CD19-CAR-γδT cell therapy is a cellular immunotherapy targeting CD19 to perform CAR modification on allogeneic γδT cells. A novel version of the CAR-γδT product by gene editing (QH103E) that has been validated for resistance to alloreactive T cell killing and enhancement of memory efficacy will be used in this study. This is a single center, prospective, open-label, single-arm, phase 1/2 study. A total of around 30 patients with relapsed or refractory (r/r) B-cell non-Hodgkin's lymphoma (NHL) will be enrolled in the study and receive QH103E product infusion. Phase 1 (n=9 to 12) is dose escalation part, and phase 2 (n=15 to 20) is expansion cohort part. The primary objective of this study was to evaluate the safety and efficacy of QH103E in patients with r/r B-cell NHL.
Phase 1 (dose escalation) In phase 1, 9-12 subjects will be enrolled. Subjects will receive 3 doses of QH103E 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: 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, 15 to 20 subjects will be enrolled and receive QH103E infusion at dose of 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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
30
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.
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 Chinsese PLA Gereral Hospital
Beijing, Beijing Municipality, China
RECRUITINGPhase 1: Incidence of Adverse Events (AEs)
AE is defined as any adverse medical event from the date of lymphodepletion to 12 months after QH103E 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, graft-versus-host disease (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.
Time frame: 12 months
Phase 1: Incidence of Dose-Limiting Toxicities (DLTs)
DLT was defined as QH103E-related events with onset within first 28 days following infusion: * Grade 3 aGVHD that does not resolve to Grade 1 or 2 within 7 days, with the exception of isolated skin involvement aGVHD; * Grade 4 CRS, or grade 3 CRS that does not resolve 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 AE related to the QH103E that lasts for ≥14 days, except hematology toxicity.
Time frame: 28 days
Phase 1: Recommended phase 2 dose (RP2D)
The recommended dose for phase 2 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 QH103E 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 QH103E infusion
Phase 2: Progression Free Survival (PFS)
PFS is defined as the time from the QH103E 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 thecriteria 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 QH103E infusion
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 after the first infusion of QH103E infusion
Pharmacokinetics: Number and copy number of QH103E (phase 1 and phase 2)
Number and copy number of QH103E were assessed by number in peripheral blood. Blood samples were collected before and one year after cell infusion (QH103E were not detected for two consecutivetimes) to detect the number and copy number of QH103E, and to evaluate the pharmacokinetics of QH103E.
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
Time frame: Up to 28 days after infusion
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