NCT07461727

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

• Status: Not Yet Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 15 (estimated)
• Sponsor: Cancer Institute and Hospital, Chinese Academy of Medical Sciences · Academic / Other
• Sex: All
• Age: 18 Years – 65 Years
• Healthy volunteers: Not accepted

Summary

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.

Detailed description

This is a single-center, open-label, single-arm, dose-escalation Phase I clinical study designed to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of EDB-102 Injection in patients with EGFR-L858R mutation-positive advanced NSCLC and liver metastases who have progressed on or are intolerant to third-generation EGFR-TKIs. Study Drug and Mechanism: EDB-102 utilizes the CRISPR-Cas9 gene-editing system delivered via lipid nanoparticles (LNPs). The sgRNA is designed to target the NGG PAM sequence generated specifically by the T\>G mutation at the EGFR L858R locus, ensuring high specificity for the mutant allele while sparing the wild-type EGFR. The LNP carrier facilitates delivery primarily to the liver, leveraging the ApoE-mediated endogenous targeting mechanism. Study Design: The study consists of a Dose Escalation Phase and a potential Expansion Phase. Dose Escalation: A modified "3+3" design will be used combined with an initial accelerated titration for the lowest dose. Three dose levels are planned: 0.1 mg/kg, 0.3 mg/kg, and 0.6 mg/kg. Accelerated Titration: For the low-dose cohort (0.1 mg/kg), single-patient cohorts may be used initially. If safety signals (≥ Grade 2 AE) occur, the design switches to standard 3+3. Standard 3+3: For intermediate and high doses (0.3 mg/kg and above), cohorts will enroll 3 to 6 patients. Dose escalation proceeds based on the incidence of Dose-Limiting Toxicities (DLTs) observed during the 28-day DLT observation period. Expansion Phase: Once the Maximum Tolerated Dose (MTD) is identified, an expansion cohort may be enrolled at the MTD level to further evaluate safety and PK/PD. Intervention: Eligible patients will receive a mandatory premedication regimen (corticosteroids, H1/H2 receptor antagonists) to mitigate infusion-related reactions. EDB-102 is administered as a single intravenous infusion over 2 hours. In the expansion phase, a multi-dose regimen (e.g., Q4W) may be explored based on safety data. Key Assessments: Safety: Monitoring of Adverse Events (AEs), SAEs, and DLTs according to CTCAE v5.0. Special attention is paid to infusion-related reactions (IRR), cytokine release syndrome (CRS), and liver toxicity. Efficacy: Tumor response assessment using RECIST 1.1 at Day 21, Week 24, and subsequent visits. Pharmacodynamics: Pre- and post-treatment liver tumor biopsies will be collected to quantify gene knockout efficiency (Indel frequency) via Next-Generation Sequencing (NGS) and to assess EGFR protein reduction via IHC. Off-target effects will be monitored using high-depth sequencing. Immunogenicity: Measurement of anti-Cas9 and anti-LNP antibodies.

Conditions

• Non-Small Cell Lung Cancer
• Metastatic Non-small Cell Lung Cancer
• Liver Metastases
• EGFR Gene Mutation
• EGFR L858R

Interventions

Type	Name	Description
GENETIC	EDB-102	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.

Timeline

• Start date: 2026-02-10
• Primary completion: 2027-01-01
• Completion: 2029-01-31
• First posted: 2026-03-10
• Last updated: 2026-03-10