Adaptive Dual-Target CAR-T Cells for Relapsed or Refractory Hematologic Malignancies

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Биопрепарат Autologous CD19/CD22 dual-target CAR-T module
  Biological: Autologous CD19/CD22 dual-target CAR-T module after lymphodepletion with fludarabine/cyclophosphamide.
• Биопрепарат Autologous CD19/CD20 dual-target CAR-T module
  Biological: Autologous CD19/CD20 dual-target CAR-T module after lymphodepletion with fludarabine/cyclophosphamide.
• Биопрепарат Autologous BCMA/CD19 dual-target CAR-T module
  Biological: Autologous BCMA/CD19 dual-target CAR-T module after lymphodepletion with fludarabine/cyclophosphamide.
• Биопрепарат Autologous BCMA/CD38 dual-target CAR-T module
  Biological: Autologous BCMA/CD38 dual-target CAR-T module after lymphodepletion with fludarabine/cyclophosphamide.
• Биопрепарат Autologous BCMA/GPRC5D dual-target CAR-T
  Biological: Autologous BCMA/GPRC5D dual-target CAR-T module after lymphodepletion with fludarabine/cyclophosphamide
• Биопрепарат Autologous CD33/CD123 dual-target CAR-T module
  Biological: Autologous CD33/CD123 dual-target CAR-T module (simultaneous or planned sequential paired infusion, module-specific) after lymphodepletion.
• Биопрепарат Autologous CD33/CLL1 dual-target CAR-T module
  Biological: Autologous CD33/CLL1 dual-target CAR-T module after lymphodepletion with fludarabine/cyclophosphamide.
• Биопрепарат Autologous CD5/CD7 dual-target CAR-T module
  Biological: Autologous CD5/CD7 dual-target CAR-T module (including sequential paired infusion if needed for manufacturing/safety) after lymphodepletion.

Первичные конечные точки

• Incidence of dose-limiting toxicities (DLTs) by module and dose level [Срок оценки: 28 days]
• Incidence of Grade 3 or higher cytokine release syndrome (CRS) [Срок оценки: 28 days]

Вторичные конечные точки (4)

• Complete response CR [Срок оценки: 6 Months]
• MRD-negative response rate by validated disease-specific assay [Срок оценки: 90 days]
• Duration of response (DoR) [Срок оценки: 24 months]
• Overall survival (OS) [Срок оценки: 24 months]

Критерии участия

Критерии включения

• 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 2.
• 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.

Критерии исключения

• \- 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Peking University Shenzhen Hospital — Шэньчжэнь

Идентификаторы

NCT: NCT07523555 · EBI-ADAPT-HEM-103

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗