A Phase 1/2, Open-label, Multicenter Study of Allogeneic Dual-target CLDN18.2/HER2 (ERBB2) CAR-NK Cells After Fludarabine/Cyclophosphamide Lymphodepletion in
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Incidence of dose-limiting toxicities (DLTs)
研究概览
简要总结
This example planning study proposes a phase 1/2 evaluation of an allogeneic, cord-blood-derived dual-target CAR-NK product directed against CLDN18.2 and HER2 (ERBB2) in adults with unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma after prior standard systemic therapy. CLDN18.2 is selected as the anchor antigen because it has the more disease-specific gastric/GEJ cell-therapy development footprint, while HER2 is retained as the complementary second antigen to address co-expressing or heterogeneous disease. Phase 1 uses a 3+3 dose-escalation design after fludarabine/cyclophosphamide lymphodepletion followed by three intravenous CAR-NK infusions on Days 0, 3, and 7. Phase 2 expansion evaluates the recommended phase 2 dose and preliminary antitumor activity
详细描述
This draft is intentionally modeled on current CLDN18.2- and HER2-directed cell-therapy studies on ClinicalTrials.gov and related primary publications. The key strategic choice is that HER2 and ERBB2 are treated as the same target; therefore the meaningful dual-target construct in gastric/GEJ cancer is CLDN18.2 plus HER2. The study is designed as a biomarker-driven, non-randomized phase 1/2 program. In phase 1, patients will receive fludarabine/cyclophosphamide lymphodepletion on Days -5 to -3, followed by three infusions of EB-DT-CAR-NK on Days 0, 3, and 7. A 3+3 dose-escalation structure with three planned dose levels will be used to determine dose-limiting toxicities, maximum tolerated dose, and/or recommended phase 2 dose.
In phase 2, patients will receive the recommended dose on the same schedule in an expansion cohort focused on CLDN18.2-positive gastric/GEJ adenocarcinoma, with prespecified subgroup analyses by HER2 status. The study will assess safety, objective response rate, disease control, durability, survival outcomes, and CAR-NK expansion/persistence. Correlative studies will explore the relationship between baseline CLDN18.2/HER2 expression and clinical outcome.
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
No masking is planned. Investigators, site staff, and participants will know cohort assignment because all enrolled patients receive the active cellular product and are assigned according to dose level or expansion stage.
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
- •Signed informed consent before any study-specific procedure.
- •Age 18 to 75 years.
- •Histologically confirmed unresectable locally advanced or metastatic gastric adenocarcinoma or gastroesophageal junction adenocarcinoma.
- •Central confirmation of CLDN18.2-positive disease by immunohistochemistry, defined for this draft as membranous CLDN18.2 expression in at least 10% of tumor cells. HER2 testing is required for all subjects; HER2-positive disease is defined as IHC 3+ or IHC 2+/ISH+ using gastric/GEJ testing criteria.
- •Disease progression after at least 2 prior systemic regimens for advanced disease, including a fluoropyrimidine and platinum agent unless contraindicated or not tolerated. If HER2-positive, prior HER2-directed therapy is expected unless unavailable, contraindicated, or not tolerated.
- •At least 1 measurable lesion according to RECIST v1.
- •ECOG performance status 0 or
- •Life expectancy of at least 12 weeks.
- •Adequate hematologic, renal, hepatic, pulmonary, and cardiac function.
- •Recovery of prior treatment-related toxicities to Grade 1 or baseline, except alopecia or stable endocrine replacement therapy.
- •Willingness to provide archival tumor tissue or fresh biopsy material if archival tissue is inadequate for central biomarker confirmation.
- •Negative pregnancy test for women of childbearing potential and agreement to use effective contraception during the protocol-defined period
排除标准
- •Prior CLDN18.2-targeted or HER2-targeted genetically modified cell therapy (CAR-T, CAR-NK, TCR-T, or similar).
- •Active or untreated central nervous system metastases or leptomeningeal disease.
- •Active uncontrolled infection, including uncontrolled HBV, HCV, or HIV viremia.
- •Active autoimmune disease requiring systemic immunosuppression.
- •Clinically significant uncontrolled cardiovascular disease, including recent myocardial infarction, unstable angina, uncontrolled arrhythmia, or severe heart failure.
- •Active gastrointestinal perforation, uncontrolled upper GI bleeding, clinically significant bowel obstruction, or unstable gastric ulcer.
- •History of solid-organ transplantation or prior allogeneic hematopoietic stem-cell transplantation with active graft-versus-host disease.
- •Requirement for systemic corticosteroids above physiologic replacement (for example, >10 mg/day prednisone equivalent) within 7 days before lymphodepletion.
- •Pregnancy or breastfeeding.
- •Another active malignancy requiring systemic therapy, except for adequately treated non-melanoma skin cancer, carcinoma in situ, or other protocol-allowed low-risk malignancies.
- •Any medical, psychiatric, or social condition that, in the investigator's judgment, would make study participation unsafe or would interfere with interpretation of study results.
研究组 & 干预措施
Dose Escalation Cohort
Participants receive fludarabine and cyclophosphamide lymphodepletion on Days -5 to -3, followed by EB-DT-CAR-NK infusions on Days 0, 3, and 7. Three planned dose levels are explored using a 3+3 design.
干预措施: EB-DT-CAR-NK (Biological)
Dose Escalation Cohort
Participants receive fludarabine and cyclophosphamide lymphodepletion on Days -5 to -3, followed by EB-DT-CAR-NK infusions on Days 0, 3, and 7. Three planned dose levels are explored using a 3+3 design.
干预措施: Fludarabine (Drug)
Dose Escalation Cohort
Participants receive fludarabine and cyclophosphamide lymphodepletion on Days -5 to -3, followed by EB-DT-CAR-NK infusions on Days 0, 3, and 7. Three planned dose levels are explored using a 3+3 design.
干预措施: Cyclophosphamide (Drug)
Dose Expansion Cohort
Participants receive the recommended phase 2 dose (RP2D) on the same lymphodepletion and infusion schedule. Expansion is centered on CLDN18.2-positive gastric/GEJ adenocarcinoma, with HER2 status captured for exploratory subgroup analysis.
干预措施: EB-DT-CAR-NK (Biological)
Dose Expansion Cohort
Participants receive the recommended phase 2 dose (RP2D) on the same lymphodepletion and infusion schedule. Expansion is centered on CLDN18.2-positive gastric/GEJ adenocarcinoma, with HER2 status captured for exploratory subgroup analysis.
干预措施: Fludarabine (Drug)
Dose Expansion Cohort
Participants receive the recommended phase 2 dose (RP2D) on the same lymphodepletion and infusion schedule. Expansion is centered on CLDN18.2-positive gastric/GEJ adenocarcinoma, with HER2 status captured for exploratory subgroup analysis.
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
Incidence of dose-limiting toxicities (DLTs)
时间窗: 28 days
DLTs graded by CTCAE v5.0, with CRS and ICANS graded using ASTCT criteria.
Determination of MTD
时间窗: 6 months
Dose-escalation decision based on DLT frequency and overall tolerability across planned cohorts.
Objective response rate (ORR)
时间窗: 12 months
Confirmed complete response plus partial response according to RECIST v1.1 in evaluable subjects in the expansion cohort.
次要结局
- Progression-free survival (PFS)(12 months)
- Overall survival (OS)(24 months)