Background: Immune checkpoint inhibitors have limited efficacy in soft tissue sarcoma (STS) due to insufficient T-cell activation and infiltration by immunosuppressive macrophages. Sotigalimab (S), a high-affinity humanized monoclonal antibody for CD40, promotes antigen presentation, stimulates T-cell responses, and reprograms immunosuppressive macrophages. Preclinical studies with CD40 agonists revealed efficacy in immune “cold” tumor types and synergy with chemotherapy. Standard first-line doxorubicin (D) provides objective response rate (ORR) < 15% and median progression free survival (mPFS) of 4-6 mos in advanced STS. We therefore conducted this first-in-human study of D+S in STS. Methods: An open-label, single-arm, multi-center, phase 2 study evaluated D+S in advanced STS. Pts had ECOG PS ≤ 1 and any number of prior lines (but were anthracycline-naïve). The study initially enrolled all STS subtypes (except KS and GIST) but was amended in 12/2020 to limit enrollment to dedifferentiated liposarcoma (DDLPS), leiomyosarcoma (LMS), and undifferentiated pleomorphic sarcoma (UPS). Pts received D 75 mg/m² IV D1 + S 0.3 mg/kg IV D1 for eight 21-day cycles, followed by S monotherapy. A safety lead-in was performed (first 6 patients). Primary endpoint was ORR. Secondary endpoints included PFS and safety. A Simon two-stage design was used. If ≥ 7/32 responded overall, the treatment would be considered promising (85% power, α = 0.05). A subset of patients underwent paired tumor biopsies. Results: 32 pts have enrolled (median age 62; 10 LMS, 10 UPS, 9 DDLPS, 3 other). 4 pts remain on treatment with median follow-up of 2.8 mos (1 UPS pt has not reached first imaging). D (75 mg/m2) + S (0.3 mg/kg) was safe and tolerable without dose limiting toxicity. Overall ORR was 16% (5/31). Objective responses occurred in UPS (2), LMS (1), other LPS (1), and epithelioid hemangioendothelioma (1). Overall mPFS was 7.5 mos (95% CI 5.6-14.9 mos) and PFS rate at 6 and 12-mos was 55% and 31%, respectively. mPFS by STS subtype was 11.9 mos (95% CI: 10.3 – NE) for DDLPS, 7.5 mos (95% CI: 1.4—NE) for UPS and 5.6 mos (95% CI: 1.3 – NE) for LMS. Overall, 17/31 (55%) pts experienced grade 3 or 4 adverse events (AEs): most commonly, neutropenia (32%), febrile neutropenia (19%), and anemia (16%). 16% of pts experienced cytokine release (all low-grade). Correlative analysis of biopsies with high-definition spatial proteomics is ongoing. Conclusions: D (75 mg/m2) + S (0.3 mg/kg) every 21 days is safe and tolerable in STS. Final analysis of the primary endpoint awaits further follow-up on recently enrolled patients. Subtype-specific analysis suggests improvement in median PFS for DDLPS over historical controls: 11.9 mos vs 4 mos (Stacchiotti S. Ann Oncol 2020; Livingston M. Sci Rep 2017). An expansion of the DDLPS cohort is planned. Clinical trial information: NCT03719430.