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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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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. |
format | Online Article Text |
id | pubmed-5471058 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
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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