Background: PEGylated IL-10 induces the expansion of tumor reactive CD8 T cells both in the periphery and within the tumor. In mice, PEG-IL-10 but not non-PEG-IL-10 induces the rejection of tumors and establishes immunological memory. Primary objectives of this FIH study were to establish the safety, tolerability and the MTD of AM0010. Secondary objectives were to assess anti-tumor-activity, pharmacokinetics, immunogenicity and induced immune activation. Methods: Patients with advanced melanoma (4), non-small cell lung cancer (1), renal cell cancer (6), colorectal cancer (16), prostate cancer (1), ovarian cancer (1) and pancreatic cancer (4) were enrolled in escalating cohorts of 3-6 patients each followed by expansion cohorts. AM0010 was self-administrated daily subcutaneously at doses of 1 to 40 μg/kg. PK, anti-drug antibodies and immune responses were monitored. Results: Since November 2013, 33 patients were enrolled in cohorts of 1, 2.5, 5, 10, 20, and 40 μg/kg. An MTD was not defined through the planned maximally administered dose. Common treatment related adverse events included injection site reaction, rash, fatigue, thrombocytopenia and anemia. Most adverse events were low grade. Eight G3 adverse events were observed including anemia (3), thrombocytopenia (1), rash (1), increased lipase (1), dyslipidemia (1), transaminitis (1). The half-life of AM0010 half-life is ~20 hrs and exposures increased linearly with increasing doses. IL-18 was dose dependently increased in the serum of all patients, IFNg, IL-4, GM-CSF and IL-7 were elevated at doses > 20 μg/kg. Activation of CD8 T cells was observed. Ongoing immune related partial responses (irPR) were observed in one RCC patient (20 μg/kg; -71% at 22 weeks) and one ocular melanoma patient (40 μg/kg; -57% at 14 weeks). Additional 9 patients had stable disease at 8 weeks (1 melanoma (duration 24+ weeks); 2 RCC (21/13); 1 CRC (40+); 3 CRC, 1 pancreatic, 1 ovarian (13)). Conclusions: AM0010 has a manageable safety profile and leads to sustained and systemic Th1 immune stimulation. The pharmacodynamics and clinical activity observed support the ongoing monotherapy expansions and future combination development in a variety of advanced malignancies. Clinical trial information: NCT02009449