e23525 Background: Doxorubicin combined with ifosfamide (IFO) is one of the preferred treatment options for non-specific soft tissue sarcomas (STS), but is limited by cumulative cardiotoxicity and severe myelosuppression. Pegylated liposomal doxorubicin (PLD) provides an effective alternative to conventional anthracyclines with reduced toxicity. However, there is no standard dose recommendation for PLD combined with IFO for STS. The present study aimed to investigate the maximum tolerated dose (MTD) of PLD combined with IFO in advanced STS patients. Methods: This was a phase I, open-label, single-center, dose-escalation study. Patients with locally advanced or metastatic STS were enrolled, except for gastrointestinal stromal tumors, Ewing's sarcomas, embryonal rhabdomyosarcomas, and alveolar rhabdomyosarcomas. We used a standard 3 + 3 dose-escalation design with progressively increasing PLD and IFO (3 g/m2 per day for 3 days, q3w) for one cycle, with a dose escalation ranged from 30 to 70 mg/m2 (5mg/m2 increment per step). The primary endpoint was determination of the MTD, and the secondary endpoint was the incidence/severity of adverse events (AEs). Results: From January 2020 to September 2022, 23 patients were enrolled in this study, including 3 patients at doses 30-45 mg/m2, 6 patients at dose 50 mg/m2, and 5 patients at 55 mg/m2. The median age was 49 years (ranges from 30 to 68 years), the male/female ratio was 12/11, and 22 (95.65%) patients had stage IV disease (AJCC staging system). Initially, no DLT was observed at doses of 30-50 mg/m2, with 3 patients in each dose phase. Two patients developed DLTs at the 55 mg/m2 dose, resulting in the 50 mg/m2 dose extending to a total of 6 patients who completed treatment without DLT. The DLTs at dose 55 mg/m2 of the first patient were grade 4 neutropenia lasting ≥ 5 days and grade 3 thrombocytopenia with hemorrhage tendency; the second patient had grade 4 neutropenia lasting ≥ 5 days, grade 4 thrombocytopenia relapsed after platelet transfusion, and grade 3 increased alanine aminotransferase. Therefore, the MTD of PLD was 50 mg/m2. The most common (≥ 10%) grade 3-4 AEs in all patients were lymphopenia (56.52%), neutropenia (82.61%), leukopenia (86.96%), and thrombocytopenia (13.04%). Conclusions: For patients with locally advanced or metastatic STS, single cycle PLD combined with IFO had a tolerable AE profile, with an MTD of 50 mg/m2 for PLD. Further researches are needed to confirm the multi-cycle recommendation. Clinical trial information: ChiCTR1900028270 .