Phase I Open-label, Multi-center Study to Evaluate the Safety, Tolerability, Dosimetry, and Preliminary Activity of [177Lu]Lu-NNS309 in Patients With Pancreatic, Lung, Breast and Colorectal Cancers
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 162
- 试验地点
- 34
- 主要终点
- Dose modifications for [177Lu]Lu-NNS309
研究概览
简要总结
The purpose of this study is to evaluate the safety, tolerability, dosimetry and preliminary efficacy of [177Lu]Lu-NNS309 and the safety, dosimetry and imaging properties of [68Ga]Ga-NNS309 in patients aged ≥ 18 years with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), HR+/HER2- ductal and lobular breast cancer (BC), triple negative breast cancer (TNBC) and colorectal cancer (CRC).
详细描述
The study will be done in two parts. The first part is called "escalation" and the second part is called "expansion". In both parts of the study, patients will initially be imaged with a [68Ga]Ga-NNS309 positron emission tomography (PET)/ computed tomography (CT) or PET/magnetic resonance imaging (MRI) scan and will be evaluated for eligibility for [177Lu]Lu-NNS309 treatment. In the escalation part, different doses of [177Lu]Lu-NNS309 will then be tested to identify recommended dose(s) (RD(s)) for further evaluation. The expansion part of the study will examine the safety and preliminary efficacy of [177Lu]Lu-NNS309 at the RD(s) determined during the escalation part. The end of study will occur when all patients per disease group in the expansion part have completed the follow-up for disease progression or discontinued from the study for any reason, and all patients have completed treatment and the 36-month long-term follow-up period.
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:
- •Locally advanced unresectable or metastatic PDAC with disease progression following, or intolerance to cytotoxic chemotherapy, unless patient was ineligible to receive such therapy
- •Locally advanced unresectable or metastatic NSCLC without any actionable genomic alterations with disease progression following, or intolerance to chemotherapy and immunotherapy, unless patient was ineligible to receive such therapy, or locally advanced unresectable or metastatic NSCLC with an actionable genomic alteration with disease progression following, or intolerance to targeted therapy, unless patient was ineligible to receive such therapy
- •Locally advanced unresectable or metastatic HR+/HER2- ductal or lobular BC with disease progression following, or intolerance to, at least 2 lines of therapy, unless patient was ineligible to receive such therapy
- •Locally advanced unresectable or metastatic TNBC with disease progression following, or intolerance to, at least 2 lines of therapy, unless patient was ineligible to receive such therapy
- •Locally advanced or metastatic unresectable CRC with disease progression following, or intolerance to cytotoxic chemotherapy, unless patient was ineligible to receive such therapy. Patients with known microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) status must also have had disease progression following, or intolerance to immune checkpoint inhibitor therapy, unless patient was ineligible to receive such therapy
- •Patients must have lesions showing 68Ga-NNS309 uptake
排除标准
- •Absolute neutrophil count (ANC) < 1.5 x 10^9/L, hemoglobin < 9 g/dL, or platelet count < 100 x 10^9/L
- •QT interval corrected by Fridericia's formula (QTcF) ≥ 470 msec
- •Calculated estimated glomerular filtration rate < 60 mL/min/1.73m2
- •Unmanageable urinary tract obstruction or urinary incontinence
- •Radiation therapy within 4 weeks prior to the first dose of [177Lu]Lu-NNS309
- •Other protocol-defined inclusion/exclusion criteria may apply.
研究组 & 干预措施
Arm 1
Patients will receive [68Ga]Ga-NNS309, and if eligible, [177Lu]Lu-NNS309
干预措施: [177Lu]Lu-NNS309 (Drug)
Arm 1
Patients will receive [68Ga]Ga-NNS309, and if eligible, [177Lu]Lu-NNS309
干预措施: [68Ga]Ga-NNS309 (Drug)
结局指标
主要结局
Dose modifications for [177Lu]Lu-NNS309
时间窗: From start of study treatment until last dose of study treatment, assessed up to approximately 24 weeks
Dose modifications (dose interruptions and reductions) for \[177Lu\]Lu-NNS309 will be assessed and summarized using descriptive statistics. The number of patients with dose modification will be summarized by treatment groups.
Number of patients with dose limiting toxicities of [177Lu]Lu-NNS309
时间窗: From start of study treatment until 6 weeks or 4 weeks after, depending on dosing schedule
A dose limiting toxicity (DLT) is defined as any adverse event or abnormal laboratory value of CTCAE (version 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 clinically significant toxicities may be considered to be DLTs, even if not Grade 3 or higher.
Dose intensity for [177Lu]Lu-NNS309
时间窗: From start of study treatment until last dose of study treatment, assessed up to approximately 24 weeks
Dose intensity for \[177Lu\]Lu-NNS309 will be assessed and summarized using descriptive statistics. Dose intensity is computed as the ratio of actual cumulative dose received and actual duration of exposure.
Incidence and severity of adverse events and serious adverse events of [177Lu]Lu-NNS309
时间窗: From start of study treatment until completion of the 36 month follow up, assessed up to approximately 42 months
The distribution of adverse events will be done via the analysis of frequencies for treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) and through the monitoring of relevant clinical and laboratory safety parameters.
次要结局
- Overall response rate (ORR)(Up to approximately 42 months)
- Duration of Response (DOR)(Up to approximately 42 months)
- Area Under the Curve (AUC) of [177Lu]Lu-NNS309(Cycle 1 Day 1 (Pre-infusion, end of infusion, Post dose (30 minutes (min), 1 hours (hr), 2hr, 4hr, 6hr, 12hr)), Cycle 1 Day 2 (24hr), Cycle 1 Day 3 (48hr), Cycle 1 Day 4 (72hr), Cycle 1 Day 8 (168hr). The duration of a cycle is 4 weeks or 6 weeks.)
- Total body clearance of [177Lu]Lu-NNS309(Cycle 1 Day 1 (Pre-infusion, end of infusion, Post dose (30 minutes (min), 1 hours (hr), 2hr, 4hr, 6hr, 12hr)), Cycle 1 Day 2 (24hr), Cycle 1 Day 3 (48hr), Cycle 1 Day 4 (72hr), Cycle 1 Day 8 (168hr). The duration of a cycle is 4 weeks or 6 weeks.)
- Disease control rate (DCR)(Up to approximately 42 months)
- Progression free survival (PFS)(Up to approximately 42 months)
- Observed maximum blood concentration (Cmax) of [177Lu]Lu-NNS309(Cycle 1 Day 1 (Pre-infusion, end of infusion, Post dose (30 minutes (min), 1 hours (hr), 2hr, 4hr, 6hr, 12hr)), Cycle 1 Day 2 (24hr), Cycle 1 Day 3 (48hr), Cycle 1 Day 4 (72hr), Cycle 1 Day 8 (168hr). The duration of a cycle is 4 weeks or 6 weeks.)
- Observed maximum radioactivity concentration (Rmax) of [177Lu]Lu-NNS309(Cycle 1 Day 1 (Pre-infusion, end of infusion, Post dose (30 minutes (min), 1 hours (hr), 2hr, 4hr, 6hr, 12hr)), Cycle 1 Day 2 (24hr), Cycle 1 Day 3 (48hr), Cycle 1 Day 4 (72hr), Cycle 1 Day 8 (168hr). The duration of a cycle is 4 weeks or 6 weeks.)
- Volume of distribution (Vz) of [177Lu]Lu-NNS309 during the terminal phase(Cycle 1 Day 1 (Pre-infusion, end of infusion, Post dose (30 minutes (min), 1 hours (hr), 2hr, 4hr, 6hr, 12hr)), Cycle 1 Day 2 (24hr), Cycle 1 Day 3 (48hr), Cycle 1 Day 4 (72hr), Cycle 1 Day 8 (168hr). The duration of a cycle is 4 weeks or 6 weeks.)
- Terminal elimination half-life (T1/2) of [177Lu]Lu-NNS309(Cycle 1 Day 1 (Pre-infusion, end of infusion, Post dose (30 minutes (min), 1 hours (hr), 2hr, 4hr, 6hr, 12hr)), Cycle 1 Day 2 (24hr), Cycle 1 Day 3 (48hr), Cycle 1 Day 4 (72hr), Cycle 1 Day 8 (168hr). The duration of a cycle is 4 weeks or 6 weeks.)
- Urinary excretion of radioactivity expressed as a percentage of injected dose (%ID)(Cycle 1: Pre-infusion, beginning of infusion to first SPECT/CT image acquisition, first SPECT/CT image acquisition to 6 hr post end of infusion (EOI), 6-24hr post EOI, 24-48hr post EOI, 48-72hr post EOI. The duration of a cycle is 4 weeks or 6 weeks.)
- Renal clearance of [177Lu]Lu-NNS309(Cycle 1: Pre-infusion, beginning of infusion to first SPECT/CT image acquisition, first SPECT/CT image acquisition to 6 hr post end of infusion (EOI), 6-24hr post EOI, 24-48hr post EOI, 48-72hr post EOI. The duration of a cycle is 4 weeks or 6 weeks.)
- Absorbed dose of [177Lu]Lu-NNS309(Cycle 1 Day 1, Cycle 1 Day 2 (24hr), Cycle 1 Day 3 (48hr), Cycle 1 Day 4 (72hr), Cycle 1 Day 8 (168hr). The duration of a cycle is 4 weeks or 6 weeks.)
- Incidence and severity of adverse events and serious adverse events of [68Ga]Ga-NNS309(From Imaging visit until 3 days after 68Ga-NNS309 administration, assessed up to approximately 3 days.)
- Visual and quantitative assessment of [68Ga]Ga-NNS309 uptake in normal tissues and tumor lesions over time(From 0 up to approximately 3 hrs after [68Ga]Ga-NNS309 dosing)
- Area Under the Curve (AUC) of [177Lu]Lu-NNS309(Samples collected pre infusion to 360 hours post end of infusion in Cycle 1. In a subset of patients, sampling is repeated in Cycle 2 and subsequent cycles. Cycle duration is 4 or 6 weeks.)
- Total body clearance of [177Lu]Lu-NNS309(Samples collected pre infusion to 360 hours post end of infusion in Cycle 1. In a subset of patients, sampling is repeated in Cycle 2 and subsequent cycles. Cycle duration is 4 or 6 weeks.)
- Observed maximum blood concentration (Cmax) of [177Lu]Lu-NNS309(Samples collected pre infusion to 360 hours post end of infusion in Cycle 1. In a subset of patients, sampling is repeated in Cycle 2 and subsequent cycles. Cycle duration is 4 or 6 weeks.)
- Observed maximum radioactivity concentration (Rmax) of [177Lu]Lu-NNS309(Samples collected pre infusion to 360 hours post end of infusion in Cycle 1. In a subset of patients, sampling is repeated in Cycle 2 and subsequent cycles. Cycle duration is 4 or 6 weeks.)
- Volume of distribution (Vz) of [177Lu]Lu-NNS309 during the terminal phase(Samples collected pre infusion to 360 hours post end of infusion in Cycle 1. In a subset of patients, sampling is repeated in Cycle 2 and subsequent cycles. Cycle duration is 4 or 6 weeks.)
- Terminal elimination half-life (T1/2) of [177Lu]Lu-NNS309(Samples collected pre infusion to 360 hours post end of infusion in Cycle 1. In a subset of patients, sampling is repeated in Cycle 2 and subsequent cycles. Cycle duration is 4 or 6 weeks.)
- Absorbed dose of [177Lu]Lu-NNS309(Samples collected 5 hours to 360 hours post end of infusion in Cycle 1. In a subset of patients, sampling is repeated in Cycle 2 and subsequent cycles. Cycle duration is 4 or 6 weeks.)
- Area Under the Curve (AUC) of [177Lu]Lu-NNS309(Samples collected pre infusion to 336 hours post end of infusion in Cycle 1. In a subset of patients, sampling is repeated in Cycle 2 and subsequent cycles. Cycle duration is 4 or 6 weeks.)
- Total body clearance of [177Lu]Lu-NNS309(Samples collected pre infusion to 336 hours post end of infusion in Cycle 1. In a subset of patients, sampling is repeated in Cycle 2 and subsequent cycles. Cycle duration is 4 or 6 weeks.)
- Observed maximum blood concentration (Cmax) of [177Lu]Lu-NNS309(Samples collected pre infusion to 336 hours post end of infusion in Cycle 1. In a subset of patients, sampling is repeated in Cycle 2 and subsequent cycles. Cycle duration is 4 or 6 weeks.)
- Observed maximum radioactivity concentration (Rmax) of [177Lu]Lu-NNS309(Samples collected pre infusion to 336 hours post end of infusion in Cycle 1. In a subset of patients, sampling is repeated in Cycle 2 and subsequent cycles. Cycle duration is 4 or 6 weeks.)
- Volume of distribution (Vz) of [177Lu]Lu-NNS309 during the terminal phase(Samples collected pre infusion to 336 hours post end of infusion in Cycle 1. In a subset of patients, sampling is repeated in Cycle 2 and subsequent cycles. Cycle duration is 4 or 6 weeks.)
- Terminal elimination half-life (T1/2) of [177Lu]Lu-NNS309(Samples collected pre infusion to 336 hours post end of infusion in Cycle 1. In a subset of patients, sampling is repeated in Cycle 2 and subsequent cycles. Cycle duration is 4 or 6 weeks.)
- Absorbed dose of [177Lu]Lu-NNS309(Samples collected 5 hours to 336 hours post end of infusion in Cycle 1. In a subset of patients, sampling is repeated in Cycle 2 and subsequent cycles. Cycle duration is 4 or 6 weeks.)
- Absorbed radiation dose of [68Ga]Ga-NNS309 in tumor lesions (dose expansion only)(Samples collected 30 minutes to 3 hours post end of injection.)
- Area Under the Curve (AUC) of [68Ga]Ga-NNS309(Samples collected 5 minutes to 245 minutes post end of injection.)