Abstract PS5-08-28: Phase I pilot of pegylated liposomal doxorubicin, CD40 agonist antibody CDX-1140, and Flt3 ligand CDX-301 in advanced HER2-negative breast cancer

Abstract Background: Immune checkpoint inhibitors deliver durable benefit to only a minority of individuals with metastatic breast cancer, in part due to a paucity of activated, antigen-presenting dendritic cells within the tumor microenvironment. Pre-clinical work from our group showed that combining pegylated liposomal doxorubicin (to release tumor antigens) with a CD40 agonist (to license dendritic cells and repolarize macrophages toward an anti-tumor phenotype) and recombinant Flt3 ligand (to expand dendritic cell precursors) produces markedly superior tumor control compared with chemotherapy alone. These findings underpin the first-in-human clinical evaluation of this triplet regimen. Methods: This is a single arm phase I pilot study of the combination of liposomal doxorubicin, CDX-1140 (CD40 agonist monoclonal antibody), and CDX-301 (recombinant Flt3 ligand) in patients with metastatic or unresectable locally advanced HER2 negative breast cancer (triple negative, TNBC; and hormone receptor positive, HR+). Two lead-in cohorts randomize participants in a 2:1 ratio to receive one cycle of either the triplet combination or pegylated liposomal doxorubicin alone, after which all patients transition to triplet therapy; paired tumor biopsies are obtained at baseline and after the lead-in to characterize early immunological changes. Eligibility originally limited enrollment to triple-negative disease but has been broadened to include HR+ tumors. Key eligibility criteria are unresectable stage III or stage IV HER2 negative breast cancer; for TNBC up to three prior therapies for metastatic disease allowed; for HR+ disease prior cyclin dependent kinase 4/6 inhibitors required and up to 3 prior lines of chemotherapy and/or antibody drug conjugates for metastatic disease allowed; and measurable disease by RECIST 1.1 criteria. Key exclusion criteria are prior exposure to an anti-CD40 antibody or Flt3 ligand, anthracycline treatment in the metastatic setting, progression on or within six months of (neo)adjuvant anthracyclines, and a history of non-infectious pneumonitis. CDX-301 is administered only during cycles 1 and 2, whereas pegylated liposomal-doxorubicin and CDX-1140 is continued until disease progression or clinically limiting toxicities. The primary endpoint is determination of a recommended phase II dose of CDX-1140 based on treatment-related adverse events and dose-limiting toxicities. Secondary endpoints include anti-tumor immune responses measured as CD8 T cell infiltration after triplet therapy and after liposomal doxorubicin alone, median progression-free survival, overall response rate, duration of response, and clinical benefit rate. As of June 24th, 2025 this trial is in dose expansion and has enrolled 23 of 30 evaluable patients (NCT05029999). The trial is currently open at University of Texas Southwestern Simmons Comprehensive Cancer Center, University of Chicago, University of Texas San Antonio Health Science Center, Johns Hopkins, and University of North Carolina. Citation Format: S. M. Reddy, C. A. Santa-Maria, N. Chen, V. Kaklamani, J. O’Shaughnessy, Y. Abdou, N. Unni, B. Santos, S. Syed, N. Sadeghi, J. Gruber, D. Klemow, Y. Fang, I. Chan, N. Peswani, I. Patel, S. Shakeel, M. Carter, K. Kyle, R. Nanda, H. McArthur, S. Conzen, C. L. Arteaga. Phase I pilot of pegylated liposomal doxorubicin, CD40 agonist antibody CDX-1140, and Flt3 ligand CDX-301 in advanced HER2-negative breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-08-28.