4-Hydroxytamoxifen or Tamoxifen Citrate in Treating Women With Newly Diagnosed Ductal Breast Carcinoma in Situ

This is a randomized, double-blind, placebo-controlled presurgical trial of 0.228%
4-hydroxy-tamoxifen (4-OHT) gel vs. oral tamoxifen (TAM) 20 mg daily. The study population
will consist of 112 pre- and postmenopausal women with any grade DCIS, ER positive,
non-palpable DCIS with no evidence of invasion found on diagnostic core needle biopsy
(DCNB). In order to accrue a total of 112 participants with DCIS over a period of 22 months,
20 eligible participants total will be screened at the three participating institutions per
month with a planned average monthly recruitment of 5 participants total per month. We
assume that 22 women (20% of the recruited population, 11 women per arm) will be inevaluable
because of the presence of unanticipated invasive disease in the therapeutic surgical
excisional (TSE) specimen, or the absence of residual DCIS in the TSE, so that a total of 90
women (45 per arm) will be evaluable for the study endpoints. These estimates are based on
numbers from the Lynn Sage Database of NU: over the six-year period 2000-2005, the fraction
of women diagnosed with DCIS on core needle biopsy who were found to have no residual DCIS
in the TSE was 2.5% and that of women with invasive disease (T1a or greater) in the TSE when
the DCNB showed pure DCIS was 13.3%, very similar to the data reported by Bonnett et. al.
[56] who found that 13% of pure DCIS lesions seen on DCNB (29/122) were in fact invasive in
the TSE. With regard to racial/ethnic groups, 25.6% of the DCIS population at NU were of
non-European ancestry (18% African, 4% Hispanic, 3.5% other). WU has higher fractions of
African American women with DCIS (24% and 21% respectively).

The participants will be consented following diagnostic core needle biopsy at the time of
initial surgical consultation. Baseline assessments include medical history, nipple aspirate
fluid (NAF) collection, explanation of gel application, BESS questionnaire (symptom
assessment) and blood draw for clinical and research labs including plasma estradiol,
progesterone and FSH (rushed), CBC, chemistry profile, liver and renal function tests,
Factor VIII, von Willebrand Factor, Factor IX, and total protein S, plasma for insulin-like
growth factor (IGF-1) and sex hormone-binding globulin (SHBG), and DNA extraction for
assessment of polymorphisms in tamoxifen metabolism genes. At Northwestern plasma and RNA
from blood will be collected pre- and post-treatment and will be stored for future proteomic
and gene expression fingerprinting

No run-in period is planned. The intervention phase will begin within 5 days following
randomization and end on the day prior to surgical resection. The 4-OHT group will apply
active gel 2 mg daily to each breast for 4-10 weeks and take oral placebo. The TAM group
will take 20 mg TAM orally daily and apply gel placebo. The last dose of study medication
will be used on the morning of the day prior to surgery.

Participants will be shipped two 100 ml canisters of 4-OHT or placebo gel plus 130 capsules
of tamoxifen or oral placebo at the time of randomization. Participants will take study
agents for 4-10 week (minimum). However, if surgery needs to be delayed beyond the 8 week
study period for clinical reasons (eg scheduling with plastic surgery) the participant will
be sent additional medication by mail to allow continuation of therapy until the day before
surgery up to a maximum duration of 10 weeks.

On the day prior to surgery, baseline assessments will be repeated (with the exception of
menopausal determination and tamoxifen metabolism gene polymorphisms, but with the addition
of blood draw for tamoxifen metabolites and E and Z 4-OHT isomer determination). Under
unavoidable circumstances, the end of intervention visit will be allowed on the day of
surgery prior to TSE. During the TSE breast adipose tissue from the surgical sample will be
snap frozen and stored at -800C for measurement of TAM metabolites. The paraffin block of
the DCNB and TSE samples will be acquired by the recruiting institution and 10 sections from
each specimen submitted to the NU Pathology Core Facility (NU PCF). The sections will be cut
in batches (with pre- and post-samples in the same batch), shipped cold, and processed for
immunohistochemistry within a week of sectioning.

Compliance assessment will occur through patient diaries, pill counts and the weighing of
returned drug (gel) canisters.

Patients will be assessed for adverse events at the post-surgical visit (approximately 7-14
days after surgery) and by phone at 30 days following the last dose of study agent.

Inclusion Criteria:

1. Diagnosis of hormone receptor positive (more than 5% cells staining for ER + and/ or
PR +), any grade (using definition of Page and Lagios) ductal carcinoma in situ
(DCIS) with or without evidence of microinvasion on diagnostic core needle biopsy
within the previous 60 days.

2. Women of age ≥ 18 years. Because no dosing or adverse event data are currently
available on the use of 4-hydroxytamoxifen in participants <18 years of age, children
are excluded from this study but will be eligible for future pediatric trials, if
applicable.

3. ECOG performance status ≥1 (Karnofsky ≥70%)

4. Participants must have normal organ and marrow function as defined below:

1. Leukocytes≥3,000/uL

2. Absolute neutrophil count (ANC)≥1,500/uL

3. Platelets≥100,000/uL

4. Total bilirubin within normal institutional limits

5. AST (SGOT)/ALT (SGPT)≤1.5 X institutional ULN

6. Creatinine within normal institutional limits

5. Women of child-bearing potential must agree to practice barrier birth control,
abstinence, or use non-hormonal IUDs from the time that the first pregnancy test is
performed throughout the duration of the study and for three months after cessation
of study drug. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her study physician immediately.

6. Ability to understand and the willingness to sign a written informed consent
document.

7. Ability and willingness to schedule surgical resection of DCIS lesion for 4-10 weeks
(28-70 days) following the start of study agent.

8. Willingness to avoid exposing breast skin to natural or artificial sunlight (i.e.
tanning beds) for the 4-10 weeks of study agent dosing.

Exclusion Criteria:

1. Prior history of, or at high risk to develop, thromboembolic disease will be
excluded.

2. Must not have taken exogenous sex hormones since biopsy diagnosing DCIS and must
agree not to use exogenous sex hormones while on study.

3. Must not have taken tamoxifen or other selective estrogen receptor modulators (SERMs)
within 2 years prior to entering the study. Women who have discontinued SERM therapy
because of thromboembolic or uterine toxicity, will be excluded regardless of
duration of use.

4. May not be receiving any other investigational agents.

5. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to 4-hydroxytamoxifen or tamoxifen.

6. 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.

7. Pregnant women are excluded from this study because tamoxifen and 4-hydroxytamoxifen
has the potential for teratogenic or abortifacient effects. Women are excluded from
enrolling within 3 months of the most recent pregnancy. Women must avoid becoming
pregnant in the 3 months following the use of study agent.

8. Women must not have breastfed within three months prior to DCNB. Women who are breast
feeding are excluded from entry into this trial because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with tamoxifen or 4-hydroxytamoxifen. Women must agree to forego breastfeeding
for three months following the use of study agent.

9. Must not have any dermatologic conditions resulting in skin breakdown in the area of
gel application.

10. Must not have a history of previous ipsilateral radiation to the affected breast.

11. Must not have had a breast reduction or augmentation within the 6 months prior to
first dose of study agents. Patients who have had breast implants more than 6 months
prior to first dose of study agents will be eligible.