Phase 1 evaluation of the safety and efficacy of rapcabtagene autoleucel (YTB323) in adult patients with Relapsed/Refractory B-cell acute lymphoblastic leukemia (r/r B-ALL)

Abstract Introduction: Most adult patients (pts) with r/r B-ALL die due to disease complications, indicating a need for more effective therapies. Rapcabtagene autoleucel is an innovative autologous next-generation CD19-directed chimeric antigen receptor (CAR)-T cell therapy that is rapidly manufactured using the T-Charge™ platform. Here we present safety and efficacy data for rapcabtagene autoleucel in adults with r/r B-ALL in a phase 1, multicenter study (NCT03960840). Methods: Eligible pts were ≥18 y of age, had CD19-positive r/r B-ALL, morphologic disease in the bone marrow, ECOG 0-1, and ≥1 of the following: prior allogeneic hematopoietic stem-cell transplantation (alloHSCT), ≥2 prior therapeutic lines, primary refractory disease, relapse within 12 mo of first remission, or Philadelphia chromosome-positive B-ALL with failure/intolerance of ≥2 different tyrosine kinase inhibitors. Pts received single-infusion rapcabtagene autoleucel at targeted dose level (DL) DL1 (2.5×106 CAR+ cells), DL2 (5×106 CAR+ cells), DL3 (7.5×106 CAR+ cells), or DL4 (12.5×106 CAR+ cells). Primary endpoints characterized safety and dose-limiting toxicities (DLTs) to identify a recommended dose. Secondary endpoints assessed antitumor activity and included best overall response (BOR) of complete remission (CR)/CR with incomplete blood count recovery (CRi) by month 3, and duration of response (DOR). Results: As of February 20, 2025 (data cutoff), 41 adult pts with r/r B-ALL were enrolled and 35 (85%) received rapcabtagene autoleucel: 10 at DL1, 6 at DL2, 12 at DL3, 6 at DL4, and 1 assigned to DL3 who actually received 18.9×106 CAR+ cells. Median age was 41.0 y, 91% received ≥2 prior lines of therapy (range 1-10), and 66% had prior alloHSCT. Sixteen pts (46%) were previously treated with blinatumomab and 13 pts (37%) with inotuzumab. Median (range) time from most recent relapse/progression to infusion was 2.3 (1.0-7.6) mo. Pts were followed for a median 27.7 (18.9-49.5) mo post infusion. All pts experienced ≥1 adverse event (AE) of any grade (Gr), and 94% had a Gr ≥3 event. DLTs were experienced by 2/10 pts at DL1 (1 pt: Gr 5 cytokine release syndrome [CRS]; 1 pt: Gr 4 neurotoxicity, Gr 3 CRS, Gr 4 bone marrow failure), 1/6 pts at DL2 (Gr 4 CRS and Gr 4 ICANS), 1/12 pts at DL3 (Gr 4 neutropenia) and 0/6 pts at DL4. CRS occurred in 30 pts (86%). Gr ≥3 CRS was reported in 8 pts (23%): 3/10, 3/6, 2/12, and 0/6 pts at DL1, DL2, DL3 and DL4; 1 pt (3%) at DL1 experienced Gr 5 CRS. CRS management included tocilizumab (70%), siltuximab (10%), corticosteroids (40%), tocilizumab plus corticosteroids (37%), and anakinra (7%). Median time to CRS onset was 8 (2-15) d and time to resolution was 6 (4-8) d. Two pts experienced Gr 2 hemophagocytic lymphohistiocytosis (1 DL1, 1 DL4); both cases resolved. ICANS was reported in 9 pts (25.7%): 2, 3, 3, and 1 pts at DL1, DL2, DL3 and DL4. Gr 3/4 ICANS was reported in 5 pts (14%): 1, 1, 2, and 1 pts at DL1, DL2, DL3 and DL4. Median times to onset and resolution of ICANS were 13 (4-35) d and 5 (1-not estimable) d, respectively. Seven pts received supportive measures for ICANS, including dexamethasone (5 pts, 71%) and anakinra (3 pts, 43%). Gr 4 cytopenias were observed in all pts post baseline. All cytopenias occurring within 4 weeks of infusion had resolved by 6 mo, except for 1 case of lymphopenia at DL4. BOR of CR/CRi by 3 mo was achieved in 70% (40% CR; 30% CRi), 100% (50% CR; 50% CRi), 92% (50% CR; 42% CRi), and 83.3% (67% CR; 17% CRi) of pts at DL1, DL2, DL3 and DL4. Among pts with a measurable residual disease (MRD) status available by month 3, 6/9 (67%) at DL1, 3/3 (100%) at DL2, 8/9 (89%) at DL3, and 1/2 (50%) at DL4 achieved MRD-negativity. Median DOR was 5.3 mo for DL1 and 10.8 mo for DL2 and not reached for DL3 or DL4. Cellular expansion was higher at DL2 (geometric mean 139,000 copies/μg DNA), DL3 (55,300 copies/μg), and DL4 (68,300 copies/μg) compared with DL1 (20,900 copies/μg). Median time to last detectable CAR19 transgene concentration was 91, 226, 57, and 181 days for DL1, DL2, DL3, and DL4. Conclusions: Phase 1 results with long follow-up suggest rapcabtagene autoleucel is active with high cellular expansion, durable efficacy for DL2–DL4, and a manageable safety profile in adult pts with r/r B-ALL. DL3—at which 92% of pts achieved BOR of CR/CRi by 3 mo, with median DOR not reached after 22 mo median follow-up—exhibited an acceptable balance of safety, efficacy, and cellular expansion.