Phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer: evaluation of circulating methylated vimentin

// Michael J. Overman 1 , Van Morris 1 , Helen Moinova 2 , Ganiraju Manyam 6 , Joe Ensor 3 , Michael S. Lee 8 , Cathy Eng 1 , Bryan Kee 1 , David Fogelman 1 , Rachna T. Shroff 1 , Thomas LaFramboise 4 , Thibault Mazard 1 , Tian Feng 1 , Stanley Hamilton 7 , Bradley Broom 6 , James Lutterbaugh 2 , Jean-Pierre Issa 5 , Sanford D. Markowitz 2 and Scott Kopetz 1 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 Correspondence to: Michael J. Overman, email: // Keywords : methylation, azacitidine, CIMP, colorectal cancer, vimentin Received : April 14, 2016 Accepted : August 10, 2016 Published : August 16, 2016 Abstract 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/m 2 /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.