First-in-human study of AMG 820, a monoclonal anti-colony-stimulating factor 1 receptor antibody, in patients with advanced solid tumors
Purpose: 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 l...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
October 2017
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| In: |
Clinical cancer research
Year: 2017, Volume: 23, Issue: 19, Pages: 5703-5710 |
| ISSN: | 1557-3265 |
| DOI: | 10.1158/1078-0432.CCR-16-3261 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1158/1078-0432.CCR-16-3261 Verlag, Volltext: http://clincancerres.aacrjournals.org/content/23/19/5703 
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| Author Notes: | Kyriakos P. Papadopoulos, Larry Gluck, Lainie P. Martin, Anthony J. Olszanski, Anthony W. Tolcher, Gataree Ngarmchamnanrith, Erik Rasmussen, Benny M. Amore, Dirk Nagorsen, John S. Hill, and Joe Stephenson Jr. |
| Summary: | Purpose: 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. Experimental Design: 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. Results: 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%). Conclusions: 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. |
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| Item Description: | Gesehen am 08.11.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1557-3265 |
| DOI: | 10.1158/1078-0432.CCR-16-3261 |