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

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Active, not recruiting

CT.gov ID

NCT03323658

Collaborator

(none)

Enrollment

Location

Arm

53.5

Anticipated Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase I trial studies the side effects and best dose of bexarotene in preventing breast cancer in patients at high risk for breast cancer. Bexarotene belongs to a class of drugs that are called rexinoids, and it may reduce the incidence of breast tumors.

Condition or Disease	Intervention/Treatment	Phase
Breast Atypical Ductal Hyperplasia Breast Atypical Lobular Hyperplasia Breast Ductal Carcinoma In Situ Breast Lobular Carcinoma In Situ Invasive Breast Carcinoma	Drug: Bexarotene Other: Questionnaire Administration	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

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:

To detect bexarotene concentration in the serum at baseline and at 4 weeks of treatment.
To detect bexarotene concentration in the breast tissue at 4 weeks of treatment in the dose escalation group.
To investigate the effects of topical bexarotene on serum biomarkers, 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.

EXPLORATORY OBJECTIVE:

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

27 participants

Allocation:

N/A

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

A Phase I Dose Escalation Study of Topical Bexarotene in Women at High Risk for Breast Cancer

Actual Study Start Date :

Jun 15, 2018

Actual Primary Completion Date :

Aug 3, 2021

Anticipated Study Completion Date :

Nov 28, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Prevention (bexarotene) Group 1 will apply 10mg bexarotene topically to one breast QOD for 4 weeks; Group 2 will apply 10mg bexarotene topically to one breast 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 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.	Drug: Bexarotene Given topically Other Names: 3-methyl TTNEB LGD1069 Targretin Other: Questionnaire Administration Ancillary studies

Arm

Intervention/Treatment

Experimental: Prevention (bexarotene)

Group 1 will apply 10mg bexarotene topically to one breast QOD for 4 weeks; Group 2 will apply 10mg bexarotene topically to one breast 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 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.

Drug: Bexarotene

Given topically

Other Names:

3-methyl TTNEB

LGD1069

Targretin

Other: Questionnaire Administration

Ancillary studies

Outcome Measures

Primary Outcome Measures

Incidence of adverse events [Up to 30 days after completion of study drug]
Will be assessed by Common Terminology Criteria for Adverse Events criteria.

Secondary Outcome Measures

Changes in markers of systemic toxicity [Baseline up to 28 days]
Serum biomarkers to be tested will be total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, thyroid-stimulating hormone, T4, T3, and calcium. Will be summarized using mean, standard deviation and median (range) for continuous variables at each time point. Wilcoxon rank-sum test may be used to examine the difference of continuous variables between participants' characteristics groups. Will be plotted as functions of time (baseline, week 1, week 2, and week 4). Linear mixed effect model will be applied to model the biomarker change over time for all participants. Appropriate transformation and regression model will be used to ensure the model fit.
Bexarotene concentration [Up to 30 days after completion of study drug]
Will be determined using liquid chromatography-mass spectrometry (MS)/MS. Will be summarized using mean, standard deviation and median (range) for continuous variables at each time point. Wilcoxon rank-sum test may be used to examine the difference of continuous variables between participants' characteristics groups. Will be plotted as functions of time (baseline, week 1, week 2, and week 4). Linear mixed effect model will be applied to model the biomarker change over time for all participants. Appropriate transformation and regression model will be used to ensure the model fit. Will be calculated along with a 95% confidence interval.
Tissue markers [Up to 28 days]
One of the four cores collected from the core biopsies from baseline (in dose expansion cohort only) and post treatment (all dose expansion cohort participants and optional for dose escalation group) will be formalin-fixed and paraffin embedded (FFPE) for histological analysis. One of the four cores collected from the core biopsies from baseline and post treatment will be placed in RNALater and utilized for gene expression of ribonucleic acid (RNA) biomarkers. Gene expression will be performed.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

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 (e.g., 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