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 1 , Anthony el-Khoueiry 2 , Jun Yin 3 , Ann L. Oberg 3 , Patrick Flynn 4 , Douglas Adkins 5 , Anup Sharma 1 , Daniel J. Weisenberger 2 , Thomas Brown 1 , Prakriti Medvari 1 , Peter A. Jones 6 , Hariharan Easwaran 1 , Ihab Kamel 1 , Nathan Bahary 7 , George Kim 8 , Joel Picus 9 , Henry C. Pitot 3 , Charles Erlichman 3 , Ross Donehower 1 , Hui Shen 6 , Peter W. Laird 6 , Richard Piekarz 9 , Stephen Baylin 1 and Nita Ahuja 1 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 9 Washington University, St. Louis, MO, USA 10 Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA Correspondence to: Nilofer S. Azad, email: // Keywords : epigenetics, colorectal cancer, DNA methyltransferases inhibitors, histone deacetylase inhibitors Received : August 11, 2016 Accepted : October 25, 2016 Published : February 05, 2017 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 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