The purpose of this study is to evaluate the safety, tolerability, dosimetry and preliminary efficacy of [225Ac]Ac-ETN029 and the safety and imaging properties of [111In]In-ETN029 in patients aged ≥ 18 years with locally advanced or metastatic DLL3 positive cancers.

This is a phase I, open-label, multi-center study to evaluate the safety, tolerability, dosimetry, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of 225Ac-ETN029 in patients with advanced DLL3-expressing solid tumors. The study consists of a dose escalation part, followed by a dose expansion part. Once the recommended radioactive dose(s) of 225Ac-ETN029 for further clinical evaluation are determined, the dose expansion part will further characterize the safety, tolerability, and preliminary anti-tumor activity of 225Ac-ETN029. The study will also enable an initial evaluation of the safety, dosimetry, PK, and imaging properties of 111In-ETN029.

Inclusion Criteria:

• Age ≥ 18 years old
• Patients with one of the following indications:
• Locally advanced, unresectable, or metastatic SCLC with disease progression following, or intolerance to, at least 1 line of systemic therapy, including platinum-containing chemotherapy, unless patient was ineligible to receive such therapy. Prior DLL3-targeted therapy is allowed. For dose expansion, patients should have received no more than 2 prior lines of systemic therapy.
• Dose escalation only: LCNEC of the lung with disease progression following, or intolerance to, at least 1 line of systemic therapy, including platinum-containing chemotherapy, unless patient was ineligible to receive such therapy.
• Dose expansion only: Locally advanced, unresectable, or metastatic de novo or castration-resistant, treatment-emergent NEPC with neuroendocrine differentiation confirmed by local histology and NEPC marker expression (e.g., chromogranin, synaptophysin) confirmed by local IHC. Prior PSMA-targeted, Lu-177-based RLT is allowed. Patients must have at least one measurable lesion (per RECIST 1.1) that shows 111In-ETN029 uptake higher than surrounding tissues on SPECT/CT as assessed by the Investigator.
• Dose expansion only: Locally advanced, unresectable, or metastatic GEP-NEC with disease progression following, or intolerance to, at least 1 line of systemic therapy, including platinum-containing chemotherapy, unless patient was ineligible to receive such therapy. Patients must have at least one measurable lesion (per RECIST 1.1) that shows 111In-ETN029 uptake higher than surrounding tissues on SPECT/CT as assessed by the Investigator.

Exclusion Criteria:

• Absolute neutrophil count (ANC) < 1.0 x 109/L, hemoglobin < 9 g/dL, or platelet count < 75 x 109/L
• QT interval corrected by Fridericia's formula (QTcF) ≥ 470 msec
• eGFR < 60 mL/min (<0.835 mL/s), calculated using the CKD-EPI 2021 formula or measured
• Unmanageable urinary tract obstruction or urinary incontinence
• Presence of leptomeningeal disease, of symptomatic CNS metastases or of CNS metastases that require local CNS-directed therapy
• History of or current interstitial lung disease or pneumonitis ≥ Grade 2
• Any prior DLL3-targeted therapy (except for SCLC) and any prior RLT (except for NEPC)

Other protocol-defined inclusion/exclusion criteria may apply.

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.