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A phase 1 safety and bioimaging trial of antibody DS-8895a against EphA2 in patients with advanced or metastatic EphA2 positive cancers

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Abstract

Ephrin type-A 2 (EphA2) is a transmembrane receptor expressed in epithelial cancers. We report on a phase I dose escalation and biodistribution study of DS-8895a, an anti-EphA2 antibody, in patients with advanced EphA2 positive cancers. DS-8895a was administered at 1, 3, 10 or 20 mg/kg every 2 weeks to determine safety, pharmacokinetics and anti-tumor efficacy. All patients underwent 89Zr trace-labelled infusion of DS-8895a (89Zr-DS-8995a) positron emission tomography imaging to determine the biodistribution of DS-8895a, and correlate findings with EphA2 expression, receptor saturation and response. Nine patients were enrolled on study. Of patients enrolled, seven patients received at least one infusion of DS-8895a: four patients received 1 mg/kg dose (Cohort 1) and three patients received 3 mg/kg dose (Cohort 2). Median age was 67.0 years (range 52—81), majority male (71%), and median number of prior systemic therapies was three (range 0—8). The primary cancer diagnosis was colorectal cancer (two patients) and one patient each had gastric, head and neck, high-grade serous adenocarcinoma, lung, and pancreatic cancers. No dose-limiting toxicities or treatment-related adverse events reported. The best response for the patients in Cohort 1 was stable disease and in Cohort 2 was progressive disease. 89Zr-DS-8895a demonstrated no normal tissue uptake and specific low-grade uptake in most tumours. DS-8895a had limited therapeutic efficacy at doses evaluated and 89Zr-DS-8895a demonstrated low tumour uptake. The biodistribution data from this study were key in halting further development of DS-8895a, highlighting the importance of biodistribution studies in drug development. (Trial registration: ClinicalTrials.gov Identifier NCT02252211).

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Data availability

All data generated or analysed during this study are included in this published article [and its supplementary information files].

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Acknowledgements

Not applicable.

Funding

We acknowledge our funding sources including Daiichi-Sankyo for the support of the trial, Operational Infrastructure Support from the Victorian Government and the Clinical Trials Management group at Ludwig Cancer Research (New York), the support of SP (La Trobe University PhD Scholarship) and AMS (NHRMC Investigator Fellowship No. 1177837). This research was also undertaken using the Solid Target Laboratory, an ANSTO-Austin-LICR-ONJCRI Partnership.

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Authors and Affiliations

  1. Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia

    Hui K. Gan, Sagun Parakh, F. T. Lee, Sze Ting Lee, Graeme J. O’Keefe, Sylvia J. Gong, Carmel Murone, Fiona E. Scott, Nancy Guo, Ingrid J. G. Burvenich & Andrew M. Scott

  2. School of Cancer Medicine, La Trobe University, Melbourne, Australia

    Hui K. Gan, Sagun Parakh, Sze Ting Lee, Fiona E. Scott, Ingrid J. G. Burvenich & Andrew M. Scott

  3. Department of Medical Oncology, Austin Health, Melbourne, Australia

    Hui K. Gan, Sagun Parakh, Niall C. Tebbutt, Malaka Ameratunga, Christine Vanrenen & Jaren Caine

  4. Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia

    Sze Ting Lee, Graeme J. O’Keefe, Sylvia J. Gong, Cameron Paine & Andrew M. Scott

  5. Faculty of Medicine, University of Melbourne, Melbourne, Australia

    Sze Ting Lee & Andrew M. Scott

  6. Ludwig Cancer Research, New York, NY, USA

    Mara Giovannetti, Mary J. Macri & Ralph Venhaus

  7. Daiichi Sankyo, Inc, Basking Ridge, NJ, USA

    Masakatsu Kotsuma & Giorgio Senaldi

Authors
  1. Hui K. Gan
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  2. Sagun Parakh
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  3. F. T. Lee
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  4. Niall C. Tebbutt
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  5. Malaka Ameratunga
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  6. Sze Ting Lee
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  7. Graeme J. O’Keefe
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  8. Sylvia J. Gong
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  9. Christine Vanrenen
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  10. Jaren Caine
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  11. Mara Giovannetti
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  12. Carmel Murone
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  13. Fiona E. Scott
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  14. Nancy Guo
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  15. Ingrid J. G. Burvenich
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  16. Cameron Paine
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  17. Mary J. Macri
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  18. Masakatsu Kotsuma
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  19. Giorgio Senaldi
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  20. Ralph Venhaus
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  21. Andrew M. Scott
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Contributions

Hui K Gan, Masakatsu Kotsuma. Giorgio Senaldi, Ralph Venhaus and Andrew M. Scott contributed to the study conception and design. Material preparation, data collection and analysis were performed by all authors. The first draft of the manuscript was written by Hui K Gan and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Hui K. Gan.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Institutional Ethics Committee (IEC) at Austin Health. Written informed consent was obtained from all patients and all methods were performed in accordance with the protocol-specified guidelines and regulations.

Consent for publication

No identifiable data or material in relation to individual patients is used in this publication. Informed consent was obtained from all individual participants included in the study.

Research involving human participants and/or animals

This study was approved by the Institutional Ethics Committee (IEC) at Austin Health. The study was conducted in accordance with the principles of the Declaration of Helsinki (fourth revision, 1996) and the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines.

Informed consent

Consent to participate; Written informed consent was obtained from all patients and all methods were performed in accordance with the protocol-specified guidelines and regulations. Consent for publication: No identifiable data or material in relation to individual patients is used in this publication. Informed consent was obtained from all individual participants included in the study.

Competing interests

Not applicable. HG received honoraria, travel support and/or research funding from AbbVie, Bristol-Myers Squibb, Eisai, EMD Serono and MSD. SP: received honoraria from AstraZeneca and MSD. NT serves as a consultant to Roche, Amgen, Bristol-Myers Squibb and Eisai Pharmaceuticals. MK and GS are employees of Daiichi Sankyo and may own stock. AMS received research funding and travel support from AbbVie; received research funding from Daiichi-Sankyo, EMD Serono, Merck, Telix, Avid, Celgene, ITM, Adalta; is a consultant and has stock in Life Science Pharmaceuticals, and has stock in Paracrine Therapeutics.

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Gan, H.K., Parakh, S., Lee, F.T. et al. A phase 1 safety and bioimaging trial of antibody DS-8895a against EphA2 in patients with advanced or metastatic EphA2 positive cancers. Invest New Drugs 40, 747–755 (2022). https://doi.org/10.1007/s10637-022-01237-3

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  • DOI: https://doi.org/10.1007/s10637-022-01237-3

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