Abstract CT137: First-in-human study of AMG 820, a monoclonal anti-CSF-1R (c-fms) antibody, in patients (pts) with advanced solid tumors
Authors: Papadopoulos Kyriakos , Gluck Larry , Martin Lainie P. , Olszanski Anthony J. , Ngarmchamnanrith Gateree , Rasmussen Erik , Amore Benny , Nagorsen Dirk , Hill John S. , Stephenson Joe 
Published: July 2016

Abstract
Background: Tumor-associated macrophages (TAMs) may contribute to tumor growth and invasion and promote an immunosuppressive tumor microenvironment, making them an attractive target for cancer immunotherapy. TAMs can be activated by the binding of colony stimulating factor-1 (CSF-1) to its receptor CSF-1R (c-fms). AMG 820 is an investigational, fully human antagonistic antibody to CSF-1R that inhibits ligand-induced receptor activation. In this open-label, sequential dose-escalation study, we evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of AMG 820.
Methods: Key eligibility criteria: age ? 18 years, advanced solid tumors relapsed or refractory to standard treatment, measurable disease per RECIST 1.1, ECOG performance status ? 2, and no primary central nervous system tumors/metastases. AMG 820 was administered by IV infusion once weekly at a starting dose of 0.5 mg/kg (cohort 1). Dosing frequency was later amended to once every 2 weeks (Q2W) with planned escalation to 1.5, 3, 6, 10, 20, and 30 mg/kg (cohorts 2–7), following a 3 + 3 design until a maximum tolerated dose (MTD, highest dose at which &lt; 33% of pts/cohort had a dose-limiting toxicity [DLT]) or highest dose was reached.
Results: A total of 25 pts received ? 1 dose of AMG 820: 3 pts at 0.5, 1.5, and 6 mg/kg; 4 pts at 3 and 10 mg/kg; 8 pts at 20 mg/kg. Median (range) age: 63 (48–80) years. Women: 56%. ECOG 0/1/2: 20%/76%/4%. MTD was not reached. One DLT was observed (20 mg/kg): nonreversible grade 3 hearing impairment in a female pt with anal cancer with confounding factors (prior treatment [tx] with cisplatin). Most pts (76%) had tx-related adverse events (TRAEs). Most common TRAEs (in &gt; 10% of pts overall) were periorbital edema (11, 44%), increased aspartate aminotransferase (7, 28%), fatigue (6, 24%), nausea (4, 16%), increased blood alkaline phosphatase (3, 12%), and blurred vision (3, 12%). Grade ? 3 TRAEs were observed in 28% of pts. There were no serious or fatal TRAEs. After the first dose of AMG 820 at 20 mg/kg, mean estimates of Cmax and AUClast (AUC from time 0 to time of last sample) were 619 μg/mL and 89,200 μg•hr/mL, respectively. Both AMG 820 AUClast and Cmax increased linearly with dose, with minimal accumulation (&lt; 2-fold) after repeated dosing. AMG 820 dosing was associated with significantly reduced skin macrophage levels compared to predose levels. At all dose levels tested, AMG 820 resulted in increases in serum CSF-1 concentrations, which were maximal at doses greater than 6 mg/kg. Of the 21 pts evaluable by central read, 8 (38%) pts had a best overall response of stable disease, including 1 pt with a 20% reduction in tumor burden (0.5 mg/kg, non-small cell lung cancer). Of the 25 pts evaluable by local read, 1 (4%) pt had a partial response with a 40% reduction in tumor burden (10 mg/kg, paraganglioma with liver metastasis), and 6 (24%) pts had stable disease.
Conclusions: AMG 820 was tolerated with manageable toxicities up to 20 mg/kg Q2W and showed linear PK, with PD response in CSF-1 serum levels and tx-related changes in skin macrophages. These results and an increasing understanding of the role of TAMs in tumor immunosuppression provide the rationale for combining AMG 820 with other immunotherapies.
Citation Format: Kyriakos Papadopoulos, Larry Gluck, Lainie P. Martin, Anthony J. Olszanski, Gateree Ngarmchamnanrith, Erik Rasmussen, Benny Amore, Dirk Nagorsen, John S. Hill, Joe Stephenson. First-in-human study of AMG 820, a monoclonal anti-CSF-1R (c-fms) antibody, in patients (pts) with advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT137.