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Pre-operative Decitabine in Colon Cancer: a Proof of Principle Study (DECO)

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ClinicalTrials.gov Identifier: NCT01882660
Recruitment Status : Terminated (Inclusion of patients was slow. Could not reach the target within the studyperiod.)
First Posted : June 20, 2013
Last Update Posted : July 2, 2018
Sponsor:
Information provided by (Responsible Party):
H.W.M. van Laarhoven, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Brief Summary:

Background of the study: Colon cancer is the second leading cause of cancer-related death world wide.

Although patients presenting with early disease (stage I-III) can be cured, prognosis varies from 90% in stage I to 50-80% in stage II and III. Therefore, prevention of metastases after early disease is of utmost importance. Derepression of Wnt targets may provide a novel target for therapy.

Objectives: The primary objective of the study is to assess in patients with primary colon cancer whether short-course pre-operative treatment with decitabine can increase Wnt target gene expression as measured in resected tumors compared to pretreatment biopsies. The secondary objective of the study is to assess in patients with primary colon cancer whether short-course pre-operative treatment with decitabine can revert CpG methylation and induce more favorable tumor characteristics as measured in resected tumors compared to pretreatment biopsies. The tertiary objective is to compare changes in Wnt target gene expression, CpG methylation and tumor characteristics for Wnt methylated and nonmethylated tumors as measured in resected tumors compared to pretreatment biopsies and identify new stratification markers.


Condition or disease Intervention/treatment Phase
Colon Cancer Drug: Decitabine Not Applicable

Detailed Description:

Rationale: Colon cancer is the second leading cause of cancer-related death world wide.

Although patients presenting with early disease (stage I-III) can be cured, prognosis varies from 90% in stage I to 50-80% in stage II and III. Therefore, prevention of metastases after early disease is of utmost importance. Extensive studies of the Wnt signal cascade have elucidated its role in colorectal cancer development and proliferation. Several well-known targets of the Wnt-cascade, like DKK1, APCDD1 and AXIN2, serve as feedback inhibitors and likely prevent pathway hyperactivation. Therefore, loss of these control mechanisms, for example due to repression of Wnt targets by CpG island methylation, serves as a potent proliferative signal. Recently, we identified a subset of colon cancers that are typified by CpG island methylation of specific Wnt target genes and have a poor prognosis. Moreover, in preclinical studies we showed that derepression of Wnt-targets by the demethylating agent decitabine resulted in tumor growth suppression. Thus, derepression of Wnt targets may provide a novel target for therapy. Objectives: The primary objective of the study is to assess in patients with primary colon cancer whether short-course pre-operative treatment with decitabine can increase Wnt target gene expression as measured in resected tumors compared to pretreatment biopsies. The secondary objective of the study is to assess in patients with primary colon cancer whether short-course pre-operative treatment with decitabine can revert CpG methylation and induce more favorable tumor characteristics as measured in resected tumors compared to pretreatment biopsies. The tertiary objective is to compare changes in Wnt target gene expression, CpG methylation and tumor characteristics for Wnt methylated and nonmethylated tumors as measured in resected tumors compared to pretreatment biopsies and identify new stratification markers.

Study design: Interventional study.

Study population:

Patients > 18 yr old with histopathologically proven or high suspicion of colon cancer.

Intervention: In patients with proven colon cancer, five extra biopsies will be taken from the tumour during endoscopy to determine CpG methylation of Wnt target genes in fresh tumor samples. Next, these patients will pre-operatively receive decitabine as a single intravenous infusion at a dose of 45 mg/m2 over 6 hr. After resection, Wnt target gene expression and CpG methylation of Wnt target genes will again be determined in fresh tumor samples.

Main study parameters: The primary study parameter is Wnt target gene expression (APCDD1, AXIN2, DKK1, LGR5 and ASCL2). Secondary study parameters are Wnt target and CIMP gene methylation, beta-catenin localization, proliferation (Ki-67), apoptosis (TUNEL and M30 assay) and tumor differentiation.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 88 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Pre-operative Decitabine in Colon Cancer: a Proof of Principle Study
Study Start Date : July 2013
Actual Primary Completion Date : January 2018
Actual Study Completion Date : January 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Decitabine

Arm Intervention/treatment
Experimental: Decitabine treatment
Treatment with decitabine
Drug: Decitabine



Primary Outcome Measures :
  1. Wnt target gene expression (APCDD1, AXIN2, DKK1, LGR5 and ASCL2) [ Time Frame: 30 minutes after surgery ]
    The primary objective of the study is to assess whether short-course pre-operative treatment with the demethylating agent decitabine can increase Wnt target gene expression as measured in resected tumors compared to pretreatment biopsies in patients with primary colon cancer.


Secondary Outcome Measures :
  1. Wnt target methylation. [ Time Frame: 30 minutes after surgery ]
    The secondary objective of the study is to assess whether short-course pre-operative treatment with decitabine can revert CpG methylation and induce more favorable tumor characteristics as measured in resected tumors compared to pretreatment biopsies in patients with primary colon cancer.

  2. CIMP gene methylation [ Time Frame: 30 minutes after surgery ]
    See above

  3. Beta-catenin localisation [ Time Frame: 30 minutes after surgery ]
    See above

  4. Proliferation (Ki-67) [ Time Frame: 30 minutes after surgery ]
    See above

  5. Apoptose (TNEL en M30 assay) [ Time Frame: 30 minutes after surgery ]
    See above.

  6. Tumor differentiation [ Time Frame: 30 minutes after surgery ]
    See above



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

In- and exclusion criteria first part:

In order to participate in the first part of the study, five extra fresh biopsies to determine tumor methylation status, a subject must meet all of the following criteria:

Inclusion criteria:

  1. Biopsy proven colon cancer or high suspicion of colon cancer on a previous endoscopy.
  2. Planned endoscopy.
  3. Age ≥ 18yr.
  4. ECOG/ WHO performance 0-2.
  5. Written informed consent.

Exclusion criteria:

1. Any psychological, familial, sociological or geographical condition potentially hampering adequate informed consent or compliance with the study protocol.

In- and exclusion criteria second part:

In order to participate in the second part of the study - treatment with decitabine - a subject must meet all of the following criteria:

Inclusion criteriä:

  1. Patients with biopsy proven colon cancer who will undergo primary tumor resection.
  2. Age ≥ 18yr.
  3. ECOG/ WHO performance 0-2.
  4. Adequate bone marrow function (ANC>1500/mm3, hemoglobin>9g/dL (which may be obtained by transfusions), platelets>100,000)
  5. Adequate hepatic function (AST and ALT <2.5x upper limit of normal (ULN)).
  6. Adequate renal function (Serum creatinine ≤1.5 x ULN or calculated creatinine of >50ml/min)
  7. Women of child-bearing age must be willing to use adequate contraception and have negative serum or urine pregnancy test within 3 days prior to registration.
  8. Written informed consent.

Exclusion criteria:

  1. Known hypersensitivity to decitabine or its additives.
  2. Surgery not planned according to time frame of the study,
  3. Other systemic or local treatment of the primary tumor in the waiting time until surgery.
  4. Administration of any experimental drug within 60 days prior to the first dose of decitabine.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01882660


Locations
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Netherlands
Academic Medical Center
Amsterdam, Netherlands, 1105 AZ
Sponsors and Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

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Responsible Party: H.W.M. van Laarhoven, Dr., Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier: NCT01882660     History of Changes
Other Study ID Numbers: NL44048.018.13
First Posted: June 20, 2013    Key Record Dates
Last Update Posted: July 2, 2018
Last Verified: June 2018

Additional relevant MeSH terms:
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Colonic Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Colonic Diseases
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Decitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors