In this single-center, single-arm, prospective, Phase 1/2 study, the safety and efficacy of autologous BCOR and ZC3H12 genes knock-out CD19-targeting chimeric antigen receptor (CAR) T-cell therapy will be evaluated in patients with refractory/relapsed (r/r) B-cell Lymphoma. For simplicity, we have termed these CD19 CAR T cells lacking ZC3H12A and BCOR as CAR19TIF( immortal-like and functional CD19 CAR T ) cells, reflecting their immortal-like and functional characteristics. In phase 1, 3 eligible patients will be enrolled and receive CAR19TIF cells at a initial dose of 5×10\^5 cells/kg. Based on the results, subsequently an additional 3-15 patients will be enrolled in a "3+3" dose-escalation/decline design to adjust the dose of CAR19TIF cells to achieve optimal safety and efficacy. The recommended Phase 2 dose (RP2D) will then be established. 10 to 12 subjects will be enrolled and receive CAR19TIF cells infusion at dose of RP2D.
Phase 1 (dose escalation/decline) In phase 1, 6-18 subjects will be enrolled. Referring to the starting dose of most CAR-T cell therapies, and to avoid exposing patients to the risk of "ineffective expansion dose", 3 patients will receive CAR19TIF cells therapy at a starting dose of 5×10\^5 cells/kg.According to the copy number of CAR-T cells were assessed by number in peripheral blood and clinical efficacy data, additional 3-15 patients will be enrolled in a "3+3" dose-escalation/decline design to adjust the dose of CAR19TIF cells to achieve optimal safety and efficacy : After obtaining effective expansion data and clinical efficacy data, a descending dose escalation model will be adopted: such as 1×10\^5 cells/kg, 5×10\^4 cells/kg. If the 5×10\^5 cells/kg dose group does not achieve efficient expansion and clinical benefit, an ascending dose escalation model will be adopted, such as 2×10\^6 cells/kg, 6×10\^6 cells/kg. 3 subjects are enrolled in a cohort corresponding to a dose level. If 1 subject in a cohort of 3 subjects experiences a DLT, 3 additional subjects will be enrolled at the current dose level. For safety purposes, the administration of CAR19TIF cells will be staggered by 28 days between the first two subjects in each cohort. And for each of the remaining cohorts, the administration of CAR19TIF cells will be staggered by 28 day. Phase 2 (expansion cohort) In phase 2, 10 to 12 subjects will be enrolled and receive cell infusion at dose of 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 CAR19TIF cells in patients with r/r B-cell Lymphoma , and determine RP2D. The primary purpose of the phase 2 study was to evaluate the efficacy of CAR19TIF cells in the above population.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
30
Phase 1 dose escalation/decline (3+3) : starting dose: 5×10\^5 cells/kg, According to effective expansion and clinical efficacy data, a descending dose escalation model will be adopted: such as 1×10\^5 cells/kg, 5×10\^4 cells/kg. If the 5×10\^5 cells/kg dose group does not achieve efficient expansion and clinical benefit, an ascending dose escalation model will be adopted, such as 2×10\^6 cells/kg, 6×10\^6 cells/kg. Phase 2 : dose of RP2D.
Intravenous fludarabine 25\~30 mg/m\^2/day on days -5, -4, and -3.
Intravenous cyclophosphamide 250\~500 mg/m\^2/day on days -5, -4, and -3.
Biotherapeutic Department of Chinsese PLA Gereral Hospital
Beijing, Beijing Municipality, China
RECRUITINGIncidence of Adverse Events (AEs)
AE is defined as any adverse medical event from the date of randomization to 12 months after CAR T cells infusion. Among them, cytokine release syndrome(CRS) and immune cell-associated neurotoxicity syndrome (ICANS) were graded according to American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Other AEs were graded according to common terminology criteria for adverse events (CTCAE) v5.0.
Time frame: 12 months
Phase 1: Incidence of Incidence of DLT.
DLT is defined as any AE related to the investigational drug that occurs within 28 days after administration of the CAR19TIF cells and meets any one of the criteria listed in the DLT criteria: * 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 CRS or ICANS; * Any other Grade ≥ 4 and Grade 3 AEs related to the CAR19TIF cells that lasts for ≥ 14 days, except hematology toxicity.
Time frame: First infusion date of CAR-T cells up to 28 days.
RP2D
The recommended dose for phase 2 was determined through phase 1 study.
Time frame: 12 months
Phase 2: Complete response (CR) rate
CR is assessed by investigators and based on the Lugano 2014 assessment criterion. CR rate is defined as the proportion of patients who have achieved CR assessed by investigators.
Time frame: 24 months
Phase 2: Objective response rate (ORR)
ORR is defined as the proportion of patients who have achieved CR and partial response (PR) assessed by investigators.
Time frame: 24 months
Phase 2: Duration of Response (DOR)
DOR is defined as the date of their first CR or PR (which is subsequently confirmed) to PD assessed by investigators, or death regardless of cause.
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: Pharmacokinetics:Level of CAR-positive T cells circulating in blood over time
Number (cells/ul)and copy number (copies/ug DNA) 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: Pharmacodynamics: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: Peak level of cytokines in serum (phase 1 and phase 2)
The cytokines mainly include interleukin-2 (IL-2 ), IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), C reactive protein .
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
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