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Dowlati A, Harvey RD, Carvajal RD, et al. LY3022855, an anti-colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody, in patients with advanced solid tumors refractory to standard therapy: phase 1 dose-escalation trial. Invest New Drugs. 2021;39(4):1057-1071doi: 10.1007/s10637-021-01084-8.
Dowlati, A., Harvey, R. D., Carvajal, R. D., Hamid, O., Klempner, S. J., Kauh, J. S. W., Peterson, D. A., Yu, D., Chapman, S. C., Szpurka, A. M., Carlsen, M., Quinlan, T., & Wesolowski, R. (2021). LY3022855, an anti-colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody, in patients with advanced solid tumors refractory to standard therapy: phase 1 dose-escalation trial. Investigational new drugs, 39(4), 1057-1071. https://doi.org/10.1007/s10637-021-01084-8
Dowlati, Afshin, et al. "LY3022855, an anti-colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody, in patients with advanced solid tumors refractory to standard therapy: phase 1 dose-escalation trial." Investigational new drugs vol. 39,4 (2021): 1057-1071. doi: https://doi.org/10.1007/s10637-021-01084-8
Dowlati A, Harvey RD, Carvajal RD, Hamid O, Klempner SJ, Kauh JSW, Peterson DA, Yu D, Chapman SC, Szpurka AM, Carlsen M, Quinlan T, Wesolowski R. LY3022855, an anti-colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody, in patients with advanced solid tumors refractory to standard therapy: phase 1 dose-escalation trial. Invest New Drugs. 2021 Aug;39(4):1057-1071. doi: 10.1007/s10637-021-01084-8. Epub 2021 Feb 23. PMID: 33624233.
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Invest New Drugs. 2021 Aug;39(4):1057-1071. doi: 10.1007/s10637-021-01084-8. Epub 2021 Feb 23.

LY3022855, an anti-colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody, in patients with advanced solid tumors refractory to standard therapy: phase 1 dose-escalation trial.

Investigational new drugs

Afshin Dowlati, R Donald Harvey, Richard D Carvajal, Omid Hamid, Samuel J Klempner, John Sae Wook Kauh, Daniel A Peterson, Danni Yu, Sonya C Chapman, Anna M Szpurka, Michelle Carlsen, Tonya Quinlan, Robert Wesolowski

Affiliations

  1. Department of Medicine Division of Hematology and Oncology, University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, OH, USA.
  2. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
  3. Department of Medicine, Division of Hematology/Oncology, Columbia University, College of Physicians and Surgeons New York, New York, NY, USA.
  4. Department of Hematology/Oncology, The Angeles Clinic and Research Institute, Cedars-Sinai Affiliate, Los Angeles, CA, USA.
  5. Department of Medicine and Oncology, Massachusetts General Hospital, Boston, MA, USA.
  6. Medical Oncology, Hutchison MediPharma Inc., Florham Park, NJ, USA.
  7. Eli Lilly and Company, Indianapolis, IN, USA.
  8. Eli Lilly and Company, Windlesham, Surrey, UK.
  9. Internal Medicine, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, 1310D Lincoln Tower, 1800 Cannon Drive, Columbus, OH, 43210, USA. [email protected].

PMID: 33624233 DOI: 10.1007/s10637-021-01084-8

Abstract

Background Tumor-associated macrophages (TAMs) promote tumor growth, metastasis, and therapeutic resistance via colony-stimulating factor-1 (CSF-1), acting through CSF-1 receptor (CSF-1R) signaling. This phase 1 study determined the safety, tolerability, pharmacokinetics-pharmacodynamics, immunogenicity, and efficacy of the anti-CSF-1R antibody LY3022855 in solid tumors. Methods Patients with advanced solid tumors refractory to standard therapy were enrolled and treated in 2 dosing cohorts: weight-based (part A) and non-weight-based (part B). Part A patients were assigned to intravenous (IV) dose-escalation cohorts: 2.5 mg/kg once per week (QW), 0.3 mg/kg QW, 0.6 mg/kg QW, 1.25 mg/kg once every 2 weeks (Q2W) and 1.25 mg/kg QW doses of LY3022855. Non-weight-based doses in part B were 100 mg and 150 mg IV QW. Results Fifty-two patients (mean age 58.6 ± 10.4 years) were treated with ≥1 dose of LY3022855 (range: 4-6). Five dose-limiting toxicities (left ventricular dysfunction, anemia, pancreatitis, rhabdomyolysis, and acute kidney injury) occurred in 4 patients. The non-weight-based 100 mg QW dose was established as the RP2D. The most common treatment-emergent adverse events were increase in liver function variables, fatigue, nausea, vomiting, diarrhea, anorexia, pyrexia, increased lipase, amylase, and lactate dehydrogenase. Clearance decreased with increasing dose and weight-based dosing had minimal effect on pharmacokinetics. Serum CSF-1, and IL-34 levels increased at higher doses and more frequent dosing, whereas TAMs and CD14dimCD16bright levels decreased. Three patients achieved stable disease. No responses were seen. Conclusions LY3022855 was well tolerated and showed dose-dependent pharmacokinetics-pharmacodynamics and limited clinical activity in a heterogenous solid tumor population. ClinicalTrials.gov ID NCT01346358 (Registration Date: May 3, 2011).

© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.

Keywords: Advanced solid tumor; CSF-1; CSF-1R inhibitor; IL-34; Immunotherapy; LY3022855; Tumor -associated macrophages

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