Intra-pemetrexed Plus Third-generation Small Molecule TKI Drugs (e.g. 'Osimertinib') Versus Third-generation Small Molecule TKI Drugs Alone for Leptomeningeal Metastasis From Epidermal Growth Factor Receptor Mutation-Positive Non-Small-cell Lung Cancer

NCT06304441 | Recruiting DMC

• 1 other identifier: IPVO
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

Intrathecal chemotherapy is one of the mainstay treatment options for leptomeningeal metastases. Pemetrexed is one of the first-line chemotherapeutic agents for non-squamous non-small cell lung cancer (NSCLC). Since 2017, intrathecal pemetrexed has shown good efficacy for patients with leptomeningeal metastases from NSCLC. It has been recommended as the preferred drug for intrathecal chemotherapy by the Chinese Society of Clinical Oncology (CSCO) guidelines. Tyrosine kinase inhibitors (TKIs) play a promising role in the treatment of non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations. Due to its small molecule properties, it can effectively penetrate the central nervous system barrier and deliver an effective antitumor effect. An international multi-center clinical study published in 2019 confirmed that double-dose of osimertinib showed significant improvement in leptomeningeal metastases from NSCLC with EGFR exon 19 deletion or exon 21 L858R/T790M mutation. It makes TKIs the mainstay of treatment for patients with EGFR-mutant NSCLC with leptomeningeal metastases. However, whether third-generation small molecule TKI drugs (e.g. 'osimertinib') combined with intrathecal pemetrexed could benefit patients with LM from EGFR- mutant NSCLC remains undetermined.

Conditions

Leptomeningeal Metastasis

Keywords

Leptomeningeal metastasis; Intrathecal chemotherapy; Pemetrexed; Third-generation small molecule TKI drugs; Osimertinib; Epidermal growth factor receptor mutation

Outcome Measures

Primary Outcomes (1)

• Clinical response rate

  The response assessment in neuro-oncology criteria (RANO) proposal for response criteria of leptomeningeal metastasis was used to assess the clinical response in this study.

  From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months.

Secondary Outcomes (2)

• Overall survival

  From the enrollment of this study until date of death from any cause, whichever came first, or the last follow-up (at least 7 months).

• Incidence of treatment-related adverse events

  From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months.

Study Arms (2)

Group A

EXPERIMENTAL

Intra-pemetrexed plus third-generation small molecule TKI drugs (e.g. 'osimertinib')

Drug: Osimertinib; Drug: Pemetrexed

Group B

ACTIVE COMPARATOR

Third-generation small molecule TKI drugs (e.g. 'osimertinib') alone

Drug: Osimertinib

Interventions

Osimertinib DRUG

Double-dose of TKI (e.g. 'osimertinib' 160 mg) was administered orally once daily until disease progression or unmanageable drug-related toxicity.

Group A; Group B

Pemetrexed DRUG

Pemetrexed 15 mg was administered with dexamethasone 5 mg via intraventricular or via lumbar puncture. First, induction intrathecal chemotherapy, twice per week for 2 weeks; then consolidation intrathecal chemotherapy, once per week for 4 weeks; and maintenance intrathecal chemotherapy, once per month until disease progression or unmanageable drug-related toxicity.

Group A

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female aged between 18 and 75 years.
• Histologically or cytologically confirmed diagnosis of NSCLC with single activating EGFR mutations (L858R or Exon19Del).
• Confirmed diagnosis of leptomeningeal metastasis according to ESMO/EANO guidelines.
• Normal liver and kidney function; WBC≥4000/mm3, Plt≥100000/mm3.
• No history of severe nervous system disease.
• No severe dyscrasia.

You may not qualify if:

• Any evidence of nervous system failure, including severe encephalopathy, grade 3 or 4 leukoencephalopathy on imaging, and Glasgow Coma Score less than 11.
• Any evidence of extensive and lethal progressive systemic diseases without effective treatment.
• Patients with poor compliance or other reasons that were unsuitable for this study.

Sponsors & Collaborators

• Guangzhou Medical University: lead

Study Sites (1)

The Third People's Hospital of Huizhou (Huizhou Hospital of Guangzhou Medical University)

Huizhou, Guangdong, China

RECRUITING

Related Publications (3)

• Pan Z, Yang G, He H, Cui J, Li W, Yuan T, Chen K, Jiang T, Gao P, Sun Y, Cong X, Li Z, Wang Y, Pang X, Song Y, Zhao G. Intrathecal pemetrexed combined with involved-field radiotherapy as a first-line intra-CSF therapy for leptomeningeal metastases from solid tumors: a phase I/II study. Ther Adv Med Oncol. 2020 Jul 17;12:1758835920937953. doi: 10.1177/1758835920937953. eCollection 2020.

  PMID: 32733606 BACKGROUND

• Pan Z, Yang G, Cui J, Li W, Li Y, Gao P, Jiang T, Sun Y, Dong L, Song Y, Zhao G. A Pilot Phase 1 Study of Intrathecal Pemetrexed for Refractory Leptomeningeal Metastases From Non-small-cell Lung Cancer. Front Oncol. 2019 Aug 30;9:838. doi: 10.3389/fonc.2019.00838. eCollection 2019.

  PMID: 31544065 BACKGROUND

• Yang JCH, Kim SW, Kim DW, Lee JS, Cho BC, Ahn JS, Lee DH, Kim TM, Goldman JW, Natale RB, Brown AP, Collins B, Chmielecki J, Vishwanathan K, Mendoza-Naranjo A, Ahn MJ. Osimertinib in Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study. J Clin Oncol. 2020 Feb 20;38(6):538-547. doi: 10.1200/JCO.19.00457. Epub 2019 Dec 6.

  PMID: 31809241 BACKGROUND

MeSH Terms

Conditions

Meningeal Carcinomatosis

Interventions

osimertinib; Pemetrexed

Condition Hierarchy (Ancestors)

Meningeal Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; 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

Zhenyu Pan

CONTACT

+8615804302753; dr-zypan@163.com

Guozi Yang

CONTACT

+8615804302755; guoziyang_1982@163.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: March 5, 2024
• First Posted: March 12, 2024
• Study Start: April 18, 2024
• Primary Completion (Estimated): June 20, 2026
• Study Completion (Estimated): September 1, 2026
• Last Updated: September 29, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Starting 6 months after publication.
• Access Criteria: Individual participant data will be public accessable via contacting with principal investigator by email within 6 months after the trial complete.

Locations

CN (1)