Phase 1/2, Biomarker-guided, Open-label Study of Allogeneic Dual-target CAR-NK Cells Directed Against HER2/ERBB2, MUC1, and/or ROR1 in Patients With Advanced or Metastatic Breast Cancer (Including HER2-positive and Triple-negative Disease).
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
- Incidence of dose-limiting toxicities (DLTs)
研究概览
简要总结
This study tests the safety and preliminary anti-tumor activity of an investigational dual-target chimeric antigen receptor natural killer (CAR-NK) cell therapy in adults with advanced breast cancer. After a tumor antigen assessment (HER2/ERBB2, MUC1, ROR1, and in some TNBC cases mesothelin), each participant will receive the most suitable dual-target CAR-NK product for their tumor profile, following short-course lymphodepleting chemotherapy.
详细描述
Natural killer (NK) cells can recognize and kill abnormal cells as part of the innate immune system. CAR engineering can enhance NK-cell recognition of tumor-associated antigens and may improve anti-tumor activity in solid tumors. This is a two-part, first-in-program study. Part A uses dose escalation to identify a safe and feasible dose of a dual-target CAR-NK cell product. Part B evaluates preliminary efficacy in biomarker-defined expansion cohorts for HER2-positive breast cancer and triple-negative breast cancer (TNBC).
Target selection is biomarker-guided. A fresh or archival tumor sample is tested by immunohistochemistry (IHC) for HER2/ERBB2, MUC1, and ROR1 expression. Participants are assigned to one of three dual-target CAR-NK constructs based on a predefined algorithm prioritizing highest and most homogeneous target expression. In TNBC, mesothelin testing may be performed to support an exploratory sub-cohort.
All participants receive lymphodepleting chemotherapy (fludarabine + cyclophosphamide) before CAR-NK infusion. The CAR-NK product is an allogeneic, cryopreserved NK-cell therapy engineered to express a dual-specific CAR and an inducible safety switch; the product is administered intravenously.
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 design; no blinding of participants, investigators, or outcome assessors.
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 confirmed breast carcinoma that is locally advanced, unresectable, or metastatic.
- •Disease subtype: HER2-positive breast cancer or triple-negative breast cancer (TNBC).
- •Progression after, intolerance to, or ineligibility for standard therapies appropriate for the disease subtype and line of therapy.
- •At least one measurable lesion per RECIST v1.
- •Tumor antigen assessment available (fresh or archival): expression of at least one candidate target antigen (HER2/ERBB2, MUC1, or ROR1). For TNBC, mesothelin assessment may be performed for exploratory analyses.
- •ECOG performance status 0-
- •Adequate organ function (example thresholds): ANC ≥ 1.0 x 10^9/L; platelets ≥ 75 x 10^9/L; hemoglobin
- •8 g/dL; AST/ALT ≤ 3x ULN (≤ 5x with liver metastases); total bilirubin ≤ 1.5x ULN; creatinine clearance
- •50 mL/min.
- •Left ventricular ejection fraction (LVEF) ≥ 45% and no uncontrolled cardiac arrhythmia.
- •Negative pregnancy test for participants of childbearing potential; agreement to use effective contraception during study treatment and for 6 months after last CAR-NK infusion.
- •Ability to understand and willingness to sign informed consent.
排除标准
- •Active, untreated central nervous system (CNS) metastases or leptomeningeal disease. Patients with treated CNS metastases may be eligible if clinically stable for ≥ 4 weeks and off high-dose steroids.
- •Prior gene-modified cellular therapy (e.g., CAR-T or CAR-NK) within 6 months or unresolved grade ≥ 2 toxicity from prior cellular therapy.
- •Clinically significant active autoimmune disease requiring systemic immunosuppression (physiologic steroid replacement permitted).
- •Uncontrolled infection, including uncontrolled HBV, HCV, or HIV infection (controlled infections may be eligible per investigator).
- •History of severe hypersensitivity to fludarabine or cyclophosphamide.
- •Pregnant or breastfeeding.
- •Concurrent participation in another interventional study that could confound safety or efficacy assessments.
- •Any condition that, in the investigator's judgment, would make the participant unsuitable for the study (e.g., uncontrolled comorbidity, inability to comply with protocol procedures).
结局指标
主要结局
Incidence of dose-limiting toxicities (DLTs)
时间窗: 28 Days
Incidence of dose-limiting toxicities (DLTs) (including cytokine release syndrome and neurotoxicity) graded by CTCAE v5.0 and ASTCT consensus criteria for CRS/ICANS
Safety profile
时间窗: 12 months
Safety profile by type, frequency, severity, and relatedness of treatment-emergent adverse events (AEs) and serious AEs.
Recommended Phase 2 Dose
时间窗: 56 days
Recommended Phase 2 Dose (RP2D) based on DLTs, overall safety, and biologic activity (CAR-NK expansion/persistence).
次要结局
- Objective response rate (ORR) by RECIST v1.1 (and iRECIST, if immunotherapy response patterns are suspected).(12 months)
- Disease control rate (DCR)(12 months)
- Duration of response (DoR).(24 months)
- Progression-free survival (PFS)(24 months)
- Overall survival (OS)(24 months)