Thiotepa Administration Via Ommaya Reservoir for Leptomeningeal Metastases in Non-Small Cell Lung Cancer Resistant to EGFR-TKI.

A Single-Arm Phase II Study of Intrathecal Thiotepa Via Ommaya Reservoir for Leptomeningeal Metastases in Non-Small Cell Lung Cancer Resistant to EGFR-TKI

The goal of this clinical trial is to learn if the Thiotepa administration via Ommaya Reservoir works to treat non-small cell lung cancer with leptomeningeal metastases resistant to EGFR TKI. The main questions to answer are:

Is Thiotepa administration via Ommaya Reservoir safe to inject? How effective is thiotepa via Ommaya Reservoir in intracranial-disease control? Participants will：

Stage 1: Intrathecal injection of 10 mg thiotepa via Ommaya reservoir, twice every week, for 4 consecutive weeks; Stage 2: Intrathecal injection of 10 mg thiotepa via Ommaya reservoir, once every week, for 4 consecutive weeks; Stage 3: Intrathecal injection of 10 mg thiotepa via Ommaya reservoir, once a month, for 4 consecutive months; Before each intrathecal administration, a preliminary intrathecal injection of dexamethasone, 2.5 mg/dose, is given.

Inclusion Criteria:

1. Age between 18 and 75 years.
2. Male or female of non-childbearing potential, or female of childbearing potential who is not pregnant or lactating.
3. ECOG performance status of 0 to 2, with no deterioration within the past 7 days.
4. Radiological and/or cerebrospinal fluid (CSF) cytological evidence of leptomeningeal metastases (LM). The diagnosis of non-small cell lung cancer (NSCLC) must be confirmed by histological and/or cytological examination.
5. Patients must meet at least one of the following criteria: failure of first- or second-generation TKI therapy with T790M mutation negative; failure of third-generation TKI therapy; or EGFR mutation negative with failure of first-line therapy.
6. If concurrent brain parenchymal metastases are present, they must have received appropriate treatment or been evaluated as stable over the past three months. Additionally, extracranial lesions must be evaluated as stable under the current treatment regimen.
7. Adequate organ and bone marrow function, as evidenced by the following laboratory parameters: HGB ≥ 90 g/L; NEUT ≥ 1.5 × 10⁹/L; PLT ≥ 80 × 10⁹/L; TBIL ≤ 1.5 × upper limit of normal (ULN); ALT and AST ≤ 2.5 × ULN (if liver metastases are present, ALT and AST ≤ 5 × ULN); creatinine clearance ≥ 50 mL/min (calculated by the Cockcroft-Gault formula); urine protein < (++) or 24-hour urine protein < 1.0 g; normal coagulation function without active bleeding; INR ≤ 1.5; APTT ≤ 1.5 × ULN.
8. Women of childbearing potential must have a negative pregnancy test (serum or urine) within 14 days prior to enrollment and must voluntarily use adequate contraception during the study period and for 8 weeks after the last dose of the study drug. Males must be surgically sterilized or agree to use adequate contraception during the study period and for 8 weeks after the last dose of the study drug.
9. Prior Ommaya reservoir implantation.
10. Estimated life expectancy of ≥ 12 weeks.
11. No history of severe neurological diseases or severe hematological abnormalities.
12. Patients who have received prior brain and/or spinal cord radiotherapy, including stereotactic radiosurgery (SRS) or stereotactic body radiation therapy (SBRT), are eligible, provided that radiotherapy was completed at least 7 days prior to the initiation of study treatment.
13. Concurrent intrathecal therapy with other agents is prohibited. For patients who have received other systemic therapies, the minimum washout periods are as follows: patients who have received prior intrathecal therapy must complete the last treatment at least 7 days before initiating study treatment; patients who have received systemic chemotherapy must complete the last treatment at least 14 days before initiating study treatment; patients who have received approved systemic immunotherapy (e.g., anti-PD-1, anti-CTLA-4) must complete the last treatment at least 14 days before initiating study treatment; patients who have received any other investigational drugs must complete the last treatment at least 14 days before initiating study treatment.
14. Ability to provide written informed consent, including compliance with the requirements and restrictions listed in the informed consent form. Patients must have good compliance, voluntarily agree to participate in the clinical study, sign the informed consent form, and be willing to cooperate with follow-up visits.

Exclusion Criteria:

1. Patients requiring ventriculoperitoneal (VP) shunt placement due to elevated intracranial pressure.
2. History of epilepsy unrelated to leptomeningeal metastases.
3. Evidence of any neurological functional failure, including severe encephalopathy, grade 3 or 4 leukoencephalopathy as shown on imaging, or a Glasgow Coma Scale (GCS) score < 11.
4. Evidence of any extensive and fatal progressive systemic disease with no effective treatment available.
5. Prior allogeneic bone marrow transplantation or solid organ transplantation. Uncontrolled hypertension prior to enrollment, defined as: systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 90 mmHg.
6. Surgical procedures involving vital organs within 3 months prior to enrollment.
7. Any disease or condition prior to enrollment that affects drug absorption. Clinically significant cardiovascular diseases, including but not limited to acute myocardial infarction, severe/unstable angina, or coronary artery bypass grafting within 6 months prior to enrollment; congestive heart failure with New York Heart Association (NYHA) classification > Grade 2; ventricular arrhythmias requiring medication; left ventricular ejection fraction (LVEF) < 50%; or other related diseases such as severe pulmonary, hepatic, or renal dysfunction, severe gastrointestinal ulcers, or coagulation dysfunction.
8. Active or uncontrolled severe infections (≥ Grade 2 infections per CTCAE v5.0).
9. Known human immunodeficiency virus (HIV) infection. Known history of clinically significant liver disease, including viral hepatitis [Known hepatitis B virus (HBV) carriers must be excluded if they have active HBV infection, defined as HBV DNA positive (>1×10⁴ copies/mL or >2000 IU/mL); known hepatitis C virus (HCV) infection with HCV RNA positive (>1×10³ copies/mL)].
10. Any other disease, clinically significant metabolic abnormalities, physical examination abnormalities, or laboratory abnormalities that, in the investigator's judgment, provide reason to suspect a disease or condition that makes the patient unsuitable for the study drug (e.g., seizures requiring treatment), will affect the interpretation of study results, or place the patient at high risk.
11. Patients with a prior history of basal cell or squamous cell skin cancer, cervical carcinoma in situ, or other cancers may be considered for enrollment if there is evidence of being disease-free for more than 5 years after treatment.
12. Severe neurological or psychiatric history; active disseminated intravascular coagulation (DIC); or other concomitant diseases that, in the investigator's judgment, seriously jeopardize patient safety or affect the patient's ability to complete the study.
13. Participation in other clinical trials, receipt of investigational drugs, or any concomitant treatments containing investigational drugs within 14 days prior to enrollment.
14. Patients deemed unsuitable for this study by the investigator.