A Phase 1/2 interventional study of TCR reserved and Power3 (SPPL3) Gene Knock-out Allogeneic CD19-targeting CAR-T cell and Fludarabine in Acute Lymphocytic Leukemia, sponsored by Chinese PLA General Hospital. Recruiting at 6 sites in China. Open to participants aged 16 Years to 70 Years. Per ClinicalTrials.gov, last updated 2026-05-08.
Sponsored by Chinese PLA General Hospital · Phase 1/2, Interventional, and Treatment
The safety and efficacy of the chimeric antigen receptor (CAR)-T, a CD19-targeting, TRAC and Power3 (SPPL3) double gene deleted allogeneic CAR-T cell product, are undergoing rigorous evaluation in non-Hodgkin's lymphoma (NHL) subjects from the ATHENA trial (NCT06014073). Unexpectedly, expansion of the initial residual CD3-positive CAR T from products were measured in patients' peripheral blood (PB) without exception. Accompanying with host immune reconstitution and appearance of the detectable B cells, the CD3-positive allogenic CAR T cells exhibited a compelling amplification advantage over CD3-negative CAR T cells. The amplification of CD3-positive CAR T cell population dynamically suppressed host B cell recovery, and presumably surveilled the recurrence or progression of tumors, but did not induce typical Graft-versus-host-disease (GvHD). Additionally, a series of in vitro experiments illustrated that the human leukocyte antigen (HLA)-mismatched fratricide between host T cells and TCR-reserved Power3 (SPPL3)-deleted allogenic CAR T cells was markedly slashed, which in combination with investigators' observed clinical safety data supported the notion that only genomic deletion of Power3 (SPPL3) gene in allo-CAR T cells is sufficient to overcome GvHD and host T cell-mediated rejection response.
In this study, investigators will disable the Power3 (SPPL3) gene of T cells from healthy donors to prepare CAR T cells (purified CAR-positive T cells > 90%). This approach harnesses the tonic signaling of CAR T cells, resulting in enhanced persistence and improved response to treatment. The purpose of this study is to evaluate the safety and efficacy of allogeneic Power3 (SPPL3) knock-out CD19 CAR-T in B-cell acute lymphoblastic leukaemia (B-ALL).
Phase 1 (dose escalation)
In phase 1, 6-18 subjects will be enrolled. Subjects will receive 3 doses of allogeneic Power3 (SPPL3) knock-out CD19 CAR-T cell therapy ( 1 × 10\^6 cells/kg、3 × 10\^6 cells/kg、6 × 10\^6 cells/kg) increases from low dose to high dose according to the "3 + 3" principle:
Three (3) subjects are enrolled in a cohort corresponding to a dose level. If 1 subject in a cohort of 3 subjects experiences a dose-limiting toxicity (DLT), 3 additional subjects will be enrolled at the current dose level. For safety purposes, the administration of allogeneic Power3 (SPPL3) knock-out CD19 CAR-T will be staggered by 28 days between the first two subjects in each cohort. And for each of the remaining cohorts, the administration of allogeneic Power3 (SPPL3) knock-out CD19 CAR-T will be staggered by 28 days before enter into the next cohort.
Phase 2 (expansion cohort)
In phase 2, 10 to 12 subjects will be enrolled and receive cell infusion at dose of recommended phase 2 dose (RP2D), which will be determined based on the maximum tolerated dose (MTD), occurrence of DLT, the obtained efficacy results, pharmacokinetics/pharmacodynamics and other data according to the phase 1.
Objectives
The primary objectives of the phase 1 were to evaluate the tolerability and safety of allogeneic Power3 (SPPL3) knock-out CD19 CAR-T in patients with refractory/relapsed (r/r) B-ALL, and determine RP2D. The primary purpose of the phase 2 study was to evaluate the efficacy of allogeneic Power3 (SPPL3) knock-out CD19 CAR-T in the above population.
2,061 studies on the registry are indexed under Precursor Cell Lymphoblastic Leukemia-Lymphoma; 490 are open to participants now.
This study's planned enrollment of 30 is below the median of 40 across 1,653 interventional studies indexed under Precursor Cell Lymphoblastic Leukemia-Lymphoma.
Browse Precursor Cell Lymphoblastic Leukemia-Lymphoma studies →Chinese PLA General Hospital is the lead sponsor of 558 studies on the registry; 202 are open to participants now.
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Patient with r/r CD19+ B-ALL, as per guidelines (NCCN, 2019)
Adequate renal, hepatic, pulmonary and cardiac function defined as:
Exclusion Criteria:
A conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by investigational treatment, Power3 (SPPL3) Gene Knock-out Allogeneic CD19-targeting CAR-T.
Biological: TCR reserved and Power3 (SPPL3) Gene Knock-out Allogeneic CD19-targeting CAR-T cell · Drug: Fludarabine · Drug: Cyclophosphamide
Phase 1 dose escalation (3+3) : dose 1 (1 × 10\^6 cells/kg) , dose 2 (3 × 10\^6 cells/kg), dose 3 (6 × 10\^6 cells/kg); Phase 2 : dose of RP2D.
Also known as: Allogeneic Power3 (SPPL3) knock-out CD19 CAR-T
Intravenous fludarabine 30\~50 mg/m\^2/day on days -5, -4, and -3.
Also known as: Fludarabine Phosphate for Injection
Intravenous cyclophosphamide 500\~1000 mg/m\^2/day on days -5, -4, and -3.
Also known as: Cyclophosphamide for Injection
Phase 1: Incidence of adverse events (AE) defined as DLT
DLT is defined as any AE related to the investigational drug that occurs within 28 days after administration of the allogeneic Power3 (SPPL3) knock-out CD19 CAR-T and meets any one of the criteria listed in the DLT criteria. The severity of AE will be assessed according to NCI-CTCAE v5.0. cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS) will be evaluated according to the standards released by ASTCT in 2019. GvHD according to criteria defined by the Mount Sinai Acute GVHD International Consortium. * Grade 3 aGVHD that does not resolve to Grade 1 or 2 within 7 days, with the exception of isolated skin involvement aGVHD; * Grade 3 CRS that does not resolve to grade 2 or lower within 2 weeks; * Grade 3 ICANS lasting for ≥ 7 days; * Any Grade ≥ 4 aGVHD or CRS or ICANS; * Any other Grade ≥ 4 and Grade 3 AE related to the allogeneic Power3 (SPPL3) knock-out CD19 CAR-T that lasts for ≥ 14 days, except hematology toxicity.
Time frame: First infusion date of CAR-T cells up to 28 days
Phase 1: RP2D
The RP2D was determined through phase 1 study.
Time frame: 12 months
Phase 2: Objective response rate (ORR)
Objective response definition: a molecular response (MRD \< 10\^-4 post treatment) assessed by multiparameter flow cytometry and/or qPCR, or a morphologic complete response (CR), or a CR with incomplete blood count recovery (CRi). ORR is defined as the proportion of patients who have achieved objective response assessed by investigators.
Time frame: 24 months
Phase 2: Overall Survival (OS)
OS is defined as the time from CAR-T cells infusion to the date of death. Subjects who have not died by the analysis data cutoff date will be censored at the last contact date.
Time frame: 24 months
Phase 2: Progression Free Survival (PFS)
PFS is defined as the time from the CAR-T cells infusion date to the date of disease progression assessed by investigators, or death any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored at the last evaluable disease assessment date.
Time frame: 24 months
Phase 1 and phase 2: Level of CAR-positive T cells circulating in blood over time
Number and copy number of CAR-T cells were assessed by number in peripheral blood. Blood samples were collected before and one year after cell infusion (until CAR-T cells were not detected for two consecutive times) to detect the number and copy number of CAR-T cells, and to evaluate the pharmacokinetics of CAR-T.
Time frame: 12 months
Phase 1 and phase 2: Level of CD19+ cells in peripheral blood
The level of CD19+ cells in peripheral blood will be detected by flow cytometry.
Time frame: Up to 28 days after infusion
Phase 1 and phase 2: Level of interleukin 6 (IL-6) in peripheral blood
The level of IL-6 in peripheral blood will be detected by enzyme-linked immuno sorbent assay.
Time frame: Up to 28 days after infusion
Phase 1: 3-month ORR
The definition of ORR has already been mentioned above
Time frame: 3 months
Phase 1: OS
The definition of OS has already been mentioned above
Time frame: 24 months
Phase 1: PFS
The definition of PFS has already been mentioned above
Time frame: 24 months
Phase 2: Incidence of AE
AE is defined as any adverse medical event from the date of enrollment to 24 months after CAR-T cells infusion.
Time frame: 24 months
Phase 1: Level of donor-specific antibodies (DSAs) in blood.
DSAs refers to the specific antibodies in the recipient's body targeting donor HLA antigens.
Time frame: 12 months
Phase 1: Level of human anti-mouse antibodies (HAMA)
The levels of human against murine scFv antibodies in blood
Time frame: 12 months
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Chinese PLA General Hospital