Background: Soft tissue sarcoma (STS) is a biologically heterogeneous disease for which existing immunotherapy approaches (e.g. anti-PD-1) have shown limited clinical activity. Cytotoxic chemotherapy with doxorubicin (D), an anthracycline, remains standard-of-care treatment for most advanced STS. Combining chemotherapy with immunomodulatory treatments may enhance antigen presentation and favorably impact the immune microenvironment (iME). APX005M (Apexigen; San Carlos, CA) is a novel CD40 agonistic antibody. Preclinically, CD40 ligation plus chemotherapy induced expression of costimulatory and major histocompatibility complex molecules on antigen presenting cells (APCs), shifted the myeloid compartment towards an M₁ phenotype and expanded T-cell receptor clonality, which are characteristics in which the sarcoma iME is deficient (2,3). In phase 1, APX005M showed dose-dependent activation of APCs in peripheral blood and favorable tolerability. We designed a phase II study evaluating D+A as a novel combination for STS. Methods: This is a single-arm, open-label, Simon 2 stage phase II study with safety lead-in evaluating D+A among 27 patients with STS. Pts have advanced STS (excluding GIST and Kaposi sarcoma) for which doxorubicin is appropriate and any prior lines of therapy, including none. Pts receive D 75 mg/m² and A 0.3 mg/m² IV day 1 in 21 day cycles. Doxorubicin is stopped after cycle 8 but APX005M may continue. The primary endpoint is the objective response rate (ORR). The study design has power of 85% to show an improvement in ORR from 10% (inactive) to 30% (active) with α = 0.04. Secondary endpoints include PFS and safety. Pts undergo collection of stool specimens at baseline and cycle 3 to evaluate composition of the gut microbiome including effects on clinical outcomes and modulation of microbiome by treatment. Pts undergo paired tumor biopsies at baseline and cycle 2 which are evaluated with gene expression and multiplex immunohistochemistry to evaluate effects of D+A on iME. The study opened in 1/2019. Clinical trial information: NCT03719430