title: First-in-human study of the antibody DR5 agonist DS-8273a in patients with advanced solid tumors.
abstract: 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.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-3300, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Forero
authors.affiliation: Sarah Cannon Research Institute, 250 25th Avenue N, Suite 200, Nashville, TN, 37203, USA.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.affiliation: Daiichi Sankyo, Inc, 399 Thornall Street, Edison, NJ, 08837, USA.
authors.forename: Prasanna
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Janisch
authors.affiliation: Daiichi Sankyo, Inc, 399 Thornall Street, Edison, NJ, 08837, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Rosen
authors.affiliation: Daiichi Sankyo, Inc, 399 Thornall Street, Edison, NJ, 08837, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Daiichi Sankyo, Inc, 399 Thornall Street, Edison, NJ, 08837, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Copigneaux
authors.affiliation: Daiichi Sankyo, Inc, 399 Thornall Street, Edison, NJ, 08837, USA.|Eli Lilly & Company, 440 Route 22 East, Bridgewater, NJ, 08807, USA.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Desai
authors.affiliation: Daiichi Sankyo, Inc, 399 Thornall Street, Edison, NJ, 08837, USA.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Senaldi
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA. michael.maitland@inova.org.|Inova Schar Cancer Institute, 3289 Woodburn Rd, Annandale, VA, 22003, USA. michael.maitland@inova.org.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Maitland
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000074322:Antineoplastic Agents, Immunological / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002452:Cell Count; D003967:Diarrhea / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000627:therapeutic use; D014839:Vomiting / Q000139:chemically induced
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C000626597:DS-8273a; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human
keywords: Apoptosis; DR5; DS-8273a; Myeloid derived suppressor cells; Pharmacokinetics; Phase 1