Abstract P2-08-06: A phase 1 study of RAD1901, a novel, oral selective estrogen receptor degrader, for the treatment of ER-positive advanced breast cancer
Authors: Kaklamani VG , Kabos P , Elledge R , Harb W , Purandare D , O'Neill A , Garner F , Bardia A 
Published: March 2017

Abstract
Background: The majority of breast cancers are defined as estrogen receptor positive (ER+) breast cancer. Despite availability of standard therapies, such as aromatase inhibitors, many women eventually relapse with aggressive disease due to acquisition of endocrine resistance, including ESR1 mutations. To help address some of the challenges associated with current therapies including exposure limitations and intramuscular administration, we have developed RAD1901, a novel, non-steroidal, oral selective estrogen receptor degrader (SERD). Preclinical studies with RAD1901 have demonstrated a dose dependent degradation of ER consistent with a SERD mechanism of action. In multiple in vivo models of breast cancer, including patient-derived xenograft models that are sensitive or resistant to standard endocrine therapies, RAD1901 has anti-tumor efficacy both as a single agent and in combination with palbociclib and everolimus. Importantly, RAD1901 has shown superior efficacy compared to fulvestrant in a number these models including those harboring and ESR1 mutation.
Methods: RAD1901-005 is a Phase 1 study currently enrolling ER+ advanced metastatic breast cancer patients (ClinicalTrials.gov identifier: NCT02338349) with a dose escalation cohort based on a standard 3+3 design followed by a safety expansion cohort at a tolerated dose. Key inclusion criteria include postmenopausal women aged 18 years or older, with advanced ER+, HER2-negative breast cancer, who have received ≤ 2 prior chemotherapy regimens in the metastatic setting and &gt; 6 months of prior endocrine therapy. In addition, circulating tumor DNA (ctDNA) was evaluated to determine ESR1 mutation status and to correlate it with clinical response.
Results: As of the cut-off date in March, 13 patients were enrolled in the dose escalation part of the study (3+3 design) at doses of 200 mg qd, 400 mg qd and 600 mg qd. RAD1901 exposure was dose dependent and the PK profile was comparable to PK data from a previous study in healthy volunteers. RAD1901 was well tolerated with the most common adverse events being low-grade nausea and dyspepsia. No DLTs were observed. A safety expansion cohort (Part B, n=20) was opened. At the cut-off date 4 of the 13 patients had been on study 4 or more months. Updated outcomes and biomarker data, including ctDNA, will be presented at the meeting.
Conclusion: RAD1901, a novel, non-steroidal, oral SERD, is well-tolerated with manageable adverse effects, and is associated with preliminary evidence of clinical activity in patients with advanced ER+ advanced postmenopausal breast cancer, including patients with ESR1 mutant tumors.
Citation Format: Kaklamani VG, Kabos P, Elledge R, Harb W, Purandare D, O'Neill A, Garner F, Bardia A. A phase 1 study of RAD1901, a novel, oral selective estrogen receptor degrader, for the treatment of ER-positive advanced breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-08-06.