Clinical Research Papers:
Phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer: evaluation of circulating methylated vimentin
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Michael J. Overman1, Van Morris1, Helen Moinova2, Ganiraju Manyam6, Joe Ensor3, Michael S. Lee8, Cathy Eng1, Bryan Kee1, David Fogelman1, Rachna T. Shroff1, Thomas LaFramboise4, Thibault Mazard1, Tian Feng1, Stanley Hamilton7, Bradley Broom6, James Lutterbaugh2, Jean-Pierre Issa5, Sanford D. Markowitz2 and Scott Kopetz1
1 Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
2 Department of Medicine and Case Comprehensive Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH, USA
3 Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX, USA
4 Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA
5 Fels Institute for Cancer and Molecular Biology, Temple University, Philadelphia, PA, USA
6 Department of Bioinformatics and Computational Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
7 Division of Pathology and Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
8 Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
Michael J. Overman, email:
Keywords: methylation, azacitidine, CIMP, colorectal cancer, vimentin
Received: April 14, 2016 Accepted: August 10, 2016 Published: August 16, 2016
Purpose: Hypermethylation of promoter CpG islands (CIMP) has been strongly implicated in chemotherapy resistance and is implicated in the pathogenesis of a subset of colorectal cancers (CRCs) termed CIMP-high.
Experimental Design: This phase I/II study in CRC (phase II portion restricted to CIMP-high CRC), treated fluoropyrimidine/oxaliplatin refractory patients with azacitidine (75 mg/m2/day subcutaneously D1-5) and CAPOX (capecitibine and oxaliplatin) every three weeks.
Results: Twenty-six patients (pts) were enrolled in this study: 15 pts (12 treated at MTD) in phase I and 11 pts in phase II. No dose limiting toxicities were observed. A total of 14 pts were CIMP-high. No responses were seen. CIMP-high status did not correlate with efficacy endpoints [stable disease (SD) or progression-free survival (PFS)] or baseline vimentin methylation level. Changes in vimentin methylation over time did not correlate with efficacy outcomes. Baseline methylated vimentin correlated with tumor volume (P<0.001) and higher levels of baseline methylation correlated with the obtainment of stable disease (P=0.04).
Conclusions: Azacitidine and CAPOX were well tolerated with high rates of stable disease in CIMP-high pts, but no objective responses. Serum methylated vimentin may be associated with benefit from a regimen including a hypomethylation agent, although this study is not able to separate a potential prognostic or predictive role for the biomarker.
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