A Clinical Study on the Safety of CLL-1-Targeted In Vivo CAR-T-Cell Immunotherapy for Relapsed/Refractory Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Incidence and Severity of Adverse Events and Serious Adverse Events
研究概览
简要总结
This is a single-center, open-label, single-arm, phase 1 dose-escalation study to evaluate the safety, tolerability, preliminary efficacy, and cellular kinetics of SL1CC Injection, an in vivo CAR-T therapy targeting CLL-1, in patients with relapsed or refractory acute myeloid leukemia (R/R AML; acute promyelocytic leukemia excluded). SL1CC Injection is administered as a single intravenous infusion without lymphodepleting conditioning. Dose escalation follows a traditional 3+3 design with planned dose levels of 1 × 10^9, 3 × 10^9, and 6 × 10^9 transducing units (TU), guided by the occurrence of dose-limiting toxicities (DLTs). Treatment-emergent adverse events and serious adverse events, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), hematologic toxicity, organ toxicity, and other immune therapy-related toxicities, will be assessed. Preliminary antitumor activity, assessed by composite complete remission (CR/CRi) and measurable residual disease (MRD) status according to the European LeukemiaNet (ELN) 2022 criteria, and the expansion and persistence of CAR-T cells in peripheral blood will also be evaluated.
详细描述
This is a single-center, single-arm, open-label, phase 1 dose-escalation study of SL1CC Injection in adults with R/R AML. SL1CC is an in vivo CAR-T product in which a lentiviral vector (LVV) encoding a CLL-1-specific chimeric antigen receptor is administered intravenously to transduce the patient's endogenous T cells in situ; no leukapheresis, ex vivo manufacturing, or lymphodepleting conditioning is required. Three dose levels are planned (1 × 10^9, 3 × 10^9, and 6 × 10^9 TU) using a traditional 3+3 escalation design, and dose-limiting toxicity (DLT) is assessed during the first 28 days after a single infusion. Anticipated enrollment is 12 participants (range 9-18, depending on the number of dose levels requiring expansion). The study includes a screening period, a treatment (infusion) period, and a follow-up period of up to 24 months. Safety assessments include adverse events and serious adverse events graded per NCI CTCAE v6.0, with CRS and ICANS graded per the ASTCT consensus criteria; hematologic recovery, infection, organ toxicity, and viral shedding (blood, saliva, and urine; qPCR) are also monitored. Disease response is assessed by bone marrow morphology according to the ELN 2022 criteria (CR, CRi, MLFS, and PR), together with MRD measured by multiparameter flow cytometry. Exploratory cellular kinetics include peripheral blood CAR transgene copies (qPCR), CAR-positive T-cell counts, Cmax, Tmax, and AUC0-28d. Long-term safety monitoring for potential insertional mutagenesis associated with integrating lentiviral vectors is planned in accordance with applicable gene therapy guidance.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
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
- •Voluntarily agrees to participate in the study, has signed the informed consent form, and is willing and able to comply with scheduled visits, study treatment, laboratory tests, and other study procedures.
- •Diagnosis of relapsed or refractory acute myeloid leukemia (AML), excluding acute promyelocytic leukemia (APL), according to the 2022 World Health Organization (WHO) classification, meeting at least one of the following:
- •Relapsed AML: Reappearance of leukemic cells in the peripheral blood after achieving complete remission (CR), bone marrow blasts ≥5% (excluding bone marrow regeneration after consolidation chemotherapy or other non-leukemic causes), or the presence of extramedullary leukemic infiltration.
- •Refractory AML: Newly diagnosed AML with no response after two courses of standard induction therapy; relapse within 12 months after achieving CR followed by consolidation/intensification therapy; relapse more than 12 months after CR with failure to respond to conventional chemotherapy; two or more relapses; or persistent extramedullary leukemia.
- •CLL-1 expression ≥50% on AML blasts, confirmed by flow cytometry on bone marrow or peripheral blood samples at the local certified laboratory.
- •Patients with targetable mutations (e.g., FLT3, IDH1/2, NPM1, or KMT2A rearrangement) must have received, be intolerant to, or be ineligible for the corresponding approved targeted therapy.
- •Recovered from acute toxicities of prior antileukemic therapy to ≤ Grade 1 (CTCAE v6.0) before SL1CC infusion, except for alopecia and hematologic abnormalities attributable to the underlying disease.
- •Male or female participants aged 18 to 75 years, inclusive.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-
- •Estimated life expectancy of more than 3 months from the date of signing the informed consent form.
- •Adequate renal, hepatic, cardiac, and pulmonary function, defined as follows:
- •Creatinine clearance (estimated by the Cockcroft-Gault formula) ≥60 mL/min or serum creatinine ≤1.5 × the upper limit of normal (ULN);
- •Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST)≤2.5×upper limit of normal (ULN), total bilirubin≤1.5×ULN;
- •Cardiac ejection fraction≥50%, no pericardial effusion on echocardiography, and no significant abnormalities on electrocardiogram (ECG);
- •No clinically significant pleural effusion, and oxygen saturation >92% on room air at baseline.
- •Participants of reproductive potential must agree to use highly effective contraception before enrollment and for at least 12 months after SL1CC infusion. A negative serum pregnancy test is required for women of childbearing potential at screening. Participants must immediately notify the investigator if pregnancy occurs or is suspected.
排除标准
- •The patient has severe cardiac dysfunction, or left ventricular ejection fraction (LVEF) <50%, or a history within the 12 months prior to enrollment of myocardial infarction, coronary angioplasty or coronary stent implantation, unstable angina, clinically significant arrhythmia, or other severe cardiovascular diseases.
- •A history of severe pulmonary disease associated with impaired lung function.
- •Concurrent progressive malignancy other than acute myeloid leukemia.
- •Severe active infection that cannot be effectively controlled.
- •Severe autoimmune disease or congenital immunodeficiency.
- •Active hepatitis B or hepatitis C infection, defined as hepatitis B virus DNA (HBV DNA) or hepatitis C virus RNA (HCV RNA) levels above the lower limit of detection.
- •Human immunodeficiency virus (HIV) infection, known acquired immunodeficiency syndrome (AIDS), or syphilis infection; has received a live vaccine within 4 weeks, or is anticipated to require a live vaccine during the study period.
- •A history of severe allergic reactions to biological products, including antibiotics.
- •Prior allogeneic hematopoietic stem cell transplantation with persistent acute graft-versus-host disease (GVHD) after discontinuation of immunosuppressive therapy for at least 1 month.
- •Prior treatment with any gene therapy product or any in vivo CAR-T therapy, or known pre-existing neutralizing immunity to the lentiviral vector.
- •Active central nervous system (CNS) leukemia or leptomeningeal involvement not controlled after adequate intrathecal therapy; cerebrospinal fluid examination is required during screening.
- •The patient has severe autoimmune disease, congenital immunodeficiency or active autoimmune disease requiring ongoing systemic immunosuppressive treatment, or is currently within the washout period after having received medications that may affect CAR-T cell immunotherapy, or is anticipated to require medications during the study period that may affect CAR-T cell immunotherapy treatment, or active GVHD requiring systemic therapy.
- •Pregnancy or breastfeeding (lactation).
- •The patient has other significant uncontrolled comorbidities that may affect protocol compliance or interpretation of results.
- •The investigator judges that the patient is unlikely to complete all visits and procedures required by the study protocol (including medium- and long-term follow-up visits), such as insufficient willingness of the patient and their family members to participate in the study, refusal to participate, inability of the patient to fully cooperate with the study arrangements, or inadequate compliance on the part of the patient and their family members.
- •Any other severe physical or psychiatric disorder or clinically significant laboratory abnormality that may increase the risk associated with study participation, interfere with the interpretation of study results, or, in the investigator's judgment, make the participant unsuitable for participation in the study.
- •- Severe infection is defined as sepsis or an infection with an uncontrolled infectious focus. Participants may be enrolled after the infection has been adequately controlled.
研究组 & 干预措施
SL1CC Treatment Group
single intravenous infusion of SL1CC Injection at one of three planned dose levels (1 × 10^9, 3 × 10^9, or 6 × 10^9 TU) assigned by a traditional 3+3 dose-escalation design; no lymphodepleting conditioning is administered. Additional dose cohorts can be added based on safety.
干预措施: SL1CC Injection (Drug)
结局指标
主要结局
Incidence and Severity of Adverse Events and Serious Adverse Events
时间窗: From SL1CC infusion through 12 months after treatment (primary safety observation period); long-term follow-up continues through 24 months
The number, percentage, severity, and relatedness of adverse events (AEs) and serious adverse events (SAEs) occurring from SL1CC infusion through the 12-month safety observation period, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), hematologic toxicity, organ toxicity, infection, and other immunotherapy-related toxicities. AEs are graded per NCI CTCAE v6.0; CRS and ICANS are graded per the ASTCT consensus criteria.
Incidence of Dose-Limiting Toxicities (DLTs)
时间窗: From Day 0 through Day 28 after a single SL1CC infusion (protocol-defined DLT observation window)
The number and percentage of participants who experience dose-limiting toxicities (DLTs) during the protocol-defined DLT observation period (Days 0-28) after a single intravenous infusion of SL1CC Injection. DLT definitions are specified in the protocol.
次要结局
- Objective Response Rate at Prespecified Follow-up Time Points(At 1, 2, 3, 6, 9, 12, 18, and 24 months after SL1CC infusion)
- Complete Response Rate(At 1, 2, 3, 6, 9, 12, 18, and 24 months after SL1CC infusion)
- Partial Remission (PR) Rate(At 1, 2, 3, 6, 9, 12, 18, and 24 months after SL1CC infusion)
- Overall Survival(From SL1CC infusion through 24 months after treatment)
- Progression-Free Survival(From SL1CC infusion through 24 months after treatment)
- Event-Free Survival(From SL1CC infusion through 24 months after treatment)
- Measurable Residual Disease (MRD) Negativity Rate(At 1, 2, 3, 6, 9, 12, 18, and 24 months after SL1CC infusion)
- CAR Transgene Copy Number in Peripheral Blood (qPCR)(From Day 0 through 24 months after SL1CC infusion)
- CAR-Positive T-Cell Counts in Peripheral Blood (Flow Cytometry)(From Day 0 through 24 months after SL1CC infusion)
- Peak Expansion of CAR-T Cells (Cmax)(From Day 0 through Day 28 after SL1CC infusion)
- Time to Peak Expansion (Tmax)(From Day 0 through Day 28 after SL1CC infusion)
- AUC from Day 0 to Day 28 (AUC0-28d)(From Day 0 through Day 28 after SL1CC infusion)
研究者
Liping Dou
Chief Physician, Professor, and Director of the Department of Hematology
Chinese PLA General Hospital