Abstract OT2-09-02: A phase I dose escalation study of topical bexarotene in women at high risk for breast cancer
Authors: Thomas PS , Patel AB , Contreras A , Liu DD , Lee JJ , Khan S , Vornik LA , Dimond EP , Perloff M , Heckman-Stoddard BM , Brown PH 
Published: May 2019

Abstract
Background: Breast cancer prevention with anti-estrogens, including tamoxifen, raloxifene, and exemestane, has been shown to reduce the incidence of hormone receptor-positive breast cancer. However, agents that can reduce the incidence of hormone receptor negative breast cancer are currently lacking. Rexinoids such as bexarotene are vitamin A analogues that have been shown to be involved in cell differentiation, growth, and apoptosis. In preclinical mouse models that develop ER-negative breast cancers, bexarotene showed a significant reduction in mammary tumor development. Oral bexarotene has been evaluated in BRCA mutation carriers and significant decreases in cyclin D1 were noted in breast cells suggesting biological activity of bexarotene on breast tissue. Systemic side effects of hyperlipidemia and hypothyroidism were also found. Data from chemoprevention studies with topical 4-hydroxytamoxifen support the concept of topical agents penetrating into the breast tissue and exhibiting biological activity in the tissue. We hypothesize that topical bexarotene can be applied to the breast as a chemoprevention agent with penetration to the breast tissue without subsequent systemic side effects and toxicity as seen with oral bexarotene.
Trial Design: Women at high risk for breast cancer will be recruited and assigned to one of three different dose levels: 10mg (1ml) every other day, 10mg (1ml) daily, 20mg (2ml) daily to one unaffected breast for 4 weeks. The primary endpoint of the study is to determine the recommended phase II dose of topical bexarotene 1% gel for evaluation in healthy at-risk women. 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 related to the study drug. A grade 2 skin adverse event that recurs and persists for at least 3 days is also a DLT. The Maximum Tolerated Dose (MTD) will be defined as the highest dose level at which no more than 2 participants experience a DLT among 10 participants treated. A conservative modification of the standard “3+3” design will be applied. The first three participants will be assigned to the lowest dose level. New cohorts of 3-4 participants will not be treated until toxicity has been fully evaluated for all current participants through 4 weeks. Once the MTD has been determined, an expansion cohort of an additional 10 patients will be recruited at the MTD to further evaluate safety and toxicity at this dose level as well bexarotene concentration in the breast tissue. Secondary endpoints include serum bexarotene level, tissue bexarotene levels, and changes in thyroid function tests, lipid profile, and calcium. The planned accrual for this study if maximally accrued to all dose levels and the dose expansion cohort will be 40 participants.
Citation Format: Thomas PS, Patel AB, Contreras A, Liu DD, Lee JJ, Khan S, Vornik LA, Dimond EP, Perloff M, Heckman-Stoddard BM, Brown PH. A phase I dose escalation study of topical bexarotene in women at high risk for breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-09-02.