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

Обзор

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.

Подробное описание

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.

Вмешательства

• Генная терапия 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

Первичные конечные точки

• Adverse Events (AEs) and Serious Adverse Events (SAEs) [Срок оценки: AE monitoring throughout the study duration (up to 2 years post-dose).]
• Incidence of Dose-Limiting Toxicity (DLT) [Срок оценки: DLT observation period is 28 days after the first dose]

Вторичные конечные точки (3)

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

Критерии участия

Критерии включения

• 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).
• 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).
• ECOG performance status of 0 or 1.
• 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.
• Ability and willingness to provide written informed consent, comply with study procedures, and cooperate with study personnel.

Критерии исключения

• 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.
• Known allergy or adverse reaction to any lipid nanoparticle (LNP) components.
• Uncontrolled hypertension (systolic BP >150 mmHg and/or diastolic BP >100 mmHg despite regular antihypertensive therapy) or history of hypertensive crisis or hypertensive encephalopathy.
• Liver disease, including cirrhosis, hepatitis, or history of hepatitis B or C infection.
• Unstable angina or acute myocardial infarction, or history of these events within the past 6 months.
• History of malignancy within the past 5 years, except for treated basal cell carcinoma, cutaneous squamous cell carcinoma, cervical cancer, or gastrointestinal cancers.
• 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.
• 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.
• Any condition deemed by the investigator to make the subject unsuitable for participation in the study.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Идентификаторы

NCT: NCT07461727 · NCC6018/NCCH6018

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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