A Phase II, Prospective, Multicenter, Two-Cohort Study of Combined Intrathecal and Systemic Therapy With Trastuzumab Rezetecan in Patients With Leptomeningeal Metastases From Solid Tumors
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 28
- 试验地点
- 1
- 主要终点
- 3-month Overall Survival Rate
研究概览
简要总结
This phase II clinical study enrolls patients with leptomeningeal metastases from solid tumors. Participants will receive intrathecal and systemic administration of Trastuzumab Rezetecan. The study aims to obtain clinical evidence about the efficacy and safety of this antibody-drug conjugate (ADC) given via intrathecal plus systemic routes. It hopes to offer a new treatment option for these patients with hard-to-manage disease and provide scientific support for optimizing treatment strategies for solid tumor patients with leptomeningeal metastases.
详细描述
This is a prospective, multicenter, single-arm, dual-cohort phase II clinical trial. It is designed to evaluate the efficacy and safety of combined intravenous and intrathecal Trastuzumab Rezetecan in adult patients with leptomeningeal metastases (LMD) from solid tumors.Participants are stratified into two cohorts based on HER2 expression and mutation status. All enrolled patients receive dualroute treatment with intravenous plus intrathecal Trastuzumab Rezetecan. The systemic intravenous dose is 4.8 mg/kg administered every 3 weeks, with a 21-day treatment cycle. The intrathecal dose is set at 20% of the single systemic dose. In terms of administration schedule, intrathecal injection is performed once weekly during Cycle 1 and Cycle 2, and once per treatment cycle starting from Cycle 3.The primary endpoint is the 3-month overall survival (OS) rate. Secondary endpoints cover intracranial tumor response and survival outcomes, cerebrospinal fluid tumor cell clearance rate, and extracranial tumor response. This study also evaluates treatment-related adverse events according to NCI-CTCAE v5.0 and assesses patients' quality of life using the EORTC QLQ-C30 questionnaire.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged ≥ 18 years of any gender; histologically confirmed solid tumor; signed informed consent form.
- •Patients with Type I LMD (defined as positive cerebrospinal fluid cytology or positive leptomeningeal biopsy) or Type II LMD (diagnosed based on clinical manifestations and neuroimaging alone) according to the European Association of Neuro-Oncology (EANO)-European Society for Medical Oncology (ESMO) clinical practice guidelines;patients with treatment-naive LMD or recurrent LMD after radiotherapy.
- •Investigators assess that immediate radiotherapy for leptomeningeal lesions is not required, or the patient declines radiotherapy.
- •Expected survival ≥ 6 weeks.
- •Left ventricular ejection fraction (LVEF) ≥ 50% measured by echocardiogram; adequate organ and bone marrow function.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-
- •All enrolled subjects will be stratified into 2 predefined cohorts based on tumor HER2 status: Cohort 1: Patients with leptomeningeal disease secondary to solid tumors without HER2 protein overexpression and without HER2-activating mutations; Cohort 2: Patients with leptomeningeal disease secondary to solid tumors with HER2 protein overexpression or harboring HER2-activating mutations.
排除标准
- •Presence of severe central nervous system (CNS) complications, such as progressive cerebral edema; recurrent seizures refractory to standardized antiepileptic therapy. Note: "refractory recurrent seizures" refers to persistent clinical seizures despite adequate standardized antiepileptic treatment. Subjects with a prior history of epilepsy with long-term seizure control on medication are not excluded by this criterion.
- •Receipt of whole-brain radiotherapy or other intrathecal therapies within the recent 4 weeks, which may interfere with efficacy assessment.
- •History of active interstitial lung disease (ILD) or pneumonia.
- •Concurrent severe systemic diseases, including but not limited to:
- •4.1 Active autoimmune disease or CNS infection; 4.2 Active infections (e.g., pulmonary tuberculosis, active hepatitis B, HIV infection); 4.3 Moderate to severe hepatic or renal dysfunction (alanine aminotransferase (ALT)/aspartate aminotransferase (AST) > 3 × ULN, creatinine clearance (CrCl) < 30 ml/min); 4.4 Uncontrolled heart failure, severe arrhythmia or hypertension; 4.5 Known inherited or acquired bleeding/thrombotic tendency (e.g., hemophilia, coagulopathy, thrombocytopenia); and/or coagulation disorders (international normalized ratio (INR) > 2.0, prothrombin time (PT) > 16 s) with bleeding risk, or receiving thrombolysis or anticoagulant treatment.
- •History of allergy or hypersensitivity to the study drug or its components.
- •Major surgery or severe traumatic injury within 28 days prior to enrollment.
研究组 & 干预措施
HER2 status
All enrolled participants receive intrathecal plus systemic administration of Trastuzumab Rezetecan. Subjects are stratified into two predefined cohorts based on HER2 status. Cohort 1: Patients with leptomeningeal disease (LMD) from solid tumors without HER2 positivity or HER2 mutations.Cohort 2: Patients with leptomeningeal disease (LMD) secondary to solid tumors with HER2 protein overexpression or HER2-activating mutations
干预措施: Intrathecal and systemic administration of Trastuzumab Rezetecan (Drug)
结局指标
主要结局
3-month Overall Survival Rate
时间窗: 3-months from the date of receiving study treatment
3-month overall survival (OS) rate is defined as the percentage of all enrolled participants who are still alive at 3-months from the date of receiving study treatment.
次要结局
- Leptomeningeal Metastasis-Progression-Free Survival (LM-PFS)(From treatment initiation until disease progression, death, or study discontinuation, assessed up to 18 months.)
- Leptomeningeal Metastasis-Objective Response Rate (LM-ORR)(From treatment initiation until disease progression, death, or study discontinuation, assessed up to 18 months.)
- Cerebrospinal Fluid Cytology Conversion Rate(6 weeks after initiation of intrathecal study treatment)
- Extracranial Objective Response Rate (EC-ORR)(From treatment initiation until disease progression, death, or study discontinuation, assessed up to 18 months.)
- Leptomeningeal Metastasis-Second Progression-Free Survival (LM-PFS2)(From the date of first leptomeningeal metastasis progression until second leptomeningeal metastasis progression, death, or study discontinuation, assessed up to 18 months.)
- Adverse events (AEs)(From treatment initiation until 30-day safety follow-up after last study drug administration, assessed up to 18 months.)
- Changes in the dimensions of the EORTC QLQ-C30 scale(FFrom treatment initiation up to 21 days after the last treatment cycle)
研究者
Jiuda Zhao
Chief Physician
Affiliated Hospital of Qinghai University