Bexarotene in Preventing Breast Cancer in Patients at High Risk for Breast Cancer

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose of topical bexarotene 1% (weight by weight
[w/w]) gel for evaluation in healthy women. (Dose Escalation Group) II. Conduct an
intervention of topical 1% bexarotene gel to an unaffected breast of healthy women at high
risk for breast cancer for 4 weeks at the maximum tolerated dose (MTD) as determined during
the dose escalation group phase to assess bexarotene concentration in the breast tissue.
(Dose Expansion Group)

SECONDARY OBJECTIVES:

I. To detect bexarotene concentration in the serum at baseline and at 4 weeks of treatment.

II. To detect bexarotene concentration in the breast tissue at 4 weeks of treatment in the
dose escalation group.

III. To investigate the effects of topical bexarotene on serum biomarkers. IV. To investigate
the biologic effects of topical bexarotene 1% gel in the breast tissue, we will determine the
change from baseline in i) lipid biomarkers (total cholesterol, triglycerides, low density
lipoprotein [LDL], high density lipoprotein [HDL]), ii) thyroid function biomarkers (thyroid
stimulating hormone [TSH], T4, T3), iii) calcium.

TERTIARY OBJECTIVES:

I. To examine changes in gene expression associated with retinoid action. (Dose Expansion
Group)

OUTLINE: This is a dose-escalation study.

Group 1 will apply 10mg bexarotene topically to one breast every other day (QOD) for 4 weeks;
Group 2 will apply 10mg bexarotene topically to one breast every other day (QOD) for 1 week
and then daily for 3 weeks after confirmation that toxicity is at an acceptable range; Group
3 will apply 10mg bexarotene topically to one breast every other day (QOD) for 1 week, then
daily for 1 week, and then 20mg daily for 2 weeks after confirmation that toxicity is at an
acceptable range.

After completion of study treatment, patients are followed up at 30 days.

Inclusion Criteria:

- Participants must be at high risk as defined by a history of breast cancer (invasive
or ductal breast carcinoma in situ [DCIS]) and be at least 5 years out from diagnosis,
or lobular carcinoma in situ (LCIS), or proliferative benign breast disease such
atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH) or genetic test
confirmation of BRCA 1/2 mutation carrier or have a breast cancer risk assessment >=
1.7% in 5 years or a lifetime risk >= 20%

- No evidence of disease (in situ or invasive cancer that would normally be treated by
resection) at trial entry as determined by the investigator; diagnosis of invasive
cancer must be at least 5 years prior to initiation on trial

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- Leukocytes >= 3,000/microliter

- Absolute neutrophil count >= 1,500/microliter

- Platelets >= 100,000/microliter

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 1.5 x institutional upper limit of normal (ULN)

- Creatinine =< 1.5 x institutional ULN

- Hemoglobin >= 10 g/dL

- Thyroid-stimulating hormone (TSH) within normal institutional limits

- Triglycerides =< 300 mg/dl

- Total cholesterol =< 300 mg/dl

- >= 6 months from all previous breast cancer treatment (including endocrine therapy)

- Participants must have adequate accessible breast tissue as determined by the treating
physician, consisting of one breast unaffected by invasive cancer, which has not been
radiated; a history of benign core biopsy of this breast will be permitted

- Participants need to have had any breast imaging with a normal/benign (bi-rads 1 or 2)
result within 180 days of day 0 and no further routine breast imaging planned during
the course of the study (4 weeks); exception: if the mammogram result was a bi-rads 0
and the imaging work-up (ultrasound and/or magnetic resonance imaging [MRI]) result
comes back normal/benign (bi-rads 1 or 2) before treatment initiation, then
participant is eligible.

- For women of childbearing potential; negative pregnancy testing within 72 hours prior
to or on study visit #1 (day 0) and willingness to use adequate contraception during
the study intervention; OR post-menopausal defined as any one of the following 1)
prior hysterectomy, 2) absence of menstrual period for 1 year in the absence of prior
chemotherapy or 3) absence of menstrual period for 2 years in women with a prior
history of chemotherapy exposure who were pre-menopausal prior to chemotherapy; in
women of childbearing potential, effective contraception must be used for one month
prior to the initiation of therapy, during therapy, and for at least one month
following discontinuation of therapy; it is recommended that two reliable forms of
contraception be used simultaneously; if participants are interested in enrolling and
have not met the requirement for contraception, they will be seen in the clinic in 1
month for re-evaluation once they have met this requirement and ensure all other
eligibility criteria is met prior to dose assignment

- Willingness to comply with all study interventions and follow-up procedures including
the ability to apply the study drug to the breast

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

- Ability to avoid exposure of the treated breast area to sunlight and artificial
ultraviolet light during the use of bexarotene gel

Exclusion Criteria:

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to bexarotene gel, oral or topical retinoids

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, thromboembolic disease, or psychiatric illness/social situations that
would limit compliance with study requirements

- Pregnant, or had given birth, or nursed at any time during the last 12 months

- Women with a history of any cancer within the last 3 years, except for non-melanoma
skin cancer; history of breast cancer must be at least > 5 years from diagnosis

- Prior bilateral breast surgery (mastectomy, segmental mastectomy, or breast
augmentation surgery including breast implants or breast reductions) or combination of
breast radiation and surgery involving both breasts

- Prior history or evidence of metastatic breast cancer

- Prior history of histologically confirmed bilateral invasive breast cancer

- Current use or < 6 months since use of selective estrogen receptor modulator (SERMS)
or aromatase inhibitors or any other investigational treatment for breast cancer
prevention or therapy

- Skin lesions that disrupt the stratum corneum (eg., eczema, ulceration) or any
breakdown of the skin

- Current use of a retinol containing agent or any retinoid analogue drug within the
last 30 days

- Dietary vitamin A intake >= 5,000 IU/day (as determined by dietary supplementation)

- Treatment with any investigational drug or investigational biologic within 30 days of
initiating study treatment or during the study

- History of human immunodeficiency virus (HIV) or active hepatitis C