title: Phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer: evaluation of circulating methylated vimentin.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Overman
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Van
authors.initials: V
authors.lastname: Morris
authors.affiliation: Department of Medicine and Case Comprehensive Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Moinova
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ganiraju
authors.initials: G
authors.lastname: Manyam
authors.affiliation: Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Ensor
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Cathy
authors.initials: C
authors.lastname: Eng
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Kee
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: David
authors.initials: D
authors.lastname: Fogelman
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Rachna T
authors.initials: RT
authors.lastname: Shroff
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: LaFramboise
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Thibault
authors.initials: T
authors.lastname: Mazard
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Feng
authors.affiliation: Division of Pathology and Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Stanley
authors.initials: S
authors.lastname: Hamilton
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Bradley
authors.initials: B
authors.lastname: Broom
authors.affiliation: Department of Medicine and Case Comprehensive Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH, USA.
authors.forename: James
authors.initials: J
authors.lastname: Lutterbaugh
authors.affiliation: Fels Institute for Cancer and Molecular Biology, Temple University, Philadelphia, PA, USA.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Issa
authors.affiliation: Department of Medicine and Case Comprehensive Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH, USA.
authors.forename: Sanford D
authors.initials: SD
authors.lastname: Markowitz
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000097:blood*; D000069287:Capecitabine / Q000008:administration & dosage / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy*; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D014746:Vimentin / Q000097:blood*
chemical_list: D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; D014746:Vimentin; D000077150:Oxaliplatin; D000069287:Capecitabine; D001374:Azacitidine
keywords: CIMP; azacitidine; colorectal cancer; methylation; vimentin