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12.07.2016 | PHASE I STUDIES | Ausgabe 5/2016

Investigational New Drugs 5/2016

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

Investigational New Drugs > Ausgabe 5/2016
Karen W. L. Yee, Hsiao-Wei T. Chen, David W. Hedley, Sue Chow, Joseph Brandwein, Andre C. Schuh, Aaron D. Schimmer, Vikas Gupta, Deborah Sanfelice, Tara Johnson, Lisa W. Le, Jamie Arnott, Mark R. Bray, Carolyn Sidor, Mark D. Minden


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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