A Phase 1/2 Biomarker-Guided Platform Study of Allogeneic Donor-Derived Single-Target or Dual-Target CAR-NK Cell Therapy Selected by Tumor Antigen Profiling (Liquid Biopsy and/or Tissue Biopsy) in Participants With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Dose- limiting toxicities
研究概览
简要总结
This Phase 1/2, open-label, biomarker-guided platform study evaluates the safety, tolerability, and preliminary anti-tumor activity of banked allogeneic donor-derived chimeric antigen receptor natural killer (CAR-NK) cells in adults with advanced solid tumors. During screening, tumor antigen profiling is performed using tissue biopsy and/or liquid biopsy (circulating tumor DNA and/or circulating tumor cells).
Participants are assigned to receive either a single-target CAR-NK product (matched to the dominant tumor antigen) or a dual-target CAR-NK product (matched to two co-expressed antigens) to reduce the risk of antigen escape.
详细描述
This example trial is designed to reflect common elements of early-phase CAR-NK studies in solid tumors, including dose escalation followed by expansion cohorts, open-label safety monitoring, and response assessment using standard radiologic criteria. Similar solid-tumor CAR-NK studies on ClinicalTrials.gov include trials targeting TROP2 (NCT06066424), NKG2D ligands (NCT03415100), and multi-target CAR-NK platforms that evaluate different antigens such as CLDN6, GPC3, mesothelin, or AXL (NCT05410717).
Antigen selection workflow (precision matching):
- Obtain tumor tissue biopsy (preferred) and/or blood for liquid biopsy at screening.
- Assess antigen expression using a prespecified panel (example panel: mesothelin, TROP2, HER2, MUC1, CLDN18.2, B7-H3/CD276, AXL, GPC3, CLDN6, EGFR).
- Assign participant to: (a) single-target cohort if one antigen meets the threshold; or (b) dual-target cohort if two antigens meet thresholds or if the investigator judges high risk of antigen heterogeneity.
- Select the matched cryopreserved allogeneic donor-derived CAR-NK product from a manufacturing bank and schedule treatment. Treatment overview: Participants receive lymphodepleting chemotherapy (e.g., fludarabine/cyclophosphamide) followed by one or more infusions of CAR-NK cells. Cytokine support (e.g., low-dose IL-2 or IL-15 agonist per institutional practice) may be given to promote CAR-NK persistence. Participants are monitored closely for cytokine release syndrome (CRS), neurotoxicity, infusion reactions, and other adverse events. Tumor imaging is performed at prespecified intervals during the first 6 months and then less frequently during follow-up.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Open-label due to the nature of cell therapy administration and the need for real-time safety monitoring.
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
- •Age 18 to 75 years at the time of consent.
- •Histologically or cytologically confirmed advanced or metastatic solid tumor that is refractory to, relapsed after, or intolerant of standard therapy, or for which no standard therapy exists.
- •At least 1 measurable lesion per RECIST v1.
- •Tumor antigen positivity documented by tissue biopsy and/or liquid biopsy using a protocol-specified assay; for dual-target cohort: co-expression of both antigens above threshold.
- •ECOG performance status 0-
- •Adequate organ function (hematologic, renal, hepatic) as defined by protocol labs.
- •Ability to undergo lymphodepleting chemotherapy (if required) and receive IV cell infusion.
- •Negative pregnancy test for individuals of childbearing potential; agreement to use effective contraception during study participation and for a protocol-defined period after infusion.
- •Willingness to provide baseline blood samples and, when feasible, tumor biopsy for biomarker analyses.
排除标准
- •Active, uncontrolled infection, including uncontrolled bacterial, fungal, or viral infection.
- •Known uncontrolled HIV infection; active hepatitis B or hepatitis C with evidence of active replication (per local testing).
- •Clinically significant cardiovascular disease (e.g., recent myocardial infarction, uncontrolled arrhythmia) that would increase risk from lymphodepletion or infusion.
- •Active central nervous system (CNS) metastases that are symptomatic or require escalating steroids.
- •(Stable treated CNS disease may be allowed per protocol.)
- •Current systemic immunosuppressive therapy (e.g., >10 mg/day prednisone equivalent) within a protocol-defined window prior to lymphodepletion.
- •Prior gene-modified cellular therapy within 3 months or any prior therapy that, in the investigator's judgment, would confound safety evaluation.
- •Prior allogeneic hematopoietic stem cell transplant within 6 months, or active graft-versus-host disease.
- •Pregnant or breastfeeding.
- •Any condition that, in the investigator's opinion, would interfere with study participation, compliance, or interpretation of results.
研究组 & 干预措施
Arm A: Single-target precision-matched CAR-NK
Participants with a single dominant tumor antigen (above a prespecified threshold) receive a matched single-target CAR-NK product manufactured from a healthy donor NK-cell source.
干预措施: EB-PT-CAR-NK-S (Biological)
Arm A: Single-target precision-matched CAR-NK
Participants with a single dominant tumor antigen (above a prespecified threshold) receive a matched single-target CAR-NK product manufactured from a healthy donor NK-cell source.
干预措施: EB-PT-CAR-NK-D (Biological)
Arm A: Single-target precision-matched CAR-NK
Participants with a single dominant tumor antigen (above a prespecified threshold) receive a matched single-target CAR-NK product manufactured from a healthy donor NK-cell source.
干预措施: Lymphodepleting chemotherapy (Drug)
Arm A: Single-target precision-matched CAR-NK
Participants with a single dominant tumor antigen (above a prespecified threshold) receive a matched single-target CAR-NK product manufactured from a healthy donor NK-cell source.
干预措施: Cytokine support (Drug)
Arm B: Dual-target precision-matched CAR-NK
Participants with co-expression of two target antigens (or high antigen heterogeneity) receive a dual-target CAR-NK product designed to recognize both antigens (e.g., tandem CAR or bicistronic CAR configuration).
干预措施: EB-PT-CAR-NK-S (Biological)
Arm B: Dual-target precision-matched CAR-NK
Participants with co-expression of two target antigens (or high antigen heterogeneity) receive a dual-target CAR-NK product designed to recognize both antigens (e.g., tandem CAR or bicistronic CAR configuration).
干预措施: EB-PT-CAR-NK-D (Biological)
Arm B: Dual-target precision-matched CAR-NK
Participants with co-expression of two target antigens (or high antigen heterogeneity) receive a dual-target CAR-NK product designed to recognize both antigens (e.g., tandem CAR or bicistronic CAR configuration).
干预措施: Lymphodepleting chemotherapy (Drug)
Arm B: Dual-target precision-matched CAR-NK
Participants with co-expression of two target antigens (or high antigen heterogeneity) receive a dual-target CAR-NK product designed to recognize both antigens (e.g., tandem CAR or bicistronic CAR configuration).
干预措施: Cytokine support (Drug)
结局指标
主要结局
Dose- limiting toxicities
时间窗: 28 days
Dose limiting toxicities refer to specific adverse events or side effects that prevent further dose escalation of an investigational drug or therapy in a clinical trial. DLTs are pre-defined based on severity, duration, and impact on patient safety, typically graded according to established criteria such as the Common Terminology Criteria for Adverse Events (CTCAE). Monitoring DLTs is a critical outcome measure in early-phase (Phase I/II) studies, as it helps determine the maximum tolerated dose (MTD) and guides safe dosing for subsequent trial phases.
次要结局
未报告次要终点