This is an open-label, phase 1/2 study has the primary objective of decitabine-primed tandem CART 19/20 in patients with B-NHL who were confirmed as r/r B cell Non-Hodgkin's Lymphoma. A total of 19 to 33 patients are planned to be enrolled and receive decitabine-primed tandem CART 19/20 cell infusion. Phase 1 (9 to 18 cases) is dose escalation part, and phase 2 (10 to 15 cases) is expansion cohort part.
Phase 1 (dose escalation) In phase 1, 9 to 18 subjects will be enrolled. Subjects will receive 3 doses of decitabine-primed tandem CART 19/20 cell therapy (0.5 × 10\^6 cells/kg, 2 × 10\^6 cells/kg, 5 × 10\^6 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 15 subjects will be enrolled and receive decitabine-primed tandem CART 19/20 cell 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. \[Objectives\] The primary objectives of the phase 1 were to evaluate the tolerability, safety, and determine recommended phase 2 dose (RP2D). The primary purpose of the phase 2 study was to evaluate the efficacy.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
33
Phase I dose escalation (3+3) : dose 1 (0.5 × 10\^6 cells per kg) dose 2 (2 × 10\^6 cells per kg) dose 3 (5 × 10\^6 cells per kg) Phase II: Appropriate dose
Intravenous fludarabine 25-30 mg/m\^2/day on days -5, -4, and -3.
Intravenous cyclophosphamide 300-500 mg/m\^2/day on days -5, -4, and -3.
Biotherapeutic Department of Chinese PLA General Hospital
Beijing, Beijing Municipality, China
Phase 1: Incidence 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, CRS and 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 Dose-Limiting Toxicities (DLTs)
DLT was defined as CAR T cells-related events with onset within first 28 days following infusion: The development of Grade (G) 3 or higher grade CRS lasting \> 2 weeks; Any CAR T cells-related AE requiring intubation; All G4 non-hematologic toxicities.
Time frame: First infusion date of CAR T cells up to 28 days
Phase 1: Maximum tolerated dose (MTD)
MTD is defined as the highest dose level of less than or equal to 2 DLT among the 6 subjects finally determined.
Time frame: 12 months
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 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 CAR 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.
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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 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: 24 months
Phase 2: Time to response (TTR)
TTR is defined as the time from CAR T infusion to first assessed CR or PR by investigators and based on the Lugano 2014 assessment criterion.
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 and based on the Lugano 2014 assessment criterion for r/r B-cell NHL, or death regardless of cause.
Time frame: 24 months
Pharmacokinetics: Number and copy number of CAR T cells (phase 1 and phase 2)
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
Pharmacokinetics: Persistence of CAR T (phase 1 and phase 2)
Persistence of CAR 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