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Randomized, dose-escalation study of the p38α MAPK inhibitor SCIO-469 in patients with myelodysplastic syndrome

Leukemia volume 27, pages 977–980 (2013)Cite this article

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Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis with peripheral cytopenias and increased propensity for progression to acute myeloid leukemia.1 p38 mitogen-activated protein kinase (MAPK) belongs to a family of widely expressed serine–threonine kinases,2 which include four isoenzymes (α,β,γ and δ) encoded by different genes with distinct tissue expression patterns. In bone marrow biopsy sections from patients with lower-risk MDS, immunohistochemical staining revealed constitutive activation of p38α MAPK in bone marrow precursors irrespective of morphologic subtype.3, 4 Increased phosphorylation of p38α MAPK correlated with interleukin (IL)-1β expression level and cleaved caspase-3, implicating the signaling pathway in the apoptotic response in MDS.5

We investigated the safety and tolerability, as well as hematologic response and pharmacodynamics, of SCIO-469 (indole-5-carboxamide), a potent selective adenosine triphosphate-competitive inhibitor of p38α MAPK.5, 6 We conducted the phase I/II randomized, open-label, multicenter, modified parallel dose escalation study in patients with low- and intermediate-1-risk MDS classified according to International Prognostic Scoring System (IPSS)7 who did not respond to prior treatment with a recombinant erythropoietin. The protocol was approved by the Institutional Review Board at each participating institution, and all patients provided informed written consent.

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Acknowledgements

We thank Ms Rasa Hamilton, Gayle Behrle and Judith M Simon for their assistance with paper editing and Dr Peter Bowers for a review of the paper. Research support: the clinical study described here was sponsored by research funding from Scios, Inc.

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Authors and Affiliations

  1. Department of Malignant Hematology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    L Sokol & A F List

  2. Department of Medicine, Indiana University Cancer Center, Indianapolis, IN, USA

    L Cripe

  3. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    H Kantarjian & G Garcia-Manero

  4. Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Foundation Taussig Cancer Center, Cleveland, OH, USA

    M A Sekeres

  5. Dallas VA Medical Center, Dallas, TX, USA

    S Parmar

  6. Department of Medicine, Stanford University Medical Center, Stanford, CA, USA

    P Greenberg

  7. Department of Medicine, John Theurer Cancer Center of Hackensack University Medical Center, Hackensack, NJ, USA

    S L Goldberg

  8. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

    V Bhushan

  9. Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA

    J Shammo

  10. Department of Internal Medicine, University of Iowa, Iowa City, IA, USA

    R Hohl

  11. Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA

    A Verma

  12. SCIOS Inc, Fremont, CA, USA

    Y-P Li, A Lowe & J Zhu

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  1. L Sokol
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  15. J Zhu
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  16. A F List
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Corresponding author

Correspondence to L Sokol.

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Competing interests

Mikkael Sekeres serves on the advisory boards/steering committees for Celgene and Amgen. The remaining authors declare no conflict of interest.

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Sokol, L., Cripe, L., Kantarjian, H. et al. Randomized, dose-escalation study of the p38α MAPK inhibitor SCIO-469 in patients with myelodysplastic syndrome. Leukemia 27, 977–980 (2013). https://doi.org/10.1038/leu.2012.264

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