Combined Intrathecal and Systemic Therapy With Trastuzumab Rezetecan for Leptomeningeal Metastases

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.

Inclusion criteria

• 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 0-4.
• 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.

Exclusion criteria

• 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.