High Efficacy and Excellent Safety Profile of Actalycabtagene Autoleucel, a Humanized CD19 CAR-T Product in r/r B-Cell Malignancies: A Phase II Pivotal Trial

Background: Commercially approved CD19 CAR-T cell therapies are effective in r/r B cell malignancies, but are associated with significant albeit manageable toxicities. These toxicities contribute to significant morbidity. We have developed a novel, humanized CD19 CAR-T cell therapy, Actalycabtagene autoleucel (Actaly-cel) and previously reported the safety in Phase I study (Dwivedi et al. Mol Cancer Ther.2021, Karulkar et al. ASH 2022). Here, we present the pooled results from Phase I and a planned interim analysis of the Phase II study evaluating Actaly-cel. Materials and methods: The Phase I study (n=10) was a single-center trial to test the safety of Actaly-cel at a dose of 1x10 7 to 5x10 9 CAR-T cells in patients with r/r DLBCL, tFL and PMBCL (CTRI/2021/04/032727). The Phase II study (n=50) was a single-arm, multi-center study conducted across 3 centers in India (CTRI/2022/12/048211). Patients with r/r B-cell malignancies (including aggressive and indolent B-cell lymphomas and acute lymphoblastic leukemia) aged ≥ 15 years, with normal organ function, ECOG PS 0-2 and measurable disease were eligible. Actaly-cel was manufactured using an integrated semi-automated system. Bridging therapy was allowed at the clinician's discretion. Patients received infusion of Actaly-cel two days after conditioning with fludarabine plus cyclophosphamide. The target dose was ≥5x10 6/kg CAR T-cells (efficacy-evaluable cohort), however doses of ≥0.5x 10 6/kg CAR-T cells were allowed. Patients who received Actaly-cel at any dose were considered in the safety analysis. The primary endpoint was objective response rate, with duration of response, adverse events, PFS and OS as the secondary endpoints. A Simon II-stage design was used to test the hypothesis that the ORR would increase from 25% (historical data) to 40% (⍺- 0.1 and β- 0.2), >15 responses were required out of 50 patients to reject the null hypothesis. The CRS and neurotoxicities (ICANS) were graded and treated as per ASTCT guidelines, other toxicities were graded as per CTCAE v5. Exploratory studies were performed to study the correlation between patient and product related characteristics with response. Results: A total of 59 patients with r/r DLBCL (41), ALL (16) and indolent lymphomas (2) were enrolled (Phase I; 06/2021 till 06/2022 and Phase II; 12/2022 till 07/2023), 56 underwent leukapheresis (ITT set) and 47 received Actaly-cel (safety set). 43 patients received the target dose (Figure 1A). The median age was