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: 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
• Journal: Investigational new drugs (Invest New Drugs) Vol. 34 Issue 5 Pg. 614-24 (10 2016) ISSN: 1573-0646 [Electronic] United States
• PMID: 27406088 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• Antineoplastic Agents
• ENMD 2076
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• STAT5 Transcription Factor
• FLT3 protein, human
• KDR protein, human
• Proto-Oncogene Proteins c-kit
• Vascular Endothelial Growth Factor Receptor-2
• fms-Like Tyrosine Kinase 3
• Aurora Kinases
• Proto-Oncogene Proteins c-akt
• Ribosomal Protein S6 Kinases
• Extracellular Signal-Regulated MAP Kinases

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Aurora Kinases (antagonists & inhibitors)
• Drug Resistance, Neoplasm
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Humans
• Leukemia, Myeloid, Acute (drug therapy, metabolism)
• Leukemia, Myelomonocytic, Chronic (drug therapy, metabolism)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Protein Kinase Inhibitors (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-kit (antagonists & inhibitors)
• Pyrazoles (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Pyrimidines (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Recurrence
• Ribosomal Protein S6 Kinases (metabolism)
• STAT5 Transcription Factor (metabolism)
• Treatment Outcome
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors)
• fms-Like Tyrosine Kinase 3 (antagonists & inhibitors)