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First-in-human study of the anti-HB-EGF antibody U3-1565 in subjects with advanced solid tumors

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Summary

U3–1565 is a monoclonal antibody directed against heparin-binding epidermal growth factor-like growth factor (HB-EGF), which mediates angiogenesis via induction of vascular endothelial growth factor (VEGF-A). This first-in-human study characterized the safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamics of U3–1565 in subjects with advanced solid tumors. In Part 1 (dose escalation following a modified 3 + 3 design), Cohorts 1–4, U3–1565 was administered at 2, 8, 16, and 24 mg/kg every 3 weeks for Cycle 1 and every 2 weeks thereafter. In Part 1, Cohort 5, and in Part 2 (dose expansion), U3–1565 was administered at 24 mg/kg every week. Thirty-six subjects were enrolled and treated (15 in Part 1; 21 in Part 2). No subject experienced dose limiting toxicity and maximum tolerated dose was not reached. All drug-related events were Grade 1 or 2 in severity, with fatigue and rash predominating. Following treatment with U3–1565, 1 subject with metastatic colorectal cancer experienced partial response and 6 subjects achieved stable disease. Four subjects completed the study main phase (first 12 cycles) and entered the extension phase. Of the 6/36 subjects with high (> 1500 pg/ml) baseline VEGF-A levels, all showed a decrease in VEGF-A (median − 60% [−22% to −97%]). Of the remaining subjects, only 19/30 showed a decrease (median − 18% [−2% to −82%]). Subjects with high VEGF-A baseline levels remained on treatment longer (3/6 entered study extension phase versus 1/30), and were more likely to show disease control (3/6 versus 4/30). In conclusion, U3–1565 demonstrates both proof of mechanism and clinical activity across different tumor types.

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Funding

The study described in this article was sponsored by Daiichi Sankyo.

Author information

Authors and Affiliations

  1. Stephenson Cancer Center, University of Oklahoma, 800 NE 10th Street, Suite 5050, Oklahoma City, OK, 73104, USA

    Kathleen N. Moore

  2. The Sarah Cannon Research Institute/Tennessee Oncology, 250 25th Avenue North, Suite 110, Nashville, TN, 37203, USA

    Kathleen N. Moore & Johanna C. Bendell

  3. Division of Hematology and Oncology, Wayne State University, 4100 John R/4-HWCRC, Detroit, MI, 48201, USA

    Patricia M. LoRusso

  4. Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, 19111, USA

    Anthony J. Olszanski

  5. U3 Pharma GmbH, 82152, Martinsried, Germany

    Esther Zwick-Wallasch

  6. Daiichi Sankyo Development Ltd., Gerrards Cross, SL9 0BG, UK

    Mendel Jansen

  7. Daiichi Sankyo Inc., 211 Mt Airy Rd, Basking Ridge, NJ, 07290, USA

    Alexander G. Vandell & Giorgio Senaldi

Authors
  1. Kathleen N. Moore
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  2. Johanna C. Bendell
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  3. Patricia M. LoRusso
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  4. Anthony J. Olszanski
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  5. Esther Zwick-Wallasch
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  6. Mendel Jansen
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  7. Alexander G. Vandell
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Corresponding author

Correspondence to Alexander G. Vandell.

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Conflict of interest

Kathleen N. Moore, Johanna C. Bendell, Patricia M. LoRusso, and Anthony J. Olszanski received funding from Daiichi Sankyo for the conduct of this this study. Esther Zwick-Wallasch and Mendel Jansen were employees of Daiichi Sankyo or its subsidiaries during the course of the study. Alexander G. Vandell and Giorgio Senaldi are current employees of Daiichi Sankyo.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Moore, K.N., Bendell, J.C., LoRusso, P.M. et al. First-in-human study of the anti-HB-EGF antibody U3-1565 in subjects with advanced solid tumors. Invest New Drugs 37, 147–158 (2019). https://doi.org/10.1007/s10637-018-0646-1

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  • DOI: https://doi.org/10.1007/s10637-018-0646-1

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