Leptomeningeal Metastasis From Lung Cancer
Conditions
Keywords
Leptomeningeal Metastasis from Lung Cancer, Non-Small Cell Lung Cancer, proton craniospinal irradiation, ctDNA, Third-generation TKIs
Brief summary
\*\*Brief Summary (English)\*\* The goal of this clinical trial is to learn if a risk-adaptive consolidation therapy, guided by cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) clearance kinetics after induction intrathecal pemetrexed, can improve intracranial progression-free survival (iPFS) compared to standard intrathecal pemetrexed consolidation in patients with leptomeningeal metastasis (LM) from EGFR-mutant non-small cell lung cancer (NSCLC) that has progressed on third-generation EGFR-TKIs. It will also learn about the safety and tolerability of proton craniospinal irradiation (pCSI) in this setting. The main questions it aims to answer are: * Does risk-adaptive consolidation therapy (pCSI with or without concurrent low-dose intrathecal pemetrexed) prolong iPFS compared to standard intrathecal pemetrexed consolidation? * What medical problems do participants have when receiving pCSI or intrathecal pemetrexed? Researchers will compare the experimental arm (risk-adaptive consolidation: pCSI for intermediate-risk, or pCSI with concurrent low-dose intrathecal pemetrexed for high-risk patients) to the control arm (standard intrathecal pemetrexed consolidation) to see if the adaptive strategy improves survival outcomes. Participants will: * Receive induction intrathecal pemetrexed (40 mg, biw, q3w for 2 cycles) via Ommaya reservoir. * Undergo CSF collection at baseline and after induction for ctDNA (maxVAF) analysis to determine risk stratification (low, intermediate, high). * If stratified as intermediate or high risk, be randomly assigned to either standard intrathecal pemetrexed consolidation or risk-adaptive consolidation (pCSI 30 GyE/10f for intermediate-risk; pCSI 30 GyE/10f with concurrent intrathecal pemetrexed 30 mg on d1, d8 for high-risk). * Receive maintenance intrathecal pemetrexed (40 mg, q4w) until intracranial progression. * Undergo regular efficacy assessments (contrast-enhanced MRI of brain and whole spine) every 8 weeks, and complete neurocognitive and quality-of-life questionnaires.
Interventions
RADIATIONproton craniospinal irradiation
Phase 1: Intrathecal pemetrexed 40 mg, biw, q3w, for 2 cycles (via Ommaya reservoir). CSF ctDNA (maxVAF) tested at baseline (C0) and post-induction (C1) for risk stratification: Low-risk: ΔctDNA \> 80% reduction or clearance. Intermediate-risk: ΔctDNA 20%-80% reduction. High-risk: ΔctDNA \< 20% reduction. Phase 2: Low-risk: Pemetrexed 40 mg, q3w, 4 cycles (no randomisation). Intermediate/High-risk - Cohort A (Control): Pemetrexed 40 mg, q3w, 4 cycles. Intermediate/High-risk - Cohort B (Experimental): Intermediate: Proton craniospinal irradiation (pCSI) 30 GyE/10 fractions. High: pCSI 30 GyE/10 fractions + concurrent low-dose intrathecal pemetrexed 30 mg (days 1 \& 8) as radiosensitizer. Phase 3: Pemetrexed 40 mg, q4w, until intracranial progression. Supportive/Concomitant: Mandatory folic acid and vitamin B12 premedication for pemetrexed; background systemic EGFR-TKI therapy p
he goal of this clinical trial is to learn if a risk-adaptive consolidation therapy, guided by cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) clearance kinetics after induction intrathecal pemetrexed, can improve intracranial progression-free survival (iPFS) compared to standard intrathecal pemetrexed consolidation in patients with leptomeningeal metastasis (LM) from EGFR-mutant non-small cell lung cancer (NSCLC) that has progressed on third-generation EGFR-TKIs. It will also learn about the safety and tolerability of proton craniospinal irradiation (pCSI) in this setting.
Sponsors
Shuanghu Yuan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Voluntary participation with written informed consent obtained prior to any study-specific procedures, and willingness and ability to comply with scheduled visits, the treatment plan, laboratory tests, and other study requirements. 2. Male or female patients aged between 18 and 75 years (inclusive) at the time of signing informed consent. 3. Primary tumour confirmed as non-small cell lung cancer (NSCLC) by cytology or histology, harbouring EGFR-sensitive mutations (including 19del and exon 21 L858R). Testing reports for EGFR mutation status must be available; if no prior report exists, submission of archived tissue or baseline biopsy for assessment is mandatory. 4. Leptomeningeal metastasis (LM) diagnosed according to the EANO-ESMO guidelines, based on cerebrospinal fluid (CSF) cytology and/or imaging evidence of leptomeningeal enhancement or ventriculomegaly. 5. Disease progression of LM documented after treatment with third-generation EGFR-TKIs (including osimertinib, almonertinib, or furmonertinib). Patients may continue their current EGFR-TKI therapy during the study, provided that extracranial disease remains stable. 6. The patient has had an Ommaya reservoir implanted or has undergone Ommaya reservoir placement prior to study entry, and is willing to undergo intrathecal injections via the reservoir throughout the study. 7. Extracranial disease is stable, defined as no progressive extracranial lesions (per RECIST v1.1) within 28 days prior to enrollment. Continuation of background systemic EGFR-TKI therapy is permitted. 8. Life expectancy ≥ 3 months as assessed by the investigator. 9. Karnofsky Performance Status (KPS) ≥ 70 at screening. 10. Medically fit to tolerate intrathecal pemetrexed and proton craniospinal irradiation (pCSI), as determined by the investigator. 11. Adequate organ and bone marrow function as defined below (within 14 days prior to initiation of study treatment), without having received blood transfusions, granulocyte colony-stimulating factor (G-CSF), or hematopoietic growth factors within 14 days prior to screening: * Hematology: * Haemoglobin (Hb) ≥ 90 g/L; * Absolute Neutrophil Count (ANC) ≥ 1.5 × 10⁹/L; * Platelets (PLT) ≥ 75 × 10⁹/L. * Blood Chemistry: * Total Bilirubin (TBIL) ≤ 2.0 × ULN (≤ 3.0 × ULN for patients with Gilbert's syndrome); * Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 5.0 × ULN; * Serum Creatinine (Cr) ≤ 1.5 × ULN or Calculated Creatinine Clearance (CrCl) ≥ 50 mL/min (using the Cockcroft-Gault formula): * Male: CrCl = ((140 - age) × weight) / (72 × serum creatinine) * Female: CrCl = ((140 - age) × weight) / (72 × serum creatinine) × 0.85 (Note: Weight in kg; Serum creatinine in mg/dL) * Coagulation Function: * International Normalized Ratio (INR) ≤ 2.0 or Prothrombin Time (PT) ≤ 6 seconds above the upper limit of normal. 12. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to the first dose of study treatment. If the urine test cannot be definitively confirmed as negative, a serum pregnancy test must be performed, and the serum result will be considered definitive. 13. Female subjects of childbearing potential who are sexually active with unsterilised male partners must agree to use highly effective contraception starting at screening and continue for 180 days after the last dose of study treatment. 14. Sexually active male subjects who have not undergone sterilisation and who are sexually active with female partners of childbearing potential must agree to use effective contraception starting at screening and continue for 180 days after the last dose of study treatment. Decisions regarding cessation of contraception beyond this timeframe should be discussed with the investigator. 15. Subjects must be willing and able to comply with the study protocol, including scheduled visits, treatment administration, laboratory tests, imaging assessments, and CSF sample collections via the Ommaya reservoir.
Exclusion criteria
* Patients with concurrent primary tumors of the brain or spinal cord. * Patients with severe central nervous system diseases (including severe cerebral herniation or coma). * Patients with life-threatening or uncontrolled systemic diseases, such as uncontrolled hypertension or active bleeding tendency. * Patients with other concurrent malignancies, except for basal cell carcinoma of the skin and carcinoma in situ. * Patients who have previously received whole-brain radiotherapy or photon radiotherapy to involved fields of the brain and spinal cord. * Patients judged by the investigator to be unsuitable for participation, or who have factors that may affect compliance with the protocol. * Toxicity from prior treatment has not recovered to normal or to grade 1 per NCI-CTCAE version 6.0. * Patients with drug allergy or metabolic disorders to the drugs used in this protocol. * Pregnant or lactating women, or female patients who plan to become pregnant during the study period or within 6 months after the last dose. * Patients who are concurrently participating in other clinical studies * Patients with pre-existing cardiac dysfunction.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Intracranial progression-free survival (iPFS) | up to 2 years | Intracranial progression-free survival (iPFS) is defined as the time from enrollment to the date of intracranial progression or death from any cause, whichever occurs first.For subjects without observed intracranial progression or death, iPFS will be censored at the time of the last valid and adequate intracranial tumour assessment. iPFS analysis will be based on the Full Analysis Set (FAS). The median iPFS and its 95% CI will be estimated using the Kaplan-Meier method, and progression-free survival curves will be generated. Treatment group comparison will be performed using stratified log-rank test, and hazard ratio (HR) with 95% CI will be estimated using the Cox proportional hazards model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival (OS) | up to 2 years | Overall Survival (OS) is defined as the time from enrollment to death from any cause. For subjects not followed up to death, OS will be censored at the time of the last valid survival follow-up. OS analysis will be based on the Full Analysis Set (FAS). The median OS (if applicable) and its 95% CI will be estimated using the Kaplan-Meier method, and survival curves will be plotted. Treatment group comparison will be performed using stratified log-rank test, and HR with 95% CI will be estimated using the Cox proportional hazards model. |
| The lead time from achieving a 20% change in CSF ctDNA to radiographic progression per RANO-LM criteria | up to 2 years | This endpoint is defined as the time interval from the first detection of a ≥20% change (increase or decrease) in CSF ctDNA maxVAF relative to the preceding baseline value to the date of subsequent radiographic intracranial progression confirmed by independent review committee (IRC) per RANO-LM criteria. This analysis will be performed only in subjects with both baseline and at least one on-treatment paired CSF sample and who achieve a ≥20% ctDNA change during treatment. The median lead time and its 95% CI will be estimated using the Kaplan-Meier method, with ctDNA change date as time zero and radiographic progression as the event. If the distribution is skewed, the lead time will be presented descriptively as median with interquartile range. |
| Incidence and Severity of Adverse Events, Serious Adverse Events, Treatment-Related Adverse Events, Immune-Related Adverse Events, and Laboratory Abnormalities | up to 2 years | The number and percentage of participants experiencing adverse events (AEs), serious adverse events (SAEs), treatment-related adverse events (TRAEs), immune-related adverse events (irAEs), and clinically significant laboratory abnormalities will be assessed. Events will be summarized by type, frequency, severity grade, seriousness, and relationship to study treatment according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 6.0. |
| Change from Baseline in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Global Health Status/Quality of Life Score | up to 2 years | The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status/Quality of Life scale consists of 2 items. The raw score is linearly transformed to a score ranging from 0 to 100. Higher scores indicate better global health status and quality of life.Change from baseline will be assessed at each scheduled post-baseline visit. Changes will be summarized descriptively by treatment group. Between-group differences will be evaluated using a mixed-effects model for repeated measures, including baseline score, treatment group, visit, and treatment-by-visit interaction. |
| Change from Baseline in the MD Anderson Symptom Inventory-Brain Tumor Module Mean Symptom Severity Score | up to 2 years | The MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) assesses 13 core cancer-related symptoms and 9 brain tumor-specific symptoms experienced during the previous 24 hours. Each symptom is rated on an 11-point numeric rating scale ranging from 0, meaning "not present," to 10, meaning "as bad as you can imagine."The mean symptom severity score is calculated as the mean of the completed symptom items and ranges from 0 to 10. Higher scores indicate greater symptom severity.Change from baseline will be assessed at scheduled post-baseline visits. Between-group differences will be evaluated using a mixed-effects model for repeated measures, including baseline score, treatment group, visit, and treatment-by-visit interaction. |
| Change from Baseline in the Montreal Cognitive Assessment Total Score | up to 2 years | Cognitive function will be assessed using the Montreal Cognitive Assessment (MoCA). The MoCA evaluates visuospatial and executive function, naming, attention, language, abstraction, delayed recall, and orientation.The total score ranges from 0 to 30. Higher scores indicate better cognitive performance. Scoring, including any protocol-specified education adjustment, will be conducted according to the authorized version of the instrument.Change from baseline in the total score will be assessed at scheduled post-baseline visits. Between-group differences will be evaluated using a mixed-effects model for repeated measures, including baseline score, treatment group, visit, and treatment-by-visit interaction. |
Countries
China
Contacts
CONTACTShangHu Yuan, MD
Outcome results
None listed