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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.

Titel:	A phase I trial of the aurora kinase inhibitor, ENMD-2076, in patients with relapsed or refractory acute myeloid leukemia or chronic myelomonocytic leukemia.
Autor/in / Beteiligte Person:	Yee, KW ; Chen, HW ; Hedley, DW ; Chow, S ; Brandwein, J ; Schuh, AC ; Schimmer, AD ; Gupta, V ; Sanfelice, D ; Johnson, T ; Le, LW ; Arnott, J ; Bray, MR ; Sidor, C ; Minden, MD
Link:	View record at Springer (Volltext)
Zeitschrift:	Investigational new drugs, Jg. 34 (2016-10-01), Heft 5, S. 614-24
Veröffentlichung:	New York : Springer ; <i>Original Publication</i>: Boston : M. Nijhoff, 1983-, 2016
Medientyp:	academicJournal
ISSN:	1573-0646 (electronic)
DOI:	10.1007/s10637-016-0375-2
Schlagwort:	Adult Aged Aged, 80 and over Aurora Kinases antagonists & inhibitors Drug Resistance, Neoplasm Extracellular Signal-Regulated MAP Kinases metabolism Female Humans Leukemia, Myeloid, Acute metabolism Leukemia, Myelomonocytic, Chronic metabolism Male Maximum Tolerated Dose Middle Aged Proto-Oncogene Proteins c-akt metabolism Proto-Oncogene Proteins c-kit antagonists & inhibitors 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 Antineoplastic Agents adverse effects Antineoplastic Agents pharmacokinetics Antineoplastic Agents pharmacology Antineoplastic Agents therapeutic use Leukemia, Myeloid, Acute drug therapy Leukemia, Myelomonocytic, Chronic drug therapy Protein Kinase Inhibitors adverse effects Protein Kinase Inhibitors pharmacokinetics Protein Kinase Inhibitors pharmacology Protein Kinase Inhibitors therapeutic use Pyrazoles adverse effects Pyrazoles pharmacokinetics Pyrazoles pharmacology Pyrazoles therapeutic use Pyrimidines adverse effects Pyrimidines pharmacokinetics Pyrimidines pharmacology Pyrimidines therapeutic use
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Clinical Trial, Phase I; Journal Article Language: English [Invest New Drugs] 2016 Oct; Vol. 34 (5), pp. 614-24. <i>Date of Electronic Publication: </i>2016 Jul 12. MeSH Terms: Antineoplastic Agents* / adverse effects ; Antineoplastic Agents* / pharmacokinetics ; Antineoplastic Agents* / pharmacology ; Antineoplastic Agents* / therapeutic use ; Protein Kinase Inhibitors* / adverse effects ; Protein Kinase Inhibitors* / pharmacokinetics ; Protein Kinase Inhibitors* / pharmacology ; Protein Kinase Inhibitors* / therapeutic use ; Pyrazoles* / adverse effects ; Pyrazoles* / pharmacokinetics ; Pyrazoles* / pharmacology ; Pyrazoles* / therapeutic use ; Pyrimidines* / adverse effects ; Pyrimidines* / pharmacokinetics ; Pyrimidines* / pharmacology ; Pyrimidines* / therapeutic use ; Leukemia, Myeloid, Acute / drug therapy ; Leukemia, Myelomonocytic, Chronic / drug therapy ; Adult ; Aged ; Aged, 80 and over ; Aurora Kinases / antagonists & inhibitors ; Drug Resistance, Neoplasm ; Extracellular Signal-Regulated MAP Kinases / metabolism ; Female ; Humans ; Leukemia, Myeloid, Acute / metabolism ; Leukemia, Myelomonocytic, Chronic / metabolism ; Male ; Maximum Tolerated Dose ; Middle Aged ; Proto-Oncogene Proteins c-akt / metabolism ; Proto-Oncogene Proteins c-kit / antagonists & inhibitors ; 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 References: Mol Cancer Ther. 2011 Jan;10(1):126-37. (PMID: 21177375) ; Blood. 2007 Sep 15;110(6):2034-40. (PMID: 17495131) ; Blood. 2008 Mar 1;111(5):2854-65. (PMID: 18160664) ; Clin Cancer Res. 2008 Mar 15;14(6):1639-48. (PMID: 18347165) ; Blood. 2008 Oct 1;112(7):2886-95. (PMID: 18633130) ; Leukemia. 2004 Feb;18(2):267-75. (PMID: 14628071) ; Leukemia. 2010 Apr;24(4):671-8. (PMID: 20147976) ; Cancer. 2002 Nov 1;95(9):1923-30. (PMID: 12404286) ; Leukemia. 2005 Apr;19(4):586-94. (PMID: 15703783) ; Haematologica. 2008 May;93(5):662-9. (PMID: 18367484) ; Oncotarget. 2015 Apr 20;6(11):9327-40. (PMID: 25871386) ; Expert Opin Investig Drugs. 2012 May;21(5):717-32. (PMID: 22397360) ; Clin Cancer Res. 2015 Sep 15;21(18):4097-109. (PMID: 25878331) ; J Clin Invest. 1988 Apr;81(4):1030-5. (PMID: 2832442) ; Blood. 2001 Sep 15;98(6):1752-9. (PMID: 11535508) ; Leuk Res Rep. 2014 Jul 05;3(2):58-61. (PMID: 25068104) ; Blood. 2009 Jul 30;114(5):937-51. (PMID: 19357394) ; Blood. 2000 Dec 1;96(12):3671-4. (PMID: 11090046) ; J Hematop. 2009 Mar;2(1):2-8. (PMID: 19669217) ; Blood. 2001 Apr 15;97(8):2434-9. (PMID: 11290608) ; Blood. 2000 Sep 15;96(6):2240-5. (PMID: 10979972) ; Cancer Res. 2001 Oct 1;61(19):7233-9. (PMID: 11585760) ; Blood. 2009 Jan 1;113(1):66-74. (PMID: 18820130) ; Am J Clin Pathol. 1996 Aug;106(2):192-5. (PMID: 8712172) ; Blood. 2003 Aug 1;102(3):972-80. (PMID: 12702506) ; J Clin Invest. 2000 Aug;106(4):511-21. (PMID: 10953026) ; Blood. 2010 Sep 30;116(13):2345-55. (PMID: 20548097) ; Eur J Cancer. 2013 Jan;49(1):121-31. (PMID: 22921155) ; Mol Cancer Ther. 2007 Jun;6(6):1851-7. (PMID: 17541033) ; Cell Cycle. 2014;13(14):2237-47. (PMID: 24874015) ; Clin Cancer Res. 2011 Feb 15;17(4):849-60. (PMID: 21131552) ; Leukemia. 2002 Jul;16(7):1302-10. (PMID: 12094254) ; Cancer Res. 1987 Feb 1;47(3):874-80. (PMID: 2433029) ; Blood. 1997 Mar 15;89(6):2079-88. (PMID: 9058730) ; J Cell Physiol. 1988 Apr;135(1):133-8. (PMID: 3259234) ; Cytometry A. 2005 Sep;67(1):4-17. (PMID: 16080188) ; J Clin Oncol. 2003 Dec 15;21(24):4642-9. (PMID: 14673054) ; Blood. 1997 Mar 15;89(6):1870-5. (PMID: 9058706) ; Nat Med. 2010 May;16(5):580-5, 1p following 585. (PMID: 20418886) ; Expert Opin Ther Pat. 2014 Sep;24(9):1021-38. (PMID: 24965505) ; Blood. 2015 Mar 26;125(13):2141-50. (PMID: 25670627) ; Blood. 2001 Jun 1;97(11):3559-67. (PMID: 11369651) ; Leuk Res. 2011 Feb;35(2):260-4. (PMID: 20732714) ; Korean J Hematol. 2012 Sep;47(3):178-85. (PMID: 23071472) Contributed Indexing: Keywords: Acute myeloid leukemia; Aurora kinase inhibitor; Chronic myelomonocytic leukemia; ENMD-2076 Substance Nomenclature: 0 (Antineoplastic Agents) ; 0 (ENMD 2076) ; 0 (Protein Kinase Inhibitors) ; 0 (Pyrazoles) ; 0 (Pyrimidines) ; 0 (STAT5 Transcription Factor) ; EC 2.7.10.1 (FLT3 protein, human) ; EC 2.7.10.1 (KDR protein, human) ; EC 2.7.10.1 (Proto-Oncogene Proteins c-kit) ; EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2) ; EC 2.7.10.1 (fms-Like Tyrosine Kinase 3) ; EC 2.7.11.1 (Aurora Kinases) ; EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) ; EC 2.7.11.1 (Ribosomal Protein S6 Kinases) ; EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) Entry Date(s): Date Created: 20160714 Date Completed: 20171214 Latest Revision: 20181113 Update Code: 20231215

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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.