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.
Administration, Intravenous
Adolescent
Adult
Aged
Antibodies, Monoclonal
/ adverse effects
Antineoplastic Agents
/ adverse effects
Cohort Studies
Dose-Response Relationship, Drug
Female
Humans
Male
Middle Aged
Neoplasms
/ drug therapy
Pyridines
/ adverse effects
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
/ antagonists & inhibitors
Young Adult
Advanced solid tumor
CSF-1
CSF-1R inhibitor
IL-34
Immunotherapy
LY3022855
Tumor -associated macrophages
Journal
Investigational new drugs
ISSN: 1573-0646
Titre abrégé: Invest New Drugs
Pays: United States
ID NLM: 8309330
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
08
11
2020
accepted:
10
02
2021
pubmed:
25
2
2021
medline:
3
2
2022
entrez:
24
2
2021
Statut:
ppublish
Résumé
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).
Identifiants
pubmed: 33624233
doi: 10.1007/s10637-021-01084-8
pii: 10.1007/s10637-021-01084-8
doi:
Substances chimiques
Antibodies, Monoclonal
0
Antineoplastic Agents
0
CSF1R protein, human
0
LY3022855
0
Pyridines
0
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
0
Banques de données
ClinicalTrials.gov
['NCT01346358']
Types de publication
Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1057-1071Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.
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