A Phase I, Single-Arm, Open-Label Clinical Study to Evaluate the Safety and Efficacy of U69 in Patients With Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia/Lymphoma (T-ALL/LBL)
概览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- The First Affiliated Hospital of Soochow University
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Dose-limiting toxicity (DLT)
概览
简要总结
Overall Introduction This single-arm, open-label clinical trial aims to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of CXCR4-enabled CCR9 chimeric antigen receptor T-cell injection (CXCR4 CCR9 CAR-T) in patients with relapsed or refractory T-lymphoblastic leukemia/lymphoma (r/r T-ALL/LBL). Additionally, the study seeks to preliminarily assess the efficacy of CXCR4 CCR9 CAR-T cells and explore the appropriate dosage and administration schedule for subsequent Phase II clinical trials. A dose escalation study following the 3+3 design was implemented across three dose cohorts, with each cohort planned to enroll 3 to 6 patients, totaling 9 to 18 participants. Following cell infusion, subjects underwent safety and efficacy follow-up, which continued until 2 years post-infusion, subject withdrawal, or study termination-whichever occurred first. For subjects with available follow-up information after study completion or early termination, long-term follow-up-including long-term safety monitoring-was conducted for up to 15 years.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 15 Years 至 75 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subjects must meet all of the following criteria to be eligible for the study:
- •Informed Consent: Voluntary provision of written informed consent and anticipated ability to complete all required study procedures and follow-up assessments.
- •Age: ≥15 and ≤75 years of age at the time of signing the informed consent form.For minors (age ≤ 18 years), informed consent must be provided by a legal guardian; minors with capacity to sign should co-sign the consent form alongside their guardian.
- •Diagnosis and Disease Status: Histologically or cytologically confirmed diagnosis of relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) according to the 2022 WHO Classification of Haematolymphoid Tumours, for which standard curative treatments are no longer effective.
- •3.1 For T-ALL: Presence of ≥5% blasts in bone marrow or peripheral blood at screening. Relapse: Defined as recurrence of blasts (≥5%) in peripheral blood or bone marrow or emergence of extramedullary disease after prior achievement of complete remission (CR/CRi). This includes early relapse (within 12 months of first remission), late relapse (≥12 months) failing to achieve remission after one multi-agent re-induction chemotherapy cycle, or relapse after autologous or allogeneic hematopoietic stem cell transplantation (HSCT).
- •Refractory: Defined as failure to achieve CR after at least two cycles of induction chemotherapy, or failure to achieve CR after one cycle of salvage therapy following relapse.
- •3.2 For T-LBL: Presence of at least one measurable lesion at screening, defined as a nodal lesion with a long axis \>15 mm or an extranodal lesion with a long axis \>10 mm, as assessed by CT or MRI per the 2014 Lugano criteria.
- •Relapsed/Refractory: Defined as relapse or disease progression after at least two prior lines of therapy; primary refractory disease (failure to achieve at least a partial response, PR, after first-line therapy); or relapse/progression after autologous or allogeneic HSCT (must be confirmed by tissue biopsy).
- •Biomarker: Confirmed CCR9 positivity on tumor cells via flow cytometry of bone marrow samples and/or via immunohistochemistry of extramedullary lesion biopsies at screening.
- •Performance Status: Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
排除标准
- •Subjects will be excluded from the study if they meet any of the following criteria:
- •Diagnosis of any other malignancy within 3 years prior to screening, except for those who have completed curative therapy and achieved over 3 years of disease-free survival with a low risk of recurrence as determined by the investigator (e.g., carcinoma in situ of the lung, basal cell carcinoma of the skin).
- •History or presence of central nervous system (CNS) disorders unrelated to the disease under study at screening or previously, such as seizure, cerebral ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease involving the CNS.
- •Prior receipt of cell therapies targeting CCR9, including but not limited to CAR-T or CAR-γδT cells.
- •Significant or active parenchymal CNS or cranial nerve lesions where, in the investigator's judgment, the risks outweigh the benefits.
- •Systemic corticosteroid use discontinued ≤72 hours prior to apheresis, except for physiological replacement doses (e.g., prednisone \<10 mg/day or equivalent).
- •Donor lymphocyte infusion (DLI) within 6 weeks prior to apheresis.
- •Treatment with any anti-T-cell antibody therapy within 4 weeks prior to apheresis.
- •Presence of any of the following: positive hepatitis B e antibody (HBe-Ab) and/or hepatitis B core antibody (HBc-Ab) with HBV-DNA above the lower limit of quantification; positive hepatitis C antibody (HCV-Ab) with HCV-RNA above the lower limit of quantification; positive treponema pallidum antibody (TP-Ab); positive human immunodeficiency virus (HIV) antibody test; or EBV-DNA or CMV-DNA levels above the lower limit of quantification by quantitative PCR.
- •Active or uncontrolled infection requiring systemic therapy at the time of screening (excluding mild genitourinary or upper respiratory tract infections), as assessed by the investigator.
研究组 & 干预措施
Low-dose group
The investigational product is the CXCR4-enhanced CCR9 Chimeric Antigen Receptor T-Cell Injection (CXCR4/CCR9 CAR-T, U69). The planned doses per cohort are:
Low Dose Cohort: 1 × 10⁶ CAR-positive T cells per kg of body weight. The product is administered as a single intravenous infusion. The actual administered dose is acceptable within a range of 70% to 130% of the target dose. The required cell number will be calculated based on the subject's body weight at the time of apheresis. The Investigator may adjust the final cell dose based on the subject's specific clinical condition.
干预措施: CXCR4 CCR9 CAR-T (Drug)
Medium dose group
The investigational product is the CXCR4-enhanced CCR9 Chimeric Antigen Receptor T-Cell Injection (CXCR4/CCR9 CAR-T, U69). The planned doses per cohort are:
Medium Dose Cohort: 3 × 10⁶ CAR-positive T cells per kg of body weight. The product is administered as a single intravenous infusion. The actual administered dose is acceptable within a range of 70% to 130% of the target dose. The required cell number will be calculated based on the subject's body weight at the time of apheresis. The Investigator may adjust the final cell dose based on the subject's specific clinical condition.
干预措施: CXCR4 CCR9 CAR-T (Drug)
High dose group
The investigational product is the CXCR4-enhanced CCR9 Chimeric Antigen Receptor T-Cell Injection (CXCR4/CCR9 CAR-T, U69). The planned doses per cohort are:
High Dose Cohort: 6 × 10⁶ CAR-positive T cells per kg of body weight. The product is administered as a single intravenous infusion. The actual administered dose is acceptable within a range of 70% to 130% of the target dose. The required cell number will be calculated based on the subject's body weight at the time of apheresis. The Investigator may adjust the final cell dose based on the subject's specific clinical condition.
干预措施: CXCR4 CCR9 CAR-T (Drug)
结局指标
主要结局
Dose-limiting toxicity (DLT)
时间窗: Within 28 days after CXCR4 CCR9 CAR-T cell infusion
DLT refers to any of the following conditions occurring within 28 days after cell reinfusion that are related to cell infusion: ① Hematologic DLT: Grade 4 toxicity (excluding lymphopenia) not caused by the underlying disease and taking more than 30 days to resolve to ≤ Grade 2. ② Non-hematologic DLT: Any toxicity ≥ Grade 4 that is possibly related to CAR-T therapy, or Grade 3 toxicity that requires ≥7 days to resolve to ≤ Grade 2 or to return to baseline.
Adverse Event (AE）
时间窗: 2 years
Record the types, occurrence frequency and severity of adverse events (AEs) related to CAR-T, with specific definitions determined according to CTCAE v5.0.The CRS and ICANS ratings do not use CTCAE but adopt the evaluation criteria in the ASTCT standards.
The Recommended Phase II Dose（RP2D）
时间窗: Within 28 days after CXCR4 CCR9 CAR-T cell infusion
The dose recommended for use in phase 2 studies on the basis of dose limiting toxicities observed in phase 1 studies.
次要结局
- Objective Response Rate (ORR)(28 days and within 3 months after infusion of CXCR4 CCR9 CAR-T cells)
- IFNγ(Within 28 days after CXCR4 CCR9 CAR-T cell infusion)
- MRD-negative rate (for T-ALL)(28 days and within 3 months after infusion of CXCR4 CCR9 CAR-T cells)
- Duration of Response (DOR)(2 years)
- Progression-Free Survival (PFS)(2 years)
- Event-Free Survival (EFS)(2 years)
- Ferritin(Within 28 days after CXCR4 CCR9 CAR-T cell infusion)
- Overall Survival (OS)(2 years)
- Pharmacokinetics-AUC(0-28)(2 years)
- Pharmacokinetics-Cmax(2 years)
- Pharmacokinetics-Tmax(2 years)
- IL-6(Within 28 days after CXCR4 CCR9 CAR-T cell infusion)
- C-reactive protein(CRP)(Within 28 days after CXCR4 CCR9 CAR-T cell infusion)
研究者
Sheng-Li Xue, MD
Prof.
The First Affiliated Hospital of Soochow University