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

Plain English Summary

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 is a Phase 1 clinical trial sponsored by Cancer Institute and Hospital, Chinese Academy of Medical Sciences studying Non-Small Cell Lung Cancer, Metastatic Non-small Cell Lung Cancer, Liver Metastases, EGFR Gene Mutation, EGFR L858R. This trial tests a new gene-editing therapy called EDB-102 for advanced lung cancer that has spread to the liver. It is for patients with a specific genetic mutation (EGFR L858R) whose cancer has not responded to previous treatments. Participants will receive a single IV infusion of EDB-102, and their response and side effects will be closely monitored. Alternative treatments may include other targeted therapies, chemotherapy, or immunotherapy, depending on the patient's specific situation. The trial aims to enroll 15 participants.

Official 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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Adults aged 18 to 75 with non-small cell lung cancer that has spread to the liver. Patients must have a specific EGFR L858R gene mutation and have previously been treated with a third-generation EGFR-TKI (like osimertinib) without success. Individuals with other specific genetic changes in their cancer or who have had gene-editing therapies before cannot join. Good general health, including adequate organ function (liver, kidney, blood) and controlled blood pressure, is required. This trial is studying Non-Small Cell Lung Cancer, Metastatic Non-small Cell Lung Cancer, Liver Metastases, EGFR Gene Mutation, EGFR L858R, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcomes measure how safe the new drug is and if it causes any serious side effects, helping to determine the right dose for future studies. The specific primary outcome measures are: 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). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 1, the first major stage of clinical testing. Phase 1 trials typically involve 20-100 participants and focus on safety, dosage levels, and side effects. The primary goal is not to test whether the treatment works but to establish that it is safe enough for further testing. About 70% of Phase 1 drugs advance to Phase 2. If successful, the treatment will proceed to Phase 2 efficacy testing.

Why This Trial Matters

This trial addresses a critical need for new treatments for lung cancer patients with liver metastases who have developed resistance to current therapies, offering a novel gene-editing approach. This research targets Non-Small Cell Lung Cancer, Metastatic Non-small Cell Lung Cancer, Liver Metastases, EGFR Gene Mutation, EGFR L858R, where improved treatment options are needed.

Investor Insight

This Phase I trial represents an early-stage investment in a novel gene-editing technology for a significant unmet need in lung cancer, with potential for high impact if successful. Phase 1 trials have approximately a 10% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about the potential benefits and risks of EDB-102, and how it compares to other treatment options. Participation involves a single IV infusion and regular clinic visits for monitoring, including blood tests and scans. You will need to provide tumor tissue samples for analysis to confirm the gene mutation and assess the drug's effectiveness. The trial is being conducted at multiple sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NA
• Model: SINGLE_GROUP
• Masking: NONE
• Enrollment: 15 participants

Interventions

• 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 b

Primary Outcomes

• 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 Outcomes

• 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)

Full Eligibility Criteria

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.

Frequently Asked Questions

Related Conditions

• Non-Small Cell Lung Cancer
• Metastatic Non-small Cell Lung Cancer
• Liver Metastases
• EGFR Gene Mutation
• EGFR L858R
• Tyrosine Kinase Inhibitor Resistance
• Advanced Lung Cancer
• Oncology
• Gene Therapy
• Targeted Therapy

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