Breast Atypical Ductal Hyperplasia, Breast Atypical Lobular Hyperplasia, Breast Ductal Carcinoma In Situ, Breast Lobular Carcinoma In Situ, Invasive Breast Carcinoma
Conditions
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.
Detailed description
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, 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: 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.
Interventions
DRUGBexarotene
Given topically
OTHERQuestionnaire Administration
Ancillary studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Incidence of Adverse Events (Dose Limiting Toxicities) | 4 weeks of treatment, Up to 30 days after completion of study drug for AE assessments | Dose Limiting Toxicity (DLT) is defined as a grade 2 skin adverse event that persists for at least 6 days or any grade 3 or greater adverse event possibly, probably, or definitely related to the study drug. In addition, a DLT will be a grade 2 skin adverse event that recurs and persists for at least 3 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With 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. |
| Number of Participants With Trace Level of Bexarotene Concentration in Plasma Detected | baseline and end of treatment, up to 4 weeks | Plasma concentrations of bexarotene were evaluated in all participants at baseline and at end of study. Plasma samples: ND = Not detected (below the quantitation limit of 0.5 ng/mL) TDL = Trace levels detected (below the LOQ of 0.5ng/mL; estimated value) |
| Number of Participants With Bexarotene Concentration in Tissue | end of treatment, up to 4 weeks | Breast tissue concentrations were available only in those women who underwent breast biopsies. Tissue samples: Not detected (below the quantitation limit of 2.5 ng/g for a 10mg sample) and Trace levels detected (below the LOQ of 2.5ng/g; estimated value). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Tissue Markers | baseline, 15, and Day 28 visits | 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. |
Countries
United States
Participant flow
Recruitment details
Women at high risk for breast cancer were recruited for the trial at the Cancer Prevention Center at MD Anderson Cancer Center.
Pre-assignment details
41 participants were consented, 17 were not randomized due to (1 )Dose escalation phase closed and (16) were not eligible.
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 Bexarotene 1 % gel 10 mg every other day | 10 |
| Dose Level 2 Bexarotene 1 % gel 10 mg daily | 4 |
| Expansion Cohort Bexarotene 1 % gel 10 mg every other day | 10 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Dose Level 2 | Expansion Cohort | Dose Level 1 | Total |
|---|---|---|---|---|
| Age, Customized 40-49 years | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Age, Customized 50-59 years | 0 Participants | 6 Participants | 3 Participants | 9 Participants |
| Age, Customized 60-69 years | 3 Participants | 2 Participants | 5 Participants | 10 Participants |
| Age, Customized 70 and over years | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 9 Participants | 10 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Menopause Post-Menopausal | 4 Participants | 7 Participants | 8 Participants | 19 Participants |
| Menopause Pre-Menopausal | 0 Participants | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 8 Participants | 8 Participants | 19 Participants |
| Region of Enrollment United States | 4 participants | 10 participants | 10 participants | 24 participants |
| Sex: Female, Male Female | 4 Participants | 10 Participants | 10 Participants | 24 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 4 | 0 / 10 |
| other Total, other adverse events | 9 / 10 | 4 / 4 | 10 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 4 | 0 / 10 |
Outcome results
Primary
Number of Participants With Incidence of Adverse Events (Dose Limiting Toxicities)
Dose Limiting Toxicity (DLT) is defined as a grade 2 skin adverse event that persists for at least 6 days or any grade 3 or greater adverse event possibly, probably, or definitely related to the study drug. In addition, a DLT will be a grade 2 skin adverse event that recurs and persists for at least 3 days.
Time frame: 4 weeks of treatment, Up to 30 days after completion of study drug for AE assessments
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level 1 | Number of Participants With Incidence of Adverse Events (Dose Limiting Toxicities) | Erythema/redness at application site | 0 Participants |
| Dose Level 1 | Number of Participants With Incidence of Adverse Events (Dose Limiting Toxicities) | Maculopapular rash with pruritus at application site | 0 Participants |
| Dose Level 2 | Number of Participants With Incidence of Adverse Events (Dose Limiting Toxicities) | Maculopapular rash with pruritus at application site | 1 Participants |
| Dose Level 2 | Number of Participants With Incidence of Adverse Events (Dose Limiting Toxicities) | Erythema/redness at application site | 1 Participants |
| Expansion Cohort | Number of Participants With Incidence of Adverse Events (Dose Limiting Toxicities) | Maculopapular rash with pruritus at application site | 1 Participants |
| Expansion Cohort | Number of Participants With Incidence of Adverse Events (Dose Limiting Toxicities) | Erythema/redness at application site | 0 Participants |
Secondary
Number of Participants With Bexarotene Concentration in Tissue
Breast tissue concentrations were available only in those women who underwent breast biopsies. Tissue samples: Not detected (below the quantitation limit of 2.5 ng/g for a 10mg sample) and Trace levels detected (below the LOQ of 2.5ng/g; estimated value).
Time frame: end of treatment, up to 4 weeks
Population: 1 participant was to analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level 1 | Number of Participants With Bexarotene Concentration in Tissue | Non Detected | 1 Participants |
| Dose Level 1 | Number of Participants With Bexarotene Concentration in Tissue | Trace Levels Detected | 1 Participants |
| Dose Level 1 | Number of Participants With Bexarotene Concentration in Tissue | Quantitation limit of 2.6-10 ng/g | 1 Participants |
| Dose Level 1 | Number of Participants With Bexarotene Concentration in Tissue | Quantitation limit of 11-20 ng/g | 1 Participants |
| Dose Level 1 | Number of Participants With Bexarotene Concentration in Tissue | Quantitation limit of 21-30 ng/g | 1 Participants |
| Dose Level 1 | Number of Participants With Bexarotene Concentration in Tissue | Quantitation limit of >30 ng/g | 0 Participants |
| Dose Level 2 | Number of Participants With Bexarotene Concentration in Tissue | Quantitation limit of >30 ng/g | 0 Participants |
| Dose Level 2 | Number of Participants With Bexarotene Concentration in Tissue | Non Detected | 0 Participants |
| Dose Level 2 | Number of Participants With Bexarotene Concentration in Tissue | Quantitation limit of 11-20 ng/g | 1 Participants |
| Dose Level 2 | Number of Participants With Bexarotene Concentration in Tissue | Quantitation limit of 21-30 ng/g | 0 Participants |
| Dose Level 2 | Number of Participants With Bexarotene Concentration in Tissue | Trace Levels Detected | 0 Participants |
| Dose Level 2 | Number of Participants With Bexarotene Concentration in Tissue | Quantitation limit of 2.6-10 ng/g | 0 Participants |
| Expansion Cohort | Number of Participants With Bexarotene Concentration in Tissue | Trace Levels Detected | 2 Participants |
| Expansion Cohort | Number of Participants With Bexarotene Concentration in Tissue | Quantitation limit of 2.6-10 ng/g | 1 Participants |
| Expansion Cohort | Number of Participants With Bexarotene Concentration in Tissue | Quantitation limit of >30 ng/g | 1 Participants |
| Expansion Cohort | Number of Participants With Bexarotene Concentration in Tissue | Quantitation limit of 11-20 ng/g | 1 Participants |
| Expansion Cohort | Number of Participants With Bexarotene Concentration in Tissue | Non Detected | 4 Participants |
| Expansion Cohort | Number of Participants With Bexarotene Concentration in Tissue | Quantitation limit of 21-30 ng/g | 0 Participants |
Secondary
Number of Participants With Changes in Markers of Systemic Toxicity
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.
Time frame: Baseline up to 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 | Number of Participants With Changes in Markers of Systemic Toxicity | 0 Participants |
| Dose Level 2 | Number of Participants With Changes in Markers of Systemic Toxicity | 0 Participants |
| Expansion Cohort | Number of Participants With Changes in Markers of Systemic Toxicity | 1 Participants |
Secondary
Number of Participants With Trace Level of Bexarotene Concentration in Plasma Detected
Plasma concentrations of bexarotene were evaluated in all participants at baseline and at end of study. Plasma samples: ND = Not detected (below the quantitation limit of 0.5 ng/mL) TDL = Trace levels detected (below the LOQ of 0.5ng/mL; estimated value)
Time frame: baseline and end of treatment, up to 4 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level 1 | Number of Participants With Trace Level of Bexarotene Concentration in Plasma Detected | Plasma Baseline Visit | 0 Participants |
| Dose Level 1 | Number of Participants With Trace Level of Bexarotene Concentration in Plasma Detected | Plasma End of Treatment Visit | 0 Participants |
| Dose Level 2 | Number of Participants With Trace Level of Bexarotene Concentration in Plasma Detected | Plasma Baseline Visit | 0 Participants |
| Dose Level 2 | Number of Participants With Trace Level of Bexarotene Concentration in Plasma Detected | Plasma End of Treatment Visit | 0 Participants |
| Expansion Cohort | Number of Participants With Trace Level of Bexarotene Concentration in Plasma Detected | Plasma End of Treatment Visit | 2 Participants |
| Expansion Cohort | Number of Participants With Trace Level of Bexarotene Concentration in Plasma Detected | Plasma Baseline Visit | 0 Participants |
Other Pre-specified
Tissue Markers
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.
Time frame: baseline, 15, and Day 28 visits