title: A phase I trial of the aurora kinase inhibitor, ENMD-2076, in patients with relapsed or refractory acute myeloid leukemia or chronic myelomonocytic leukemia.
abstract: 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.
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada. karen.yee@uhn.ca.
authors.forename: Karen W L
authors.initials: KW
authors.lastname: Yee
authors.affiliation: Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada.
authors.forename: Hsiao-Wei T
authors.initials: HW
authors.lastname: Chen
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.|Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada.
authors.forename: David W
authors.initials: DW
authors.lastname: Hedley
authors.affiliation: Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada.
authors.forename: Sue
authors.initials: S
authors.lastname: Chow
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.|Division of Clinical Hematology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Brandwein
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.
authors.forename: Andre C
authors.initials: AC
authors.lastname: Schuh
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.
authors.forename: Vikas
authors.initials: V
authors.lastname: Gupta
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.
authors.forename: Deborah
authors.initials: D
authors.lastname: Sanfelice
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.
authors.forename: Tara
authors.initials: T
authors.lastname: Johnson
authors.affiliation: Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Lisa W
authors.initials: LW
authors.lastname: Le
authors.affiliation: EntreMed, Inc, Durham, North Carolina, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Arnott
authors.affiliation: EntreMed, Inc, Durham, North Carolina, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Bray
authors.affiliation: EntreMed, Inc, Durham, North Carolina, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Sidor
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D064127:Aurora Kinases / Q000037:antagonists & inhibitors; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D012008:Recurrence; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; C551397:ENMD 2076; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; C497970:FLT3 protein, human; C000588866:KDR protein, human; D019009:Proto-Oncogene Proteins c-kit; D040301:Vascular Endothelial Growth Factor Receptor-2; D051941:fms-Like Tyrosine Kinase 3; D064127:Aurora Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Acute myeloid leukemia; Aurora kinase inhibitor; Chronic myelomonocytic leukemia; ENMD-2076