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

Trial Information

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.

Inclusion 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.

Type of Study:

Interventional

Study Design:

Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label

Outcome Measure:

Wnt target gene expression (APCDD1, AXIN2, DKK1, LGR5 and ASCL2)

Outcome Description:

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.

Outcome Time Frame:

30 minutes after surgery

Safety Issue:

Authority:

Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Study ID:

NL44048.018.13

NCT ID:

NCT01882660

Start Date:

July 2013

Completion Date:

July 2016

Related Keywords:

Colon Cancer
Colonic Neoplasms

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