title: Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat: a phase 2 consortium/stand up 2 cancer study.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Nilofer S
authors.initials: NS
authors.lastname: Azad
authors.affiliation: University of Southern California, Los Angeles, CA, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: El-Khoueiry
authors.affiliation: Mayo Clinic, Rochestor, MN, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yin
authors.affiliation: Mayo Clinic, Rochestor, MN, USA.
authors.forename: Ann L
authors.initials: AL
authors.lastname: Oberg
authors.affiliation: Metro-Minnesota CCOP, Minneapolis, MN, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Flynn
authors.affiliation: Washington University, St. Louis, MO, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Adkins
authors.affiliation: Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Anup
authors.initials: A
authors.lastname: Sharma
authors.affiliation: University of Southern California, Los Angeles, CA, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisenberger
authors.affiliation: Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brown
authors.affiliation: Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Prakriti
authors.initials: P
authors.lastname: Medvari
authors.affiliation: Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Jones
authors.affiliation: Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Hariharan
authors.initials: H
authors.lastname: Easwaran
authors.affiliation: Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Ihab
authors.initials: I
authors.lastname: Kamel
authors.affiliation: University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Bahary
authors.affiliation: Mayo Clinic, Jacksonville, FL, USA.
authors.forename: George
authors.initials: G
authors.lastname: Kim
authors.affiliation: Washington University, St. Louis, MO, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Picus
authors.affiliation: Mayo Clinic, Rochestor, MN, USA.
authors.forename: Henry C
authors.initials: HC
authors.lastname: Pitot
authors.affiliation: Mayo Clinic, Rochestor, MN, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
authors.affiliation: Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Ross
authors.initials: R
authors.lastname: Donehower
authors.affiliation: Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Laird
authors.affiliation: Washington University, St. Louis, MO, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Piekarz
authors.affiliation: Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Baylin
authors.affiliation: Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Nita
authors.initials: N
authors.lastname: Ahuja
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000494:pharmacology; D001374:Azacitidine / Q000008:administration & dosage* / Q000494:pharmacology; D001549:Benzamides / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects*; D004334:Drug Administration Schedule; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage* / Q000494:pharmacology; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D011725:Pyridines; C118739:entinostat; D001374:Azacitidine
keywords: DNA methyltransferases inhibitors; colorectal cancer; epigenetics; histone deacetylase inhibitors