Background: IL-10 induces activation of STAT3 in CD8 T cells leads to increased survival, proliferation and cytotoxicity of CD8 T cells. In preclinical studies, PEG-IL-10 induces CD8 mediated tumor rejection and synergizes with cytotoxic chemotherapies. Anti-tumor activity of AM0010 alone was established in the ongoing phase 1 basket trial. Objective responses were observed in pts with renal cell cancer (RCC; 4 of 15pts), uveal melanoma and cutaneous T cell lymphoma. Methods: Pts with advanced pancreatic cancer (PDAC) were treated daily with AM0010 alone (n = 24) or in combination with FOLFOX (5), capecitabine (5) or gemcitabine/nab-paclitaxel (6). Pts with colorectal cancer (n = 16) were treated with AM0010 alone. Tumor responses were monitored following irRC. Immune responses were monitored through analysis of serum cytokines, activation of blood derived T cells, immunosequencing for peripheral T cell clonality and immunohistochemistry for the infiltration of tumors by CD8 T cells. Results: In 24 PDAC pts and 16 CRC pts treated with AM0010 monotherapy (1-20 mg/kg), G3/4 TrAEs were observed in 16 pts, including anemia (5), thrombocytopenia (9), fatigue (2) rash (3) and transaminitis (1). Most TrAEs were transient, only one patient discontinued treatment due to anemia. Colitis, pneumonitis or endocrine abnormalities were not observed. In 16 pts with PDAC treated with AM0010 plus chemotherapy, TrAEs were observed in 11 pts, including thrombocytopenia (10). At 8 weeks, 8 of 17 pts with PDAC and in 4 of 15 pts with CRC on AM0010 alone had stable disease (SD). 11 of 15 PDAC pts had a reduction of CA 19-9. 4 patients (3 PDAC, 1 CRC) had prolonged PFS > 6 months. The median overall survival of PDAC was 5.1 months (n = 20), and CRC was 15.4 months (n = 13; observation > 15mo). 13 of 15 PDAC pts treated with AM0010 and chemotherapy had SD, 2 had a PR. AM0010 increased PD-1+ activated CD8 T cells and the de-novo oligoclonal expansion of T cell clones in the blood. AM0010 increased tumor infiltrating Phospho STAT3+, Granzyme+ and PD1+ CD8+ T cells in tumors. Conclusions: The preliminary clinical activity and the mechanistic data indicating enhanced immune stimulation encourages continued exploration of AM0010 in “immune resistant” cancers. Clinical trial information: NCT02009449