Cervical Neuroendocrine Carcinoma, Gastroenteropancreatic Neuroendocrine Carcinoma, Genitourinary Neuroendocrine Carcinoma, Large Cell Neuroendocrine Carcinoma of the Lung, Medullary Thyroid Carcinoma, Merkel Cell Carcinoma, Neuroendocrine Prostate Cancer, Non-prostate Extrapulmonary Neuroendocrine Carcinoma, Small Cell Lung Carcinoma, Thymic Neuroendocrine Carcinoma, Unknown Primary Neuroendocrine Carcinomas
Conditions
Keywords
Small Cell Lung Carcinoma (SCLC), Large Cell Neuroendocrine Carcinoma of the Lung (LCNEC), Neuroendocrine Prostate Cancer (NEPC), Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC), Cervical Neuroendocrine Carcinoma, Thymic Neuroendocrine Carcinoma, Genitourinary Neuroendocrine Carcinoma (GU-NEC), Unknown Primary Neuroendocrine Carcinomas, Merkel cell carcinoma (MCC), Medullary thyroid carcinoma (MTC), DLL3, Neuroendocrine neoplasms, Radioligand therapy (RLT), [225Ac]Ac-ETN029, [111In]In-ETN029
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.
Interventions
DRUG225Ac-ETN029
Radioligand therapy
DRUG111In-ETN029
Radioligand imaging agent
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years old * Patients with one of the following indications: Dose Escalation Only: * Locally advanced, unresectable, or metastatic SCLC with disease progression following, or intolerance to, at least 1 line of systemic therapy, including platinum-containing chemotherapy (prior DLL3-targeted therapy allowed). * LCNEC of the lung with disease progression following, or intolerance to, at least 1 line of systemic therapy, including platinum-containing chemotherapy. * Metastatic de novo or treatment-emergent neuroendocrine prostate cancer (NEPC) confirmed by local histopathology, for whom no standard therapy is available, tolerated, or appropriate, in the investigator's judgment. Prior RLT is not allowed, though exceptions can be made following discussion with Novartis Medical Monitor. * Locally advanced, unresectable, or metastatic GEP-NEC, cervical NEC, genitourinary NEC, thymic NEC, Merkel cell carcinoma, or unknown primary NEC with disease progression following, or intolerance to, at least one line of systemic therapy (including platinum-containing chemotherapy for non-MCC indications, or PD-1 or PD-L1 inhibition for MCC, unless patient was ineligible to receive such therapy), and for whom no standard therapy is available, tolerated, or appropriate, in the investigator's judgment. * Locally advanced, unresectable, or metastatic medullary thyroid cancer with disease progression following, or intolerance to, at least 1 line of systemic therapy (unless patient was ineligible to receive such therapy), and for whom no standard therapy is available, tolerated, or appropriate, in the investigator's judgment. Dose expansion only: * Locally advanced, unresectable, or metastatic SCLC with disease progression following, or intolerance to, at least 1 line of systemic therapy, including platinum-containing chemotherapy (prior DLL3-targeted therapy allowed). Patients should have received no more than 2 prior lines of systemic therapy. * 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. 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. * 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.
Exclusion criteria
* Absolute neutrophil count (ANC) \< 1.0 x 10\^9/L, hemoglobin \< 9 g/dL, or platelet count \< 75 x 10\^9/L * QT interval corrected by Fridericia's formula (QTcF) ≥ 470 msec * eGFR \< 60 mL/min/1.73m2 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) * Any prior RLT (except for NEPC patients in expansion) Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 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 |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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). |
| 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 |
Countries
Canada, South Korea, United States
Contacts
CONTACTNovartis Pharmaceuticals
Outcome results
None listed