Background: JNJ-64457107 (JNJ-107) is an agonistic human monoclonal (IgG1) antibody targeting CD40, a novel target for anti-tumor immunotherapy with a central role in adaptive and innate immunity. Methods: JNJ-107 was administered intravenously Q2W in treatment cycles of 28 days. Dose escalation was pursued with (w) and without (wo) pre-infusion steroids for mitigation of infusion related reactions (IRRs). Dose-limiting toxicity (DLT), safety, PK, PD and antitumor activity were evaluated. Results: 95 pts of age 18-80 years (median 59) were enrolled in 7 cohorts (n = 50, 75µg/kg – 2000 µg/kg) w/steroids and 5 cohorts (n = 45, 75 µg/kg – 1200 µg/kg) wo/steroids and received 1-26 (median 3) cycles of JNJ-107. Two DLTs occurred: Grade (G) 3 headache lasting 5 days at 1200 µg/kg w/steroids and G3 ALT/AST + G2 bilirubin increase at 1200 µg/kg wo/steroids. Most frequent adverse events (≥20%) were pyrexia (41%), fatigue (39%), pruritus (39%), headache (26%), chills (26%), nausea (22%) and rash (21%). IRRs were reported in 51% of pts (G1-G2 50%, G3 1%). Most commonly reported IRRs (≥10%) were pruritus (31%), rash (15%), chills (13%) and flushing (12%). Cetirizine and Montelukast premedication during dose escalation wo/steroids significantly reduced IRRs. Preliminary PK of JNJ-107 suggest target mediated drug disposition with rapid decline in serum concentrations (half-life of ~13h at 600 µg/kg and ~ 24h at doses ≥1200 µg/kg). Dose proportional increase in C_max and AUC(last) was observed at doses ≥1200 µg/kg and more than dose proportional increase was seen at lower doses. PD of JNJ-107 demonstrated dose-independent reduction in peripheral blood B cells recovering in a dose-dependent manner. MCP-1, IP-10, MIP-1a, and MIP-1b cytokines showed high-level responses with cytokine/chemokine secretion kinetics consistent, but not confirmatory, for activation of antigen presenting cells. IFNg, TNF, and IL-8 showed moderate responses reflecting downstream T cell activation. Other tested cytokines were at low levels. A partial response lasting 9.2 months was observed in 1 pt with renal cell cancer. 13 (14%) and 10 (11%) pts showed stable disease lasting ≥3 months and ≥ 6 months, respectively. Conclusions: The CD40 agonist JNJ-107 has a manageable safety profile with favorable PK and PD properties. Future clinical development will require combination with either chemotherapy, or other immunotherapies such as antitumor vaccines or checkpoint inhibitors. Clinical trial information: NCT02829099