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Oncotarget. 2017 May 23;8(21):35326-35338. doi: 10.18632/oncotarget.15108.

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

Author information

1
Johns Hopkins University, Baltimore, MD, USA.
2
University of Southern California, Los Angeles, CA, USA.
3
Mayo Clinic, Rochestor, MN, USA.
4
Metro-Minnesota CCOP, Minneapolis, MN, USA.
5
Washington University, St. Louis, MO, USA.
6
Van Andel Research Institute, Grand Rapids, MI, USA.
7
University of Pittsburgh, Pittsburgh, PA, USA.
8
Mayo Clinic, Jacksonville, FL, USA.

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.

KEYWORDS:

DNA methyltransferases inhibitors; colorectal cancer; epigenetics; histone deacetylase inhibitors

PMID:
28186961
PMCID:
PMC5471058
DOI:
10.18632/oncotarget.15108
[Indexed for MEDLINE]
Free PMC Article

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