Ameli-01: A Phase I Trial of UCART123v1.2, an Anti-CD123 Allogeneic CAR-T Cell Product, in Adult Patients with Relapsed or Refractory (R/R) CD123+ Acute Myeloid Leukemia (AML)

Introduction: UCART123v1.2 is a genetically modified allogeneic T-cell product manufactured from healthy donor cells. Donor-derived T-cells are transduced using a lentiviral vector to express the anti-CD123 chimeric antigen receptor and are further modified using Cellectis' TALEN® technology to disrupt the T-cell receptor alpha constant (TRAC) and CD52 genes to minimize risk of graft-vs-host disease (GvHD) and allow use of anti-CD52-directed therapy as part of lymphodepletion (LD). AMELI-01 (NCT04106076) is a phase 1, open-label, dose-escalation trial evaluating the safety, tolerability, expansion, and persistence of UCART123v1.2 given at escalating dose levels after LD with either fludarabine and cyclophosphamide (FC) or FC with alemtuzumab (FCA) in patients (pts) with R/R CD123+ AML. Alemtuzumab was added to the LD regimen to sustain host T- and NK-cell depletion and to promote UCART123v1.2-cell expansion and persistence. Methods: Key eligibility criteria include pts 18-65 yrs, adequate organ function, ECOG PS ≤ 1, and blasts positive for CD123 by flow cytometry. Pts must have received ≥2 cycles of chemotherapy (one with standard dose cytarabine), ≥ 1 cycle of a high/intermediate dose cytarabine containing regimen, ≥ 2 cycles of an HMA combination regimen, or prior allogeneic HSCT. After LD with FC or FCA, pts received UCART123v1.2 at one of the following dose levels: 2.5x105 cells/kg (DL1); 6.25x105 cells/kg (DL2); 1.5x106 cells/kg (DL2i); or 3.03x106 cells/kg (DL3). The primary endpoint is the safety, tolerability, and MTD/RP2D of UCART123v1.2. DLTs are assessed over a 28d observation period after UCART123v1.2 infusion. Additional endpoints include investigator assessed anti-leukemic activity per 2017 ELN criteria, and expansion, trafficking, and persistence of UCART123v1.2 (assessed in peripheral blood [PB] and bone marrow [BM] by flow cytometry and vector copy number [VCN]). Measurable residual disease (MRD) was analyzed by local multiparameter flow cytometry with a sensitivity of 0.02%. Results: As of July 1, 2022, 16 pts received LD and UCART123v1.2; 8 pts received UCART123v1.2 after FC (DL1 [n=2]; DL2 [n=3]; DL2i [n=2]; DL3 [n=1]), and 8 pts received UCART123v1.2 after FCA (DL2). Pts were high risk and heavily pretreated with disease characteristics outlined in Table 1. Median baseline BM and PB % blasts was 37% (0-88%) and 19% (0-79%), and median baseline CD123 positivity by central flow cytometry in the FC and FCA arms was 82% (17-98%) and 84% (25-97%), respectively. Four pts experienced DLTs: 3 pts in FC arm (G4 CRS [1pt in DL2i and 1pt in DL3] and G3 ICANS [1pt in DL2i]); and 1 pt in FCA arm (G5 CRS in DL2). Cytokine release syndrome (CRS) occurred in 15/16 pts (FC arm [n=7]; FCA arm [n=8]), of which 3 pts experienced ≥ G3 CRS which were classified as DLTs as noted above (FC arm G4 [n=2]; FCA arm G5 [n=1]). Responses were assessed beginning on D28. Evidence of UCART123v1.2 activity was observed in 4/16 pts with best overall responses as follows: FC arm (DL2: 1 SD; DL2i: 1 MLFS); FCA arm (DL2: 1 SD and 1 MRD-negative CR). The pt in the DL2 FCA arm with SD achieved greater than 90% BM blast reduction (60% to 5%) at D28. The pt with CR, who had failed 5 prior lines of therapy including HSCT and had baseline G4 cytopenias, had CRi at D28 with full count recovery at D56 and remains in an MRD-negative CR beyond the 8-month f/u visit. Adequate lymphodepletion was not achieved in the FC arm, as host lymphocyte recovery was observed in 7/8 pts prior to D28, and only 3/8 pts had UCART123v1.2 expansion (Cmax ranged from 3,757 to 27,828 copies/μg DNA). In contrast, FCA LD resulted in robust lymphodepletion for greater than 28 days in all pts, and 6/8 demonstrated UCART123v1.2 expansion, with Cmax ranging from 13,177 to 330,530 copies/μg DNA, an almost 9-fold increase compared with FC LD. An increase in inflammatory markers, notably serum ferritin, and serum cytokines (including IL-2, IL-6, IL-10, IL-15, IFN-γ, and TNF-α) in the FCA arm correlated with both UCART123v1.2 expansion and CRS. Conclusions: Adding alemtuzumab to the FC regimen was associated with improved LD and significantly higher UCART123v1.2 cell expansion and persistence, which correlated with improved activity and safety, including one pt in the DL2 FCA arm who achieved a durable MRD-negative CR. Overall, these data support the safety and activity of UCART123v1.2 after FCA LD in pts with CD123+ R/R AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal