Intrathecal Pemetrexed for Leptomeningeal Metastasis in EGFR-Mutant NSCLC

NCT05805631 | Recruiting Phase 2

• 1 other identifier: 2022-12-005C
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

Leptomeningeal metastasis (LM) is a complication of advanced non-small cell lung cancer (NSCLC). The incidence of LM in NSCLC patients is around 3-5 %, reaching 9.4 % of those with an epidermal growth factor receptor (EGFR) mutation. Generally, the efficacy of systemic treatment for LM is limited due to the blood-brain barrier. Osimertinib has a high central nervous system penetration rate, making it the preferred first-line treatment for EGFR-mutant NSCLC. Previous studies indicated that osimertinib had shown promising efficacy in pretreated patients harboring EGFR mutations and LM. However, intracranial disease progression eventually develops, and the prognosis of patients with LM progression after osimertinib is poor. Recently, intrathecal chemotherapy with pemetrexed (IP) was reported to be an alternative treatment in patients with NSCLC and LM. The results from a phase I/II trial examining the efficacy and safety of IP in patients with EGFR-mutant NSCLC after the failure of previous TKI, and 83% of study enrollees received osimertinib before IP. The clinical response rate was 84.6%, and the median overall survival was 9.0 months. Despite initial promising efficacy, further trials are needed to verify these results. Therefore, the investigators plan to conduct a prospective study to examine the safety and effectiveness of IP combined with EGFR-TKI for patients with EGFR mutant NSCLC after osimertinib failure.

Conditions

Epidermal Growth Factor Receptor; Carcinoma, Non-Small-Cell Lung; Leptomeningeal Metastasis

Outcome Measures

Primary Outcomes (1)

• Disease control rate (DCR)

  The response to treatment was determined by combining neurological examination, CSF cytology, and radiographic evaluation by RANO-LM proposal.

  Every 6 weeks till disease progression, an average of 6 months

Secondary Outcomes (3)

• Progression-free Survival, LM (PFS-LM)

  Every 6 weeks till disease progression, an average of 6 months

• Progression-free Survival (PFS)

  Every 3 months till disease progression, an average of 6 months

• Overall survival (OS)

  Every 3 months through study completion , an average of 12 months

Study Arms (1)

Experimental arm

EXPERIMENTAL

Intrathecal pemetrexed combined with EGFR-TKI (physician choice)

Drug: Pemetrexed

Interventions

Pemetrexed DRUG

Intrathecal Pemetrexed

Experimental arm

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• At least 20 years of age.
• Patients with metastatic non-squamous NSCLC harboring known EGFR activating mutation and with a diagnosis of probable or confirmed LM by the European Association of Neuro-Oncology-European Society for Medical Oncology (EANO-ESMO) guideline. \[5\] EGFR activating mutations include exon19 deletion, T790M, L858R, G719X, L861Q, or S768I.
• Intracranial disease progression after osimertinib use, proved by contrast-enhanced MRI
• Stable extra-cranial disease status, judged by investigators.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-3 and a minimum life expectancy of 12 weeks
• Normal bone marrow and organ function as defined below:
• Marrow: Hemoglobin ≥9gm/dL, ANC ≥1500/mm3 platelets ≥100,000/mm3
• Hepatic: Serum total bilirubin ≤1.5 x upper limit of normal (ULN), ALT (SGPT) and AST (SGOT) ≤3 x ULN.
• Renal: Creatinine clearance (Ccr) ≥45 mL/min.
• For female patients of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception that results in a low failure rate (\< 1% per year) when used consistently and correctly, and to continue its use for 5 months after the last dose of IP. Such methods include: combined (estrogen and progestogen containing) hormonal contraception, progestogen-only hormonal contraception associated with inhibition of ovulation together with another additional barrier method always containing a spermicide, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner (on the understanding that this is the only one partner during the whole study duration), and sexual abstinence.
• Ability to understand and willingness to sign an IRB approved written informed consent document.
• Willing to provide CSF and plasma samples for ctDNA analysis.

You may not qualify if:

• Uncontrolled extra-CNS disease which needs other systemic treatment than EGFR-TKI.
• Uncontrolled tumor-related pain
• Uncontrolled or symptomatic hypercalcemia (\> 1.5 mmol/L ionized calcium or Ca \> 12 mg/dL or corrected serum calcium \> ULN). Patients who are receiving denosumab prior to study enrollment must be willing and eligible to receive a bisphosphonate instead while in the study.
• Malignancies other than NSCLC within 5 years prior to study enrollment, with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year OS \> 90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous-cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent)
• On chronic systemic steroid therapy more than 20 mg prednisolone per day (or equivalent) or on any other form of immunosuppressive medication
• Has received a live-virus vaccination within 30 days of planned treatment start
• Systemic cytotoxic chemotherapy or major surgery within 2 weeks of the first dose of study medication
• Active infection requiring therapy
• History of Human Immunodeficiency Virus (HIV) infection.
• Hepatitis B carrier: Patients with HBV infection were required to be receiving effective antiviral therapy and have a viral load less than 100 IU/mL at screening
• Active Hepatitis C
• Has received intrathecal chemotherapy within 2 weeks before the start of IP
• Has received whole-brain radiotherapy (WBRT) within 2 weeks before the start of IP
• Uncontrolled epilepsy
• History of allergic reaction to intravenous pemetrexed.

Sponsors & Collaborators

• Taipei Veterans General Hospital, Taiwan: lead

Study Sites (1)

Department of Chest Medicine, Taipei Veterans General Hospital

Taipei, Taiwan, 11217, Taiwan

RECRUITING

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Meningeal Carcinomatosis

Interventions

Pemetrexed

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Meningeal Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic

Central Study Contacts

Chi-Lu Chiang, MD

CONTACT

886228712121; clchiang@vghtpe.gov.tw

Yung-Hung Luo, MD, PhD

CONTACT

886228712121; yhluo@vghtpe.gov.tw

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Attending physician

Study Record Dates

• First Submitted: March 14, 2023
• First Posted: April 10, 2023
• Study Start: August 1, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027
• Last Updated: March 24, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

TW (1)