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

Nilofer S. Azad, Anthony El-Khoueiry, Jun Yin, Ann L Oberg, Patrick Flynn, Douglas Adkins, Anup Sharma, Daniel J. Weisenberger, Thomas Brown, Prakriti Medvari, Peter A. Jones, Hariharan Easwaran, Ihab Kamel, Nathan Bahary, George Kim, Joel Picus, Henry Clement Pitot, Charles Erlichman, Ross Donehower, Hui ShenPeter W. Laird, Richard Piekarz, Stephen Baylin, Nita Ahuja

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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 2nd 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.

Original languageEnglish (US)
Pages (from-to)35326-35338
Number of pages13
JournalOncotarget
Volume8
Issue number21
DOIs
StatePublished - 2017

Fingerprint

Azacitidine
Epigenomics
Colorectal Neoplasms
Neoplasms
Therapeutics
Biopsy
Histone Deacetylase Inhibitors
Tumor Suppressor Genes
Disease-Free Survival
Cluster Analysis
entinostat
Research Design
Safety
Cell Line
Survival
Liver
DNA
Growth

Keywords

  • Colorectal cancer
  • DNA methyltransferases inhibitors
  • Epigenetics
  • Histone deacetylase inhibitors

ASJC Scopus subject areas

  • Oncology

Cite this

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 Clement; Erlichman, Charles; Donehower, Ross; Shen, Hui; Laird, Peter W.; Piekarz, Richard; Baylin, Stephen; Ahuja, Nita.

In: Oncotarget, Vol. 8, No. 21, 2017, p. 35326-35338.

Research output: Contribution to journalArticle

Azad, NS, El-Khoueiry, A, Yin, J, Oberg, AL, Flynn, P, Adkins, D, Sharma, A, Weisenberger, DJ, Brown, T, Medvari, P, Jones, PA, Easwaran, H, Kamel, I, Bahary, N, Kim, G, Picus, J, Pitot, HC, Erlichman, C, Donehower, R, Shen, H, Laird, PW, Piekarz, R, Baylin, S & Ahuja, N 2017, 'Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat; a phase 2 consortium/stand Up 2 cancer study', Oncotarget, vol. 8, no. 21, pp. 35326-35338. https://doi.org/10.18632/oncotarget.15108
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 Clement ; 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. In: Oncotarget. 2017 ; Vol. 8, No. 21. pp. 35326-35338.
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AU - El-Khoueiry, Anthony

AU - Yin, Jun

AU - Oberg, Ann L

AU - Flynn, Patrick

AU - Adkins, Douglas

AU - Sharma, Anup

AU - Weisenberger, Daniel J.

AU - Brown, Thomas

AU - Medvari, Prakriti

AU - Jones, Peter A.

AU - Easwaran, Hariharan

AU - Kamel, Ihab

AU - Bahary, Nathan

AU - Kim, George

AU - Picus, Joel

AU - Pitot, Henry Clement

AU - Erlichman, Charles

AU - Donehower, Ross

AU - Shen, Hui

AU - Laird, Peter W.

AU - Piekarz, Richard

AU - Baylin, Stephen

AU - Ahuja, Nita

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N2 - 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 2nd 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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