Abstract PS8-12: Interim analysis of a phase I dose escalation study of topical bexarotene in women at high risk for breast cancer
Authors: Thomas Parijatham S , Patel Anisha B , Liu Diane , Lee J. Jack , Khan Seema , Muzzio Miguel , Contreras Alejandro , Vornik Lana , Dimond Eileen P , Perloff Marjorie , Heckman-Stoddard Brandy , Brown Powel H 
Published: February 2021

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. We hypothesize that topical bexarotene can be applied to the breast as a prevention agent with penetration into the breast tissue and without subsequent systemic side effects as seen with oral bexarotene. Methods: Women at high risk for breast cancer were recruited and assigned to escalating doses of 1% topical bexarotene: 10mg (1ml) every other day, 10mg (1ml) daily and 20mg (2ml) daily for 4 weeks. Cohorts of 3-4 participants were enrolled and fully evaluated through 4 weeks prior to enrolling the next cohort. Each dose level enrolled a maximum of 10 participants. The primary endpoint of the study was to determine the recommended phase II dose of topical bexarotene 1% gel for evaluation in healthy at-risk women. Dose Limiting Toxicity (DLT) was 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) was defined as the highest dose level at which no more than 2 participants experience a DLT among 10 participants treated. Once the MTD was determined, interim biomarker analysis will be completed to assess bexarotene levels in serum and tissue samples. An expansion cohort of an additional 10 patients will be recruited at the MTD to further evaluate safety and toxicity. Secondary endpoints include serum bexarotene level, tissue bexarotene levels, and changes in thyroid function tests, lipid profile, and calcium. Results: Ten women were enrolled at the dose level of 10mg every other day and 9/10 participants experienced Grade 1 skin related events at the application site. Two participants reported Grade 2 skin related events at the application site but did not last long enough to be considered DLTs. Four women were enrolled at the second dose level of 10mg daily and 3/4 experience Grade 2 skin related events including 2 DLTs which stopped accrual to the study. Therefore, the MTD was determined to be 10mg every other day. No laboratory abnormalities were noted across either dose level and no grade 3 or 4 adverse events were reported. Conclusion: Maculopapular rash at treatment site was the most common adverse event related to study drug and resolved with discontinuation. Analysis is ongoing to assess bexarotene drug levels in serum and breast tissue samples.
Citation Format: Parijatham S Thomas, Anisha B Patel, Diane Liu, J. Jack Lee, Seema Khan, Miguel Muzzio, Alejandro Contreras, Lana Vornik, Eileen P Dimond, Marjorie Perloff, Brandy Heckman-Stoddard, Powel H Brown. Interim analysis of a phase I dose escalation study of topical bexarotene in women at high risk for breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-12.