A Phase 1/2, Open-Label, Dose-Escalation and Dose-Expansion Study of Allogeneic Dual-Target GPC3/B7-H3 (CD276) Chimeric Antigen Receptor Natural Killer Cells in Adults With Unresectable, Relapsed/Refractory, or Metastatic Hepatocellular Carcinoma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Incidence of dose-limiting toxicities (DLTs)
研究概览
简要总结
open-label trial of an allogeneic dual-target CAR-NK product directed against GPC3 and B7-H3 for adults with advanced hepatocellular carcinoma. The design intentionally uses GPC3 as the primary target anchor because GPC3 is the dominant HCC cell-therapy antigen in current clinical development, while adding B7-H3 to reduce antigen escape and to broaden coverage across tumor and tumor-microenvironment compartments. The study first evaluates safety and dose-limiting toxicities, then expands at the recommended phase 2 dose.
详细描述
Hepatocellular carcinoma (HCC) remains a high-mortality solid tumor, and many patients progress after or are not candidates for surgery, transplant, locoregional therapy, immune-checkpoint inhibitors, or tyrosine-kinase inhibitors.
Among HCC-associated cell-surface targets, GPC3 has the strongest disease-specific cell-therapy track record and is widely used as the anchor antigen in HCC CAR-T programs. However, not all HCCs express GPC3 uniformly, and loss or low-density expression may contribute to resistance and escape. B7-H3 is an attractive secondary co-target because it is frequently expressed in HCC tumor and stromal/vascular compartments, is associated with immune suppression and aggressive biology, and may complement GPC3 when antigen heterogeneity is present.
The investigational product in this draft is an allogeneic donor-derived peripheral blood NK-cell product genetically engineered to express a dual-target CAR recognizing GPC3 and B7-H3. To keep this example realistic and conservative, the core registration fields below assume a standard dual-target CAR-NK product plus fludarabine/cyclophosphamide lymphodepletion. If the sponsor later prefers an armored platform , those features can be added in a subsequent protocol version or IND-enabling package.
The study is structured as a phase 1/2 single-group trial. Phase 1 uses dose-escalation to determine safety, the recommended phase 2 dose (RP2D), and feasibility. Phase 2 expands at the RP2D to estimate preliminary anti-tumor activity. Participants receive lymphodepleting chemotherapy before CAR-NK infusion, then undergo protocol-defined safety monitoring, serial imaging, and translational assessments including CAR-NK persistence, serum AFP, cytokine profiling, and ctDNA dynamics.
Because B7-H3 can also be detected at low levels in some normal tissues, the trial is intentionally conservative: it uses central biomarker confirmation, stepwise dose escalation, strict liver function eligibility, and close monitoring for infusion reactions, cytokine-release syndrome, immune effector cell-associated neurotoxicity, hepatotoxicity, cytopenias, infection, and any evidence of off-tumor toxicity.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Masking is not used because this is an early-phase cell-therapy study in which real-time safety management, product-specific monitoring, and dose-escalation decisions require investigators and treating teams to know the intervention
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.
- •Histologically or cytologically confirmed HCC, or radiologically diagnosed HCC with mandatory tissue confirmation of target expression before enrollment.
- •Unresectable, locally advanced, or metastatic HCC not amenable to curative surgery, transplant, or further locoregional therapy; BCLC stage C, or stage B that is not suitable for or has progressed after locoregional therapy.
- •Disease progression on, intolerance to, or ineligibility for at least 1 prior standard systemic regimen.
- •Central pathology showing GPC3 positivity in >=25% of viable tumor cells by IHC and B7-H3 positivity in >=10% of tumor cells and/or tumor-associated stromal/vascular cells by IHC.
- •At least 1 measurable lesion by RECIST 1.1; intrahepatic lesions must be assessable by contrast-enhanced triphasic CT or MRI.
- •ECOG performance status 0 to
- •Child-Pugh class A or stable Child-Pugh B7 without uncontrolled ascites or recent encephalopathy.
- •Estimated life expectancy >=12 weeks.
- •Adequate organ function: WBC >=2.5 x 10^9/L; platelets >=60 x 10^9/L; hemoglobin >=9 g/dL; serum albumin >=30 g/L; creatinine clearance >=40 mL/min; AST/ALT <=5 x ULN; total bilirubin <=2.5 x ULN; INR/prothrombin time within protocol-defined range.
- •If HBsAg positive or anti-HBc positive, HBV DNA must be <200 IU/mL and the participant must be on appropriate antiviral therapy before lymphodepletion. Controlled HCV is allowed if per protocol.
- •Negative serum pregnancy test for participants of childbearing potential and agreement to effective contraception.
- •Ability to understand and sign informed consent.
排除标准
- •Prior gene-modified cellular therapy (for example prior CAR-T, CAR-NK, or TCR-engineered therapy) within the protocol-defined washout period or with unresolved clinically significant toxicity.
- •Active, uncontrolled infection, including uncontrolled bacterial, viral, or fungal infection; uncontrolled HIV; active HBV or HCV with uncontrolled viral load; or active tuberculosis.
- •Known active CNS metastases or leptomeningeal disease requiring escalating steroids or urgent local intervention.
- •Liver transplant or other solid-organ transplant history, or current requirement for chronic immunosuppression.
- •Clinically significant ascites requiring frequent drainage, grade >=2 hepatic encephalopathy within 4 weeks, or recent clinically significant variceal/GI bleeding.
- •Extensive liver replacement by tumor (for example >=70%) or complete major portal vein/hepatic venous obstruction judged to create excessive treatment risk.
- •Major surgery, locoregional therapy, radiotherapy, or systemic anticancer therapy too close to lymphodepletion per protocol-defined washout period.
- •Active autoimmune disease requiring systemic immunosuppressive therapy, or chronic systemic corticosteroids above protocol threshold.
- •Clinically significant cardiovascular disease (recent myocardial infarction, unstable arrhythmia, uncontrolled heart failure), uncontrolled pulmonary disease, or other serious comorbidity that materially increases study risk.
- •Pregnant or breastfeeding.
- •Any other active malignancy that is progressing or requires current systemic treatment.
- •Any medical or psychiatric condition that, in the investigator's judgment, would compromise safety, protocol compliance, or interpretation of results.
结局指标
主要结局
Incidence of dose-limiting toxicities (DLTs)
时间窗: 28 Days
Incidence, type, and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)
时间窗: 12 months
次要结局
- Duration of response (DoR)(12 months)
- response rate (ORR) by RECIST 1.1 and mRECIST(6 months)
- Disease control rate (DCR)(6 months)
- Progression-free survival (PFS)(12 months)
- Overall survival (OS)(24 months)