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Background: With proven single-agent activity and favorable toxicity profile of MEK-1/2 inhibition in advanced leukemia, investigation into combination strategies to overcome proposed resistance pathways is warranted. Resistance to MEK inhibition is secondary to upstream hyperactivation of RAS/RAF or activation of the PI3K/PTEN/AKT/mTOR pathway. This phase II multi-institution Cancer Therapy Evaluation Program-sponsored study was conducted to determine efficacy and safety of the combination of the ATP-competitive pan-AKT inhibitor GSK2141795, targeting the PI3K/AKT pathway, and the MEK inhibitor trametinib in RAS-mutated relapsed/refractory acute myeloid leukemia (AML).

Patients and Methods: The primary objective was to determine the proportion of patients achieving a complete remission. Secondary objectives included assessment of toxicity profile and biologic effects of this combination. Twenty-three patients with RAS-mutated AML received the combination. Two dose levels were explored (dose level 1: 2 mg trametinib, 25 mg GSK2141795 and dose level 2: 1.5 mg trametinib, 50 mg GSK2141795).

Results: Dose level 1 was identified as the recommended phase II dose. No complete remissions were identified in either cohort. Minor responses were recognized in 5 (22%) patients. The most common drug-related toxicities included rash and diarrhea, with dose-limiting toxicities of mucositis and colitis. Longitudinal correlative assessment of the modulation of MEK and AKT pathways using reverse phase protein array and phospho-flow analysis revealed significant and near significant down-modulation of pERK and pS6, respectively. Combined MEK and AKT inhibition had no clinical activity in patients with RAS-mutated AML.

Conclusion: Further investigation is required to explore the discrepancy between the activity of this combination on leukemia cells and the lack of clinical efficacy.

Titel:	Oral MEK 1/2 Inhibitor Trametinib in Combination With AKT Inhibitor GSK2141795 in Patients With Acute Myeloid Leukemia With RAS Mutations: A Phase II Study.
Autor/in / Beteiligte Person:	Ragon, BK ; Odenike, O ; Baer, MR ; Stock, W ; Borthakur, G ; Patel, K ; Han, L ; Chen, H ; Ma, H ; Joseph, L ; Zhao, Y ; Baggerly, K ; Konopleva, M ; Jain, N
Zeitschrift:	Clinical lymphoma, myeloma & leukemia, Jg. 19 (2019-07-01), Heft 7, S. 431-440.e13
Veröffentlichung:	2011-: [New York] : Elsevier ; <i>Original Publication</i>: Dallas, Tex. : Cancer Media Group, 2019
Medientyp:	academicJournal
ISSN:	2152-2669 (electronic)
DOI:	10.1016/j.clml.2019.03.015
Schlagwort:	Administration, Oral Adult Aged Aged, 80 and over Antineoplastic Combined Chemotherapy Protocols adverse effects Diamines administration & dosage Female Humans Leukemia, Myeloid, Acute diagnosis Male Middle Aged Pyrazoles administration & dosage Pyridones administration & dosage Pyrimidinones administration & dosage Treatment Outcome Young Adult Antineoplastic Combined Chemotherapy Protocols therapeutic use Genes, ras Leukemia, Myeloid, Acute drug therapy Leukemia, Myeloid, Acute genetics MAP Kinase Kinase 1 antagonists & inhibitors MAP Kinase Kinase 2 antagonists & inhibitors Mutation Proto-Oncogene Proteins c-akt antagonists & inhibitors
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Clinical Trial, Phase II; Journal Article; Multicenter Study; Research Support, N.I.H., Extramural Language: English [Clin Lymphoma Myeloma Leuk] 2019 Jul; Vol. 19 (7), pp. 431-440.e13. <i>Date of Electronic Publication: </i>2019 Mar 26. MeSH Terms: Genes, ras* ; Mutation* ; Antineoplastic Combined Chemotherapy Protocols / therapeutic use ; Leukemia, Myeloid, Acute / drug therapy ; Leukemia, Myeloid, Acute / genetics ; MAP Kinase Kinase 1 / antagonists & inhibitors ; MAP Kinase Kinase 2 / antagonists & inhibitors ; Proto-Oncogene Proteins c-akt / antagonists & inhibitors ; Administration, Oral ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols / adverse effects ; Diamines / administration & dosage ; Female ; Humans ; Leukemia, Myeloid, Acute / diagnosis ; Male ; Middle Aged ; Pyrazoles / administration & dosage ; Pyridones / administration & dosage ; Pyrimidinones / administration & dosage ; Treatment Outcome ; Young Adult References: Blood. 2001 Mar 15;97(6):1823-34. (PMID: 11238126) ; J Clin Invest. 2001 Sep;108(6):851-9. (PMID: 11560954) ; Annu Rev Cell Dev Biol. 2001;17:615-75. (PMID: 11687500) ; Science. 2002 May 31;296(5573):1655-7. (PMID: 12040186) ; Blood. 2003 Aug 1;102(3):972-80. (PMID: 12702506) ; Leukemia. 2003 Sep;17(9):1783-93. (PMID: 12970778) ; Leukemia. 2004 Feb;18(2):267-75. (PMID: 14628071) ; Leukemia. 2005 Apr;19(4):586-94. (PMID: 15703783) ; Leukemia. 2005 Sep;19(9):1543-9. (PMID: 16001087) ; Cancer Res. 2005 Nov 1;65(21):9643-50. (PMID: 16266983) ; Leukemia. 2006 Jun;20(6):911-28. (PMID: 16642045) ; Mol Cancer Ther. 2006 Oct;5(10):2512-21. (PMID: 17041095) ; Biochim Biophys Acta. 2007 Aug;1773(8):1263-84. (PMID: 17126425) ; Cancer Res. 2007 Jan 15;67(2):684-94. (PMID: 17234779) ; Best Pract Res Clin Haematol. 2007 Mar;20(1):39-48. (PMID: 17336253) ; Crit Rev Oncol Hematol. 2007 Sep;63(3):215-30. (PMID: 17658267) ; J Clin Oncol. 2008 May 1;26(13):2139-46. (PMID: 18390968) ; Nat Med. 2008 Dec;14(12):1351-6. (PMID: 19029981) ; Cancer Res. 2009 May 15;69(10):4286-93. (PMID: 19401449) ; Clin Cancer Res. 2009 Jul 15;15(14):4649-64. (PMID: 19567590) ; Int J Cancer. 2009 Nov 15;125(10):2332-41. (PMID: 19637312) ; Clin Cancer Res. 2010 Mar 1;16(5):1613-23. (PMID: 20179232) ; EMBO Mol Med. 2010 May;2(5):146-58. (PMID: 20432502) ; Leukemia. 2011 Jul;25(7):1080-94. (PMID: 21494257) ; Cell Signal. 2012 Jan;24(1):17-24. (PMID: 21906675) ; J Clin Oncol. 2011 Dec 10;29(35):4688-95. (PMID: 22025163) ; Clin Cancer Res. 2012 Mar 15;18(6):1716-25. (PMID: 22167413) ; Clin Cancer Res. 2012 Apr 15;18(8):2316-25. (PMID: 22261800) ; Blood. 2012 Apr 12;119(15):3578-84. (PMID: 22389253) ; Cancer. 2012 Nov 15;118(22):5550-9. (PMID: 22569880) ; Lancet Oncol. 2012 Aug;13(8):782-9. (PMID: 22805292) ; Blood. 2012 Sep 27;120(13):2679-89. (PMID: 22826565) ; PLoS One. 2012;7(8):e44146. (PMID: 22952903) ; N Engl J Med. 2013 May 30;368(22):2059-74. (PMID: 23634996) ; Am Soc Clin Oncol Educ Book. 2013;:null. (PMID: 23714559) ; Leuk Res. 2013 Nov;37(11):1461-7. (PMID: 23993427) ; Curr Pharm Des. 2014;20(24):3944-57. (PMID: 24138714) ; Clin Cancer Res. 2013 Dec 15;19(24):6976-86. (PMID: 24141624) ; Clin Cancer Res. 2014 Jan 15;20(2):490-8. (PMID: 24178622) ; Trends Pharmacol Sci. 2014 Jan;35(1):41-50. (PMID: 24361003) ; Clin Cancer Res. 2014 Apr 15;20(8):2226-35. (PMID: 24583795) ; PLoS One. 2014 Jun 30;9(6):e100880. (PMID: 24978597) ; Oncogene. 2015 Jul;34(28):3617-26. (PMID: 25263438) ; EMBO Rep. 2015 Mar;16(3):280-96. (PMID: 25680965) ; Ann Oncol. 2015 Jul;26(7):1504-10. (PMID: 25908604) ; JAMA Oncol. 2015 Sep;1(6):820-8. (PMID: 26181162) ; N Engl J Med. 2015 Sep 17;373(12):1136-52. (PMID: 26376137) ; Ann Oncol. 2016 May;27(5):770-8. (PMID: 26802152) ; Cancer. 2016 Jun 15;122(12):1871-9. (PMID: 26990290) ; N Engl J Med. 2016 Jun 9;374(23):2209-2221. (PMID: 27276561) ; J Hematol Oncol. 2016 Sep 10;9(1):85. (PMID: 27613060) ; Leuk Lymphoma. 2017 Sep;58(9):1-17. (PMID: 28140720) ; Cell. 2017 Apr 20;169(3):381-405. (PMID: 28431241) ; Clin Cancer Res. 2018 Aug 15;24(16):3967-3980. (PMID: 29666304) Grant Information: P30 CA016672 United States CA NCI NIH HHS; R50 CA221675 United States CA NCI NIH HHS Contributed Indexing: Keywords: AML; Developmental therapeutics; Drug resistance; Neoplasia-myeloid leukemias and dysplasias; Phase II clinical trials Substance Nomenclature: 0 (Diamines) ; 0 (GSK2141795) ; 0 (Pyrazoles) ; 0 (Pyridones) ; 0 (Pyrimidinones) ; 33E86K87QN (trametinib) ; EC 2.7.1.- (MAP2K2 protein, human) ; EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) ; EC 2.7.12.2 (MAP Kinase Kinase 1) ; EC 2.7.12.2 (MAP Kinase Kinase 2) ; EC 2.7.12.2 (MAP2K1 protein, human) Entry Date(s): Date Created: 20190507 Date Completed: 20200804 Latest Revision: 20200804 Update Code: 20240513 PubMed Central ID: PMC6626580

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Oral MEK 1/2 Inhibitor Trametinib in Combination With AKT Inhibitor GSK2141795 in Patients With Acute Myeloid Leukemia With RAS Mutations: A Phase II Study.