An Open-Label, Single-Arm, Dose-Escalation Phase I Study Evaluating the Safety, Tolerability, and Preliminary Efficacy of EDB-102 in Patients With EGFR L858R-Mutant, Third-Generation TKI-Resistant Advanced Non-Small Cell Lung Cancer With Liver Metastases
SponsorCancer Institute and Hospital, Chinese Academy of Medical Sciences
About this trial
The purpose of this study is to evaluate the safety, tolerability, and preliminary efficacy of EDB-102 Injection in patients with advanced non-small cell lung cancer (NSCLC) who have liver metastases. The study specifically targets patients harboring the EGFR-L858R mutation who have disease progression after treatment with third-generation EGFR tyrosine kinase inhibitors (TKIs, e.g., osimertinib).
EDB-102 is a novel in vivo gene-editing therapy. It consists of CRISPR-Cas9 mRNA and a single-guide RNA (sgRNA) encapsulated in lipid nanoparticles (LNPs). The drug is designed to specifically identify and disrupt the mutant EGFR-L858R gene in tumor cells, thereby inhibiting tumor growth. Due to the liver-targeting properties of the LNP carrier, this therapy is particularly aimed at patients with liver metastases.
This is a Phase I, open-label, dose-escalation study. Participants will receive a single intravenous (IV) infusion of EDB-102. The study will follow a "3+3" design to determine the maximum tolerated dose (MTD) and the recommended Phase II dose (RP2D). Participants will be monitored for adverse events, and tumor biopsies will be collected to assess the gene-editing efficiency of the drug.
Eligibility criteria
Qualifiers
Age ≥18 and ≤75 years, any sex.
Histologically or cytologically confirmed, unresectable locally advanced or metastatic (stage IV) non-small cell lung cancer (NSCLC)
Prior treatment with at least one third-generation EGFR-TKI (e.g., osimertinib) with radiologically confirmed disease progression according to RECIST 1.1 or intolerance, and no concomitant anticancer therapy during this period.
Availability of tumor tissue obtained after progression on third-generation EGFR-TKI, with EGFR L858R mutation confirmed in the post-progression tumor tissue or blood sample by central laboratory- or study site-validated methods (e.g., WES or RNAseq).
Disqualifiers
Prior exposure to any gene-editing therapies (e.g., CRISPR, TALEN, ZFN)
Receipt of chemotherapy, radiotherapy, biologic therapy, endocrine therapy, targeted therapy, immunotherapy, or other anticancer agents within 4 weeks prior to the first dose of study drug. For oral fluoropyrimidines or small-molecule targeted agents, the washout period is 2 weeks or 5 half-lives of the drug, whichever is longer
Receipt of any investigational, unapproved therapy within 4 weeks prior to the first dose of study drug.
Presence of other known driver gene alterations conferring TKI resistance, excluding EGFR mutations, unless these occur as co-mutations, including: Bypass pathway activation: High-level MET amplification: detected by WES (gene copy number >5) or FISH (MET/CEP7 ratio ≥2.0). High-level HER2 amplification: detected by ISH (gene copy number ≥6 per nucleus, HER2/CEP17 ratio ≥2.0). Other acquired resistance driver mutations: Newly emerged confirmed resistance mutations, e.g., KRAS or BRAF-V600E. Activating mutations in PI3K/AKT/mTOR pathway genes (e.g., PIK3CA). Loss of primary EGFR mutation: absence of the original EGFR L858R mutation in post-resistance tumor tissue.
Trial design
Treatments tested in this trial
EDB-102
Treatment groups
15 Participants
are divided into 1 treatment group
Locations
This trial has no locations
Sponsors and collaborators
Cancer Institute and Hospital, Chinese Academy of Medical Sciences