An Open-Label, Multicentre, Phase 1 Clinical Study to Evaluate the Safety and Efficacy of Zorifertinib Combined With Osimertinib in Patients With Advanced Non-Small Cell Lung Cancer With Meningeal Progression After Osimertinib Treatment
This is a clinical trial that aims to test Zorifertinib when used together with a known drug, Osimertinib. The goal is to learn if this combination is safe and works for people with advanced Non-Small Cell Lung Cancer (NSCLC) whose cancer has spread to the membranes surrounding the brain and spinal cord (a condition called leptomeningeal metastases) after being treated with Osimertinib.
• For inclusion in the study, patients must meet all of the following criteria.
• The patient or the guardian is required to understand and sign the informed consent form of this study.
• During the screening period, subjects must have a previous histological or cytological diagnosis of NSCLC with a sensitising EGFR mutation (including L858R and/or Exon19Del).
• Only patients who have developed meningeal progression after osimertinib treatment (at a standard dose of 80 mg QD; if the dose is 160 mg QD, it must be reduced to 80 mg QD for at least 1 week before receiving study treatment) (new-onset meningeal progression, or patients with existing meningeal progression that is poorly controlled using osimertinib combined with available conventional treatment \[CNS symptoms not relieved or CSF cytology not turning negative\], but the available conventional treatment must be washed out for at least 4 weeks) and have no extracranial progression are allowed to be enrolled.
• Subjects with leptomeningeal metastases should have the positive results of cerebrospinal fluid (CSF) cytology. Subjects with negative CSF cytology but highly suspected of leptomeningeal metastases in combination with CSF biochemical test and brain or spinal cord MRI imaging examination are allowed to be enrolled into the study.
• Subjects with meningeal progression and brain parenchyma progression are allowed to be enrolled.
• Subjects must have at least one repeatedly evaluable, measurable target lesion (intracranial and/or extracranial) according to mRECIST 1.1 criteria or a repeatedly evaluable lesion according to RANO-LM criteria.
• Subjects must be ≥ 18 years old before signing the informed consent form (ICF).
• If there are neurological symptoms, the following conditions must be met: Able to take and swallow oral medication; No need to increase the hormone dose to enhance control of central nervous system symptoms for at least 1 week before study treatment. If a patient is taking hormone for the purpose of treating endocrine dysfunction or tumor-related symptoms (not central nervous system-related), the dose must be stable or reduced within 5 days before the study medication. Note: The hormone dose should be stable 5 days before the baseline brain MRI.
• All toxicities related to anti-tumor therapy (including radiotherapy) must have resolved to ≤ Grade 1 (CTCAE 5.0, it is sufficient for neurotoxicity related to platinum treatment to resolve to ≤ Grade 2 \[CTCAE\]) before starting the study treatment. Patients with alopecia of any grade are allowed to be enrolled.
⁃ The screening period examination of patients must meet the followings:
∙ Neutrophil count ≥ 1.5 x 109/L
‣ Platelet ≥ 100 x 109/L
‣ Hemoglobin ≥ 9 g/dL
‣ Blood creatinine ≤ 1.5 x ULN, or creatinine clearance (Cockcroft-Gault formula) ≥ 50 mL/min
‣ Total bilirubin ≤ 1.5 x ULN (for patients with Gilbert's syndrome or metastases to liver, ≤3 x ULN is acceptable)
‣ Glutamic-oxaloacetic transferase ≤ 2 x ULN (for patients with metastases to liver, ≤ 3 x ULN is acceptable)
‣ Glutamic-pyruvic transaminase ≤ 2 x ULN (for patients with metastases to liver, ≤ 3 x ULN is acceptable)
⁃ The estimated survival time of subjects is ≥ 6 weeks.
⁃ Karnofsky Performance Status (KPS) scale score ≥ 60.