Background: Doxorubicin (DOX) is the standard of care for unresectable soft tissue sarcomas (STS). DOX induces immunogenic cell death in numerous preclinical models. Immune checkpoint inhibitors (ICIs) including antibodies (ab) to PD-1 and CTLA-4 have shown modest activity, but most STS are immune “cold” tumors and do not respond. We hypothesized that concurrent DOX would improve immunogenicity of STS and boost efficacy of ICIs, including anti-CTLA-4 ab zalifrelimab (ZAL) and anti-PD-1 ab balstilimab (BAL). Methods: We conducted a single arm Phase 2 trial of combination DOX/ZAL/BAL for patients (pts) with advanced/metastatic STS in the 1^st/2^nd treatment lines without prior DOX or ICI (NCT04028063). The study was a Simon minimax 2-stage design to accrue 28 pts evaluable for primary endpoint of progression-free survival rate at 6 months (PFS_6mo) by RECIST 1.1. We aimed to improve PFS_6mo by 20% with DOX/ZAL/BAL over null rate of 43.4% based on average PFS of 2 prior DOX monotherapy trials. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), duration of response (DOR), and adverse events (AEs). All pts received up to 6 DOX cycles with concurrent ZAL/BAL; pts on stage 1 began DOX at cycle 2 with ZAL/BAL at cycle 1, pts on stage 2 began DOX/ZAL/BAL at cycle 1. Imaging was obtained prior to the first dose of DOX (baseline), and thenevery 6 weeks (wks) to 6 mo, and thereafter every 9 wks. Tumor biopsies/peripheral blood were obtained at baseline, on-treatment, and progression for immune profiling. Results: 35 patients were accrued as of 1/25/23. 25 pts are currently evaluable for primary endpoint of PFS_6mo and 28 for efficacy (at least one post-treatment scan). PFS_6mo is estimated at 52% (95%CI 31-72), with mPFS of 25.6 wks (24.0-44.9). ORR was 36% (19-56), and DCR was 86% (67-96). Median DOR was 12.8 wks (range 6 – 105). Most pts with PR who progressed did so on BAL after DOX completion. Responses were observed in pts with intimal sarcoma, angiosarcoma, MPNST, LPS, LMS, endometrial stromal sarcoma, UPS, and sclerosing epithelioid fibrosarcoma. Improved outcomes were observed in stage 1 pts compared to stage 2 pts, including PFS_6mo (56.3% v. 25.0%), mPFS (31.7 v. 25.3 wks), ORR (56% v. 8.3%), and DCR (94% v. 75%). Toxicity was as expected with grade 3/4 TRAEs in 48% of 31 evaluable pts, primarily DOX-related hematologic AEs, and immune-related AEs requiring steroids in 19% of pts. Conclusions: Combination DOX/BAL/ZAL led to meaningful efficacy, including favorable PFS_6mo and responses in several STS subtypes unlikely to respond to DOX or ICI monotherapy. Further investigation is required to determine if the stage 1 priming dose of ZAL/BAL prior to DOX improved clinical outcomes. An ongoing cohort is exploring a next-generation CTLA-4 inhibitor, botensilimab in combination with DOX +/- BAL. Clinical trial information: NCT04028063.