ATHENA chimeric antigen receptor (CAR)-T, a CD19-directed CAR-T cell immunotherapy comprised of allogeneic T cells prepared for the treatment of relapsed or refractory (r/r) B-cell non-Hodgkin's lymphoma (NHL). The cells are from healthy adult volunteer donors that are knocked out of TRAC and Power3 (SPPL3) genes ex vivo using CRISPR-Cas9 gene editing components. In this study, a second-generation anti-CD19 CAR prototype was constructed, bearing murine FMC63 single-chain variant fragment (scFv) together with intracellular CD28 co-stimulatory and CD3ζ signaling domains linked by a CD28 sequence comprising the hinge and transmembrane domains. This is a single center, prospective, open-label, single-arm, phase 1/2 study. A total of around 30 patients with r/r B-cell NHL will be enrolled in the study and receive allogeneic CD19-CAR-T cell infusion. Phase 1 (n=6 to 18) is a dose escalation part, and phase 2 (n=10 to 12) is a expansion cohort part. The primary objective of this study was to evaluate the safety and efficacy of ATHENA CAR-T cell therapy in patients with r/r B-cell NHL.
Phase 1 (dose escalation) In phase 1, 6-18 subjects will be enrolled. Subjects will receive 3 doses of ATHENA CAR-T cell therapy ( 1× 10\^6 cells/kg、3× 10\^6 cells/kg、1 × 10\^7 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 ATHENA 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 ATHENA 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 ATHENA CAR-T 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 ATHENA CAR-T in patients with r/r B-cell NHL, and determine RP2D. The primary purpose of the phase 2 study was to evaluate the efficacy of ATHENA CAR-T in the above population.
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 (1 × 10\^7 cells/kg); Phase 2 : dose of RP2D. No more than 2 × 10\^5 per kilogram of allogenic residual CD3+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, Chinese PLA General Hospital
Beijing, China
RECRUITINGEdiGene Inc
Beijing, China
RECRUITINGSchool of Life Sciences, Peking University
Beijing, China
RECRUITINGPhase 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 ATHENA 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. Graft-versus-host-disease(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 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 ATHENA 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: 3-month objective response rate (ORR)
ORR is defined as the proportion of patients who have achieved complete response (CR) and partial response (PR) assessed by investigators and based on the Lugano 2014 assessment criterion.
Time frame: 3 months
Phase 2: CR rate
CR rate is defined as the proportion of patients who have achieved CR assessed 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
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.
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 1 and phase 2: Pharmacokinetics: Levels of ATHENA CAR-positive T cells circulating in blood over time
Number and copy number of ATHENA 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: Levels of CD19+ cells and serum cytokines in peripheral blood
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.
Time frame: Up to 28 days after infusion
Phase 1: 3-month ORR
ORR is defined as the proportion of patients who have achieved CR and PR assessed by investigators and based on the Lugano 2014 assessment criterion.
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 and clinical significant changes in safety lab values
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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