The team has developed the synthetic T cell receptor (TCR) and antigen receptor (STAR) T cells which were demonstrated safety in relapsed or refractory (r/r) B-cell non-Hodgkin' s lymphoma (B-NHL) (NCT05631912). Based on this research, allogeneic STAR-T cell products utilized the CRISPR-Cas9 gene editing tool to knock out endogenous receptor α constant (TRAC), human leukocyte antigen (HLA)-A/B, CIITA, and programmed death 1 (PD-1) genes simultaneously in T cells from healthy donors, and integrated the STAR molecule into the TRAC locus using adenovirus associated virus. This strategy can reduce graft-versus-host-disease (GvHD) toxicity and host-versus-graft response, decrease the sensitivity of STAR T cells to immunosuppressive signals, and improve their anti-tumor activity. In this single center, prospective, open-label, single-arm, phase 1/2 study, the safety and efficacy of allogeneic CD19-targeting STAR T cell therapy will be evaluated in patients with r/r B-NHL.
Phase 1 (dose escalation) In phase 1, 6 to 18 subjects will be enrolled. Subjects will receive 3 doses of allogeneic CD19-STAR T cell therapy (2 × 10\^6 cells/kg, 6 × 10\^6 cells/kg, 1.8 × 10\^7 cells/kg) from low dose to high dose according to the "3 + 3" principle: 1. Three patients were enrolled in the lowest dose group. 2. Subsequent patients were enrolled according to the following rules: 1. If the incidence of dose limiting toxicity (DLT) was 0/3, 3 patients were enrolled in the next high-dose group. 2. If the incidence of DLT was 1/3, 3 patients were enrolled at the same dose; If the incidence of DLT was 1/3 + 0/3, 3 patients were enrolled in the next high-dose group. If the incidence of DLT was 1/3 + 1/3, this dose was defined as maximum tolerated dose (MTD); If the incidence of DLT was 1/3 + 2/3 or 1/3 + 3/3, the previous dose was MTD. 3. If the incidence of DLT was 2/3 or 3/3, the previous dose was MTD. To ensure the safety of the subjects, the first subject in each dose group was observed for at least 28 days after the cell infusion. If no DLT occurred, the remaining two subjects could be enrolled and treated at the same dose level. The safety data of all subjects in each dose group until day 28 should be reviewed and tolerated before proceeding to the next dose group trial. No dose escalation was allowed for the same subject during the trial. If a subject drop out during the observation period due to non-DLT reasons, new subjects should be enrolled to make up for the number of subjects who drop out. Phase 2 (expansion cohort) In phase 2, 10 to 12 subjects will be enrolled and receive allogeneic CD19-STAR T cell infusion at dose of recommended phase 2 dose (RP2D), which will be determined based on the 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 are to evaluate the tolerability, safety, and determine RP2D. The primary purpose of the phase 2 study is to evaluate the efficacy.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
30
Phase 1 dose escalation (3+3): dose 1 (2×10\^6 cells/kg), dose 2 (6×10\^6 cells/kg), dose 3 (1.8×10\^7 cells/kg); Phase 2: dose of RP2D. No more than 5 × 10\^4 per kilogram of allogenic residual TCR-positive T cells harbouring in grafts can only be released for recipient infusion.
Intravenous fludarabine 30-50 mg/m\^2/day on days -5, -4, and -3.
Intravenous cyclophosphamide 500-1000 mg/m\^2/day on days -5, -4, and -3.
Biotherapeutic Department of Chinese PLA General Hospital
Beijing, Beijing Municipality, China
RECRUITINGSchool of medicine, Tsinghua University & Changping Laboratory
Beijing, China
RECRUITINGPhase 1: Incidence of Adverse Events (AEs) defined as DLT
DLT is defined as any AE related to the investigational drug that occurs within 28 days after administration of the STAR T cells and meets any one of the criteria listed in the DLT criteria. Cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS) were graded according to American Society for Transplantation and Cellular Therapy (ASTCT) 2019 criteria. GvHD according to criteria defined by the Mount Sinai Acute GVHD International Consortium. Other AEs were graded according to common terminology criteria for adverse events (CTCAE) v5.0. * Grade 3 acute GVHD (aGVHD) that is not resolved to Grade 1 or 2 within 7 days, with the exception of isolated skin involvement aGVHD; * Grade 4 CRS or grade 3 CRS that is not resolved to grade 2 or lower within 2 weeks; * Grade 3 ICANS lasting for ≥7 days or Grade 4 ICANS; * Any other Grade ≥4 and Grade 3 AEs related to the STAR T that lasts for ≥14 days, except hematology toxicity.
Time frame: 12 months
Phase 1: RP2D
The RP2D was determined through phase 1 study.
Time frame: 12 months
Phase 2: Best objective Response Rate
The incidence of complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or unevaluable (UE) as the best response to treatment assessed by investigators and based on the Lugano 2014 assessment criterion.
Time frame: 12 months
Phase 2: Overall Survival (OS)
OS is defined as the time from CD19-STAR T cells infusion to the date of death. Subjects who have not died by the analysis data cutoff date will be censored at their last contact date.
Time frame: 12 months after the first infusion of CD19-STAR T cells
Phase 2: Progression Free Survival (PFS)
PFS is defined as the time from the CD19-STAR T cells infusion date to the date of disease progression assessed by investigators and based on the Lugano 2014 assessment criterion, or death any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date.
Time frame: 12 months after the first infusion of CD19-STAR T cells
Phase 2: Time to response (TTR)
TTR is defined as the time from CD19-STAR T infusion to first assessed CR or PR by investigators and based on the Lugano 2014 assessment criterion.
Time frame: 12 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 and based on the Lugano 2014 assessment criterion for r/r B-cell NHL, or death regardless of cause.
Time frame: 12 months
Pharmacokinetics: Number and copy number of CD19-STAR T cells (phase 1 and phase 2)
Number and copy number of CD19-STAR T cells were assessed by number in peripheral blood. Blood samples were collected before and one year after cell infusion (until CD19-STAR T cells were not detected for two consecutive times) to detect the number and copy number of CD19-STAR T cells, and to evaluate the pharmacokinetics of CD19-STAR T.
Time frame: 12 months
Pharmacokinetics: Persistence of CD19-STAR T (phase 1 and phase 2)
Persistence of CD19-STAR T cell assessed by number in peripheral blood.
Time frame: 12 months
Pharmacodynamics: 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 (CRP), ferritin. Peak was defined as the maximum post-baseline level of the cytokine.
Time frame: Up to 28 days after infusion
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