Dynamic Adaptive Radiotherapy for Non-Small Cell Lung Cancer With Leptomeningeal Metastasis After Resistance to Third-Generation TKIs in the Consolidation Phase: A Multicenter Randomized Controlled Trial Comparing Outcomes Between Proton Craniospinal Irradiation and Intrathecal Pemetrexed (DART-LM)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 84
- 试验地点
- 3
- 主要终点
- Intracranial progression-free survival (iPFS)
研究概览
简要总结
**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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •Male or female patients aged between 18 and 75 years (inclusive) at the time of signing informed consent.
- •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.
- •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.
- •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.
- •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.
- •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.
- •Life expectancy ≥ 3 months as assessed by the investigator.
- •Karnofsky Performance Status (KPS) ≥ 70 at screening.
- •Medically fit to tolerate intrathecal pemetrexed and proton craniospinal irradiation (pCSI), as determined by the investigator.
- •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.
- •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.
- •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.
- •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.
- •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.
排除标准
- •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.
- •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.
研究组 & 干预措施
risk-adaptive proton craniospinal irradiation cohort
Phase 1 : Intrathecal pemetrexed (40 mg, twice weekly, every 3 weeks, for 2 cycles).
Phase 2 : 1）Intermediate-risk patients receive proton craniospinal irradiation (pCSI) at 30 GyE in 10 fractions；2）High-risk patients receive pCSI at 30 GyE in 10 fractions with concurrent low-dose.
Phase 3 : Intrathecal chemotherapy (pemetrexed 40 mg, every 4 weeks) until intracranial progression.
干预措施: proton craniospinal irradiation (Radiation)
Intrathecal pemetrexed Cohort
Phase 1 : Intrathecal pemetrexed (40 mg, twice weekly, every 3 weeks, for 2 cycles).
Phase 2 : Standard intrathecal chemotherapy regimen (pemetrexed 40 mg, every 3 weeks, for 4 cycles).
Phase 3 : Intrathecal chemotherapy (pemetrexed 40 mg, every 4 weeks) until intracranial progression.
干预措施: Intrathecal pemetrexed (Drug)
risk-adaptive proton craniospinal irradiation cohort
Phase 1 : Intrathecal pemetrexed (40 mg, twice weekly, every 3 weeks, for 2 cycles).
Phase 2 : 1）Intermediate-risk patients receive proton craniospinal irradiation (pCSI) at 30 GyE in 10 fractions；2）High-risk patients receive pCSI at 30 GyE in 10 fractions with concurrent low-dose.
Phase 3 : Intrathecal chemotherapy (pemetrexed 40 mg, every 4 weeks) until intracranial progression.
干预措施: Intrathecal pemetrexed (Drug)
结局指标
主要结局
Intracranial progression-free survival (iPFS)
时间窗: 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.
次要结局
- Overall survival (OS)(up to 2 years)
- The lead time from achieving a 20% change in CSF ctDNA to radiographic progression per RANO-LM criteria(up to 2 years)
- Incidence and Severity of Adverse Events, Serious Adverse Events, Treatment-Related Adverse Events, Immune-Related Adverse Events, and Laboratory Abnormalities(up to 2 years)
- 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)
- Change from Baseline in the MD Anderson Symptom Inventory-Brain Tumor Module Mean Symptom Severity Score(up to 2 years)
- Change from Baseline in the Montreal Cognitive Assessment Total Score(up to 2 years)
研究者
Shuanghu Yuan
Professor
Anhui Provincial Cancer Hospital