This study is a Phase I, single-arm, single-center, dose-escalation clinical trial designed to investigate the safety and efficacy of intrathecal injection of sacituzumab tirumotecan (sac-TMT) in patients with EGFR mutation-positive non-small cell lung cancer and leptomeningeal metastasis who have progressed after prior EGFR-TKI therapy, and to determine the optimal dose (RP2D). The study employs an "accelerated titration" combined with a "3+3" dose-escalation design, with a starting dose of 0.05 mg/kg, sequentially escalating to 0.5 mg/kg. The drug is administered via intrathecal injection through an Ommaya reservoir once every 14 days, along with concomitant intrathecal injection of dexamethasone 5 mg to prevent chemical meningitis. The primary endpoints are safety (incidence, severity, and grading of adverse events and serious adverse events) and the recommended dose (RP2D). Secondary endpoints include intracranial objective response rate, time to treatment failure, progression-free survival, and overall survival. The study plans to enroll 8-15 subjects. Efficacy assessment is based on evaluation of neurological symptoms, cerebrospinal fluid cytology, and neuroimaging changes. Special attention is given to adverse events of special interest, including neurotoxicity and bone marrow suppression. This study aims to provide a new treatment strategy for patients with leptomeningeal metastasis after EGFR-TKI resistance and to generate pioneering data for the intrathecal administration of ADC drugs.

Study Title: Safety and Efficacy of Intrathecal Injection of Sacituzumab Tirumotecan (SKB264) in the Treatment of Leptomeningeal Metastasis from EGFR-TKI-Resistant Non-Small Cell Lung Cancer: A Phase I Dose-Escalation Study (LUKE 01)

Study Type: Phase I, single-arm, single-center, open-label, dose-escalation clinical trial

Background and Rationale:

Leptomeningeal metastasis (LM) is a devastating complication of advanced non-small cell lung cancer (NSCLC), particularly in patients with epidermal growth factor receptor (EGFR) mutations. The incidence of LM in EGFR-mutant NSCLC patients is approximately 9.4%, and median overall survival after LM diagnosis is only 3-11 months despite available therapies. Although third-generation EGFR-TKIs such as osimertinib and high-dose furmonertinib have shown some efficacy in LM, most patients eventually develop resistance. After resistance to EGFR-TKIs, effective treatment options for LM are extremely limited.

Intrathecal (IT) administration of chemotherapeutic agents, such as pemetrexed, has been explored in LM patients, but resistance to IT pemetrexed inevitably develops. Sacituzumab tirumotecan (sac-TMT), a novel TROP-2-directed antibody-drug conjugate (ADC), has demonstrated superior efficacy over pemetrexed in phase III trials (OptiTROP-Lung04) for EGFR-TKI-resistant advanced NSCLC, with a manageable safety profile. However, intravenous administration of sac-TMT cannot achieve adequate drug concentrations in the cerebrospinal fluid (CSF) due to the blood-brain barrier. IT injection of sac-TMT may overcome this limitation and directly deliver the ADC to LM lesions. This study represents the first-in-human investigation of IT administration of an ADC for LM from NSCLC.

Primary Objectives:

To evaluate the safety and tolerability of IT sac-TMT in patients with LM from EGFR-TKI-resistant NSCLC.

To determine the recommended phase 2 dose (RP2D) of IT sac-TMT.

Secondary Objectives:

To assess the intracranial objective response rate (ORR) based on RANO criteria.

To evaluate time to treatment failure (TTF), progression-free survival (PFS), and overall survival (OS).

To explore preliminary pharmacokinetics (optional CSF and plasma sampling).

Study Population:

Patients aged ≥18 years with pathologically confirmed EGFR mutation-positive NSCLC, cytologically confirmed LM (positive CSF cytology), documented radiographic or clinical progression after prior EGFR-TKI therapy, ECOG performance status ≤3, and stable neurological symptoms for ≥7 days. Key exclusion criteria include active infection, ECOG ≥4, history of severe hypersensitivity to monoclonal antibodies, and severe immunodeficiency.

Study Design and Dose Escalation:

This is a single-center, open-label phase I trial using an "accelerated titration" followed by a "3+3" dose-escalation design. The starting dose is 0.05 mg/kg (1/100 of the standard intravenous dose of 5 mg/kg), based on preclinical mouse LM model data showing no significant adverse effects at this dose level. Subsequent dose levels are: 0.1, 0.2, 0.3, 0.4, and 0.5 mg/kg.

In the accelerated titration phase, one patient is enrolled per dose level. If no dose-limiting toxicity (DLT) occurs, escalation continues to the next level. If a DLT or a grade ≥2 neurological toxicity potentially related to the study drug occurs, the cohort expands to 3 patients, and the trial transitions to the standard "3+3" design. The DLT observation period is 21 days after the first dose. DLT is defined as any treatment-related grade ≥3 non-hematologic toxicity or grade ≥4 hematologic toxicity. The maximum tolerated dose (MTD) is the highest dose at which ≤1/3 of patients experience DLT. RP2D will be determined based on DLT incidence, overall safety, tolerability, and preliminary efficacy signals.

Treatment Regimen:

Sac-TMT is reconstituted according to the manufacturer's instructions and administered via IT injection through an implanted Ommaya reservoir over 15-30 minutes using a micro-infusion pump. Each cycle is 14 days (range ±3 days). The drug is given once per cycle (every 2 weeks). To reduce the risk of chemical meningitis/arachnoiditis, 5 mg of dexamethasone is co-injected intrathecally with each sac-TMT dose. Premedication (diphenhydramine, acetaminophen, dexamethasone IV, and H2 blocker) is administered prior to the first four doses per the product label, with optional corticosteroids thereafter.

Study Procedures:

Before each IT injection, intracranial pressure is measured, and approximately 10 mL of CSF is withdrawn for cytology and biomarker research. Peripheral blood is collected for safety monitoring. Neurological examinations, CSF cytology, and neuroimaging (contrast-enhanced MRI of brain and spine) are performed at baseline and every 3 cycles (6 weeks) ±7 days for efficacy assessment.

Safety Monitoring:

Adverse events (AEs) and serious adverse events (SAEs) are graded using CTCAE version 5.0. Safety assessments are conducted before each dose and continue for 2 weeks after the last dose. Adverse events of special interest (AESI) include: chemical meningitis, neurotoxicity (seizures, cognitive impairment, peripheral neuropathy), severe bone marrow suppression (grade ≥4 neutropenia, thrombocytopenia, or febrile neutropenia), intracranial infection, and bleeding complications associated with thrombocytopenia.

Efficacy Assessment:

Response assessment for LM is based on the RANO (Response Assessment in Neuro-Oncology) LM criteria, integrating three domains: neurological examination, CSF cytology, and imaging. Neurological status is scored across 10 domains (e.g., gait, muscle strength, sensation, cranial nerves). CSF cytology is categorized as negative, suspicious, or positive. Imaging assessment uses contrast-enhanced T1-weighted 3D MRI of the entire neuraxis. Measurable nodular lesions (≥5×10 mm) are tracked. Overall response is determined by a multidisciplinary team of experienced oncologists.

Statistical Methods:

Descriptive statistics will be used for baseline characteristics, AEs, and response rates. Continuous variables will be summarized using mean, median, standard deviation, and range. Categorical variables will be presented as frequencies and percentages. Time-to-event endpoints (PFS, OS, TTF) will be analyzed using Kaplan-Meier methods. No formal hypothesis testing is planned for this phase I study. The sample size is estimated as 8-15 patients based on the "accelerated titration + 3+3" design, accounting for approximately 20% dropout.

Data Monitoring and Ethical Considerations:

The study will be conducted in accordance with the Declaration of Helsinki and ICH-GCP guidelines. The protocol and informed consent form have been approved by the Institutional Review Board (IRB) of Henan Cancer Hospital. Written informed consent will be obtained from all participants or their legal representatives before any study-specific procedures. A Data and Safety Monitoring Board (DSMB) will oversee the trial, particularly the dose-escalation phase, to ensure patient safety.

Expected Outcomes:

This study will provide the first clinical data on intrathecal administration of an ADC for LM from EGFR-TKI-resistant NSCLC. If safety and preliminary efficacy are demonstrated, it may establish a novel treatment paradigm for this lethal condition and inform future development of intrathecal ADC therapy for CNS malignancies.

Study Duration:

Approximately 24-36 months for enrollment and follow-up.

Inclusion Criteria:

Age ≥ 18 years;

Pathologically diagnosed as EGFR mutation-positive non-small cell lung cancer;

Leptomeningeal metastasis confirmed by detection of tumor cells in cerebrospinal fluid cytology;

Previously received targeted therapy against EGFR mutation and progressed;

ECOG performance status ≤ 3;

Neurological symptoms stable for more than 7 days (defined as no new or worsening neurological symptoms and no more than a 1-point change in ECOG score);

If radiotherapy (including whole-brain radiotherapy, stereotactic radiotherapy, etc.) has been received, at least 7 days after completion; if other intrathecal therapy has been received, a washout period of at least 7 days;

Absolute neutrophil count ≥ 1.5 × 10⁹/L, hemoglobin ≥ 80 g/L, platelet count ≥ 75 × 10⁹/L;

Prothrombin time/international normalized ratio and partial thromboplastin time ≤ 1.5 × upper limit of normal;

Total bilirubin ≤ 1.5 × upper limit of normal, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (elevations of total bilirubin and transaminases caused by tumor may be relaxed to 3× and 5×, respectively), creatinine ≤ 2 × upper limit of normal; calculated creatinine clearance ≥ 50 mL/min.

Exclusion Criteria:

Active infectious disease within 7 days before the start of study drug treatment;

ECOG performance status ≥ 4;

History of allergy to any component of the study drug;

History of severe hypersensitivity reaction to any monoclonal antibody;

Patients currently participating in other interventional studies;

Previous or current severe immunodeficiency disease;

Any other condition that, in the investigator's judgment, makes the patient unsuitable for participation in this study.