First-in-Human Study of AMG 820, a Monoclonal Anti-Colony-Stimulating Factor 1 Receptor Antibody, in Patients with Advanced Solid Tumors.

Abstract

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. Clin Cancer Res; 23(19); 5703-10. ©2017 AACR.

• Authors: 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, Joe Stephenson Jr
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 19 Pg. 5703-5710 (Oct 01 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 28655795 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• CSF1R protein, human
• IL36A protein, human
• Interleukin-1
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
• Macrophage Colony-Stimulating Factor

Topics

• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (administration & dosage, adverse effects, blood)
• Dose-Response Relationship, Drug
• Drug-Related Side Effects and Adverse Reactions (pathology)
• Female
• Humans
• Interleukin-1 (blood)
• Macrophage Colony-Stimulating Factor (blood, genetics)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy, genetics, pathology)
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor (antagonists & inhibitors, blood, immunology)
• Treatment Outcome