A Phase 1/2, Open-Label, Nonrandomized, Multi-arm Umbrella Study of Biomarker-Selected Dual-Target CAR-T Cell Modules in Adults With Relapsed or Refractory Hematologic Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 96
- 试验地点
- 1
- 主要终点
- Incidence of dose-limiting toxicities (DLTs) by module and dose level
研究概览
简要总结
Phase 1/2 umbrella study evaluates biomarker-selected dual-target CAR-T cell modules for adults with relapsed or refractory hematologic malignancies. After central antigen co-expression screening, participants are assigned to the most appropriate active dual-target module: CD19/CD22, CD19/CD20, BCMA/CD19, BCMA/CD38, BCMA/GPRC5D, CD33/CD123, CD33/CLL1, or CD5/CD7. Phase 1 determines safety, dose-limiting toxicities, and the recommended phase 2 dose for each module; phase 2 estimates preliminary antitumor activity, including overall response rate and MRD-negative response.
Lymphodepletion with fludarabine/cyclophosphamide precedes infusion. The design is intended to reduce antigen escape by matching disease biology and target co-expression to a rational dual-target strategy.
详细描述
Rationale. Relapse after single-target CAR-T therapy is often driven by antigen down-regulation, lineage plasticity, or pre-existing subclonal heterogeneity. A dual-target framework attempts to preserve depth of response while lowering the probability of escape through loss of one surface antigen. This example therefore uses a master protocol with disease-specific target modules rather than a one-size-fits-all construct. Screening and target selection. All participants undergo central immunophenotyping on bone marrow, peripheral blood, and/or involved tissue within 21 days before enrollment. A module is considered eligible when both antigens are detected on malignant cells by validated flow cytometry or equivalent assay and the anticipated on-target/off-tumor risk is acceptable. If more than one module qualifies, the target selection committee ranks options by disease-specific biology, antigen density, prior antigen-directed therapy, predicted escape risk, and manufacturability.
Treatment schema. Participants undergo leukapheresis, optional bridging therapy, fludarabine/cyclophosphamide lymphodepletion, and infusion of the selected dual-target CAR-T module on Day 0.
Depending on the module, the dual-target strategy may be delivered as a tandem/bicistronic product, compound product, or predefined sequential paired infusion if that is safer or more manufacturable for that antigen pair. Participants are monitored intensively through Day 28, followed for efficacy through Month 24, and may enter long-term gene-modified cell safety follow-up for up to 15 years if required by the final regulatory strategy.
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
盲法说明
Open-label treatment is necessary because products are individually manufactured, biomarker-matched, and require real-time toxicity management
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.
- •Pathologically or cytologically confirmed eligible disease: B-ALL; B-cell NHL/CLL/SLL; multiple myeloma/plasma cell leukemia; AML/high-risk MDS/BPDCN; or T-ALL/T-LBL/peripheral T-cell lymphoma.
- •Relapsed or refractory disease after at least 2 prior lines of therapy, or no curative/approved standard option judged appropriate by the investigator.
- •Central laboratory confirmation that at least one active dual-target module is suitable based on malignant-cell antigen co-expression and safety review.
- •Measurable or otherwise evaluable disease by disease-specific response criteria.
- •ECOG performance status 0 to
- •Adequate organ function: LVEF >= 45%; creatinine clearance >= 40 mL/min; AST/ALT <= 3 x ULN; total bilirubin <= 1.5 x ULN unless due to Gilbert syndrome; oxygen saturation >= 92% on room air.
- •Adequate hematologic reserve unless cytopenia is clearly disease-related.
- •Ability to undergo leukapheresis and willingness to comply with study procedures and follow-up.
- •If prior allogeneic HSCT: at least 100 days from transplant, no uncontrolled GVHD, and no systemic immunosuppression above physiologic steroid replacement.
- •Negative pregnancy test for participants of childbearing potential and agreement to use effective contraception during protocol-defined risk periods.
- •Written informed consent obtained before any study-specific procedure.
排除标准
- •- Active uncontrolled infection, including uncontrolled bacterial, fungal, or viral infection, or clinical sepsis.
- •Active symptomatic CNS involvement requiring escalating therapy; previously treated/stable CNS disease may be allowed if defined prospectively in the final protocol.
- •Prior gene-modified cellular therapy within 12 weeks before leukapheresis, or unresolved >= Grade 3 toxicity from prior anticancer therapy
- •Need for urgent cytoreduction such that manufacturing delay would create unacceptable clinical risk.
- •Active autoimmune disease requiring systemic immunosuppression, except limited replacement-dose steroids or protocol-permitted topical/inhaled therapy.
- •Prior solid organ transplant.
- •Clinically significant cardiovascular disease, uncontrolled arrhythmia, decompensated heart failure, myocardial infarction within 6 months, or recent stroke within 6 months.
- •Uncontrolled HIV, HBV, or HCV viremia.
- •Pregnancy or breastfeeding.
- •Another active malignancy requiring systemic therapy, unless low-risk and definitively treated per protocol-defined exceptions.
- •Known hypersensitivity to fludarabine, cyclophosphamide, or critical product excipients.
- •Inability to manufacture a releaseable CAR-T product or failure to meet module-specific product-release criteria.
- •Any medical, psychiatric, or social condition that, in the investigator's judgment, would increase risk, impair compliance, or confound interpretation of study results.
研究组 & 干预措施
Arm A1 CD19/CD22
B-ALL, DLBCL, FL, MCL, PMBCL, CLL/SLL, or Richter transformation with confirmed CD19-positive / CD22-positive disease.
干预措施: Autologous CD19/CD22 dual-target CAR-T module (Biological)
Arm A2 CD19/CD20
B-NHL or CLL/SLL with CD19-positive / CD20-positive disease, especially mature B-cell phenotype or relapse after prior CD19-directed therapy.
干预措施: Autologous CD19/CD20 dual-target CAR-T module (Biological)
Arm B1 BCMA/CD19
Multiple myeloma or plasma cell leukemia with BCMA-positive disease plus evidence of a CD19-positive minor clone, precursor phenotype, or marked clonal heterogeneity.
干预措施: Autologous BCMA/CD19 dual-target CAR-T module (Biological)
Arm B2 BCMA/CD38
Multiple myeloma or plasma cell leukemia with BCMA-positive / CD38-positive disease and a plasma-cell-dominant phenotype.
干预措施: Autologous BCMA/CD38 dual-target CAR-T module (Biological)
Arm B3 BCMA/ GPRC5D
Multiple myeloma or plasma cell leukemia with BCMA-positive / GPRC5D-positive disease, especially after prior BCMA exposure or with high escape risk.
干预措施: Autologous BCMA/GPRC5D dual-target CAR-T (Biological)
Arm C1 CD33/CD123
AML, high-risk MDS, or BPDCN with CD33-positive / CD123-positive disease
干预措施: Autologous CD33/CD123 dual-target CAR-T module (Biological)
Arm C2 CD33/CLL1
AML with CD33-positive / CLL1(CLEC12A)-positive disease, particularly stem-cell-rich or measurable residual disease patterns.
干预措施: Autologous CD33/CLL1 dual-target CAR-T module (Biological)
Arm D1 CD5/CD7
T-ALL, T-LBL, or peripheral T-cell lymphoma with dual CD5-positive / CD7-positive expression and a feasible fratricide-mitigation plan.
干预措施: Autologous CD5/CD7 dual-target CAR-T module (Biological)
结局指标
主要结局
Incidence of dose-limiting toxicities (DLTs) by module and dose level
时间窗: 28 days
Incidence of Grade 3 or higher cytokine release syndrome (CRS)
时间窗: 28 days
次要结局
- Complete response CR(6 Months)
- MRD-negative response rate by validated disease-specific assay(90 days)
- Duration of response (DoR)(24 months)
- Overall survival (OS)(24 months)