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A phase I trial of the aurora kinase inhibitor, ENMD-2076, in patients with relapsed or refractory acute myeloid leukemia or chronic myelomonocytic leukemia

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Summary

ENMD-2076 is a novel, orally-active molecule that inhibits Aurora A kinase, as well as c-Kit, FLT3 and VEGFR2. A phase I study was conducted to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and toxicities of ENMD-2076 in patients with acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). Patients received escalating doses of ENMD-2076 administered orally daily [225 mg (n = 7), 375 mg (n = 6), 325 mg (n = 9), or 275 mg (n = 5)]. Twenty-seven patients were treated (26 AML; 1 CMML-2). The most common non-hematological toxicities of any grade, regardless of association with drug, were fatigue, diarrhea, dysphonia, dyspnea, hypertension, constipation, and abdominal pain. Dose-limiting toxicities (DLTs) consisted of grade 3 fatigue, grade 3 typhilitis, grade 3 syncope and grade 3 QTc prolongation). Of the 16 evaluable patients, one patient achieved a complete remission with incomplete count recovery (CRi), three experienced a morphologic leukemia-free state (MLFS) with a major hematologic improvement in platelets (HI-P), and 5 other patients had a reduction in marrow blast percentage (i.e. 11–65 %). The RP2D in this patient population is 225 mg orally once daily.

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Conflict of Interest Disclosures

Jaime Arnott, Mark R. Bray and Carolyn Sidor were employees of EntreMed, Inc. Karen WL Yee received research funding from EntreMed, Inc.

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Author notes

  1. Joseph Brandwein

    Present address: Division of Clinical Hematology, University of Alberta, Edmonton, AB, Canada

Authors and Affiliations

  1. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada

    Karen W. L. Yee, David W. Hedley, Joseph Brandwein, Andre C. Schuh, Aaron D. Schimmer, Vikas Gupta, Deborah Sanfelice, Tara Johnson & Mark D. Minden

  2. Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada

    Hsiao-Wei T. Chen, David W. Hedley & Sue Chow

  3. Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, ON, Canada

    Lisa W. Le

  4. EntreMed, Inc, Durham, North Carolina, USA

    Jamie Arnott, Mark R. Bray & Carolyn Sidor

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  1. Karen W. L. Yee
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Correspondence to Karen W. L. Yee.

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Yee, K.W.L., Chen, HW.T., Hedley, D.W. et al. A phase I trial of the aurora kinase inhibitor, ENMD-2076, in patients with relapsed or refractory acute myeloid leukemia or chronic myelomonocytic leukemia. Invest New Drugs 34, 614–624 (2016). https://doi.org/10.1007/s10637-016-0375-2

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