Phase I Study of [225Ac]Ac-ETN029 in Patients With Advanced DLL3-expressing Solid Tumors
- Conditions
- Small Cell Lung CarcinomaLarge Cell Neuroendocrine Carcinoma of the LungNeuroendocrine Prostate CancerGastroenteropancreatic Neuroendocrine Carcinoma
- Interventions
- Drug: 225Ac-ETN029Drug: 111In-ETN029
- Registration Number
- NCT07006727
- Lead Sponsor
- Novartis Pharmaceuticals
- 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.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 116
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Arm 1 225Ac-ETN029 Patients will receive 225Ac-ETN029, with some patients also receiving 111In-ETN029 Arm 1 111In-ETN029 Patients will receive 225Ac-ETN029, with some patients also receiving 111In-ETN029
- Primary Outcome Measures
Name Time Method Dose modifications for 225Ac-ETN029 From the start of study treatment until last dose of study treatment, assessed as approximately 24 weeks Number of dose modifications (e.g, dose interruptions and reductions) for 225Ac-ETN029
Number of patients with dose limiting toxicities of 225Ac-ETN029 From the start of study treatment until 6 weeks after 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.
Incidence and severity of adverse events and serious adverse events of 225Ac-ETN029 From start of study treatment until completion of the 36 month follow up, assessed up to approximately 42 months 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
Dose intensity for 225Ac-ETN029 From start of study treatment until last dose of study treatment, assessed as approximately 24 weeks Dose intensity of 225Ac-ETN029 defined as the ratio of actual cumulative dose received and actual duration of exposure
- Secondary Outcome Measures
Name Time Method Disease control rate (DCR) Up to approximately 42 months DCR is defined as the proportion of patients with a BOR of CR, PR, or stable disease according to RECIST v1.1 guidelines.
Progression free survival (PFS) Up to approximately 42 months 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.
Area under the curve (AUC) of 225Ac-ETN029 and 111In-ETN029 During the first ~14 days following 225Ac-ETN029 administration and ~5 days following 111In-ETN029 administration Area under the concentration time curve. AUC is a PK parameter that will be determined using non-compartmental analysis (NCA).
Observed maximum blood concentration (Cmax) of 225Ac-ETN029 and 111In-ETN029 During the first ~14 days following 225Ac-ETN029 administration and ~5 days following 111In-ETN029 administration The maximum (peak) observed blood drug concentration after single dose administration. Cmax is a PK parameter that will be determined using non-compartmental analysis (NCA).
Overall response rate (ORR) Up to approximately 42 months 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.
Duration of response (DOR) Up to approximately 42 months 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.
Volume of distribution (Vz) of 225Ac-ETN029 and 111In-ETN029 during the terminal phase During the first ~14 days following 225Ac-ETN029 administration and ~5 days following 111In-ETN029 administration The apparent volume of distribution during terminal phase. Vz is a PK parameter that will be determined using non-compartmental analysis (NCA).
Terminal elimination half-life (T1/2) of 225Ac-ETN029 and 111In-ETN029 During the first ~14 days following 225Ac-ETN029 administration and ~5 days following 111In-ETN029 administration The elimination half-life associated with the terminal slope of a semi logarithmic concentration-time curve. T1/2 (associated with a terminal slope) is a PK parameter that will be determined using non-compartmental analysis (NCA).
Total body clearance of 225Ac-ETN029 and 111In-ETN029 During the first ~14 days following 225Ac-ETN029 administration and ~5 days following 111In-ETN029 administration The total body clearance of drug from the plasma. Clearance is a PK parameter that will be determined using non-compartmental analysis (NCA).
Observed maximum radioactivity concentration (Rmax) of 225Ac-ETN029 During the first ~14 days following 225Ac-ETN029 administration and ~5 days following 111In-ETN029 administration The maximum (peak) observed blood radioactivity concentration after single dose administration. Rmax is a PK parameter that will be determined using non-compartmental analysis (NCA).
Absorbed dose of 225Ac-ETN029 and 111In-ETN029 During the first ~14 days following 225Ac-ETN029 administration and ~5 days following 111In-ETN029 administration The absorbed dose will be determined based on time activity curves (TACs) obtained from the radiotracer uptake (as percentage of injected dose) via quantification of images.
Incidence and severity of adverse events and serious adverse events of 111In-ETN029 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) Incidence and severity of treatment-emergent adverse events and serious adverse events
Visual and quantitative assessment of 111In-ETN029 uptake in normal tissues over time During the first ~5 days following 111In-ETN029 administration Quantitative assessment expressed as standardized uptake values (SUVs) of 111In-ETN029 uptake in normal tissues