Intrathecal Pemetrexed Combined With High-dose Furmonertinib and Beva for EGFR-m NSCLC With Leptomeningeal Metastases

The Efficacy and Safety of Intrathecal Pemetrexed With High-dose Furmonertinib Plus Bevacizumab for EGFR-mutant NSCLC Patients With Leptomeningeal Metastases Resistant to Third-generation EGFR-TKIs: A Phase II Study.

This study aimed to evaluate the efficacy and safety of intrathecal pemetrexed with high-dose Furmonertinib plus bevacizumab for EGFR-mutant non-small cell lung cancer patients with leptomeningeal metastases after resistance to third-generation EGFR-TKIs.

Study Overview

• Status: Not yet recruiting
• Conditions: Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: Intrathecal Pemetrexed and high-dose Furmonertinib plus bevacizumab

Detailed Description

This prospective interventional study aimed to evaluate the efficacy and safety of intrathecal pemetrexed with high-dose Furmonertinib plus bevacizumab for EGFR-mutant NSCLC patients with leptomeningeal metastases after resistance to third-generation EGFR-TKIs.

Approximately 30 EGFR-mutant Non-small cell lung cancer patients with leptomeningeal metastasis or leptomeningeal progression after resistant to third generation EGFR-TKIs were enrolled and treated with intrathecal pemetrexed with high-dose furmonertinib plus bevacizumab. cerebrospinal fluid and blood samples will be collected before and after pemetrexed resistance to analyze molecular mechanisms. Second-generation gene detection will be performed to identify potential resistance mechanisms to pemetrexed. The study is expected to commence recruitment in mainland China in about August 2024. It is expected that the trial will end in April 2026.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yongchang Zhang, MD; Phone Number: 7+861383123436 +8613873123436; Email: zhangyongchang@csu.edu.cn
• Study Contact Backup: Name: Liang Zeng, MD; Phone Number: 15974139200

Study Locations

• China
  • Hunan
    • Changsha, Hunan, China, 410013
      • Hunan Cancer Hospital
      • Contact: Yongchang Zhang, MD; Phone Number: +86 731 89762323; Email: zhangyongchang@csu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 1. Understand the requirements and contents of the clinical trial, and provide a signed and dated informed consent form.
• 2. Age ≥ 18 years.
• 3. Histopathology confirmed Non-small cell lung cancer.
• 4. confirmed or probable leptomeningeal metastases according to EANO-ESMO guidelines or known leptomeningeal metastases progression after third generation of EGFR-TKIs failure.
• 5.Leptomeningeal metastasis (LM) is defined by the presence of typical clinical symptoms, positive cerebrospinal fluid (CSF) cytology, detection of cell-free DNA (cfDNA) in CSF by next-generation sequencing (NGS), or imaging findings consistent with typical meningeal metastases.
• 6.ECOG 0 - 2.
• 7. Predicted survival ≥ 12 weeks.
• 8. Adequate bone marrow hematopoiesis and organ function.

Exclusion Criteria:

• 1. Previously received intrathecal pemetrexed therapy for locally advanced or metastatic disease.
• 2. Subjects who have received any of the following treatments must be excluded: Have received radiation within 14 days prior to the first dose or have not recovered from radiation-related toxicity. Chest and extra-brain palliative radiotherapy, stereotactic radiosurgery, and stereotactic body radiotherapy may be performed 7 days prior to the first dose.
• 3. Presence of spinal cord compression.
• 4. History of other malignant tumors within 2 years.
• 5. Adverse events (except alopecia of any degree) of CTCAE > grade 4 due to prior treatment (e.g., adjuvant chemotherapy, radiotherapy, etc.) prior to the first dose.
• 6. History of stroke or intracranial hemorrhage within 6 months prior to the first dose.
• 7. The presence of any severe or poorly controlled systemic disease, including poorly controlled hypertension and active bleeding in the judgment of the investigator.
• 8. Subjects with persistent or active infection, including but not limited to hepatitis B (HBV), hepatitis C (HCV), human immunodeficiency virus (HIV) and COVID-19 infection.
• 9. Heart-related diseases or abnormalities
• 10. Past history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid therapy or interstitial lung disease with active clinical symptoms, immune pneumonia caused by immunotherapy.
• 11. Refractory nausea and vomiting, chronic gastrointestinal disease, difficulty swallowing drugs, or inability to adequately absorb Furmonertinib due to previous bowel resection.
• 12. Live vaccine was given 2 weeks before the first medication.
• 13. Women who are breastfeeding or pregnant.
• 14. Hypersensitivity to the test drug and the ingredients.
• 15. Other conditions assessed by the investigator to be unsuitable for participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intrathecal Pemetrexed with double Furmonertinib plus bevacizumab	Drug: Intrathecal Pemetrexed and high-dose Furmonertinib plus bevacizumab; Intrathecal pemetrexed(50mg) twice a week for 1 week (day 1 and day 5) as induction treatment, then once monthly;; Furmonertinib(160mg QD);; bevacizumab(5mg/kg，once monthly) until progressive disease.; Other Names: intrathecal pemetrexed, high-dose furmonertinib, bevacizumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
LM-overall survival	LM-OS was defined as the duration from the start of intrathecal pemetrexed to patient death	Time from first subject dose to study completion, or up to last follow up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Extracranial progression-free survival	Extracranial Progression-Free survival was defined as the duration from the start of intrathecal pemetrexed to the progression of extracranial disease or patient death or last follow up	Time from first dose to the progression of extracranial disease or patient death or last follow up
Clinical response rate	Clinical Response Rate was defined as the ratio of the patient whose neurological symptoms and KPS improved according to the criteria of clinical response	Time from first dose to the improvement of neurological symptoms and KPS score
Adverse events (AEs)	Number of participants with adverse events (AEs) according to CTCAE 5.0	From first dose until 28 days after the last dose, up to 24 month

Collaborators and Investigators

• Sponsor: Hunan Province Tumor Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): September 30, 2024
• Primary Completion (Estimated): August 31, 2025
• Study Completion (Estimated): April 30, 2026

Study Registration Dates

• First Submitted: July 31, 2024
• First Submitted That Met QC Criteria: August 1, 2024
• First Posted (Actual): August 5, 2024

Study Record Updates

• Last Update Posted (Actual): September 20, 2024
• Last Update Submitted That Met QC Criteria: September 17, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Folic Acid Antagonists; Bevacizumab; Pemetrexed; Aflutinib
• Other Study ID Numbers: 20240801

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No