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 (3) , Joe Ensor , Michael Lee (4) , Cathy Eng (1) , Bryan Kee (1) , David Fogelman (1) , Rachna T Shroff (1) , Thomas Laframboise (2) , Thibault Mazard (5) , Tian Feng (1) , Stanley Hamilton (1) , Bradley Broom , James Lutterbaugh (2) , Jean-Pierre Issa (3) , Sanford D Markowitz (2) , Scott Kopetz (1)

1 The University of Texas M.D. Anderson Cancer Center [Houston]
2 Case Western Reserve University [Cleveland]
3 Temple University [Philadelphia]
4 UNC - University of North Carolina [Charlotte]
5 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier

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.

Mots clés: CIMP; azacitidine; colorectal cancer; methylation; vimentin

Domaines: Cancer; Hépatologie et Gastroentérologie; Pharmacologie

Michael J Overman, Van Morris, Helen Moinova, Ganiraju Manyam, Joe Ensor, et al.. Phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer: evaluation of circulating methylated vimentin. Oncotarget, 2016, 7 (41), pp.67495-67506. ⟨10.18632/oncotarget.11317⟩. ⟨hal-02298775⟩