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
This trial does not accept healthy volunteers
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
Design model
Single group
Treatments tested in this trial
EDB-102
Genetic
1. Premedication:
To reduce immune and infusion-related reactions to the LNP vector, subjects must receive one of the following before dosing: (i) IV corticosteroid (e.g., dexamethasone 10 mg or equivalent); (ii) H1 antagonist, IV (e.g., diphenhydramine 20 mg) or oral (e.g., cetirizine 10 mg); or (iii) H2 antagonist, IV or oral (e.g., famotidine 20 mg).
2. Intervention:
The investigational product will be administered by 2-hour IV infusion. If infusion reactions occur, the infusion may be slowed or extended, but total time from vial opening to completion must not exceed 4 hours. Subjects will be hospitalized for ≥96 hours post-dose; observation may be prolonged if clinically indicated.
3. Frequency:
Dose Escalation: Single IV dose on Day 0, followed by a 28-day DLT observation period.
Dose Expansion (post-MTD): Q4W dosing for up to 3 cycles, subject to safety data.
Treatment groups
15 Participants
are divided into 1 treatment group
Group A: EDB-102Experimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame
AE monitoring throughout the study duration (up to 2 years post-dose).
2
Incidence of Dose-Limiting Toxicity (DLT)
Time frame
DLT observation period is 28 days after the first dose
Secondary outcomes
1
Objective Response Rate (ORR)
Time frame
Day 28 after administration, end of follow-up, and at early withdrawal.
2
EGFR Protein Expression Level
Time frame
Baseline (Pre-dose) and Post-treatment (e.g., Day 21 or Day 28).
3
Knockout Efficiency of EGFR-L858R Mutant Gene
Time frame
Baseline and Day 28 post-administration
Other outcomes
Locations
This trial has no locations.
Sponsors and contacts
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