ACE-Breast-03: A phase II study patients with HER2-positive metastatic breast cancer whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens treated with ARX788

The HER2 receptor is an oncogenic driver that is overexpressed on 15-20% of breast cancers. HER2+ targeted therapy has improved survival in both early and advanced disease, but new treatments are needed for recurrent and refractory disease. ARX788 is a next-generation ADC using a HER2-specific monoclonal antibody conjugated with Amberstatin269, a potent cytotoxic tubulin inhibitor (DAR=2). Site-specific, highly homogenous, and stable covalent conjugation leads to slow release and prolonged peak of serum pAF-AS269, with lower systemic toxicity, increased targeted delivery, and lower effective dose. Previous study, ACE-Breast-01 had a confirmed ORR of 16/29 (66%) and a DCR of 29/29 (100%) in the 1.5 mg/kg cohort. ARX788 was generally well tolerated with most adverse events being Grade 1 or 2 and manageable. ACE-Breast-03 is a global, single arm, phase II study assessing anticancer activity and safety of ARX788 in patients with metastatic HER2 positive BC. Patients whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens are eligible. Brain metastasis must be radiographically stable and steroid independent. Patients must have adequate organ function. In the safety lead-in, subjects (n=20) will be randomized between 2 dosages (1.6 mg/kg or 1.7 mg/kg Q3W). After RP2D, approximately 200 subjects with advanced HER2-positive BC will be enrolled in the main study. Efficacy will be assessed using RECIST 1.1 via imaging every 6 weeks. Primary endpoint is ORR, and secondary endpoints include DOR, TR, BOR, DCR, PFS, and OS. Safety and tolerability will be assessed. Blood samples will be collected at specified time points to determine serum concentrations of ARX788 (intact ADC), total antibody, and metabolite pAF-AS269. Biomarkers (e.g., cfDNA, serum HER2 extracellular domain, others) at baseline and on-treatment will be analyzed for exploratory research. Descriptive statistics will be used to evaluate anticancer activity, safety, and tolerability. The first patient enrolled in 07-Feb-2022 under protocol version 2. The study is currently recruiting patients. NCT04829604 EudraCT 2021-001246-36. Darryl Z. L'Heureux, Ambrx. Ambrx, Inc. Ambrx, Inc.