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ctDNA-driven Adaptive Proton Craniospinal Irradiation in Non-Small Cell Lung Cancer With Leptomeningeal Metastasis After Resistance to Third-Generation TKIs in the Consolidation Phase

NCT07751536 · Status: RECRUITING · Phase: NA · Type: INTERVENTIONAL · Enrollment: 84

Last updated 2026-08-07

No results posted yet for this study

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.

Conditions

  • Leptomeningeal Metastasis From Lung Cancer

Interventions

RADIATION

proton 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

DRUG

Intrathecal pemetrexed

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 & Collaborators

  • Shuanghu Yuan

    lead OTHER

Study Design

Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
NONE
Model
PARALLEL

Eligibility

Min Age
18 Years
Max Age
75 Years
Sex
ALL
Healthy Volunteers
No

Timeline & Regulatory

Start
2026-08-05
Primary Completion
2028-07-31
Completion
2028-07-31

Countries

  • China

Study Locations

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Read the full study record

This page highlights key information. For complete eligibility criteria, study locations, investigator contacts, and the full protocol, visit the original record on ClinicalTrials.gov.

View NCT07751536 on ClinicalTrials.gov