Clinical trial NCT07006727: Phase I Study of [225Ac]Ac-ETN029 in Patients With Advanced DLL3-expressing Solid Tumors
Official title: A Phase I, Open-label, Multi-center Study to Evaluate the Safety, Tolerability, Dosimetry, and Preliminary Activity of [225Ac]Ac-ETN029 in Patients With Advanced DLL3-expressing Solid Tumors
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
Conditions: Small Cell Lung Carcinoma
Large Cell Neuroendocrine Carcinoma of the Lung
Neuroendocrine Prostate Cancer
Gastroenteropancreatic Neuroendocrine Carcinoma
Keywords: Small Cell Lung Carcinoma (SCLC)
Large Cell Neuroendocrine Carcinoma of the Lung (LCNEC)
Neuroendocrine Prostate Cancer (NEPC)
Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC)
DLL3
Neuroendocrine neoplasms
Radioligand therapy (RLT)
[225Ac]Ac-ETN029
[111In]In-ETN029
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2025-06-05
Enrollment: 116
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of patients with dose limiting toxicities of 225Ac-ETN029
timeFrame: From the start of study treatment until 6 weeks after
measure: Incidence and severity of adverse events and serious adverse events of 225Ac-ETN029
timeFrame: From start of study treatment until completion of the 36 month follow up, assessed up to approximately 42 months
measure: Dose modifications for 225Ac-ETN029
timeFrame: From the start of study treatment until last dose of study treatment, assessed as approximately 24 weeks
measure: Dose intensity for 225Ac-ETN029
timeFrame: From start of study treatment until last dose of study treatment, assessed as approximately 24 weeks
Secondary outcomes:
measure: Overall response rate (ORR)
timeFrame: Up to approximately 42 months
measure: Disease control rate (DCR)
timeFrame: Up to approximately 42 months
measure: Duration of response (DOR)
timeFrame: Up to approximately 42 months
measure: Progression free survival (PFS)
timeFrame: Up to approximately 42 months
measure: Area under the curve (AUC) of 225Ac-ETN029 and 111In-ETN029
timeFrame: During the first ~14 days following 225Ac-ETN029 administration and ~5 days following 111In-ETN029 administration
measure: Observed maximum blood concentration (Cmax) of 225Ac-ETN029 and 111In-ETN029
timeFrame: During the first ~14 days following 225Ac-ETN029 administration and ~5 days following 111In-ETN029 administration
measure: Volume of distribution (Vz) of 225Ac-ETN029 and 111In-ETN029 during the terminal phase
timeFrame: During the first ~14 days following 225Ac-ETN029 administration and ~5 days following 111In-ETN029 administration
measure: Terminal elimination half-life (T1/2) of 225Ac-ETN029 and 111In-ETN029
timeFrame: During the first ~14 days following 225Ac-ETN029 administration and ~5 days following 111In-ETN029 administration
measure: Total body clearance of 225Ac-ETN029 and 111In-ETN029
timeFrame: During the first ~14 days following 225Ac-ETN029 administration and ~5 days following 111In-ETN029 administration
measure: Observed maximum radioactivity concentration (Rmax) of 225Ac-ETN029
timeFrame: During the first ~14 days following 225Ac-ETN029 administration and ~5 days following 111In-ETN029 administration
measure: Absorbed dose of 225Ac-ETN029 and 111In-ETN029
timeFrame: During the first ~14 days following 225Ac-ETN029 administration and ~5 days following 111In-ETN029 administration
measure: Incidence and severity of adverse events and serious adverse events of 111In-ETN029
timeFrame: From the start of 111In-ETN029 to the day before the first 225Ac-ETN029 administration or until the completion of 30 day follow up (assessed as approximately 30 days)
measure: Visual and quantitative assessment of 111In-ETN029 uptake in normal tissues over time
timeFrame: During the first ~5 days following 111In-ETN029 administration
Other outcomes:
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