Phase I Study of [225Ac]Ac-ETN029 in Patients With Advanced DLL3-expressing Solid Tumors

Phase 1RecruitingNCT07006727

Novartis Pharmaceuticals116 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

116

Conditions

Small Cell Lung Carcinoma Large Cell Neuroendocrine Carcinoma of the Lung

Eligibility

Sex: ALLMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

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.

Locations (4)

University Of Iowa

Iowa City, Iowa, United States

RECRUITING

Massachusetts General Hospital

Boston, Massachusetts, United States

RECRUITING

Novartis Investigative Site

Montreal, Quebec, Canada

RECRUITING

Novartis Investigative Site

Seoul, Korea, South Korea

RECRUITING

Outcomes

Primary Outcomes

Number of patients with dose limiting toxicities of 225Ac-ETN029

A dose limiting toxicity (DLT) is defined as any adverse event or abnormal laboratory value of CTCAE 5.0 grade 3 or higher that occurs within the DLT evaluation period and that is not primarily related to disease, disease progression, intercurrent illness, or concomitant medications with a few exceptions defined in the study protocol. Other significant toxicities may be considered to be DLTs, even if not Grade 3 or higher.

Time frame: From the start of study treatment until 6 weeks after

Incidence and severity of adverse events and serious adverse events of 225Ac-ETN029

Incidence and severity of treatment-emergent adverse events and serious adverse events, including changes in laboratory values, vital signs, and electrocardiograms qualifying and reported as AEs

Time frame: From start of study treatment until completion of the 36 month follow up, assessed up to approximately 42 months

Dose modifications for 225Ac-ETN029

Number of dose modifications (e.g, dose interruptions and reductions) for 225Ac-ETN029

Time frame: From the start of study treatment until last dose of study treatment, assessed as approximately 24 weeks

Dose intensity for 225Ac-ETN029

Dose intensity of 225Ac-ETN029 defined as the ratio of actual cumulative dose received and actual duration of exposure

Time frame: From start of study treatment until last dose of study treatment, assessed as approximately 24 weeks

Secondary Outcomes

Overall response rate (ORR)

ORR is defined as the proportion of patients with a BOR of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines.

Time frame: Up to approximately 42 months

Disease control rate (DCR)

DCR is defined as the proportion of patients with a BOR of CR, PR, or stable disease according to RECIST v1.1 guidelines.

Time frame: Up to approximately 42 months

Duration of response (DOR)

DOR is defined as the time between the first documented response (CR or PR) and the date of progression according to RECIST v1.1 guidelines, or death due to any cause.

Time frame: Up to approximately 42 months

Progression free survival (PFS)

PFS is defined as the time from the date of start of treatment to the date of the first documented progression according to RECIST v1.1 guidelines or death due to any cause.

Time frame: Up to approximately 42 months

Area under the curve (AUC) of 225Ac-ETN029 and 111In-ETN029

Area under the concentration time curve. AUC is a PK parameter that will be determined using non-compartmental analysis (NCA).