Background: Agenus AGEN2034 is a fully-human IgG4 monoclonal antibody antagonist targeting Programmed Cell Death Protein-1 (PD-1). The objective was to assess safety, MTD, pharmacokinetic (PK) and pharmacodynamics (PD) characteristics of AGEN2034 in patients (pts) with advanced, refractory malignancies. Analyses of PD-1 receptor occupancy on circulating CD8+ and CD4+ effector memory T lymphocytes was completed. Methods: Thirty pts were enrolled in escalating dose cohorts of 1, 3, and 10 mg/kg. AGEN2034 is administered intravenously Q2W for up to 2 years with cohorts evaluating q3wk dosing at 6 and 10 mg/kg are underway. Results: Ten subjects were enrolled at each dose level. Median age was 58 years (range 23–77) with ECOG 0–1. No DLTs were observed. Immune-related adverse events consistent with this drug class were observed of pneumonitis, colitis, diarrhea, rash and pruritus. 21 of 30 pts had treatment-related adverse events (TRAEs). 13 subjects (43%) discontinued (d/c) due to disease progression and 2 pts d/c due to TRAEs of hepatitis (n = 1) and pneumonitis (n = 1). In 25 evaluable heavily pre-treated pts, three partial responses (two confirmed) were noted in patients with cervical, ovarian and breast cancers in 1mg/kg and 3mg/kg cohorts. At the time of data cut-off, 13 patients had stable disease, including 5 of 5 with ovarian cancer. AGEN2034 demonstrates a dose-proportional C_max of 19.6 µg/mL at 1 mg/kg and 73.6 µg/mL at 3 mg/kg in 12 patient samples analyzed in the first two cohorts. Average PD-1 receptor occupancy on circulating CD8+ and CD4+ effector memory T lymphocytes (n = 18) demonstrated > 59% saturation at all dose levels at day 15. Conclusions: AGEN2034 is a pharmacologically active, well-tolerated PD-1 antagonist antibody, demonstrating early signals of clinical activity in cervical and ovarian cancers. PK and RO results are comparable to commercial PD-1 antagonists. A phase 2 expansion in pts with relapsed/refractory cervical cancer is underway. Clinical trial information: NCT03104699