Abstract OT1-01-04: Phase 1 study of D-0502, an orally bioavailable SERD with optimized pharmacological and PK/PD property for ER-positive breast cancer

Background: Endocrine therapy such as selective estrogen receptor degrader (SERD) fulvestrant has been used effectively to extend the life of HR+ (ER+ and PR+) and HER2- breast cancer patient, either alone or in combination with CDK4/6 inhibitors such as palbociclib or abemaciclib. D-0502 is an orally bioavailable SERD with potent activity in various HR+ and HER2- breast cancer cell lines and xenograft models. Its combination with palbociclib in both MCF-7 xenograft model and ESR-1 mutated (Y537S) patient derived breast cancer xenograft models resulted in further tumor growth inhibition or regression. Drug metabolism and pharmacokinetic studies both in vitro and in vivo demonstrated that D-0502 exhibits favorable PK profiles suitable for clinical development. Trial Design: D-0502 is currently being evaluated in a phase 1 trial of women with advanced or metastatic HR+, HER2- breast cancer (MBC) (NCT03471663). This is a multicenter, open-label phase I study of D-0502 single agent and D-0502 in combination with standard dose of palbociclib. The primary objective is to characterize the safety and tolerability of D-0502 and D-0502 in combination with palbociclib, to identify an MTD and/or RP2D. The secondary objective is to evaluate the PK properties and the preliminary anti-tumor activities. Patients will receive D-0502 orally every day and treatment will be administered as 28-day cycles. The study has two parts: Dose Escalation (phase 1a) and Dose Expansion and Combination (phase 1b). In phase Ia, patients will be enrolled using a conventional dose-escalation algorithm (3+3 subjects per dose level) with 4 sequential dose cohorts to identify the MTD and RDE (recommended dose for expansion) in phase 1b) which will be at or below MTD. In phase 1b, there will be 2 cohorts, one is D-0502 single agent administered at RDE and the other is D-0502 in combination with standard dose of palbociclib, each with approximately 12 patients. Key Eligibility Criteria: Eligible patients included women with confirmed HR+, HER2- MBC who have previously received no more than 2 prior chemotherapies for MBC; ECOG 0-1; evaluable (phase 1a) or measurable (phase 1b) disease (RECIST v1.1); premenopausal or postmenopausal status; adequate hematologic, hepatic and renal functions. Current Status and Contact Information: At the time of abstract submission, the first cohort of 50 mg patients have started the study treatment. For inquiry of the study, please contact ling.zhang@inventisbio.com. Citation Format: Zhang L, Dai D, Shi Z, Jiang J, Wang Y. Phase 1 study of D-0502, an orally bioavailable SERD with optimized pharmacological and PK/PD property for ER-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 OT1-01-04.