A phase 3 trial of inotuzumab ozogamicin for high-risk B-ALL: Second safety phase results from Children's Oncology Group AALL1732

10016 Background: Inotuzumab ozogamicin (InO) is effective in adults and children with relapsed/refractory (R/R) CD22+ B-acute lymphoblastic leukemia (B-ALL). Children’s Oncology Group AALL1732 is a phase 3 randomized trial evaluating InO for newly diagnosed patients (pts) with high-risk B-ALL. Given known hepatic, hematologic, and infectious toxicities, two safety phases were completed. Methods: Pts with residual marrow disease < 0.01% by end consolidation are randomized to chemotherapy (Arm A) or chemotherapy plus 2 cycles of InO (Arm B) after consolidation and interim maintenance 1 (IM1). Modifications after safety phase 1 [SP1; McNeer et al. Blood (2021) 138 (Suppl 1):3398] included reducing InO to 1.2mg/m 2 /cycle, increasing hydration during IM1 on Arm B, and enhancing supportive care in delayed intensification (DI) with antimicrobials. Safety phase 2 (SP2) assessed methotrexate (MTX) clearance, treatment delays and infectious/hepatic toxicity. Planned interim analysis is reported. Results: Fifty pts were randomized and evaluable (25 Arm A, 25 Arm B). There was no difference in gr ≥3 ALT or bilirubin elevations. Sinusoidal obstruction syndrome (SOS) occurred in 4 Arm B pts during DI including 3 (1 gr 3, 2 gr 4) in DI part 2 (DI2). IM1 day 1 MTX clearance was similar 65.4 (range 52.6-154) vs 70.2 hrs (range 56.5-267) on Arm A vs B, p = 0.27. Mean duration of IM1 was 74.8 (sd 11.8) vs 84 days (sd 13.3) on Arm A vs B, p = 0.013. Arm B IM1 duration in SP2 was shorter than SP1 [90 days (sd 15.3)]. DI part 1 (DI1) duration was similar between Arms. Arm B DI2 was longer than Arm A [53.8 (sd 20.2) vs 42.6 days (sd 9.5), p = 0.025]. Sepsis occurred in DI1 in 0 Arm A and 5 Arm B pts and in DI2 in 1 Arm A and 5 Arm B pts (Table). In DI2 1 pt on each Arm had gr 5 multiorgan failure (MOF) with sepsis. In DI1 50% of Arm A and 87.5% of Arm B pts had absolute neutrophil count (ANC) < 500 (p = 0.011). In DI2 all Arm A and 92.5% of Arm B pts had ANC < 500 with longer duration on Arm B [19.3 (sd 8.1) vs 7.8 days (sd 12.4), p = 0.015]. Compliance with prophylactic antibiotics was higher on Arm B (DI1 Arm A 41.7% vs Arm B 80.9%; DI2 Arm A 52.2% vs Arm B 85%). Conclusions: While SP2 modifications improved MTX clearance and duration of IM1, SOS and infections remain concerning on Arm B, particularly during DI. Most SOS events occurred proximal to thioguanine in DI2. Neutropenia was more pronounced in DI on Arm B but compliance with antimicrobials was high. Higher sepsis rates, primarily gr 3, were observed on Arm B with no increase in gr 5 infections. Additional modifications are planned for Arm B to further mitigate toxicity during post InO chemotherapy blocks. Clinical trial information: NCT03959085 . [Table: see text]