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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Non-Small Cell Lung Cancer; Liver Metastases; EGFR Gene Mutation; EGFR L858R; Metastatic Non-small Cell Lung Cancer
• Intervention / Treatment: Genetic: EDB-102

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.

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Shuhang Wang, PhD; Phone Number: 13581809307; Email: wangshuhang@cicams.ac.cn
• Study Contact Backup: Name: Aiwen Jian, Bachelor; Phone Number: 18259205792; Email: jaw_evin@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 and ≤75 years, any sex.
2. Histologically or cytologically confirmed, unresectable locally advanced or metastatic (stage IV) non-small cell lung cancer (NSCLC)
3. 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.
4. 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).
5. At least one measurable hepatic lesion per RECIST 1.1, confirmed by biopsy, with the EGFR L858R mutation verified in the lesion by central laboratory- or study site-validated methods (e.g., WES or RNAseq).
6. ECOG performance status of 0 or 1.
7. Adequate organ and bone marrow function: a) Hematologic: within 14 days prior to enrollment and without recent transfusion or growth factor therapy: ANC ≥1.5×10⁹/L, Hb ≥90 g/L, PLT ≥75×10⁹/L, WBC >3.0×10⁹/L. b) Hepatic: TBIL ≤1.5×ULN, ALT ≤5×ULN, AST ≤5×ULN. c) Renal: serum creatinine ≤1.5×ULN or creatinine clearance (CrCl) ≥50 mL/min. d) Coagulation: PT ≤1.5×ULN, APTT ≤1.5×ULN, INR ≤1.5×ULN.
8. Ability and willingness to provide written informed consent, comply with study procedures, and cooperate with study personnel.

Exclusion Criteria:

1. Prior exposure to any gene-editing therapies (e.g., CRISPR, TALEN, ZFN)
2. 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
3. Receipt of any investigational, unapproved therapy within 4 weeks prior to the first dose of study drug.
4. 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.
5. Known allergy or adverse reaction to any lipid nanoparticle (LNP) components.
6. Uncontrolled hypertension (systolic BP >150 mmHg and/or diastolic BP >100 mmHg despite regular antihypertensive therapy) or history of hypertensive crisis or hypertensive encephalopathy.
7. Liver disease, including cirrhosis, hepatitis, or history of hepatitis B or C infection.
8. Unstable angina or acute myocardial infarction, or history of these events within the past 6 months.
9. History of malignancy within the past 5 years, except for treated basal cell carcinoma, cutaneous squamous cell carcinoma, cervical cancer, or gastrointestinal cancers.
10. Pregnant, breastfeeding, positive pregnancy test, or unwillingness to use contraception in premenopausal women. Women are considered postmenopausal if amenorrheic for ≥2 years. Male patients unwilling to use contraception during the study are also excluded.
11. Leptomeningeal, brainstem, or spinal metastases, or active CNS metastases with compression. Subjects with previously treated brain metastases may participate if clinically stable ≥4 weeks prior to first study drug administration and off corticosteroids for ≥14 days.
12. Any condition deemed by the investigator to make the subject unsuitable for participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: EDB-102; Participants will receive a single intravenous infusion of EDB-102. This study follows a dose-escalation design with planned dose cohorts at 0.1 mg/kg, 0.3 mg/kg, and 0.6 mg/kg.

Genetic: EDB-102; 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).; 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.; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Adverse Events (AEs) and Serious Adverse Events (SAEs)	AE monitoring throughout the study duration (up to 2 years post-dose).
Incidence of Dose-Limiting Toxicity (DLT)	DLT observation period is 28 days after the first dose

Secondary Outcome Measures

Outcome Measure	Time Frame
Objective Response Rate (ORR)	Day 28 after administration, end of follow-up, and at early withdrawal.
EGFR Protein Expression Level	Baseline (Pre-dose) and Post-treatment (e.g., Day 21 or Day 28).
Knockout Efficiency of EGFR-L858R Mutant Gene	Baseline and Day 28 post-administration

Collaborators and Investigators

• Sponsor: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
• Investigators: Principal Investigator: Ning Li, PhD, Chinese Academy of Medical Sciences & Peking Union Medical College

Study record dates

Study Major Dates

• Study Start (Estimated): February 10, 2026
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 31, 2029

Study Registration Dates

• First Submitted: March 5, 2026
• First Submitted That Met QC Criteria: March 5, 2026
• First Posted (Actual): March 10, 2026

Study Record Updates

• Last Update Posted (Actual): March 10, 2026
• Last Update Submitted That Met QC Criteria: March 5, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: CRISPR-Cas9; TKI Resistance; EGFR L858R; Lipid Nanoparticles (LNP); EDB-102; In vivo Gene Editing; Osimertinib Resistance
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: NCC6018/NCCH6018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No