Phase I Trial Of Endoxifen Gel Versus Placebo Gel In Women Undergoing Breast Surgery.

TPS1588 Background: Despite large Phase III clinical trials that have established the success of selective estrogen receptor modulators (SERMs) for breast cancer prevention and therapy of duct carcinoma in situ (DCIS), acceptance by women likely to benefit has been low, primarily because of toxicity related to systemic exposure. Local drug delivery to the breast in gel form is an attractive alternative since low systemic levels could minimize toxicity. Endoxifen (ENX) is an active metabolite of tamoxifen, that has unique activity compared with 4-hydroxytamoxifen (4-OHT). It is smaller and more polar than 4-OHT making it potentially more suitable for transdermal delivery. The NCI PREVENT program has developed ENX transdermal alcoholic gel products. Methods: We are conducting a randomized, double-blinded, placebo-controlled, Phase I trial to establish the dermal tolerability and safety of endoxifen (ENX) gel. 38 women planning unilateral or bilateral mastectomy will be enrolled across 3 institutions in 3 cohorts: (a) ENX gel 10mg (N = 8) vs. placebo gel (N = 4) daily; (b) ENX gel 20mg (N = 8) vs. placebo gel (N = 4) daily; (c) the maximum tolerated dose (N = 8) with last dose 72 hours prior to surgery. Treatment duration will be 4 ± 1 weeks. All participants will be evaluated for toxicity and skin tolerability. Secondary endpoints include TAM metabolite measurements in breast tissue and plasma; serum hormone concentrations, serum estrogenic response, changes in coagulation parameters, gene expression changes reflective of therapeutic effects, and experienced symptoms. 65 potential participants have been pre-screened for eligibility. 33 were ineligible prior to contact, most commonly due to the use of neoadjuvant chemotherapy. Of 32 potential participants who have been eligible to be contacted, 21 did not consent for screening, most commonly because they were too overwhelmed with their recent diagnosis. 7 have consented, 4 are pending consent, and 6 have started study intervention. No adverse events have been reported to date. This pre-surgical trial testing transdermal ENX for breast cancer prevention is accruing as projected. The results will establish the skin safety of this agent, provide data on skin permeability, and the duration of drug retention in the breast. Clinical trial information: NCT03317405.