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…
ID
Source
Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary study parameter is Wnt target gene expression (APCDD1, AXIN2, DKK1,
LGR5 and ASCL2).
Secondary outcome
Secondary study parameters are Wnt target and CIMP gene methylation,
beta-catenin localization, proliferation (Ki-67), apoptosis (TUNEL and M30
assay) and tumor differentation.
Background summary
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.
Study objective
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
non-methylated tumors as measured in resected tumors compared to pretreatment
biopsies and identify new stratification markers.
Study design
Interventional study.
Intervention
In patients with proven colon cancer, five extra biopsies during planned
endoscopy will be taken from the tumour during endoscopy to determine CpG
methylation of Wnt target genes in fresh tumor samples. Otherwise, tumor
material obtained during previous endoscopy will be used. Next, these patients
will pre-operatively receive decitabine as an intravenous infusion at a dose
of 25 mg/m2 over 1 hr on two consecutive days. After resection, Wnt target gene
expression and CpG methylation of Wnt target genes will again be determined in
tumor samples.
Study burden and risks
Patients undergoing extra biopsies during endoscopy have a very small
additional risk of intestinal bleeding and perforation. Patients who are
treated with decitabine have a risk of experiencing decitabine induced side
effects, including neutropenia, anorexia and fatigue.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
In order to participate in the first part of the study, determination of methylation status on tumor biopsies, a subject must meet all of the following criteria:
1. Biopsy proven colon cancer or high suspicion of colon cancer.
2. Age >= 18yr.
3. Written informed consent.;In order to participate in the second part of the study - treatment with decitabine - a subject must meet all of the following criteria:
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 clearance 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.;In order to participate part IIB of the study - obtaining tumor material - a subject must meet all of the following criteria:
1. Patients with biopsy proven colon cancer who will undergo primary tumor resection.
2. Age >= 18yr.
3. Karnofsky Performance Score 70.
4. Written informed consent.
Exclusion criteria
A potential subject for the first part of the study - determination of methylation status on tumor biopsies - who meets any of the following criteria will be excluded from participation in this study:
1. Any psychological, familial, sociological or geographical condition potentially hampering adequate informed consent or compliance with the study protocol.;A potential subject for the second part of the study - treatment with decitabine - who meets any of the following criteria will be excluded from participation in this study:
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.
5. Women of child-bearing age who are pregnant or lactating.
6. Sexual active males who have intercourse with women of child-bearing age and do not take adequate contraceptive measures.
7. Any psychological, familial, sociological or geographical condition potentially hampering adequate informed consent or compliance with the study protocol.;A potential subject for part IIB of the study - obtaining tumor material - who meets any of the following criteria will be excluded from participation in this study:
1. Surgery not planned according to time frame of the study
2. Other systemic or local treatment of the primary tumor in the waiting time until surgery.
3. Any psychological, familial, sociological or geographical condition potentially hampering adequate informed consent or compliance with the study protocol.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-001060-38-NL |
| ClinicalTrials.gov | NCT01882660 |
| CCMO | NL44048.018.13 |