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The goal of this clinical trial is to clarify the efficacy and safety of the high-dose alternate-day furmonertinib in NSCLC with leptomeningeal metastasis. It will also explore the mechanism by which the high-dose alternate-day administration regimen enhances efficacy from a pharmacokinetic perspective, and investigate the impact of co-occurring mutations on the efficacy and prognosis of furmonertinib in the treatment of EGFR-mutant NSCLC with leptomeningeal metastasis. The main questions it aims to answer are:
Does the high-dose alternate-day administration regimen have definite efficacy? Does the high-dose alternate-day administration regimen have favorable safety? Does the high-dose alternate-day administration regimen improve efficacy by increasing the cerebrospinal fluid (CSF) concentration and CSF penetration rate of the drug? Which co-occurring mutations may affect the efficacy and prognosis of patients with EGFR-mutant NSCLC and leptomeningeal metastasis? Participants will enter Cohort A (320mg qod po) or Cohort B (160mg qd po) to receive furmonertinib based on their own willingness and the clinician's decision, until disease, progression or uncontrollable adverse reactions occur. All patients in Cohort A will undergo efficacy and safety evaluation, with some also participating in pharmacokinetic study; patients in Cohort B will only undergo pharmacokinetic study.
Efficacy and safety evaluation will be conducted through imaging examinations, neurological function assessment scales, quality of life self-assessment scales, and adverse event records. Pharmacokinetic study will be carried out by detecting the plasma concentrations and CSF concentrations of furmonertinib and its active metabolites, and calculating the CSF penetration rate for evaluation.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort A | Experimental | furmonertinib 320mg qod po |
|
| Cohort B | Other | furmonertinib 160mg qd po |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Furmonertinib 320mg qod po | Drug | furmonertinib 320mg qod po until disease, progression or uncontrollable adverse reactions occur. |
|
| Measure | Description | Time Frame |
|---|---|---|
| LM-DCR | Leptomeningeal metastasis-disease control rate, calculated as the proportion of patients with leptomeningeal metastasis who achieve remission or stable disease, which will be determined based on the modified imaging assessment method formulated by the RANO-LM working group with imaging assessments. | From date of first administration of the study drug until the date of first documented leptomeningeal disease progression or date of death from any cause, whichever came first, assessed up to 3 years. |
| Measure | Description | Time Frame |
|---|---|---|
| LM-ORR | Leptomeningeal metastasis objective response rate, calculated as the proportion of patients with leptomeningeal metastasis who achieve remission, which will be determined based on the modified imaging assessment method formulated by the RANO-LM working group with imaging assessments. | From date of first administration of the study drug until the date of first documented leptomeningeal disease progression or date of death from any cause, whichever came first, assessed up to 3 years. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Yanjuan Zhu, M.D. | Contact | 86-20-81887233 | 34830 | zyjsophy@gzucm.edu.cn |
| Name | Affiliation | Role |
|---|---|---|
| Haibo Zhang, M.D. | Guangdong Provincial Hospital of Traditional Chinese Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Guangdong Provincial Hospital of Chinese Medicine | Recruiting | Guangzhou | Guangdong | 510120 | China |
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| Furmonertinib 160mg qd po | Drug | furmonertinib 160mg qd po until disease, progression or uncontrollable adverse reactions occur. |
|
| neurological function | measured by NANO-LM standardized neurological examination | From date of first administration of the study drug until the date of first documented leptomeningeal disease progression or date of death from any cause, whichever came first, assessed up to 3 years. |
| iDoR | Intracranial duration of response means the time from the first achievement of intracranial disease remission to the first disease progression or death from any cause. Investigators will assess lesions other than leptomeningeal metastases according to the modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), while investigators and neuroradiological Independent Central Review (ICR) will evaluate the response of leptomeningeal metastases based on the modified neuroradiological criteria formulated by the RANO-LM working group. | From date of first administration of the study drug until the date of first documented leptomeningeal disease progression or date of death from any cause, whichever came first, assessed up to 3 years. |
| iPFS | Intracranial progression-free survival means the time from the date of enrollment to the first occurrence of intracranial disease progression or death from any cause. Investigators will assess lesions other than leptomeningeal metastases according to the modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), while investigators and neuroradiological Independent Central Review (ICR) will evaluate the response of leptomeningeal metastases based on the modified neuroradiological criteria formulated by the RANO-LM working group. | From date of enrollment until the date of first documented leptomeningeal disease progression or date of death from any cause, whichever came first, assessed up to 3 years. |
| PFS | Progression-free survival means the time from the date of enrollment to the first occurrence of disease progression or death from any cause. Investigators will assess lesions other than leptomeningeal metastases according to the modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), while investigators and neuroradiological Independent Central Review (ICR) will evaluate the response of leptomeningeal metastases based on the modified neuroradiological criteria formulated by the RANO-LM working group. | From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years. |
| OS | Overall survival refers to the time from the date of enrollment to the date of death from any cause. | From date of enrollment until the date of death from any cause, assessed up to 5 years. |
| Quality of life evaluation | Patient self-assessments of quality of life will be conducted using the Chinese versions of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). The EORTC QLQ-C30 is a 30-item questionnaire comprising 5 functional scales, 3 symptom scales, 1 global health/QoL scale and 6 single items. The score of this questionnaire ranges between 1 and 4 in functional scales, symptom scales, and single items. The score ranges between 1 and 7 in global health/QoL scale. The higher score indicates the worse quality of life. | From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years. |
| Quality of life evaluation | Patient self-assessments of quality of life will be also conducted using the Chinese versions of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Brain Cancer Module (EORTC QLQ-BN20). The QLQ-BN20 is a 20-item questionnaire that assesses future uncertainty, visual disorder, motor dysfunction, and communication deficit, as well as seven single items (headaches, seizures, drowsiness, hair loss, itchy skin, weakness of legs, bladder control). The score of this questionnaire ranges between 1 and 4. The higher score indicates the worse quality of life. | From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years. |
| AEs | Adverse events will be recorded according to Common Terminology Criteria for Adverse Events version 6.0 (CTCAE v6.0) | From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years. |
| CSF Penetration Rate | Cerebrospinal fluid penetration rate refers to the ratio of the drug's concentration in cerebrospinal fluid to its concentration in plasma. | Patients will undergo twice of specimen collection: the first before treatment (-14 to 0 days) and the second 4 weeks after treatment (4weeks ±7 days). |
| Gene Mutation | Testing the gene mutation of plasma, CSF and the tumor tissue by NGS | at baseline and date of progression (assessed up to 3 years) |
| ID | Term |
|---|---|
| D002289 | Carcinoma, Non-Small-Cell Lung |
| D055756 | Meningeal Carcinomatosis |
| ID | Term |
|---|---|
| D002283 | Carcinoma, Bronchogenic |
| D001984 | Bronchial Neoplasms |
| D008175 | Lung Neoplasms |
| D012142 | Respiratory Tract Neoplasms |
| D013899 | Thoracic Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D008577 | Meningeal Neoplasms |
| D016543 | Central Nervous System Neoplasms |
| D009423 | Nervous System Neoplasms |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| C000705711 | aflutinib |
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