A phase IIB pre-surgical trial of oral tamoxifen (TAM) versus transdermal 4-hydroxytamoxifen (4-OHT) in women with DCIS of the breast.

TPS1595 Background: Ductal carcinoma in situ (DCIS) is diagnosed in 60,000 women annually in the US. TAM is proven to reduce risk of local recurrence and new primary breast cancer in women with estrogen receptor (ER) positive DCIS. However, acceptance of TAM has been low, primarily because of toxicity related to systemic exposure. Local delivery to the breast is an attractive alternative as low systemic levels could minimize toxicity. 4-OHT is an active metabolite of TAM. When formulated as a gel and applied to the breast, it is well tolerated, and results in 4-OHT breast tissue drug levels comparable to oral TAM. In small pilot studies, its anti-proliferative effects on invasive breast tumors and DCIS are also similar to oral TAM [Lee O, et al. PMID 25028506]. The goal of our study is to validate these results in preparation for a Phase III trial of 4-OHT gel compared to oral TAM. Methods: We are conducting a randomized, double-blinded, placebo-controlled, Phase IIB pre-surgical trial to demonstrate that daily application of 4-OHT gel will result in a reduction in the Ki-67 labeling index of DCIS lesions that is not inferior to that seen in women receiving daily oral TAM. Ki-67 of the base-line diagnostic core needle biopsy will be compared to that of the therapeutic surgical excision sample after oral TAM or 4-OHT gel for 8 ± 2 weeks. Secondary endpoints include changes in Oncotype DCIS-Score, IHC markers, hormone levels, coagulation markers, drug concentration in the plasma and breast, and experienced symptoms. 100 women (assuming 20% non-evaluable samples or non-compliance) with DCIS (10% ER-positive) will be enrolled across 6 institutions into two intervention arms: oral TAM 20mg daily, placebo gel and 4-OHT gel 4mg daily (2mg/breast), placebo capsule. All participants will be evaluable for toxicity from first dose. To date 8 of 100 participants have been enrolled. Since study open, 39 potential participants have been contacted, 28 did not consent for screening, 9 consented, 2 are pending consent, and 9 have started study intervention. The most common reason potential participants chose not to consent is wanting to schedule surgery as soon as possible. Funding Source: NCI Contract # HHSN2612201200035I. Clinical trial information: NCT02993159.