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Lessons learned from early closure of a clinical trial for steroid-refractory acute GVHD

Bone Marrow Transplantation volume 57, pages 302–303 (2022)Cite this article

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Steroid-refractory acute graft vs. host disease (SR-aGVHD) is highly lethal with mortality in excess of 70% [1, 2]. Ruxolitinib has the highest documented efficacy as a salvage treatment [3], but with a complete response (CR) rate of less than 35% [3, 4], new treatments, preferably with a different mechanism of action, are crucial. T-Guard is an immunotoxin combination of two equal amounts of murine monoclonal antibodies against CD3 and CD7 each conjugated to ricin toxin A, that induces apoptosis of T cells (preferentially activated T cells) and NK cells and reduces T cell activation by blocking the TCR/CD3 complex [5, 6]. A phase I/II trial of 20 patients showed a day 28 overall response rate of 60%, with a CR rate of 50% and a day 180 overall survival of 60% [7]. Additional patients treated on an expanded access program showed similar outcomes [8]. With these promising results, Xenikos (The Netherlands) and the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) opened a single arm phase III trial of T-Guard in SR-aGVHD (BMT CTN 1802, NCT04128319). Eligibility included grade II-IV SR-aGVHD (progression after 3 days or no improvement after 7 days of 2 mg/kg/d prednisone equivalent or aGVHD developing in a new organ despite prednisone 1 mg/kg/d equivalent) [9]. Exclusion criteria included GVHD overlap syndrome, treatment for aGVHD other than steroids, an uncontrolled infection, evidence of malignancy, severe hypoalbuminemia, or markedly elevated creatinine kinase. Dosing of T-Guard was the same as in the Phase I/II trial, at 4 mg/m2 body surface area, capped at 2.5 m2, every 2 days for a total of 4 doses. Steroid treatment was continued.

Three participants enrolled from December 2019 to January 2020. Enrollment was put on hold after two participant deaths were observed within 30 days of initiating study treatment. The trial was stopped after the third enrolled participant died before study day 30, triggering a pre-specified day 30 overall mortality stopping guideline.

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Acknowledgements

The authors wish to acknowledge the support provided by Xenikos and Grant Numbers U10HL069294 and U24HL138660 to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung and Blood Institute and the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Authors and Affiliations

  1. Department of Medicine, Oregon Health and Science University, Knight Cancer Institute, Portland, OR, USA

    Gabrielle Meyers

  2. BMT & Cellular Therapy Program, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

    Mehdi Hamadani

  3. Medical College of Wisconsin, Milwaukee, WI, USA

    Michael Martens

  4. Division of Leukemia, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical, Duarte, CA, USA

    Haris Ali

  5. Division of Hematology, The Ohio State University Comprehensive Cancer Center—James, Columbus, OH, USA

    Hannah Choe

  6. The Emmes Company, Rockville, MD, USA

    Peter Dawson

  7. MSK Kids Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Andrew C. Harris

  8. Xenikos BV, Nijmegen, The Netherlands

    Eric van Hooren, Willem Klaassen & Ypke van Oosterhout

  9. National Heart, Lung, and Blood Institute, Bethesda, MD, USA

    Eric Leifer

  10. Blood and Marrow Transplantation & Cellular Therapy Program, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA

    Margaret L. MacMillan

  11. H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Lia Perez

  12. Division of Oncology, BMT and Leukemia Section, Washington University School of Medicine, St. Louis, MO, USA

    Iskra Pusic

  13. Clinical Research Division, Fred Hutchinson Cancer Research Center, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA

    Phuong Vo

  14. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    John E. Levine

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  1. Gabrielle Meyers
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Contributions

GM, MH, MLM, HA, HC, PD, AH, WK, LP and JEL designed the research and wrote the paper. MM and EL analyzed the data and wrote the paper. IP, EvH, and YvO designed the research, performed research and wrote the paper. PV performed research and wrote the paper.

Corresponding author

Correspondence to Gabrielle Meyers.

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Competing interests

MH: Research Support/Funding: Takeda Pharmaceutical Company; Consultancy: Incyte Corporation; ADC Therapeutics; Pharmacyclics, Omeros, Kite. Speaker’s Bureau: Sanofi Genzyme, AstraZeneca, BeiGene. HA: Consultant and speaker bureau for Incyte, BMS. Research grant from Incyte. IP: Syndax Advisory Board. EvH, WK, and YvO: are employees of Xenikos and own equity in Xenikos. JEL: Research support from Biogen, Incyte, Kamada, and Mesoblast; consulting for Bluebird, Incyte, Jazz, Mesoblast, Omeros, Symbio, Talaris, and X4 Pharmaceuticals; GVHD biomarkers patent and royalties from Viracor.

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Meyers, G., Hamadani, M., Martens, M. et al. Lessons learned from early closure of a clinical trial for steroid-refractory acute GVHD. Bone Marrow Transplant 57, 302–303 (2022). https://doi.org/10.1038/s41409-021-01529-x

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