rapcabtagene autoleucel (YTB323)

P1/2, N=28, Not yet recruiting, Novartis Pharmaceuticals

P2, N=123, Not yet recruiting, Novartis Pharmaceuticals

P2, N=86, Recruiting, Novartis Pharmaceuticals

P1/2, N=225, Recruiting, Novartis Pharmaceuticals | Trial completion date: Jun 2027 --> May 2028

P1/2, N=28, Not yet recruiting, Novartis Pharmaceuticals

P2, N=144, Recruiting, Novartis Pharmaceuticals

In this issue of Cancer Discovery, Dickinson and colleagues present clinical data from a first-in-human study of YTB323, a novel autologous CD19-directed chimeric antigen receptor T-cell therapy generated on the T-Charge platform with preserved naive state and stemness phenotypes. Their cell doses are up to 25-fold lower than with tisagenlecleucel. See related article by Dickinson et al., p. 1982 (10).

Rapcabtagene autoleucel, a next-generation, autologous CD19- directed CAR T-cell therapy, preserved T-cell stemness, demonstrated promising durable efficacy with manageable safety. DL2 (12.5x106) CAR+ viable T cells is recommended for phase II/III studies.

Clinically, at doses 25-fold lower than tisagenlecleucel, YTB323 showed 1) promising overall safety (CRS [any-grade, 35%; grade ≥3, 6%], neurotoxicity [any-grade, 25%; grade ≥3, 6%]); 2) ORR of 75% and 80% for DL1 and DL2, respectively; 3) comparable CAR T-cell expansion; and 4) preservation of T-cell phenotype. Current data support continued development of YTB323 for r/r DLBCL.

P1/2, N=225, Recruiting, Novartis Pharmaceuticals | Phase classification: P1 --> P1/2

P1, N=225, Recruiting, Novartis Pharmaceuticals | N=110 --> 225 | Trial completion date: Oct 2025 --> Jun 2027 | Trial primary completion date: Oct 2025 --> Jun 2027

Rapcabtagene autoleucel showed remarkable in vivo expansion at DL2 by qPCR (geometric mean Cmax 26,500 copies/μg DNA) that was at the higher end of tisagenlecleucel expansion at a 25-fold lower dose, with no further increases in expansion at higher doses (Fig 2). Rapcabtagene autoleucel is a next-generation, autologous CD19-directed CAR-T cell therapy that preserves T-cell stemness, translating into durable efficacy and a manageable safety profile. DL2 (12.5×10 6 ) CAR+ viable T cells is the recommended dose for Phase II/III studies.

CRS was managed with tocilizumab, corticosteroids, and vasopressors in 7 (70%), 3 (30%), and 1 (10%) pts at DL2, respectively, and 1 DL3 pt (50%) received tocilizumab...ICANS management was based on dexamethasone, methylprednisolone, and anakinra in 2 (67%), 1 (33%), and 1 (33%) pts at DL2, respectively, and 1 DL4 pt (50%) received dexamethasone...At a 25-fold lower dose, rapcabtagene autoleucel expansion at DL2 was comparable by qPCR to tisagenlecleucel expansion in JULIET... Rapcabtagene autoleucel is a potent new CD19-directed CAR-T cell tx with distinct cellular kinetics, durable efficacy, and a manageable safety profile. DL2 (12.5×106) CAR+ viable T cells is the recommended dose for Phase III studies, based on the CR rate, favorable safety profile, and cellular kinetics. Updated results with expanded cellular kinetics and biomarker analyses will be presented at the meeting.

Tocilizumab and corticosteroids were used for CRS management in 4 (80%) and 2 (40%) pts at DL2, respectively...YTB323 expansion (C max and AUC 0-28d ) with 12.5×10 6 CAR+ cells (DL2) was comparable to a median tisagenlecleucel dose of 312×10 6 CAR+ cells in pts with DLBCL, a 25-fold lower median dose (Awasthi R, et al...Conclusion YTB323 is a potent new CAR-T cell tx with distinct cellular kinetics, encouraging early efficacy results across DL1 and DL2, and a manageable safety profile. Updated results will be presented at the meeting along with a recommended dose for subsequent trials.

T cells were enriched from healthy donor leukapheresis, followed by activation and transduction with a lentiviral vector encoding for the same CAR used for tisagenlecleucel. The novel manufacturing platform T-Charge™ used for YTB323 is simplified, shortened, and expansionless. It thereby preserves T-cell stemness, associated with improved in vivo CAR-T expansion and antitumor efficacy. Compared to approved CAR-T therapies, YTB323 has the potential to achieve higher clinical efficacy at its respective lower doses.

Tocilizumab and corticosteroids were administered for CRS management in 2 (13%) and 1 (7%) pts, respectively. YTB323 recruitment is ongoing at DL3; RP2D remains to be identified. At DL2, YTB323 showed promising efficacy and a favorable safety profile. Current data support continued development of YTB323 in r/r DLBCL pts.

P1, N=110, Recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2024 --> Oct 2025 | Trial primary completion date: Mar 2024 --> Oct 2025

P1, N=110, Recruiting, Novartis Pharmaceuticals | N=50 --> 110 | Trial completion date: Jan 2023 --> Mar 2024 | Trial primary completion date: Jan 2023 --> Mar 2024