration in transdermal and oral
groups.

III. To measure changes in cell proliferation (marker of proliferation Ki-67 [Ki67] labeling
index) and apoptosis (terminal deoxynucleotidyl transferase deoxyuridine triphosphate [dUTP]
nick end labeling [TUNEL]) in breast cancer samples obtained at diagnostic core needle biopsy
(of cancer) or research core needle biopsy (of unaffected breast) with tissue samples
obtained at mastectomy. Measure protein expression of related targets in the following order
of priority: progesterone receptor isoforms (progesterone receptor [PR]A and PRB), and
estrogen receptor alpha (ERα) and TUNEL using immunohistochemistry (IHC) at baseline and
after treatment.

IV. Explore changes in gene expression in breast tissue related to telapristone therapy.

V. Assess change in serum progesterone associated with telapristone therapy. VI. Assess the
safety and tolerability of oral and transdermal administration.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I (TRANSDERMAL TELAPRISTONE ACETATE): Patients receive telapristone acetate transdermally
and placebo orally (PO) once daily (QD) for 4 weeks.

ARM II (ORAL TELAPRISTONE ACETATE): Patients receive placebo transdermally and telapristone
acetate PO QD for 4 weeks.

After completion of study treatment, patients are followed up at day 60.

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
(breast cancer, early onset [BRCA] mutation carriers, women with strong family history
or lobular carcinoma in situ or other conditions where prophylactic mastectomy has
been elected)

- 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 (i.e. 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
the 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