Abstract CT107: A phase 1a/b, open-label, dose-escalation study of 225Ac-ABD147 for locally advanced or metastatic small cell lung cancer and large cell neuroendocrine carcinoma of the lung following platinum-based chemotherapy

Abstract Background: 225Ac-ABD147 is a targeted radioligand therapy that uses actinium-225 (225Ac), an alpha-emitting radionuclide, coordinated to a VHH-Fc -chelator conjugate ABD147. It targets with high affinity the delta-like ligand 3 (DLL3) receptor, commonly overexpressed on high-grade neuroendocrine tumors including Small Cell Lung Cancer (SCLC) and Large Cell Neuroendocrine Carcinoma (LCNEC) of the Lung but not on normal tissue. 111In-ABD147, a single-photon emission computerized tomography (SPECT) imaging agent, serves as a surrogate to assess tumor targeting and normal organ dosimetry. Preclinical studies have shown specific, high affinity binding of ABD147 to DLL3-expressing cancer cells, minimal uptake in normal tissues and preferential accumulation in tumor tissue. In vivo studies demonstrated significant antitumor activity and extended survival in SCLC xenograft models. Objectives: This open-label, Phase 1a/b, first-in-human study aims to evaluate the tolerability, biodistribution, pharmacokinetics (PK), and preliminary antitumor activity of 225Ac-ABD147 in patients with locally advanced or metastatic SCLC and LCNEC of the lung post platinum-based chemotherapy. Methods: Phase 1a involves escalating doses to determine the safety, tolerability, dosimetry, PK, and the dose for Phase 1b expansion. Phase 1b will assess safety and preliminary efficacy to recommend the Phase 2 dose (RP2D). Dosimetry assessments involve up to 10 patients for 111In-ABD147 and 3 to 6 patients for 225Ac-ABD147. Inclusion criteria include confirmed locally advanced or metastatic SCLC or LCNEC, completion of platinum-based chemotherapy (and a checkpoint inhibitor if approved as standard of care). Subjects must have measurable disease by RECIST v1.1. Exclusion criteria include primary resistant disease, hypersensitivity to 225Ac or 111In, active infection, uncontrolled bleeding, or non-healing wound and prior EBRT to >25% of the bone marrow. Phase 1a dose escalation is ongoing in the US. (NCT06736418) Citation Format: Babak Saboury, Lisa Bodei, Gary A. Ulaner, Jowell Go, Guanying Wang, Charles M. Rudin. A phase 1a/b, open-label, dose-escalation study of 225Ac-ABD147 for locally advanced or metastatic small cell lung cancer and large cell neuroendocrine carcinoma of the lung following platinum-based chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT107.