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 (C_max 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 C_max 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.

Sallman:Syntrix Pharmaceuticals: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Nemucore: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Magenta: Consultancy; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees; Lixte: Patents & Royalties: LB-100; Intellia: Membership on an entity's Board of Directors or advisory committees. DeAngelo:Blueprint Medicines Corporation: Consultancy, Research Funding; Incyte: Consultancy; Autolos: Consultancy; Forty-Seven: Consultancy; Gilead: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Servier: Consultancy; Kite, a Gilead Company: Consultancy; Shire: Consultancy; Takeda: Consultancy; AbbVie: Research Funding; Glycomimetics: Research Funding; Amgen: Consultancy; Agios: Consultancy. Pemmaraju:stemline: Consultancy; abbvie: Consultancy; immunogen: Consultancy; mustangbio: Research Funding; incyte: Consultancy; novartis: Research Funding; pacylex: Consultancy, Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; cellectis: Research Funding; cellularity: Research Funding. Gill:Novartis: Patents & Royalties, Research Funding; Astra Zeneca: Honoraria; Hemogenyx: Honoraria, Research Funding; Interius: Current holder of stock options in a privately-held company, Research Funding; Asher Bio: Research Funding; Carisma: Current holder of stock options in a privately-held company, Research Funding; Immpact Bio: Honoraria; Mission Bio: Membership on an entity's Board of Directors or advisory committees. Olin:Cellectis: Other: NA; Actinium: Consultancy; Astellas: Consultancy; Abbvie: Consultancy. Wang:Novartis: Consultancy, Honoraria, Other: Advisory Board; Rafael Pharmaceuticals: Other: Data Safety Monitoring Committee; Macrogenics: Consultancy; Genentech: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory Board; Dava Oncology: Consultancy, Speakers Bureau; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory Board; Gilead: Consultancy, Honoraria, Other: Advisory Board; Takeda: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: member of data monitoring committee ; Kura Oncology: Consultancy, Honoraria, Other: Advisory Board, Steering Committee, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Astellas: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board. Konopleva:AbbVie, Genentech, F. Hoffman La-Roche, Stemline Therapeutics, Amgen, Forty-Seven, Kisoji; Janssen: Consultancy; Stocks, Reata Pharmaceuticals: Current equity holder in publicly-traded company; AbbVie, Genentech, F. Hoffman La-Roche, Eli Lilly, Cellectis, Calithera, Ablynx, Stemline Therapeutics, Agios, Ascentage, Astra Zeneca; Rafael Pharmaceutical; Sanofi, Forty-Seven: Research Funding; Forty-Seven; F. Hoffman LaRoche: Honoraria; Reata Pharmaceuticals, Novartis and Eli Lilly: Patents & Royalties; Stemline Therapeutics, F. Hoffman La-Roche; Janssen: Membership on an entity's Board of Directors or advisory committees. Stark:Cellectis, Inc.: Current Employment, Current equity holder in publicly-traded company. Korngold:Cellectis, Inc.: Current Employment. Haider:Cellectis, Inc.: Current Employment, Current equity holder in publicly-traded company. Backhouse:Cellectis, Inc.: Current Employment, Current equity holder in publicly-traded company. Figliola:Cellectis, Inc.: Current Employment, Current equity holder in publicly-traded company. Lee:Cellectis, Inc.: Current Employment, Current equity holder in publicly-traded company. Frattini:Cellectis, Inc.: Current Employment, Current equity holder in publicly-traded company. Brownstein:Cellectis, Inc.: Current Employment, Current equity holder in publicly-traded company. Roboz:Astellas: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Other: travel and accommodation expenses, Research Funding; GlaxoSmithKline: Consultancy; Janssen: Consultancy, Other: travel and accommodation expenses, Research Funding; Jasper Therapeutics: Consultancy; Jazz: Consultancy, Other: travel; Takeda: Consultancy; Astex Pharmaceuticals: Consultancy, Other: Travel and Accommodation expenses, Research Funding; MedImmune: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel and accommodation expenses, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel and accommodation expenses; Bayer: Consultancy, Other: Travel and accommodation expenses; Celltrion: Consultancy, Other: Travel and accommodation expenses; Genentech/Roche: Consultancy, Other: Travel and accommodation expenses; Sandoz: Consultancy, Other: Travel and accommodation expenses; Daiichi Sankyo: Consultancy; MEI Pharma: Consultancy, Research Funding; Otsuka: Consultancy; Bristol Myers Squibb: Consultancy; Roche: Consultancy; Helsinn Therapeutics: Consultancy; Mesoblast: Consultancy; Amphivena Therapeutics: Other: Travel and accommodation expenses, Research Funding; Array BioPharma: Other: Travel and accommodation expenses; Clovis Oncology: Other: Travel and accommodation expenses; Sunesis Pharmaceuticals: Other: Travel and accommodation expenses, Research Funding; Eisai: Other: Travel and accommodation expenses; CTI: Research Funding; Karyopharm Therapeutics: Research Funding; Mofitt Cancer Center: Research Funding; Amgen: Consultancy, Other: travel; Agios: Other: travel, Research Funding; Onconova Therapeutics: Research Funding; Tensha Therapeutics: Research Funding; AbbVie: Consultancy, Other: travel and accommodations, Research Funding; Amgen: Consultancy; Agios: Consultancy, Research Funding; Actinium: Consultancy.

Alemtuzumab, an anti-CD52 monoclonal antibody, is being used as part of a lymphodepletion regimen for UCART123v1.2, an allogeneic CAR-T cell product directed against CD123 where the CD52 gene has been deleted.