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
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 116
- 试验地点
- 8
- 主要终点
- Dose modifications for 225Ac-ETN029
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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/exclusion criteria may apply.
研究组 & 干预措施
Arm 1
Patients will receive 225Ac-ETN029, with some patients also receiving 111In-ETN029
干预措施: 111In-ETN029 (Drug)
Arm 1
Patients will receive 225Ac-ETN029, with some patients also receiving 111In-ETN029
干预措施: 225Ac-ETN029 (Drug)
结局指标
主要结局
Dose modifications for 225Ac-ETN029
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
次要结局
- Disease control rate (DCR)(Up to approximately 42 months)
- Progression free survival (PFS)(Up to approximately 42 months)
- 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)
- 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)
- Overall response rate (ORR)(Up to approximately 42 months)
- Duration of response (DOR)(Up to approximately 42 months)
- 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)
- 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)
- 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)
- Observed maximum radioactivity concentration (Rmax) of 225Ac-ETN029(During the first ~14 days following 225Ac-ETN029 administration and ~5 days following 111In-ETN029 administration)
- Absorbed dose of 225Ac-ETN029 and 111In-ETN029(During the first ~14 days following 225Ac-ETN029 administration and ~5 days following 111In-ETN029 administration)
- 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))
- Visual and quantitative assessment of 111In-ETN029 uptake in normal tissues over time(During the first ~5 days following 111In-ETN029 administration)