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Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat: a phase 2 consortium/stand Up 2 cancer study

PURPOSE: Therapy with demethylating agent 5-azacitidine and histone deacetylase inhibitor entinostat shows synergistic re-expression of tumor-suppressor genes and growth inhibition in colorectal (CRC) cell lines and in vivo studies. EXPERIMENTAL DESIGN: We conducted a phase II, multi-institutional s...

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Autores principales: Azad, Nilofer S., el-Khoueiry, Anthony, Yin, Jun, Oberg, Ann L., Flynn, Patrick, Adkins, Douglas, Sharma, Anup, Weisenberger, Daniel J., Brown, Thomas, Medvari, Prakriti, Jones, Peter A., Easwaran, Hariharan, Kamel, Ihab, Bahary, Nathan, Kim, George, Picus, Joel, Pitot, Henry C., Erlichman, Charles, Donehower, Ross, Shen, Hui, Laird, Peter W., Piekarz, Richard, Baylin, Stephen, Ahuja, Nita
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471058/
https://www.ncbi.nlm.nih.gov/pubmed/28186961
http://dx.doi.org/10.18632/oncotarget.15108
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author Azad, Nilofer S.
el-Khoueiry, Anthony
Yin, Jun
Oberg, Ann L.
Flynn, Patrick
Adkins, Douglas
Sharma, Anup
Weisenberger, Daniel J.
Brown, Thomas
Medvari, Prakriti
Jones, Peter A.
Easwaran, Hariharan
Kamel, Ihab
Bahary, Nathan
Kim, George
Picus, Joel
Pitot, Henry C.
Erlichman, Charles
Donehower, Ross
Shen, Hui
Laird, Peter W.
Piekarz, Richard
Baylin, Stephen
Ahuja, Nita
author_facet Azad, Nilofer S.
el-Khoueiry, Anthony
Yin, Jun
Oberg, Ann L.
Flynn, Patrick
Adkins, Douglas
Sharma, Anup
Weisenberger, Daniel J.
Brown, Thomas
Medvari, Prakriti
Jones, Peter A.
Easwaran, Hariharan
Kamel, Ihab
Bahary, Nathan
Kim, George
Picus, Joel
Pitot, Henry C.
Erlichman, Charles
Donehower, Ross
Shen, Hui
Laird, Peter W.
Piekarz, Richard
Baylin, Stephen
Ahuja, Nita
author_sort Azad, Nilofer S.
collection PubMed
description PURPOSE: Therapy with demethylating agent 5-azacitidine and histone deacetylase inhibitor entinostat shows synergistic re-expression of tumor-suppressor genes and growth inhibition in colorectal (CRC) cell lines and in vivo studies. EXPERIMENTAL DESIGN: We conducted a phase II, multi-institutional study of the combination in metastatic CRC patients. Subcutaneous azacitidine was administered at 40 mg/m2 days 1-5 and 8-10 and entinostat was given 7 mg orally on days 3 and 10. An interim analysis indicated toxicity crossed the pre-specified safety boundary but was secondary to disease. A 2(nd) cohort with added eligibility restrictions was accrued: prior therapies were limited to no more than 2 or 3 (KRAS-mutated and KRAS-wildtype cancers, respectively) and <30% of liver involvement. The primary endpoint was RECIST response. Serial biopsies were performed at baseline and after 2 cycles of therapy. RESULTS: Forty-seven patients were enrolled (24:Cohort 1, 23:Cohort 2). Patients were heavily pre-treated (median prior therapies 4: Cohort 1 and 2.5: cohort 2). No responses were observed. Median progression-free survival was 1.9 months; overall survival was 5.6 and 8.3 months in Cohorts 1 and 2, respectively. Toxicity was tolerable and as expected. Unsupervised cluster analysis of serial tumor biopsies suggested greater DNA demethylation in patients with PFS above the median. CONCLUSION: In this first trial of CRC patients with combination epigenetic therapy, we show tolerable therapy without significant clinical activity as determined by RECIST responses. Reversal of hypermethylation was seen in a subset of patients and correlated with improved PFS.
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spelling pubmed-54710582017-06-27 Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat: a phase 2 consortium/stand Up 2 cancer study Azad, Nilofer S. el-Khoueiry, Anthony Yin, Jun Oberg, Ann L. Flynn, Patrick Adkins, Douglas Sharma, Anup Weisenberger, Daniel J. Brown, Thomas Medvari, Prakriti Jones, Peter A. Easwaran, Hariharan Kamel, Ihab Bahary, Nathan Kim, George Picus, Joel Pitot, Henry C. Erlichman, Charles Donehower, Ross Shen, Hui Laird, Peter W. Piekarz, Richard Baylin, Stephen Ahuja, Nita Oncotarget Clinical Research Paper PURPOSE: Therapy with demethylating agent 5-azacitidine and histone deacetylase inhibitor entinostat shows synergistic re-expression of tumor-suppressor genes and growth inhibition in colorectal (CRC) cell lines and in vivo studies. EXPERIMENTAL DESIGN: We conducted a phase II, multi-institutional study of the combination in metastatic CRC patients. Subcutaneous azacitidine was administered at 40 mg/m2 days 1-5 and 8-10 and entinostat was given 7 mg orally on days 3 and 10. An interim analysis indicated toxicity crossed the pre-specified safety boundary but was secondary to disease. A 2(nd) cohort with added eligibility restrictions was accrued: prior therapies were limited to no more than 2 or 3 (KRAS-mutated and KRAS-wildtype cancers, respectively) and <30% of liver involvement. The primary endpoint was RECIST response. Serial biopsies were performed at baseline and after 2 cycles of therapy. RESULTS: Forty-seven patients were enrolled (24:Cohort 1, 23:Cohort 2). Patients were heavily pre-treated (median prior therapies 4: Cohort 1 and 2.5: cohort 2). No responses were observed. Median progression-free survival was 1.9 months; overall survival was 5.6 and 8.3 months in Cohorts 1 and 2, respectively. Toxicity was tolerable and as expected. Unsupervised cluster analysis of serial tumor biopsies suggested greater DNA demethylation in patients with PFS above the median. CONCLUSION: In this first trial of CRC patients with combination epigenetic therapy, we show tolerable therapy without significant clinical activity as determined by RECIST responses. Reversal of hypermethylation was seen in a subset of patients and correlated with improved PFS. Impact Journals LLC 2017-02-05 /pmc/articles/PMC5471058/ /pubmed/28186961 http://dx.doi.org/10.18632/oncotarget.15108 Text en Copyright: © 2017 Azad et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Clinical Research Paper
Azad, Nilofer S.
el-Khoueiry, Anthony
Yin, Jun
Oberg, Ann L.
Flynn, Patrick
Adkins, Douglas
Sharma, Anup
Weisenberger, Daniel J.
Brown, Thomas
Medvari, Prakriti
Jones, Peter A.
Easwaran, Hariharan
Kamel, Ihab
Bahary, Nathan
Kim, George
Picus, Joel
Pitot, Henry C.
Erlichman, Charles
Donehower, Ross
Shen, Hui
Laird, Peter W.
Piekarz, Richard
Baylin, Stephen
Ahuja, Nita
Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat: a phase 2 consortium/stand Up 2 cancer study
title Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat: a phase 2 consortium/stand Up 2 cancer study
title_full Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat: a phase 2 consortium/stand Up 2 cancer study
title_fullStr Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat: a phase 2 consortium/stand Up 2 cancer study
title_full_unstemmed Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat: a phase 2 consortium/stand Up 2 cancer study
title_short Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat: a phase 2 consortium/stand Up 2 cancer study
title_sort combination epigenetic therapy in metastatic colorectal cancer (mcrc) with subcutaneous 5-azacitidine and entinostat: a phase 2 consortium/stand up 2 cancer study
topic Clinical Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471058/
https://www.ncbi.nlm.nih.gov/pubmed/28186961
http://dx.doi.org/10.18632/oncotarget.15108
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