Background: XmAb23104 is a bispecific antibody targeting T cells that simultaneously express PD-1, an immune checkpoint, and ICOS, a costimulatory molecule expressed after T cell activation. DUET-3 is a Phase 1, first-in-human, dose-escalation and expansion study in subjects with advanced solid tumors, designed to assess safety, tolerability and to identify the maximum tolerated dose (MTD) of XmAb23104. Secondary objectives are to assess pharmacokinetics (PK), immunogenicity, and preliminary anti-tumor activity. We report preliminary data from the completed dose-escalation phase. Methods: A 3+3 monotherapy dose escalation with 9 dose levels from 0.002 to 15 mg/kg has been completed. Subjects with measurable disease who progressed on prior standard therapy were eligible. A minimum 6-week washout from prior pembrolizumab was required. XmAb23104 was administered biweekly and RECIST 1.1 assessment was performed every 8 weeks. Results: Sixty-two subjects were treated in escalation at doses up to 15 mg/kg; no dose-limiting toxicities were observed and an MTD was not reached. These subjects had advanced disease, 92% were Stage IV at screening, the median number of prior therapies was 3, and 37% had previous checkpoint therapy. Thirty-seven subjects (59.7%) experienced a treatment-related adverse event (TRAE); the most common were diarrhea (9.7%), decreased appetite (9.7%), and fatigue (9.7%). The majority of TRAEs were Grades 1 or 2, with 6 subjects (9.7%) having a Grade 3 or higher TRAE. Thirteen immunotherapy-related adverse events (irAEs) occurred in 8 subjects; no individual irAE occurred in more than 1 subject. Most irAEs were mild (Grades 1 and 2) with 1 Grade 3 pruritus and 1 asymptomatic Grade 4 lipase elevation. Partial responses were observed in 3 subjects (sarcoma; prior PD-1 head and neck squamous cell carcinoma [HNSCC] and renal cell carcinoma [RCC]), and stable disease > 12 months was observed in 2 subjects with colorectal cancer (CRC; 1 MSS and 1 MSI-H). A dose of 10 mg/kg was selected after consideration of PK, safety, and clinical activity data in consultation with the investigators and continues to be evaluated in the expansion part of the study. Conclusions: The dose escalation part of this study indicates XmAb23104 was generally well tolerated at doses up to 15 mg/kg and has shown clinical activity in subjects with advanced solid tumors. CTLA4 blockade has been found to increase the frequency of ICOS-expressing T cells in prostate cancer, bladder cancer, melanoma, and hepatocellular cancer (Chen, 2009; Liakou, 2008; Wei, 2017) and may be applicable to other immunogenic tumor types. XmAb23104 is currently being studied alone or in combination with ipilimumab in expansion in non-squamous non-small cell lung carcinoma, melanoma, CRC, undifferentiated pleomorphic sarcoma, HNSCC, and RCC. Clinical trial information: NCT03752398.