Background: Hormone receptor-positive (HR+) breast cancer accounts for about 75% of breast cancer cases. Despite initial response to ER-targeted therapies, subsequent tumor progression remains an important clinical problem, highlighting the need for new therapies with activity in endocrine-resistant tumors.

The androgen receptor (AR) is expressed in up to 90% of ER+ breast cancers, and until the 1970s, breast cancer was commonly treated with androgens with single-agent response rates ranging from 20% to 25%. However, androgen-based therapy for breast cancer declined due to lack of tissue selectivity, potential for aromatization to estrogen, and the emergence of ER-targeted agents such as tamoxifen.

RAD140 is an oral nonsteroidal selective androgen receptor modulator (SARM) that cannot be converted to estrogen by aromatase. RAD140 has high AR affinity and target selectivity, demonstrating marked tissue-selective AR agonist activity comparable to natural androgens in breast cancer cells, but lacking agonist activity in prostate cancer cells. Preclinical efficacy studies in multiple in vivo and in vitro models of AR+/ER+ breast cancer demonstrate potent anti-tumor activity of RAD140 as a single agent and in combination with a CDK4/6 inhibitor. This first-in-human study will evaluate the safety, tolerability, pharmacokinetics (PK) and clinical activity of RAD140 in patients with HR+ breast cancer.

Trial Design and Specific Aims: This is a Phase I, open-label dose escalation and safety expansion study of RAD140 in postmenopausal patients (pts) with advanced HR+ breast cancer for whom no standard therapy is available. During dose escalation (Part A), pts are assigned sequentially to escalating doses of RAD140 using a standard 3+3 design to establish a maximum tolerated dose (MTD) and/or recommended dose (RD) based on safety, PK and preliminary clinical activity. The Safety Expansion (Part B) will further evaluate the safety, tolerability and clinical activity of the RD.

Eligibility Criteria: Pts must be post-menopausal females ≥18 years old with locally advanced or metastatic ER+/HER2- (Part A) or ER+/AR+/HER2- (Part B) breast cancer and ECOG 0 or 1. Part A pts must not be eligible for standard therapy. Pts in Part B must have had at least 1 line of prior systemic therapy in the metastatic setting and at least 6 months of prior endocrine therapy in the metastatic setting and progressed on the most recent endocrine therapy. Measurable disease by RECIST 1.1 is also required for enrollment in Part B.

Statistical Methods: Descriptive statistics (including mean, standard deviation, median for continuous variables; frequency counts and percentages for categorical variables) will be presented by dose. Plasma or serum PK parameters for RAD140 will be estimated using non-compartmental methods.

Present Accrual and Target Accrual: The study will enroll up to 40 pts, including up to approximately 24 pts enrolled in cohorts of 3 to 6 in Part A, and another 15 pts enrolled in Part B. As of June 2018, 11 pts have enrolled at 5 sites. (NCT03088527)

Citation Format: Hamilton E, Vidula N, Ma C, LoRusso P, Saeh J, Reichert V, Yu Z, Annett M, Weitzman A, Hattersly G, O'Neill A, Weise A. A phase 1, first-in-human, multi-part study of RAD140, an oral nonsteroidal selective androgen receptor modulator, in postmenopausal women with hormone receptor positive 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 OT1-02-02.