Ameli-01: Phase I, Open Label Dose-Escalation and Dose-Expansion Study to Evaluate the Safety, Expansion, Persistence and Clinical Activity of UCART123 (allogeneic engineered T-cells expressing anti-CD123 chimeric antigen receptor), Administered in Patients with Relapsed/Refractory Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults, with an incidence that increases with age, and a generally poor prognosis. The prognosis remains especially grim for those who are older, have secondary AML, or relapsed or refractory (R/R) disease, in which 5-year OS is 5-10%. Therefore, novel therapeutic approaches are needed. CD123(IL3Rα) is a cell surface target that is expressed on normal, committed hematopoietic progenitor cells, and a variety of hematological neoplasms, including AML, myelodysplastic syndrome (MDS), and blastic plasmacytoid dendritic cell neoplasm (BPDCN). UCART123 is genetically modified, allogeneic (“off-the-shelf”), anti-CD123 CAR T cell product candidate in which the TCR alpha constant gene is disrupted to reduce the risk of GvHD, and the CD52 gene is disrupted to permit the use of alemtuzumab for selective and prolonged host lymphodepletion. Also, the CAR is co-expressed with a suicide mechanism (RQR8), which can be activated by using rituximab. In vitro data have demonstrated that UCART123 efficiently targets primary AML cells, with minimal effect on normal progenitors. Also, in PDX mouse models of AML, UCART123 cells can eliminate tumor cells in vivo, prevent relapse, and improve survival; in a competitive BM/AML PDX model, UCART123 cells demonstrated preferential targeting of AML blasts (Guzman; Blood 2016).

Methods: AMELI-01 is a phase 1, multi-center clinical trial of UCART123 that employs an mTPI design to evaluate the safety, tolerability and preliminary anti-leukemia activity of UCART123 in patients (pts) with R/R AML. Additional objectives include determination of the MTD; characterization of the expansion, trafficking and persistence of UCART123; assessment of cytokine, chemokine and CRP levels after UCART123 infusion; and assessment of immune cell depletion, reconstitution and immune response. Dose escalation will include up to 28 pts. The dose expansion portion follows a Simon 2-stage design and will enroll up to an additional 37 pts. Eligible pts must be ≤ 65 years of age with R/R AML, adequate organ function, a confirmed donor for potential back-up stem cell transplantation, and no ongoing > G1 toxicity from prior treatment. Pts with APL, prior gene or cellular therapy, > 1 allogeneic SCT, or those with a clinically relevant CNS disorder (including CNS leukemia) are not eligible. Pts receive a lymphodepletion (LD) regimen of either fludarabine and cyclophosphamide (FC) or fludarabine, cyclophosphamide plus alemtuzumab (FCA) starting on Day -5, followed by an infusion of UCART123 at one of 5 dose levels on Day 0. Pts are evaluated for the presence of dose-limiting toxicities (DLT) during a 28-day observation period, which extends to 42 days in the setting of marrow aplasia and/or persistent clinically significant cytopenias without residual AML. DL1 has cleared safety without DLT, and enrollment at the next dose levels are proceeding.

ClinicalTrials.gov Identifier: NCT03190278

Monica L. Guzman, et al; Allogeneic TCRα/β Deficient CAR T-Cells Targeting CD123 Prolong Overall Survival of AML Patient-Derived Xenografts. Blood 2016; 128 (22): 765. doi: https://doi.org/10.1182/blood.V128.22.765.765