Binding of colony-stimulating factor 1 (CSF1) ligand to the CSF1 receptor (CSF1R) regulates survival of tumor-associated macrophages, which generally promote an immunosuppressive tumor microenvironment. AMG 820 is an investigational, fully human CSF1R antibody that inhibits binding of the ligands CSF1 and IL34 and subsequent ligand-mediated receptor activation. This first-in-human phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AMG 820. Adult patients with relapsed or refractory advanced solid tumors received intravenous AMG 820 0.5 mg/kg once weekly or 1.5 to 20 mg/kg every 2 weeks until disease progression, adverse event (AE), or consent withdrawal. Twenty-five patients received ≥1 dose of AMG 820. AMG 820 was tolerated up to 20 mg/kg; the MTD was not reached. One dose-limiting toxicity was observed (20 mg/kg; nonreversible grade 3 deafness). Most patients (76%) had treatment-related AEs; the most common were periorbital edema (44%), increased aspartate aminotransferase (AST; 28%), fatigue (24%), nausea (16%), increased blood alkaline phosphatase (12%), and blurred vision (12%). No patients had serious or fatal treatment-related AEs; 28% had grade ≥3 treatment-related AEs. Grade 3 AST elevations resolved when treatment was withheld. AMG 820 showed linear pharmacokinetics, with minimal accumulation (<2-fold) after repeated dosing. Pharmacodynamic increases in serum CSF1 concentrations and reduced numbers of skin macrophages were observed. Best response was stable disease in 8 patients (32%). AMG 820 was tolerated with manageable toxicities up to 20 mg/kg every 2 weeks. Pharmacodynamic response was demonstrated, and limited antitumor activity was observed. .

51 % male, 95 % white, median age 78 years (range, 70-88), 73 % ECOG=1, 97 % Stage IV, 83 % adenocarcinoma, 44 % prior surgery, 19 % prior radiation. With a median of 2 cycles (range, 1-16), DCR=63 %, OR=7 % (0 CR, 4 PR). Median follow-up=5.8 months (all; 15.9 months survivors), median PFS =3.0 months (range, <1-25.1), median TTP=4.5 months (range, <1-25.1), and 1-year survival=26.4 % [95 % CI: 15.9, 38.2]. QOL declined initially, but improved over time. TREATMENT-related adverse events included: fatigue (48.3 %); diarrhea (38.3 %); thrombocytopenia (33.3 %), anorexia (26.7 %), mucositis (25.0 %); nausea (25.0 %), dysgeusia (20.0 %), and neutropenia (20.0 %). Conclusions The study met its primary endpoint. S produced acceptable DCR and QOL improved; however, OR was disappointing (7 %) and toxicity was greater than expected. A biomarker to identify patients more likely to benefit from S is needed.

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