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First-in-human study of the antibody DR5 agonist DS-8273a in patients with advanced solid tumors
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First-in-human study of the antibody DR5 agonist DS-8273a in patients with advanced solid tumors
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Journal Article
First-in-human study of the antibody DR5 agonist DS-8273a in patients with advanced solid tumors
2017
Overview
Summary
Background
DR5 is a transmembrane receptor that transduces extracellular ligand-binding to activate apoptosis signaling cascades. This phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of a new monoclonal antibody potent DR5 agonist, DS-8273a, in subjects with advanced solid tumors.
Methods
The study comprised dose escalation and dose expansion cohorts. The dose escalation cohorts intended to determine the safety and to identify the maximum tolerated dose (MTD) or maximum administered dose (MAD) and to characterize the pharmacokinetics and pharmacodynamics by a conventional 3 + 3 design (starting at 2 mg/kg and escalating through 8, 16 and 24 mg/kg once every 3 weeks). In the dose expansion cohort, additional subjects were treated at the MAD for further evaluation of PK and safety.
Results
Thirty two subjects were enrolled and treated, 16 in the dose escalation cohorts and 16 in the dose expansion cohort. No subjects experienced a dose limiting toxicity (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14 (44%) of which were attributed to study-drug; all drug-related events were grade 1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea. Measures of plasma exposure increased dose-proportionally and the mean terminal elimination half-life was 11 days. Blood samples available from a subset of patients treated at 24 mg/kg revealed declines in myeloid derived suppressor cells (MDSC) at 2 weeks. No objective responses were observed in any subjects.
Conclusions
DS-8273a was well tolerated and demonstrated linear pharmacokinetics. Decreases in MDSC were temporally associated with DS-8273a exposure. This agent could be studied further in combination with other agents, pending further proof-of-target-engagement.
Publisher
Springer US,Springer Nature B.V
Subject
/ Aged
/ Antibodies, Monoclonal - adverse effects
/ Antibodies, Monoclonal - pharmacokinetics
/ Antibodies, Monoclonal - pharmacology
/ Antibodies, Monoclonal - therapeutic use
/ Antineoplastic Agents - adverse effects
/ Antineoplastic Agents - pharmacokinetics
/ Antineoplastic Agents - pharmacology
/ Antineoplastic Agents - therapeutic use
/ Diarrhea
/ Diarrhea - chemically induced
/ Exposure
/ Fatigue
/ Fatigue - chemically induced
/ Female
/ Humans
/ Male
/ Medicine
/ Myeloid-Derived Suppressor Cells - drug effects
/ Nausea
/ Oncology
/ Receptors, TNF-Related Apoptosis-Inducing Ligand - agonists
/ Safety
/ Studies
/ Toxicity
/ Tumors
/ Vomiting
