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; Van Morris; Helen Moinova; Ganiraju Manyam; Joe Ensor; Michael S. Lee; Cathy Eng; Bryan Kee; David Fogelman; Rachna T. Shroff; Thomas LaFramboise; Thibault Mazard; Tian Feng; Stanley Hamilton; Bradley Broom; James Lutterbaugh; Jean Pierre Issa; Sanford D. Markowitz; Scott Kopetz

doi:10.18632/oncotarget.11317

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, Van Morris, Helen Moinova, Ganiraju Manyam, Joe Ensor, Michael S. Lee, Cathy Eng, Bryan Kee, David Fogelman, Rachna T. Shroff, Thomas LaFramboise, Thibault Mazard, Tian Feng, Stanley Hamilton, Bradley Broom, James Lutterbaugh, Jean Pierre Issa, Sanford D. Markowitz, Scott Kopetz

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

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/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.

Original language	English (US)
Pages (from-to)	67495-67506
Number of pages	12
Journal	Oncotarget
Volume	7
Issue number	41
DOIs	https://doi.org/10.18632/oncotarget.11317
State	Published - Aug 16 2016

Keywords

Azacitidine
CIMP
Colorectal cancer
Methylation
Vimentin

ASJC Scopus subject areas

Oncology

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10.18632/oncotarget.11317

Cite this

Overman, M. J., Morris, V., Moinova, H., Manyam, G., Ensor, J., Lee, M. S., Eng, C., Kee, B., Fogelman, D., Shroff, R. T., LaFramboise, T., Mazard, T., Feng, T., Hamilton, S., Broom, B., Lutterbaugh, J., Issa, J. P., Markowitz, S. D., & Kopetz, S. (2016). Phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer: evaluation of circulating methylated vimentin. Oncotarget, 7(41), 67495-67506. https://doi.org/10.18632/oncotarget.11317

Overman, MJ, Morris, V, Moinova, H, Manyam, G, Ensor, J, Lee, MS, Eng, C, Kee, B, Fogelman, D, Shroff, RT, LaFramboise, T, Mazard, T, Feng, T, Hamilton, S, Broom, B, Lutterbaugh, J, Issa, JP, Markowitz, SD & Kopetz, S 2016, 'Phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer: evaluation of circulating methylated vimentin', Oncotarget, vol. 7, no. 41, pp. 67495-67506. https://doi.org/10.18632/oncotarget.11317

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

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/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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author = "Overman, {Michael J.} and Van Morris and Helen Moinova and Ganiraju Manyam and Joe Ensor and Lee, {Michael S.} and Cathy Eng and Bryan Kee and David Fogelman and Shroff, {Rachna T.} and Thomas LaFramboise and Thibault Mazard and Tian Feng and Stanley Hamilton and Bradley Broom and James Lutterbaugh and Issa, {Jean Pierre} and Markowitz, {Sanford D.} and Scott Kopetz",

year = "2016",

month = aug,

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doi = "10.18632/oncotarget.11317",

language = "English (US)",

volume = "7",

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T1 - Phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer

T2 - evaluation of circulating methylated vimentin

AU - Overman, Michael J.

AU - Morris, Van

AU - Moinova, Helen

AU - Manyam, Ganiraju

AU - Ensor, Joe

AU - Lee, Michael S.

AU - Eng, Cathy

AU - Kee, Bryan

AU - Fogelman, David

AU - Shroff, Rachna T.

AU - LaFramboise, Thomas

AU - Mazard, Thibault

AU - Feng, Tian

AU - Hamilton, Stanley

AU - Broom, Bradley

AU - Lutterbaugh, James

AU - Issa, Jean Pierre

AU - Markowitz, Sanford D.

AU - Kopetz, Scott

PY - 2016/8/16

Y1 - 2016/8/16

N2 - 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.

AB - 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.

KW - Azacitidine

KW - CIMP

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KW - Methylation

KW - Vimentin

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ER -

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

Abstract

Keywords

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