Abstract PO3-19-07: AC699-001, a first in human Phase 1 trial utilizing a novel estrogen receptor chimeric degrader in patients with advanced or metastatic breast cancer

Abstract Background Estrogen receptors (ER) are hormone-regulated transcription factors that play a critical role in breast cancer initiation and proliferation. Modulation of estrogen activity with therapeutics such as tamoxifen and aromatase inhibitors have been the mainstay therapeutic strategy for ER-positive breast cancer. Several ER-directed therapies have been developed to antagonize the oncogenic ER function, including Selective ER Degraders (SERDs) such as fulvestrant which is approved to treat patients with advanced or metastatic breast cancer. However, it requires intramuscular injection and has poor solubility, thereby limiting its administered dose and therefore its efficacy. In addition to SERDs, a newly emerging technology, E3 ligase-engaged chimeric degraders, has been used to induce potent and deeper ER degradation. Empowered by Accutar's proprietary Protein-Protein Interaction Targeting Chimeras (PPI-TAC) platform, AC699 was meticulously designed as a chimeric degrader to target and degrade the protein of interest, ERα. By effectively linking an ER ligand to an E3-ligase recruiting ligand, AC699 brings ERα in proximity to an E3 ligase, thereby inducing subsequent ubiquitination and degradation of ERα. Notably, chimeric ER degraders possess the unique advantage of degrading the ER protein without the inherent risk of activating an ER signal. Moreover, these molecules are not degraded alongside the target protein allowing for their efficient recycling within the cell. This direct mechanism enables chimeric ER degraders to achieve potent ER degradation with increased specificity, thereby potentially providing a higher therapeutic index compared to SERDs. This abstract describes a first-in-human Phase 1 trial of AC699, a novel ER degrader. Study Description The AC699-001 Phase 1 dose escalation study will enroll up to 60 patients with locally advanced or metastatic ER-positive, human epidermal growth factor receptor 2-negative, breast cancer. Patients must have progressed on standard treatment including at least two prior endocrine regimens or at least one prior line of therapy if combined with a CDK4/6 inhibitor. Prior chemotherapy is not required but must not exceed three prior cytotoxic regimens. Patients must have at least one measurable lesion or at least one predominantly lytic bone lesion. AC699 is given orally, once daily, with doses ranging from 100 mg to 600 mg in a standard 3+3 dose escalation design. The primary objective is to evaluate the safety and tolerability of AC699 using CTCAE 5.0. Secondary objectives include assessing preliminary anti-tumor activity according to RECIST 1.1 and characterizing the pharmacokinetic profile of single and multiple doses of AC699. Enrollment began in December 2022 with five sites in the United States planned. NCT05654532. Citation Format: Manish R Patel, Rachel Layman, Joy Nolte Fong, Hui Zhang, Su Kim, Erika Hamilton. AC699-001, a first in human Phase 1 trial utilizing a novel estrogen receptor chimeric degrader in patients with advanced or metastatic breast cancer abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-19-07.