Alrizomadlin (APG-115) alone or in combination with lisaftoclax (APG-2575) for the treatment of pediatric patients with relapsed/metastatic rhabdomyosarcoma (RMS) or other soft-tissue sarcomas (STSs).

10012 Background: Pediatric tumors rarely harbor TP53 mutations but often overexpress antiapoptotic BCL-2 family proteins (BCL-2, BCL-XL, MCL-1), making MDM2 and BCL-2 inhibitors attractive therapeutic approaches. Preclinical data have shown that dual targeting these proteins results in synthetic lethality, which may overcome chemoresistance in pediatric patients with STSs. The study evaluated the safety and preliminary efficacy of alrizomadlin alone or combined with lisaftoclax in heavily pretreated relapsed/metastatic pediatric RMS, neuroblastoma (NB) and other STSs. Methods: This Chinese multicenter trial (NCT05701306; APG115XC103) assessed alrizomadlin (± lisaftoclax) in children with heavily pretreated relapsed/metastatic RMS, Ewing sarcoma (EWS), NB, or other STSs; Lansky or Karnofsky PS ≥ 50; and no CNS metastases. Alrizomadlin alone was administered orally at 30, 60, or 90 mg/m 2 QOD (2 weeks on, 1 week off). When combined with lisaftoclax (250, 375, or 500 mg/m 2 oral QD), alrizomadlin dose was 90 mg/m 2 QOD in 21-day cycles until progression or toxicity. The primary endpoints were safety and RP2D for the combination. ORR was assessed per INRC for NB or RECIST v1.1 for other solid tumors. Results: As of January 16, 2025, 16 pediatric patients received alrizomadlin monotherapy at 30 (n = 5), 60 (n = 4), or 90 mg/m 2 (n = 7). No DLT was observed; the recommended dose was 90 mg/m 2 when combined with lisaftoclax. Most common TRAEs were gastrointestinal and hematologic. Grade ≥ 3 TRAEs included thrombocytopenia (42.9%) and neutropenia (28.6%). One patient (14.3%) experienced treatment-related SAEs (thrombocytopenia, febrile neutropenia, and leukopenia). No treatment-related discontinuation or death occurred. In the combination arm, 18 patients were treated with alrizomadlin (90 mg/m 2 ) combined with lisaftoclax at 250 (n = 13) or 375 mg/m 2 (n = 5). No DLT was observed. Most common TRAEs were gastrointestinal and hematologic. Grade ≥ 3 TRAEs included thrombocytopenia (38.9%), neutropenia (33.3%), leukopenia (27.8%), and anemia (27.8%). One (5.6%) treatment-related SAE of thrombocytopenia was reported. No treatment-related discontinuation or death occurred. In monotherapy, 1 patient with refractory RMS achieved CR; 2 patients with STSs maintained stable disease. In the combination arm, 10 patients were evaluable for response, showing 1 CR (EWS), 1 PR among 4 patients with RMS, and 1 PR among 3 patients with NB. ORR (CR + PR) was 30% and DCR 80%. Conclusions: Alrizomadlin alone or in combination with lisaftoclax showed a manageable safety profile, with preliminary antitumor activity in heavily pretreated R/R RMS, EWS, and NB. The potential mechanisms, safety, and efficacy of alrizomadlin combined with lisaftoclax for pediatric RMS and other STSs warrant further investigation. Clinical trial information: NCT05701306 .