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First-in-human study of the antibody DR5 agonist DS-8273a in patients with advanced solid tumors

Investigational New Drugs volume 35, pages 298–306 (2017)Cite this article

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.

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Acknowledgments

The MDSC analysis was conducted in the laboratory of Dr. Dmitry Gabrilovich, Wistar Institute, Philadelphia, PA. The authors thank the patients and their families for their contributions to this study.

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Author notes

  1. Madhuri Desai

    Present address: Eli Lilly & Company, 440 Route 22 East, Bridgewater, NJ, 08807, USA

  2. Michael L. Maitland

    Present address: Inova Schar Cancer Institute, 3289 Woodburn Rd, Annandale, VA, 22003, USA

Affiliations

  1. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-3300, USA

    Andres Forero

  2. Sarah Cannon Research Institute, 250 25th Avenue N, Suite 200, Nashville, TN, 37203, USA

    Johanna C. Bendell

  3. Daiichi Sankyo, Inc, 399 Thornall Street, Edison, NJ, 08837, USA

    Prasanna Kumar, Michael Rosen, Qiang Wang, Catherine Copigneaux, Madhuri Desai & Giorgio Senaldi

  4. Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA

    Linda Janisch & Michael L. Maitland

Authors
  1. Andres Forero
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  2. Johanna C. Bendell
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  3. Prasanna Kumar
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  4. Linda Janisch
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  5. Michael Rosen
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  6. Qiang Wang
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  7. Catherine Copigneaux
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  8. Madhuri Desai
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  10. Michael L. Maitland
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Corresponding author

Correspondence to Michael L. Maitland.

Ethics declarations

Conflict of interest

Dr. Forero declares no conflict of interest.

Dr. Bendell declares no conflict of interest.

Prasanna Kumar is an employee of Daiichi Sankyo and holds equity in the company.

Linda Janisch declares no conflict of interest.

Michael Rosen is an employee of Daiichi Sankyo and holds equity in the company.

Qiang Wang is an employee of Daiichi Sankyo and holds equity in the company.

Catherine Copigneaux is an employee of Daiichi Sankyo and holds equity in the company.

Madhuri Desai was an employee of Daiichi Sankyo at the time the study was conducted and has held equity in the company.

Giorgio Senaldi is an employee of Daiichi Sankyo and holds equity in the company.

Dr. Maitland reports funds provided to the University of Chicago to cover the costs of conducting the study.

Funding

The study was funded by Daiichi Sankyo.

Ethical approval

The study was conducted in compliance with the clinical study protocol, the ethical principles that have their origin in the Declarations of Helsinki, the International Conference on Harmonisation (ICH) consolidated Guideline E6 for Good Clinical Practice (GCP); and the United States (US) Food and Drug Administration (FDA) GCP Guidelines: Code of Federal Regulations (CFR) Title 21, parts 11, 50, 54, 56, and 312, as appropriate. The study was approved by the institutional review boards (IRB) at each of the participating investigational sites.

Informed consent

was obtained from all individual participants included in this study.

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Forero, A., Bendell, J.C., Kumar, P. et al. First-in-human study of the antibody DR5 agonist DS-8273a in patients with advanced solid tumors. Invest New Drugs 35, 298–306 (2017). https://doi.org/10.1007/s10637-016-0420-1

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  • DOI: https://doi.org/10.1007/s10637-016-0420-1

Keywords

  • DS-8273a
  • DR5
  • Phase 1
  • Pharmacokinetics
  • Apoptosis
  • Myeloid derived suppressor cells