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


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Article Info

DATE

2021-02-23

AUTHORS

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

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 IDNCT01346358 (Registration Date: May 3, 2011). More... »

PAGES

1057-1071

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10637-021-01084-8

DOI

http://dx.doi.org/10.1007/s10637-021-01084-8

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1135661771

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/33624233


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27 schema:description 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 IDNCT01346358 (Registration Date: May 3, 2011).
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33 schema:keywords CSF-1 receptor signaling
34 IL-34 levels
35 Methods Patients
36 Part B
37 QW
38 RP2D.
39 Results Fifty
40 TAMs
41 activity
42 advanced solid tumors
43 adverse events
44 amylase
45 anorexia
46 antibodies
47 background tumors
48 clearance
49 clinical activity
50 cohort
51 colony-stimulating factor-1
52 common treatment-emergent adverse events
53 dehydrogenase
54 diarrhea
55 disease
56 dose
57 dose-escalation cohorts
58 dose-escalation trial
59 dose-limiting toxicity
60 doses
61 dosing
62 effect
63 efficacy
64 events
65 factor 1
66 fatigue
67 fifties
68 frequent dosing
69 function variables
70 growth
71 high doses
72 immunogenicity
73 increase
74 levels
75 lipase
76 liver function variables
77 macrophages
78 metastasis
79 minimal effect
80 monoclonal antibodies
81 nausea
82 part
83 patients
84 pharmacokinetics
85 phase 1 dose-escalation trial
86 phase 1 study
87 population
88 pyrexia
89 receptor monoclonal antibody
90 receptor signaling
91 resistance
92 response
93 safety
94 signaling
95 solid tumor population
96 solid tumors
97 stable disease
98 standard therapy
99 study
100 therapeutic resistance
101 therapy
102 tolerability
103 toxicity
104 treatment-emergent adverse events
105 trials
106 tumor growth
107 tumor population
108 tumors
109 variables
110 vomiting
111 weeks
112 weight-based dosing
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