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

  • Clin Cancer Res. 2017 Oct 1;23(19):5703-5710. doi: 10.1158/1078-0432.CCR-16-3261.
Kyriakos P Papadopoulos  1 ,  Larry Gluck  2 ,  Lainie P Martin  3 ,  Anthony J Olszanski  3 ,  Anthony W Tolcher  4 ,  Gataree Ngarmchamnanrith  5 ,  Erik Rasmussen  6 ,  Benny M Amore  7 ,  Dirk Nagorsen  5 ,  John S Hill  5 ,  Joe Stephenson Jr  2
Affiliations
  • 1. Hematology/Oncology, START (South Texas Accelerated Research Therapeutics), San Antonio, Texas. [email protected].
  • 2. Medical Oncology/Hematology, Greenville Health System Cancer Institute, Greenville, South Carolina.
  • 3. Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
  • 4. Clinical Research, START (South Texas Accelerated Research Therapeutics), San Antonio, Texas.
  • 5. Early Development, Hematology and Oncology, Amgen Inc., Thousand Oaks, California.
  • 6. Biostatistical Sciences, Amgen Inc., Thousand Oaks, California.
  • 7. Clinical Pharmacology, Modeling and Simulation, Amgen Inc., South San Francisco, California.
PMID: 28655795 DOI: 10.1158/1078-0432.CCR-16-3261
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.

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