Phase I study of [ ²²⁵ Ac]Ac-ETN029, a DLL3-targeted radioligand therapy, in patients with advanced DLL3-expressing solid tumors.

Abstract

TPS3174 Background: Delta-like ligand 3 (DLL3) is an atypical Notch ligand that is highly expressed in small cell lung cancer (SCLC) and other neuroendocrine carcinomas, with minimal expression in normal adult tissues. [ 225 Ac]Ac-ETN029 ( 225 Ac-ETN029) is a novel, DLL3-targeted, macrocyclic peptide-based radioligand therapy (RLT) demonstrating potent antitumor activity in DLL3-positive, SCLC cell line–derived, xenograft mouse models. Here, we describe CESP359A12101 (NCT07006727), a global first-in-human phase 1 study evaluating 225 Ac-ETN029 in patients with selected advanced DLL3-expressing solid tumors. Methods: The primary objectives of the study are to assess the safety and tolerability of 225 Ac-ETN029 and to identify the recommended radioactive dose(s) of 225 Ac-ETN029 for further clinical evaluation. Secondary objectives are to assess the preliminary antitumor activity of 225 Ac-ETN029, characterize the pharmacokinetics (PK) and dosimetry of 225 Ac-ETN029, and characterize the safety, PK, dosimetry, and imaging properties of [ 111 In]In-ETN029 ( 111 In-ETN029). Study participants are expected to receive 4 cycles of 225 Ac-ETN029 at 6-week intervals, although a lower or higher number of cycles may be explored if deemed beneficial and safe. The study includes dose escalation and dose expansion parts. During dose escalation, increasing levels of administered activity per cycle will be assessed across cohorts. Dose escalation decisions will be based on a review of all available data, including safety, tolerability, dosimetry, PK, pharmacodynamics, and preliminary efficacy, and guided by the Bayesian logistic regression model using the escalation with overdose control principle. Dose expansion will begin once recommended radioactive dose(s) of 225 Ac-ETN029 for further clinical investigation have been determined. Eligible patients must be ≥18 years old; have locally advanced, unresectable, or metastatic disease measurable per RECIST v1.1; and be diagnosed with one of the following: (1) SCLC, (2) large cell neuroendocrine carcinoma (LCNEC) of the lung (escalation only), (3) de novo or castration-resistant, treatment-emergent, neuroendocrine prostate cancer (NEPC; expansion only), or (4) gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC; expansion only). Patients with SCLC, LCNEC, and GEP-NEC must have disease progression following, or intolerance of, ≥1 prior line of systemic therapy. Patients with NEPC and GEP-NEC must have ≥1 measurable lesion (per RECIST 1.1) demonstrating 111 In-ETN029 uptake higher than surrounding tissues on SPECT/CT as assessed by the investigator. Patients with prior DLL3-targeted therapy (except for SCLC) or prior RLT (except for NEPC) will be excluded. Patient enrollment began in October 2025. Clinical trial information: NCT07006727 .