A Phase 1/2, Open-label, Biomarker-guided Study of Dual-target Chimeric Antigen Receptor Natural Killer (CAR-NK) Cells Targeting Mesothelin (MSLN) With EGFR or HER2/ERBB2, or EGFR With HER2/ERBB2, in Participants With Advanced/Metastatic Non-small Cell Lung Cancer (NSCLC)
概览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- Beijing Biotech
- 入组人数
- 48
- 试验地点
- 1
- 主要终点
- Incidence of dose-limiting toxicities (DLTs)
概览
简要总结
This is a two-part, biomarker-guided Phase 1/2 study evaluating the safety, feasibility, and preliminary anti-tumor activity of off-the-shelf dual-target CAR-NK cells in participants with advanced or metastatic NSCLC whose tumors co-express at least two of the following antigens: Mesothelin (MSLN), EGFR, and HER2/ERBB2.
Participants will receive lymphodepleting chemotherapy followed by infusion of the CAR-NK product matched to their tumor antigen profile. A data-driven interim assessment will be used to select the most suitable construct for expansion.
详细描述
The study includes Part A (dose escalation) and Part B (dose expansion). In Part A, participants are assigned to one of three dual-target CAR-NK constructs based on tumor antigen co-expression (IHC and/or RNA profiling): MSLN/EGFR, MSLN/HER2, or EGFR/HER2. Dose escalation within each construct follows a standard 3+3 design to identify a recommended Phase 2 dose (RP2D). In Part B, the study expands at the RP2D and may adaptively prioritize the construct demonstrating the most favorable benefit-risk profile (e.g., acceptable safety with early signals of response). Key exploratory objectives include CAR-NK persistence, immune pharmacodynamics, cytokine profiling, and correlations between antigen density and clinical outcomes. This document is an example ClinicalTrials.gov-style registration template for planning purposes only and is not an actual registered study
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically or cytologically confirmed NSCLC that is unresectable Stage IIIB/IIIC or Stage IV, with radiographic progression on or after standard-of-care therapy (including platinum-based chemotherapy and immune checkpoint inhibitor when appropriate).
- •At least one measurable lesion per RECIST v1.
- •Archival tumor tissue available (or willingness to undergo a fresh biopsy) for antigen testing.
- •Tumor co-expression of at least two of the following antigens at screening: MSLN, EGFR, HER2/ERBB
- •Example thresholds: IHC ≥2+ in ≥50% of tumor cells for each required antigen (or an equivalent RNA expression threshold).
- •ECOG performance status 0-
- •Adequate organ function (hematologic, hepatic, renal) as defined by protocol laboratory limits.
- •Life expectancy ≥12 weeks.
- •Negative pregnancy test for individuals of childbearing potential; agreement to use effective contraception for the study-defined period.
- •Ability to understand and willingness to sign written informed consent.
排除标准
- •Active, uncontrolled central nervous system (CNS) metastases. Participants with previously treated/stable CNS disease may be eligible if clinically stable and off high-dose corticosteroids.
- •Prior gene-modified cellular therapy (e.g., CAR-T, CAR-NK, TCR-T) within 3 months, or any prior therapy that in the investigator's judgment increases risk of severe toxicity.
- •History of severe cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) with prior therapies.
- •Clinically significant interstitial lung disease or pneumonitis requiring systemic steroids, or uncontrolled pulmonary comorbidity that would confound toxicity monitoring.
研究组 & 干预措施
EB-DuoNK-MSLN/EGFR
Participants with tumors co-expressing MSLN and EGFR (meeting screening thresholds) receive lymphodepletion followed by EB-DuoNK-MSLN/EGFR infusion at the assigned dose level.
干预措施: Dual-target CAR-NK cells (Biological)
EB-DuoNK-MSLN/EGFR
Participants with tumors co-expressing MSLN and EGFR (meeting screening thresholds) receive lymphodepletion followed by EB-DuoNK-MSLN/EGFR infusion at the assigned dose level.
干预措施: Lymphodepleting chemotherapy (Drug)
EB-DuoNK-MSLN/EGFR
Participants with tumors co-expressing MSLN and EGFR (meeting screening thresholds) receive lymphodepletion followed by EB-DuoNK-MSLN/EGFR infusion at the assigned dose level.
干预措施: Supportive Care (Other)
EB-DuoNK-MSLN/HER2
Participants with tumors co-expressing MSLN and HER2/ERBB2 receive lymphodepletion followed by EB-DuoNK-MSLN/HER2 infusion at the assigned dose level.
干预措施: Dual-target CAR-NK cells (Biological)
EB-DuoNK-MSLN/HER2
Participants with tumors co-expressing MSLN and HER2/ERBB2 receive lymphodepletion followed by EB-DuoNK-MSLN/HER2 infusion at the assigned dose level.
干预措施: Lymphodepleting chemotherapy (Drug)
EB-DuoNK-MSLN/HER2
Participants with tumors co-expressing MSLN and HER2/ERBB2 receive lymphodepletion followed by EB-DuoNK-MSLN/HER2 infusion at the assigned dose level.
干预措施: Supportive Care (Other)
EB-DuoNK-EGFR/HER2
Participants with tumors co-expressing EGFR and HER2/ERBB2 receive lymphodepletion followed by EB-DuoNK-EGFR/HER2 infusion at the assigned dose level.
干预措施: Dual-target CAR-NK cells (Biological)
EB-DuoNK-EGFR/HER2
Participants with tumors co-expressing EGFR and HER2/ERBB2 receive lymphodepletion followed by EB-DuoNK-EGFR/HER2 infusion at the assigned dose level.
干预措施: Lymphodepleting chemotherapy (Drug)
EB-DuoNK-EGFR/HER2
Participants with tumors co-expressing EGFR and HER2/ERBB2 receive lymphodepletion followed by EB-DuoNK-EGFR/HER2 infusion at the assigned dose level.
干预措施: Supportive Care (Other)
结局指标
主要结局
Incidence of dose-limiting toxicities (DLTs)
时间窗: 28 Days
Objective response rate (ORR)
时间窗: 6 months
次要结局
- Duration of response (DOR) per RECIST v1.1.(12 months)
- Progression-free survival (PFS).(12 months)
- Overall survival (OS)(24 months)