Patients with EGFR mutation-positive NSCLC who have developed leptomeningeal metastasis following resistance to third-generation EGFR-TKIs, with no extracranial progression.
Conditions
Interventions
Trial Group:Zolitinib 200mg BID combined with standard-dose third-generation EGFR-TKIs (osimertinib, fumertinib, or amutable) treatment
Sponsors
West China Hospital of Sichuan University
Eligibility
Sex/Gender
All
Age
18 Years to 75 Years
Inclusion criteria
Inclusion criteria: 1. The subject has given written informed consent voluntarily after receiving a full explanation of the study. 2. The subject was aged 18 to 75 years at the time of signing the Informed Consent Form (ICF). 3. During the screening phase, the subject must have a prior histological or cytological diagnosis of NSCLC with EGFR sensitizing mutations (including L858R and/or Exon19Del). 4. Subjects who have developed leptomeningeal progression following third-generation EGFR-TKI monotherapy, with no extracranial progression (if dose escalation was applied, the dose must be reduced to the standard dose for at least one week prior to enrollment). 5. Subjects with confirmed leptomeningeal metastasis must have positive cerebrospinal fluid (CSF) cytology results. For subjects with negative CSF cytology but clinically diagnosed with leptomeningeal metastasis based on symptoms and brain or spinal cord MRI imaging, enrollment is also permitted; however, CSF cytology must be retested at least twice after enrollment. 6. Subjects with leptomeningeal progression concurrent with brain parenchymal progression are allowed to be enrolled. 7. If neurological symptoms are present, the following conditions must be met: the subject must be able to take oral medication and swallow pills; and the corticosteroid dose must not have been increased for at least one week prior to study treatment to enhance control of central nervous system symptoms. 8. All toxicities related to prior antitumor therapy (including radiotherapy) must have resolved to Grade = 1.5 x 10^9/L (2) Platelet count >= 90 x 10^9/L (3) Hemoglobin >= 80 g/L (4) Serum creatinine = 45 mL/min (5) Total bilirubin = 3 months. 11. ECOG PS <=2.
Exclusion criteria
Exclusion criteria: 1. Subjects with a history of radiotherapy within 28 days prior to the first dose of the investigational drug are not eligible for enrollment; palliative bone radiotherapy occurring within 14 days prior to the first dose of the investigational drug is also an exclusion criterion. 2. Subjects who have undergone major surgery (e.g., intrathoracic, intra-abdominal, or pelvic surgery) within 4 weeks prior to the first dose of the investigational treatment or who have not recovered from the side effects associated with such surgery are not eligible for enrollment. 3. Presence of other malignancies requiring treatment in addition to NSCLC. 4. Clinically significant, uncontrolled cardiac disease and/or cardiac-related events within the past 6 months: (1) Myocardial infarction within 6 months prior to screening or a documented history of heart failure (NYHA Class III-IV); (2) Uncontrolled hypertension: systolic blood pressure =160 mmHg and/or diastolic blood pressure =100 mmHg, with or without antihypertensive medication; adjustment of antihypertensive drugs prior to screening is permitted; (3) Drug-resistant arrhythmias; (4) QTcF >470 ms at screening; (5) Left ventricular ejection fraction (LVEF) <50%. 5. Gastrointestinal diseases or severe gastrointestinal dysfunction that may significantly affect drug absorption (e.g., ulcerative disease, uncontrollable nausea, vomiting, diarrhea, or malabsorption syndrome). 6. The following medications cannot be discontinued within 1 week prior to the first dose of the investigational drug and during the study period: (1) Strong CYP3A4 inducers or strong inhibitors; (2) Drugs primarily metabolized by CYP3A4; (3) Drugs that may cause QT interval prolongation or torsades de pointes. 7. Subjects with a history of or co-infection with HIV are not eligible for enrollment. HCV antibody-positive subjects are eligible if HCV-RNA is undetectable (the lower limit of normal for HCV-RNA detection is determined by each center) and there is no co-infection with hepatitis B virus (HBV). HBV-infected subjects are eligible if they meet the following conditions: (1) Patients with active hepatitis B must meet the following criteria: antiviral therapy must have been initiated for at least 6 weeks prior to the start of investigational treatment, HBV DNA must be <100 IU/mL, and ALT and AST levels must be <ULN; (2) Patients with resolved hepatitis B or chronic hepatitis B must meet the following criteria: patients must have received prophylactic antiviral therapy for at least 2 weeks prior to the start of investigational treatment, HBV DNA must be below 100 IU/ml (if an inactive carrier), and ALT and AST levels must be <ULN. 8. Pregnant or lactating women; women of childbearing potential must use highly effective contraception methods during dosing and for 3 months after discontinuation; men of reproductive potential must also use highly effective contraception methods during dosing and for 6 months after discontinuation. 9. History of interstitial lung disease, including clinically significant radiation pneumonitis (e.g., affecting daily activities or requiring therapeutic intervention). 10. Subjects who have previously received zolitinib drug or active pharmaceutical ingredient treatment. 11. Known hypersensitivity to the active substance or excipients of zolitinib or to drugs with similar chemical structures or classes to zolitinib. 12. Co-existing diseases or other factors where the investigator believes that participation in
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Safety of combination therapy;Pharmacokinetic evaluation; | — |
Secondary
| Measure | Time frame |
|---|---|
| Pia mater ORR;Progression-free survival of the pia mater;Overall survival;Overall progression-free survival;CNS symptom improvement;CSF response rate based on cerebrospinal fluid (CSF) pathological cytology; | — |
Countries
China
Contacts
Public ContactWang Yongsheng
West China Hospital of Sichuan University
Outcome results
None listed