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Acute Leukemias

A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias

Leukemia volume 24, pages 1437–1444 (2010)Cite this article

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Abstract

We report the results of a phase I dose escalation trial of the multikinase inhibitor sorafenib in relapsed and refractory acute leukemia patients using an intermittent dosing regimen. Fifteen patients with advanced leukemia (12 with acute myeloid leukemia, 2 with acute lymphoblastic leukemia, 1 with biphenotypic) and a median age of 63 (range 37–85) years were enrolled and treated on a dose escalation trial. Toxicities ⩾grade 3 were present in 55% of cycles and the maximum tolerated dose (MTD) was determined to be 400 mg b.i.d. × 21days in a 28-day cycle. Plasma inhibitory assays of kinase targets extracellular signal-regulated kinase (ERK) and FLT3-internal tandem duplication (ITD) showed excellent target inhibition, with FLT3-ITD silencing occurring below the MTD. The N-oxide metabolite of sorafenib seemed to be a more potent inhibitor of FLT3-ITD than the parent compound. Despite marked ex vivo FLT-3 ITD inhibition, no patients met the criteria for complete or partial response in this monotherapy study. Out of 15 patients, 11 experienced stable disease as best response. Although sorafenib showed only modest clinical activity as a single agent in this heavily treated population, robust inhibition of FLT3 and ERK suggests that there may be a potential important role in combination therapies.

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Acknowledgements

We thank Carol Hartke, Ping He, Aleksandr Mnatsakanyan, Yelena Zabelina and Linping Xu for their technical assistance; and Susan Davidson for quality assurance of the pharmacokinetic data. This work was supported by National Institutes of Health grants P30CA006973, U01CA70095, UL1 RR025005, NCI Leukemia SPORE P50 CA100632-06, R01 CA128864 and the by American Society of Clinical Oncology (MJL). MJL is a Clinical Scholar of the Leukemia and Lymphoma Society.

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Authors and Affiliations

  1. Division of Hematologic Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

    K W Pratz, E Cho, M J Levis, J E Karp, S D Gore, M McDevitt, A Stine, M Zhao, M A Carducci, M A Rudek & B D Smith

  2. Pharmaceutical Sciences Department, St Jude Children's Research Hospital, Memphis, TN, USA

    S D Baker

  3. Investigational Drug Branch, National Cancer Institute, Bethesda, MD, USA

    J J Wright

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  1. K W Pratz
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Correspondence to K W Pratz.

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Additional information

Contribution: KWP designed and performed correlative assays, analyzed correlative assays, analyzed clinical trial results and wrote the paper. EC helped in analyzing correlative assays and writing the paper. MJL helped to design and interpret correlative studies and contributed patients to the study. JEK, SDG, MM each contributed to the study design, contributed patients to the study and helped to edit the paper. MAC and JJW contributed to the study design and helped to edit the paper. AS processed clinical trial specimens and helped to conduct laboratory experiments. MAR, MZ and SDB designed, conducted and interpreted the pharmacokinetic studies. BDS developed the study design and wrote the protocol, contributed patients to the study, served as the protocol PI, analyzed the clinical trial results, contributed patients to the study and helped to edit the paper.

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Pratz, K., Cho, E., Levis, M. et al. A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias. Leukemia 24, 1437–1444 (2010). https://doi.org/10.1038/leu.2010.132

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